A Study MLN2480 in Combination With MLN0128 or Alisertib,... | NCT02327169

ID	Type	Description	Link
2014-003340-12	EudraCT Number
U1111-1159-5831	Other Identifier	World Health Organization

Label	Type	Description	Intervention Names
MLN2480 + MLN0128	Experimental	Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and MLN0128 2 mg, capsules, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles.	Drug: MLN2480 Drug: MLN0128
MLN2480 + Alisertib	Experimental	Dose Escalation Phase: MLN2480 100-200 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30-40 mg, tablets, orally, twice daily (BID) on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle.	Drug: MLN2480 Drug: Alisertib
MLN2480 + Paclitaxel	Experimental	Dose Escalation Phase: MLN2480 100-200 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 milligram per square meter (mg/m^2), intravenous (IV) infusion, once weekly (QW) for 3 weeks in each 28-day cycle for up to 12 cycles or MLN2480 400-600 mg tablets, orally, QW on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care.	Drug: MLN2480 Drug: Paclitaxel
MLN2480 + Cetuximab	Experimental

Name	Type	Description	Arm Group Labels	Other Names
MLN2480	Drug	MLN2480 tablets.	ML2480 + Irinotecan MLN2480 + Alisertib MLN2480 + Cetuximab MLN2480 + MLN0128 MLN2480 + Paclitaxel

Measure	Description	Time Frame
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product; the untoward medical occurrence does not necessarily have a causal relationship with this treatment. An SAE means any untoward medical occurrence that at any dose results in death, is life-threatening, requires in patient hospitalization or prolongation of an existing hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly/birth defect or is a medically important event.	From Day 1, Cycle 1 through 30 days after the last dose of study drug (up to 13 months)
Number of Participants With Dose-Limiting Toxicities (DLTs)	DLT was defined using National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 and included: any drug-related hematologic toxicity ≥Grade 4 with the exception of Grade 4 neutropenia <7 days duration; Grade 3 or 4 neutropenia with fever >38.5 degrees Celsius and/or infection or neutropenia requiring colony-stimulating factor OR non-hematologic DLTs that were any Grade 3, 4, or 5 toxicity with the following exceptions: Grade 3 nausea, vomiting, diarrhea, and dehydration occurring in a setting of inadequate treatment; inadequately treated hypersensitivity reactions; Grade 3 elevated transaminases or urine electrolyte abnormality ≤1 week in duration; Grade 3 serum electrolyte abnormality ≤72 hours in duration. DLTs also included: drug-related adverse experience that lead to a dose modification; unresolved drug-related toxicity resulted in delay in initiation of Cycle 2.	From Day 1, Cycle 1 through 30 days after the last dose in Cycle 1 (up to 8 weeks)
Maximum Tolerated Dose (MTD) for MLN2480		Day 1, Cycle 1 up to 28 days
Recommended Phase 2 Dose (RP2D) of MLN2480		Day 1, Cycle 1 up to 28 days

Measure	Description	Time Frame
Cmax : Maximum Observed Plasma Concentration for MLN2480		Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose
Cmax: Maximum Observed Plasma Concentration for MLN0128		Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

All Treatment Arms:

Male or female participants 18 years or older.
Participants who, in the opinion of the treating physician, have failed standard therapies and for whom a phase 1 trial is an appropriate option.
Radiographically or clinically evaluable tumor. For expansion phase: Tumors must be measurable and of the protocol specified genetic mutational status, where applicable.
Recovered (ie, less than or equal to [<=] Grade 1 toxicity) from adverse effects (except alopecia) of prior therapy.
Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
Expected survival time of at least 3 months in the opinion of the investigator.
Block of banked tumor tissue and/or greater than or equal to (>=) 10 unstained slides. Participants who satisfy all other eligibility criteria but do not have banked tissue/slides may be asked to consent to baseline biopsy.
Suitable vein access for the study-required blood sampling.
Thyroid function tests consistent with stable thyroid function. Note: Participants on a stable dose of thyroid replacement therapy for a suggested minimum of 12 weeks before Cycle 1, Day 1 are eligible.
Left ventricular ejection fraction (LVEF) of 50 percent (%) or greater, as measured by echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA), within 28 days before the first dose of MLN2480
Female participants who are post-menopausal for at least 1 year, surgically sterile, or agree to practice 2 effective methods of contraception through 120 days (4 months) after the last dose of study drug for participants in Arms 1, 2, and 5, and through 6 months for participants in Arms 3 and 4, or agree to practice true abstinence.
Male participants who, even if surgically sterilized, agree to practice effective barrier contraception through 120 days (4 months) after the last dose of study drug for participants in Arms 1, 2, and 5, and through 6 months for participants in Arms 3, and 4, or agree to practice true abstinence.
Additional inclusion criteria for arm 3 expansion only (MLN2480 + paclitaxel):

a. Participants with Kirsten rat sarcoma viral oncogene homolog (KRAS) exon 2 or BRAF non-V600 mutation-positive non-small cell lung cancer (NSCLC) who have received a minimum of 1 but not more than 2 prior cytotoxic-approved regimens.
Additional inclusion criteria for arms 4 and 5 expansion only (MLN2480 + cetuximab; MLN2480 + irinotecan):
1. Participants with CRC who have received a minimum of 1 but not more than 2 prior cytotoxic-approved regimens.

Exclusion Criteria:

All treatment arms:

Female participants who are pregnant or currently breastfeeding.
History of any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with safe protocol completion.
History of uncontrolled brain metastasis unless: previously treated with surgery, whole-brain radiation, or stereotactic radiosurgery; stable disease for >= 60 days without steroid use (or stable steroid dose established for >= 28 days before the first dose of MLN2480).
Ongoing seizure disorder or a requirement for antiepileptics.
Recent prior therapies, including: chemotherapy and hormonal therapy <= 4 weeks or 4 half lives, whichever occurs first, before administration of study drug; immunotherapy/monoclonal antibody use <= 4 weeks before administration of MLN2480; or radiation therapy <= 3 weeks before administration of study drug.
Chronic therapeutic corticosteroid use with the exception of replacement therapy for adrenal insufficiency or corticosteroid inhalers.
Known history of human immunodeficiency virus infection, hepatitis B, or hepatitis C; Prior allogeneic bone marrow or organ transplantation, or active condition of chronic immune suppression is not allowed.
Concomitant use, or administration <= 14 days before first dose of study drug(s), of clinically significant enzyme inducers.
Treatment with gemfibrozil (strong Cytochrome P4502C8 [CYP2C8] inhibitor) within 14 days before the first dose of MLN2480.
History of or current illicit drug use, drug abuse, or alcohol abuse.
Major surgery within 14 days before the first dose of study drug.
Inability to comply with study requirements.
Other unspecified reasons that, in the opinion of the investigator or Millennium, make the participant unsuitable for enrollment.
Additional exclusion criteria for arms 3, 5, and 6 expansion only (MLN2480 + paclitaxel; MLN2480 + irinotecan; MLN2480 monotherapy):

a. Prior treatment with rapidly accelerated fibrosarcoma (RAF), extracellular signal-regulated kinases (MEK), or other inhibitors of the mitogen-activated protein kinase (MAPK) pathway.
Additional exclusion criteria for arm 2 only (MLN2480 + alisertib):

a. History of uncontrolled sleep apnea syndrome and other conditions that could result in excessive daytime sleepiness, such as severe chronic obstructive pulmonary disease.
Additional exclusion criteria for arm 3 only (MLN2480 + paclitaxel):

a. Known hypersensitivity to paclitaxel, or its components or other drugs formulated in Cremophor® EL (polyoxyethylated castor oil).
Additional exclusion criteria for arm 5 only (MLN2480 + irinotecan):
1. Use of strong or moderate Cytochrome P4503A (CYP3A) inhibitors <= days of the first dose of irinotecan.

Name	Affiliation	Role
Medical Director Clinical Science	Takeda	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
Massachusetts General Hospital Cancer Center		Boston	Massachusetts	2114	United States
Beth Israel Deaconess Medical Center

ID	Title	Description
FG000	MLN2480 100 mg + MLN0128 2 mg	Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and MLN0128 2 mg, capsules, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles.
FG001	MLN2480 100 mg + Alisertib 30 mg

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot_SAP	Yes	Yes	No	Study Protocol and Statistical Analysis Plan	Feb 8, 2018

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)

An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product; the untoward medical occurrence does not necessarily have a causal relationship with this treatment. An SAE means any untoward medical occurrence that at any dose results in death, is life-threatening, requires in patient hospitalization or prolongation of an existing hospitalization, results in persistent or significant disability or incapacity, is a congenital anomaly/birth defect or is a medically important event.

Safety population was defined as all participants who received any amount of MLN2480.

Posted

Count of Participants

Participants

From Day 1, Cycle 1 through 30 days after the last dose of study drug (up to 13 months)

ID	Title	Description
OG000	MLN2480 100 mg + MLN0128 2 mg	Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and MLN0128 2 mg, capsules, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles.
OG001	MLN2480 100 mg + Alisertib 30 mg	Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30 mg, tablets, orally, twice daily (BID) on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle.
OG002	MLN2480 160 mg + Alisertib 30 mg	Dose Escalation Phase: MLN2480 160 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30 mg, tablets, orally, twice daily (BID) on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle.
OG003	MLN2480 200 mg + Alisertib 30 mg	Dose Escalation Phase: MLN2480 200 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30 mg, tablets, orally, BID on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle.
OG004	MLN2480 100 mg + Alisertib 40 mg	Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 40 mg, tablets, orally, BID on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle.
OG005	MLN2480 100 mg + Paclitaxel 80 mg/m^2	Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 milligram per square meter (mg/m^2), intravenous (IV) infusion, once weekly (QW) for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care.
OG006	MLN2480 160 mg + Paclitaxel 80 mg/m^2	Dose Escalation Phase: MLN2480 160 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care.
OG007	MLN2480 200 mg + Paclitaxel 80 mg/m^2	Dose Escalation Phase: MLN2480 200 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care.
OG008	MLN2480 400 mg + Paclitaxel 80 mg/m^2	Dose Escalation Phase: MLN2480 400 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care.
OG009	MLN2480 600 mg + Paclitaxel 80 mg/m^2	Dose Escalation Phase: MLN2480 600 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care.
OG010	MLN2480 400 mg + Cetuximab 250 mg/m^2	Dose Escalation Phase: MLN2480 400 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and cetuximab administered intravenously at a loading dose of 400 mg/m^2 (cycle 1 Day 1), then at 250 mg/m^2 QW on Days 8, 15, and 22 of cycle 1 and Days 1, 8, 15, and 22 in each additional 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in cetuximab dose was based on the standard of care.
OG011	MLN2480 600 mg + Cetuximab 250 mg/m^2	Dose Escalation Phase: MLN2480 600 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and cetuximab administered intravenously at a loading dose of 400 mg/m^2 (cycle 1 Day 1), then at 250 mg/m^2 QW on Days 8, 15, and 22 of cycle 1 and Days 1, 8, 15, and 22 in each additional 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in cetuximab dose was based on the standard of care.
OG012	ML2480 300 mg + Irinotecan 180 mg/m^2	Dose Escalation Phase: MLN2480 300 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and irinotecan 180 mg/m^2, IV infusion over 90 minutes, every other week (Q2W) for 2 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in irinotecan dose was based on the standard of care.
OG013	ML2480 400 mg + Irinotecan 180 mg/m^2	Dose Escalation Phase: MLN2480 400 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and irinotecan 180 mg/m^2, IV infusion over 90 minutes, every other week (Q2W) for 2 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in irinotecan dose was based on the standard of care.
OG014	Dose Expansion: MLN2480 600 mg + Paclitaxel 80 mg/m^2	Dose Expansion Phase: MLN2480 600 mg, tablets, orally, once per week on Days 2, 9, 16 and 23 of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, once on 1, 8, and 15 of a 28-day cycle for up to 12 cycles.

Units	Counts
Participants	OG0004 OG0013 OG0027 OG003

Title

Denominators

Categories

AEs

Title	Measurements
	OG0004 OG0013 OG0027 OG003

Primary

Number of Participants With Dose-Limiting Toxicities (DLTs)

DLT was defined using National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 and included: any drug-related hematologic toxicity ≥Grade 4 with the exception of Grade 4 neutropenia <7 days duration; Grade 3 or 4 neutropenia with fever >38.5 degrees Celsius and/or infection or neutropenia requiring colony-stimulating factor OR non-hematologic DLTs that were any Grade 3, 4, or 5 toxicity with the following exceptions: Grade 3 nausea, vomiting, diarrhea, and dehydration occurring in a setting of inadequate treatment; inadequately treated hypersensitivity reactions; Grade 3 elevated transaminases or urine electrolyte abnormality ≤1 week in duration; Grade 3 serum electrolyte abnormality ≤72 hours in duration. DLTs also included: drug-related adverse experience that lead to a dose modification; unresolved drug-related toxicity resulted in delay in initiation of Cycle 2.

The DLT-evaluable population was defined as all participants in the dose escalation phase of the study who either experienced DLT during cycle 1, or completed at least 75% of the scheduled doses in cycle 1 without DLT.

Posted

Count of Participants

Participants

From Day 1, Cycle 1 through 30 days after the last dose in Cycle 1 (up to 8 weeks)

ID	Title	Description
OG000	MLN2480 100 mg + MLN0128 2 mg	Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and MLN0128 2 mg, capsules, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles.
OG001

Primary

Maximum Tolerated Dose (MTD) for MLN2480

Posted

Number

Day 1, Cycle 1 up to 28 days

ID	Title	Description
OG000	MLN2480 100 mg + MLN0128 2 mg	Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and MLN0128 2 mg, capsules, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles.
OG001	MLN2480 100 mg + Alisertib 30 mg	Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30 mg, tablets, orally, twice daily (BID) on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle.
OG002	MLN2480 160 mg + Alisertib 30 mg	Dose Escalation Phase: MLN2480 160 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30 mg, tablets, orally, twice daily (BID) on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle.

Primary

Recommended Phase 2 Dose (RP2D) of MLN2480

Posted

Number

Day 1, Cycle 1 up to 28 days

ID	Title	Description
OG000	MLN2480 100 mg + MLN0128 2 mg	Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and MLN0128 2 mg, capsules, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles.
OG001	MLN2480 100 mg + Alisertib 30 mg	Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30 mg, tablets, orally, twice daily (BID) on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle.
OG002	MLN2480 160 mg + Alisertib 30 mg	Dose Escalation Phase: MLN2480 160 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30 mg, tablets, orally, twice daily (BID) on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle.

Secondary

Cmax : Maximum Observed Plasma Concentration for MLN2480

The limited PK data did not allow to estimate the PK parameters defined in the protocol.

Posted

Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose

ID	Title	Description
OG000	MLN2480 100 mg + MLN0128 2 mg	Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and MLN0128 2 mg, capsules, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles.
OG001	MLN2480 100 mg + Alisertib 30 mg	Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30 mg, tablets, orally, twice daily (BID) on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle.
OG002	MLN2480 160 mg + Alisertib 30 mg	Dose Escalation Phase: MLN2480 160 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30 mg, tablets, orally, twice daily (BID) on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle.

Secondary

Cmax: Maximum Observed Plasma Concentration for MLN0128

The limited PK data did not allow to estimate the PK parameters defined in the protocol.

Posted

Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose

ID	Title	Description
OG000	MLN2480 100 mg + MLN0128 2 mg	Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and MLN0128 2 mg, capsules, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles.

Units	Counts
Participants	OG0000

Secondary

Cmax: Maximum Observed Plasma Concentration for Alisertib

The limited PK data did not allow to estimate the PK parameters defined in the protocol.

Posted

Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose

ID	Title	Description
OG000	MLN2480 100 mg + Alisertib 30 mg	Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30 mg, tablets, orally, twice daily (BID) on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle.
OG001	MLN2480 160 mg + Alisertib 30 mg	Dose Escalation Phase: MLN2480 160 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30 mg, tablets, orally, twice daily (BID) on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle.
OG002	MLN2480 200 mg + Alisertib 30 mg	Dose Escalation Phase: MLN2480 200 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30 mg, tablets, orally, BID on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle.

Secondary

Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for MLN2480

The limited PK data did not allow to estimate the PK parameters defined in the protocol.

Posted

Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose

ID	Title	Description
OG000	MLN2480 100 mg + MLN0128 2 mg	Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and MLN0128 2 mg, capsules, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles.
OG001	MLN2480 100 mg + Alisertib 30 mg	Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30 mg, tablets, orally, twice daily (BID) on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle.
OG002	MLN2480 160 mg + Alisertib 30 mg	Dose Escalation Phase: MLN2480 160 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30 mg, tablets, orally, twice daily (BID) on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle.

Secondary

Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for MLN0128

The limited PK data did not allow to estimate the PK parameters defined in the protocol.

Posted

Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose

ID	Title	Description
OG000	MLN2480 100 mg + MLN0128 2 mg	Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and MLN0128 2 mg, capsules, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles.

Units	Counts
Participants	OG0000

Secondary

Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for Alisertib

The limited PK data did not allow to estimate the PK parameters defined in the protocol.

Posted

Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose

ID	Title	Description
OG000	MLN2480 100 mg + Alisertib 30 mg	Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30 mg, tablets, orally, twice daily (BID) on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle.
OG001	MLN2480 160 mg + Alisertib 30 mg	Dose Escalation Phase: MLN2480 160 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30 mg, tablets, orally, twice daily (BID) on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle.
OG002	MLN2480 200 mg + Alisertib 30 mg	Dose Escalation Phase: MLN2480 200 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30 mg, tablets, orally, BID on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle.

Secondary

AUC(0-tau): Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval for MLN2480

The limited PK data did not allow to estimate the PK parameters defined in the protocol.

Posted

Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose

ID	Title	Description
OG000	MLN2480 100 mg + MLN0128 2 mg	Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and MLN0128 2 mg, capsules, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles.
OG001	MLN2480 100 mg + Alisertib 30 mg	Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30 mg, tablets, orally, twice daily (BID) on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle.
OG002	MLN2480 160 mg + Alisertib 30 mg	Dose Escalation Phase: MLN2480 160 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30 mg, tablets, orally, twice daily (BID) on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle.

Secondary

AUC(0-tau): Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval for MLN0128

The limited PK data did not allow to estimate the PK parameters defined in the protocol.

Posted

Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose

ID	Title	Description
OG000	MLN2480 100 mg + MLN0128 2 mg	Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and MLN0128 2 mg, capsules, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles.

Units	Counts
Participants	OG0000

Secondary

AUC(0-tau): Area Under the Plasma Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval for Alisertib

The limited PK data did not allow to estimate the PK parameters defined in the protocol.

Posted

Cycle 1, Day 10 pre-dose and at multiple timepoints (Up to 48 hours) post-dose

ID	Title	Description
OG000	MLN2480 100 mg + Alisertib 30 mg	Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30 mg, tablets, orally, twice daily (BID) on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle.
OG001	MLN2480 160 mg + Alisertib 30 mg	Dose Escalation Phase: MLN2480 160 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30 mg, tablets, orally, twice daily (BID) on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle.
OG002	MLN2480 200 mg + Alisertib 30 mg	Dose Escalation Phase: MLN2480 200 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30 mg, tablets, orally, BID on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle.

Secondary

Cmax: Maximum Observed Plasma Concentration for Paclitaxel

The limited PK data did not allow to estimate the PK parameters defined in the protocol.

Posted

Cycle 1, Day 15 pre-dose and at multiple timepoints (Up to 48 hours) post-dose

ID	Title	Description
OG000	MLN2480 100 mg + Paclitaxel 80 mg/m^2	Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 milligram per square meter (mg/m^2), intravenous (IV) infusion, once weekly (QW) for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care.
OG001	MLN2480 160 mg + Paclitaxel 80 mg/m^2	Dose Escalation Phase: MLN2480 160 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care.
OG002	MLN2480 200 mg + Paclitaxel 80 mg/m^2	Dose Escalation Phase: MLN2480 200 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care.

Secondary

AUC(0-last): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Paclitaxel

The limited PK data did not allow to estimate the PK parameters defined in the protocol.

Posted

Cycle 1, Day 15 pre-dose and at multiple timepoints (Up to 48 hours) post-dose

ID	Title	Description
OG000	MLN2480 100 mg + Paclitaxel 80 mg/m^2	Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 milligram per square meter (mg/m^2), intravenous (IV) infusion, once weekly (QW) for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care.
OG001	MLN2480 160 mg + Paclitaxel 80 mg/m^2	Dose Escalation Phase: MLN2480 160 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care.
OG002	MLN2480 200 mg + Paclitaxel 80 mg/m^2

Secondary

AUC(0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity, Calculated Using the Observed Value of the Last Quantifiable Concentration for Paclitaxel

The limited PK data did not allow to estimate the PK parameters defined in the protocol.

Posted

Cycle 1, Day 15 pre-dose and at multiple timepoints (Up to 48 hours) post-dose

ID	Title	Description
OG000	MLN2480 100 mg + Paclitaxel 80 mg/m^2	Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 milligram per square meter (mg/m^2), intravenous (IV) infusion, once weekly (QW) for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care.
OG001	MLN2480 160 mg + Paclitaxel 80 mg/m^2	Dose Escalation Phase: MLN2480 160 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care.
OG002	MLN2480 200 mg + Paclitaxel 80 mg/m^2

Secondary

Terminal Elimination Half-life (T1/2) for Paclitaxel

The limited PK data did not allow to estimate the PK parameters defined in the protocol.

Posted

Cycle 1, Day 15 pre-dose and at multiple timepoints (Up to 48 hours) post-dose

ID	Title	Description
OG000	MLN2480 100 mg + Paclitaxel 80 mg/m^2	Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 milligram per square meter (mg/m^2), intravenous (IV) infusion, once weekly (QW) for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care.
OG001	MLN2480 160 mg + Paclitaxel 80 mg/m^2	Dose Escalation Phase: MLN2480 160 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care.
OG002	MLN2480 200 mg + Paclitaxel 80 mg/m^2	Dose Escalation Phase: MLN2480 200 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care.

Secondary

Objective Response Rate (ORR) Based on Response Evaluation Criteria in Solid Tumors (RECIST)

ORR was defined as the percentage of participants with complete response (CR) or partial response (PR) using Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1. CR: Disappearance of all target lesions, non-target lesions, no new lesions, and normalization of tumor marker level. PR: At least a 30% decrease in the sum of diameters of target lesions, no progression in non-target lesion, and no new lesions.

Response-evaluable population was defined as participants who received at least 1 dose of study drug, had measurable disease at baseline, and 1 postbaseline response assessment.

Posted

Number

95% Confidence Interval

percentage of participants

Baseline then every 2 cycles beginning at Cycle 2, Day 27, until disease progression, death or end of study (Up to 13 months)

ID	Title	Description
OG000	MLN2480 100 mg + MLN0128 2 mg	Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and MLN0128 2 mg, capsules, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles.
OG001	MLN2480 100 mg + Alisertib 30 mg	Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30 mg, tablets, orally, twice daily (BID) on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle.

Secondary

Duration of Response

Duration of Response (DOR) was defined as the time in months from the first documented CR or PR per RECIST v. 1.1 to disease recurrence or disease progression (PD) whichever occurs first.

Responders from response-evaluable population was defined as participants who received at least 1 dose of study drug, had measurable disease at baseline, and 1 postbaseline response assessment. For a participant that has not progressed, DOR was censored at the last response assessment.

Posted

Median

95% Confidence Interval

months

From first documented response until disease progression (Up to 13 months)

ID	Title	Description
OG000	MLN2480 100 mg + MLN0128 2 mg	Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and MLN0128 2 mg, capsules, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles.
OG001	MLN2480 100 mg + Alisertib 30 mg	Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30 mg, tablets, orally, twice daily (BID) on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle.
OG002

Secondary

Time to Response

Time to response was defined as the time in months from the date of first dose of study treatment to the date of the first documentation of a PR or better response.

Response-evaluable population was defined as all participants with measurable disease at baseline who received any amount of MLN2480 and have at least 1 post baseline response assessment.

Posted

Median

95% Confidence Interval

months

From date of enrollment to the date of the first documentation of a confirmed response (Up to 13 months)

ID	Title	Description
OG000	MLN2480 100 mg + MLN0128 2 mg	Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and MLN0128 2 mg, capsules, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles.
OG001	MLN2480 100 mg + Alisertib 30 mg	Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30 mg, tablets, orally, twice daily (BID) on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle.
OG002	MLN2480 160 mg + Alisertib 30 mg

Secondary

Progression Free Survival (PFS)

PFS is defined as the time in months from the date of first study drug administration to the date of first documented PD or death due to any cause. PD was based on response evaluation criteria in solid tumors (RECIST V1.1), defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm.

Safety population is defined as all participants who received any amount of MLN2480. For a participant that has not progressed and has not died, PFS was censored at the last response assessment that is SD or better. Participants with no response assessment were censored at the date of first dose.

Posted

Median

95% Confidence Interval

months

Baseline then every 2 cycles beginning at Cycle 2, Day 27, until disease progression, death or end of study (Approximately up to 13 months)

ID	Title	Description
OG000	MLN2480 100 mg + MLN0128 2 mg	Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and MLN0128 2 mg, capsules, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles.
OG001	MLN2480 100 mg + Alisertib 30 mg	Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30 mg, tablets, orally, twice daily (BID) on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle.

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Notes	Statistical Information
Abdominal pain	Gastrointestinal disorders	20.0	Systematic Assessment		EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG0031 affected3 at risk EG0040 affected8 at risk EG0051 affected4 at risk EG0060 affected3 at risk EG0071 affected4 at risk EG0080 affected6 at risk EG0090 affected8 at risk EG0100 affected6 at risk EG0110 affected7 at risk EG0120 affected1 at risk EG0131 affected7 at risk EG0140 affected10 at risk
Nausea	Gastrointestinal disorders	20.0	Systematic Assessment		EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Vomiting	Gastrointestinal disorders	20.0	Systematic Assessment		EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Post-tussive vomiting	Gastrointestinal disorders	20.0	Systematic Assessment		EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Small intestinal obstruction	Gastrointestinal disorders	20.0	Systematic Assessment		EG0000 affected4 at risk EG0011 affected3 at risk EG0020 affected7 at risk EG003
Gastrointestinal haemorrhage	Gastrointestinal disorders	20.0	Systematic Assessment		EG0000 affected4 at risk EG0010 affected3 at risk EG0021 affected7 at risk EG003
Upper gastrointestinal haemorrhage	Gastrointestinal disorders	20.0	Systematic Assessment	One treatment-emergent death occurred during treatment with MLN2480 + Alisertib and was not related.	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Pancreatitis acute	Gastrointestinal disorders	20.0	Systematic Assessment		EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Diarrhoea	Gastrointestinal disorders	20.0	Systematic Assessment		EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Intestinal obstruction	Gastrointestinal disorders	20.0	Systematic Assessment		EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Gastrointestinal perforation	Gastrointestinal disorders	20.0	Systematic Assessment	One treatment-emergent death occurred during treatment with MLN2480 + Alisertib and was not related.	EG0000 affected4 at risk EG0010 affected3 at risk EG0021 affected7 at risk EG003
Oesophagitis ulcerative	Gastrointestinal disorders	20.0	Systematic Assessment		EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Ascites	Gastrointestinal disorders	20.0	Systematic Assessment		EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Pneumonia	Infections and infestations	20.0	Systematic Assessment	One treatment-emergent death occurred during treatment with MLN2480 + Paclitaxel in dose expansion phase and was related.	EG0000 affected4 at risk EG0010 affected3 at risk EG0021 affected7 at risk EG003
Lung infection	Infections and infestations	20.0	Systematic Assessment		EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Respiratory tract infection	Infections and infestations	20.0	Systematic Assessment		EG0000 affected4 at risk EG0010 affected3 at risk EG0021 affected7 at risk EG003
Sepsis	Infections and infestations	20.0	Systematic Assessment	One treatment-emergent death occurred during treatment with MLN2480 + Alisertib and was not related.	EG0000 affected4 at risk EG0010 affected3 at risk EG0021 affected7 at risk EG003
Cellulitis	Infections and infestations	20.0	Systematic Assessment		EG0000 affected4 at risk EG0010 affected3 at risk EG0021 affected7 at risk EG003
Abdominal infection	Infections and infestations	20.0	Systematic Assessment		EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Urinary tract infection	Infections and infestations	20.0	Systematic Assessment		EG0001 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Colorectal cancer	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	20.0	Systematic Assessment	One treatment-emergent death occurred during treatment with MLN2480 + Cetuximab and was not related.	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Gastrointestinal carcinoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	20.0	Systematic Assessment	One treatment-emergent death occurred during treatment with MLN2480 + Cetuximab and was not related.	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Malignant neoplasm progression	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	20.0	Systematic Assessment	One treatment-emergent death occurred during treatment with MLN2480 + Cetuximab and was not related.	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Neoplasm progression	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	20.0	Systematic Assessment	One treatment-emergent death occurred during treatment with MLN2480 + Cetuximab and was not related.	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Lung adenocarcinoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	20.0	Systematic Assessment	One treatment-emergent death occurred during treatment with MLN2480 + Paclitaxel in dose expansion phase and was related.	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Tumour pain	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	20.0	Systematic Assessment		EG0000 affected4 at risk EG0010 affected3 at risk EG0021 affected7 at risk EG003
Metastatic malignant melanoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	20.0	Systematic Assessment		EG0000 affected4 at risk EG0010 affected3 at risk EG0021 affected7 at risk EG003
Dyspnoea	Respiratory, thoracic and mediastinal disorders	20.0	Systematic Assessment		EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Chronic obstructive pulmonary disease	Respiratory, thoracic and mediastinal disorders	20.0	Systematic Assessment		EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Haemoptysis	Respiratory, thoracic and mediastinal disorders	20.0	Systematic Assessment		EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Pneumonia aspiration	Respiratory, thoracic and mediastinal disorders	20.0	Systematic Assessment		EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Pulmonary oedema	Respiratory, thoracic and mediastinal disorders	20.0	Systematic Assessment		EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Anaemia	Blood and lymphatic system disorders	20.0	Systematic Assessment		EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Febrile neutropenia	Blood and lymphatic system disorders	20.0	Systematic Assessment		EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Neutropenia	Blood and lymphatic system disorders	20.0	Systematic Assessment		EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Splenic haemorrhage	Blood and lymphatic system disorders	20.0	Systematic Assessment		EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Atrial fibrillation	Cardiac disorders	20.0	Systematic Assessment		EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Atrial flutter	Cardiac disorders	20.0	Systematic Assessment		EG0001 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Arrhythmia	Cardiac disorders	20.0	Systematic Assessment		EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Pyrexia	General disorders	20.0	Systematic Assessment		EG0000 affected4 at risk EG0010 affected3 at risk EG0021 affected7 at risk EG003
General physical health deterioration	General disorders	20.0	Systematic Assessment		EG0000 affected4 at risk EG0010 affected3 at risk EG0021 affected7 at risk EG003
Cholangitis	Hepatobiliary disorders	20.0	Systematic Assessment		EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Cholelithiasis	Hepatobiliary disorders	20.0	Systematic Assessment		EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Hyperbilirubinaemia	Hepatobiliary disorders	20.0	Systematic Assessment		EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Bile duct obstruction	Hepatobiliary disorders	20.0	Systematic Assessment		EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Hypophosphataemia	Metabolism and nutrition disorders	20.0	Systematic Assessment		EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Fluid overload	Metabolism and nutrition disorders	20.0	Systematic Assessment		EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Subdural haematoma	Injury, poisoning and procedural complications	20.0	Systematic Assessment		EG0000 affected4 at risk EG0010 affected3 at risk EG0021 affected7 at risk EG003
Pain in extremity	Musculoskeletal and connective tissue disorders	20.0	Systematic Assessment		EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Haematuria	Renal and urinary disorders	20.0	Systematic Assessment		EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Rash maculo-papular	Skin and subcutaneous tissue disorders	20.0	Systematic Assessment		EG0001 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Deep vein thrombosis	Vascular disorders	20.0	Systematic Assessment		EG0000 affected4 at risk EG0010 affected3 at risk EG0021 affected7 at risk EG003

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Hypophosphataemia	Metabolism and nutrition disorders	20.0	Systematic Assessment	EG0001 affected4 at risk EG0010 affected3 at risk EG0026 affected7 at risk EG0032 affected3 at risk EG0041 affected8 at risk EG0050 affected4 at risk EG0063 affected3 at risk EG0072 affected4 at risk EG0084 affected6 at risk EG0097 affected8 at risk EG0106 affected6 at risk EG0114 affected7 at risk EG0120 affected1 at risk EG0135 affected7 at risk EG0146 affected10 at risk
Decreased appetite	Metabolism and nutrition disorders	20.0	Systematic Assessment	EG0002 affected4 at risk EG0011 affected3 at risk EG0025 affected7 at risk EG003
Hypocalcaemia	Metabolism and nutrition disorders	20.0	Systematic Assessment	EG0001 affected4 at risk EG0011 affected3 at risk EG0021 affected7 at risk EG003
Hypokalaemia	Metabolism and nutrition disorders	20.0	Systematic Assessment	EG0001 affected4 at risk EG0011 affected3 at risk EG0020 affected7 at risk EG003
Hypomagnesaemia	Metabolism and nutrition disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0011 affected3 at risk EG0021 affected7 at risk EG003
Dehydration	Metabolism and nutrition disorders	20.0	Systematic Assessment	EG0001 affected4 at risk EG0011 affected3 at risk EG0020 affected7 at risk EG003
Hyperglycaemia	Metabolism and nutrition disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Hypoalbuminaemia	Metabolism and nutrition disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0011 affected3 at risk EG0020 affected7 at risk EG003
Hypercholesterolaemia	Metabolism and nutrition disorders	20.0	Systematic Assessment	EG0001 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Hyperuricaemia	Metabolism and nutrition disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Hyponatraemia	Metabolism and nutrition disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Vitamin D deficiency	Metabolism and nutrition disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0021 affected7 at risk EG003
Hyperkalaemia	Metabolism and nutrition disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Hypoglycaemia	Metabolism and nutrition disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0011 affected3 at risk EG0020 affected7 at risk EG003
Lactic acidosis	Metabolism and nutrition disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Nausea	Gastrointestinal disorders	20.0	Systematic Assessment	EG0002 affected4 at risk EG0011 affected3 at risk EG0023 affected7 at risk EG003
Diarrhoea	Gastrointestinal disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0011 affected3 at risk EG0022 affected7 at risk EG003
Constipation	Gastrointestinal disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0012 affected3 at risk EG0023 affected7 at risk EG003
Vomiting	Gastrointestinal disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0011 affected3 at risk EG0022 affected7 at risk EG003
Abdominal pain	Gastrointestinal disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0011 affected3 at risk EG0020 affected7 at risk EG003
Abdominal distension	Gastrointestinal disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0012 affected3 at risk EG0020 affected7 at risk EG003
Stomatitis	Gastrointestinal disorders	20.0	Systematic Assessment	EG0001 affected4 at risk EG0010 affected3 at risk EG0021 affected7 at risk EG003
Dry mouth	Gastrointestinal disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0011 affected3 at risk EG0020 affected7 at risk EG003
Dyspepsia	Gastrointestinal disorders	20.0	Systematic Assessment	EG0001 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Gastrooesophageal reflux disease	Gastrointestinal disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0011 affected3 at risk EG0020 affected7 at risk EG003
Haematochezia	Gastrointestinal disorders	20.0	Systematic Assessment	EG0001 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Dysphagia	Gastrointestinal disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0021 affected7 at risk EG003
Mouth ulceration	Gastrointestinal disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Retching	Gastrointestinal disorders	20.0	Systematic Assessment	EG0001 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Abdominal pain upper	Gastrointestinal disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0021 affected7 at risk EG003
Ascites	Gastrointestinal disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0012 affected3 at risk EG0020 affected7 at risk EG003
Epigastric discomfort	Gastrointestinal disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Gingival bleeding	Gastrointestinal disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Rectal haemorrhage	Gastrointestinal disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0021 affected7 at risk EG003
Abdominal discomfort	Gastrointestinal disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Abdominal mass	Gastrointestinal disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Abdominal pain lower	Gastrointestinal disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Abdominal tenderness	Gastrointestinal disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Anal fistula	Gastrointestinal disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Aphthous ulcer	Gastrointestinal disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Colitis	Gastrointestinal disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Faecal vomiting	Gastrointestinal disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0021 affected7 at risk EG003
Faeces discoloured	Gastrointestinal disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Gastric haemorrhage	Gastrointestinal disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0011 affected3 at risk EG0020 affected7 at risk EG003
Glossitis	Gastrointestinal disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Haemorrhoidal haemorrhage	Gastrointestinal disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0011 affected3 at risk EG0020 affected7 at risk EG003
Ileus	Gastrointestinal disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Mouth haemorrhage	Gastrointestinal disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Oral pain	Gastrointestinal disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Pancreatitis	Gastrointestinal disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Proctalgia	Gastrointestinal disorders	20.0	Systematic Assessment	EG0001 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Tongue coated	Gastrointestinal disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Toothache	Gastrointestinal disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Fatigue	General disorders	20.0	Systematic Assessment	EG0003 affected4 at risk EG0013 affected3 at risk EG0025 affected7 at risk EG003
Asthenia	General disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0022 affected7 at risk EG003
Pyrexia	General disorders	20.0	Systematic Assessment	EG0002 affected4 at risk EG0011 affected3 at risk EG0022 affected7 at risk EG003
Oedema peripheral	General disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0022 affected7 at risk EG003
Chills	General disorders	20.0	Systematic Assessment	EG0001 affected4 at risk EG0010 affected3 at risk EG0021 affected7 at risk EG003
Face oedema	General disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Non-cardiac chest pain	General disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0011 affected3 at risk EG0020 affected7 at risk EG003
Pain	General disorders	20.0	Systematic Assessment	EG0001 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Catheter site pain	General disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Localised oedema	General disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Administration site extravasation	General disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Catheter site oedema	General disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Chest pain	General disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Early satiety	General disorders	20.0	Systematic Assessment	EG0001 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Inflammation	General disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0021 affected7 at risk EG003
Infusion site pain	General disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Malaise	General disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Unevaluable event	General disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Vaccination site reaction	General disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0011 affected3 at risk EG0020 affected7 at risk EG003
Alopecia	Skin and subcutaneous tissue disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0012 affected3 at risk EG0021 affected7 at risk EG003
Rash maculo-papular	Skin and subcutaneous tissue disorders	20.0	Systematic Assessment	EG0002 affected4 at risk EG0010 affected3 at risk EG0022 affected7 at risk EG003
Dermatitis acneiform	Skin and subcutaneous tissue disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0011 affected3 at risk EG0021 affected7 at risk EG003
Pruritus	Skin and subcutaneous tissue disorders	20.0	Systematic Assessment	EG0001 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Rash	Skin and subcutaneous tissue disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Rash papular	Skin and subcutaneous tissue disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Skin lesion	Skin and subcutaneous tissue disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Actinic keratosis	Skin and subcutaneous tissue disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Dermatitis contact	Skin and subcutaneous tissue disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Dry skin	Skin and subcutaneous tissue disorders	20.0	Systematic Assessment	EG0001 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Ephelides	Skin and subcutaneous tissue disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Erythema	Skin and subcutaneous tissue disorders	20.0	Systematic Assessment	EG0001 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Hair colour changes	Skin and subcutaneous tissue disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0011 affected3 at risk EG0020 affected7 at risk EG003
Keratosis pilaris	Skin and subcutaneous tissue disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Miliaria	Skin and subcutaneous tissue disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Nail disorder	Skin and subcutaneous tissue disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Night sweats	Skin and subcutaneous tissue disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Nodular rash	Skin and subcutaneous tissue disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Onychoclasis	Skin and subcutaneous tissue disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Onycholysis	Skin and subcutaneous tissue disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Petechiae	Skin and subcutaneous tissue disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Pigmentation disorder	Skin and subcutaneous tissue disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Rash erythematous	Skin and subcutaneous tissue disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Systemic lupus erythematosus rash	Skin and subcutaneous tissue disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0011 affected3 at risk EG0020 affected7 at risk EG003
Urticaria	Skin and subcutaneous tissue disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Cough	Respiratory, thoracic and mediastinal disorders	20.0	Systematic Assessment	EG0001 affected4 at risk EG0012 affected3 at risk EG0021 affected7 at risk EG003
Dyspnoea	Respiratory, thoracic and mediastinal disorders	20.0	Systematic Assessment	EG0001 affected4 at risk EG0010 affected3 at risk EG0022 affected7 at risk EG003
Dyspnoea exertional	Respiratory, thoracic and mediastinal disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0012 affected3 at risk EG0021 affected7 at risk EG003
Oropharyngeal pain	Respiratory, thoracic and mediastinal disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0011 affected3 at risk EG0020 affected7 at risk EG003
Pleural effusion	Respiratory, thoracic and mediastinal disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Upper-airway cough syndrome	Respiratory, thoracic and mediastinal disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0011 affected3 at risk EG0020 affected7 at risk EG003
Wheezing	Respiratory, thoracic and mediastinal disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Dysphonia	Respiratory, thoracic and mediastinal disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Epistaxis	Respiratory, thoracic and mediastinal disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Nasal congestion	Respiratory, thoracic and mediastinal disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0011 affected3 at risk EG0021 affected7 at risk EG003
Sinus congestion	Respiratory, thoracic and mediastinal disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0011 affected3 at risk EG0020 affected7 at risk EG003
Haemoptysis	Respiratory, thoracic and mediastinal disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0021 affected7 at risk EG003
Hypoxia	Respiratory, thoracic and mediastinal disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Acute respiratory failure	Respiratory, thoracic and mediastinal disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Hiccups	Respiratory, thoracic and mediastinal disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Oropharyngeal discomfort	Respiratory, thoracic and mediastinal disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Painful respiration	Respiratory, thoracic and mediastinal disorders	20.0	Systematic Assessment	EG0001 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Pneumonia aspiration	Respiratory, thoracic and mediastinal disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Productive cough	Respiratory, thoracic and mediastinal disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0011 affected3 at risk EG0020 affected7 at risk EG003
Rales	Respiratory, thoracic and mediastinal disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Respiratory tract congestion	Respiratory, thoracic and mediastinal disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Rhinorrhoea	Respiratory, thoracic and mediastinal disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Anaemia	Blood and lymphatic system disorders	20.0	Systematic Assessment	EG0001 affected4 at risk EG0010 affected3 at risk EG0025 affected7 at risk EG003
Neutropenia	Blood and lymphatic system disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0011 affected3 at risk EG0021 affected7 at risk EG003
Iron deficiency anaemia	Blood and lymphatic system disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Leukocytosis	Blood and lymphatic system disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Lymphadenopathy	Blood and lymphatic system disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Thrombocytopenia	Blood and lymphatic system disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0021 affected7 at risk EG003
Febrile neutropenia	Blood and lymphatic system disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Lymphopenia	Blood and lymphatic system disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0011 affected3 at risk EG0020 affected7 at risk EG003
Weight decreased	Investigations	20.0	Systematic Assessment	EG0001 affected4 at risk EG0011 affected3 at risk EG0020 affected7 at risk EG003
Aspartate aminotransferase increased	Investigations	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0021 affected7 at risk EG003
Neutrophil count decreased	Investigations	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0021 affected7 at risk EG003
Transaminases increased	Investigations	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Blood bilirubin increased	Investigations	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0021 affected7 at risk EG003
Blood calcium decreased	Investigations	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Gamma-glutamyltransferase increased	Investigations	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Haemoglobin decreased	Investigations	20.0	Systematic Assessment	EG0001 affected4 at risk EG0011 affected3 at risk EG0020 affected7 at risk EG003
Vitamin D decreased	Investigations	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Weight increased	Investigations	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Adjusted calcium decreased	Investigations	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Alanine aminotransferase increased	Investigations	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Blood phosphorus decreased	Investigations	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Blood potassium decreased	Investigations	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Electrocardiogram QT prolonged	Investigations	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0021 affected7 at risk EG003
International normalised ratio increased	Investigations	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Blood alkaline phosphatase increased	Investigations	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Blood magnesium decreased	Investigations	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Blood triglycerides increased	Investigations	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Blood urea increased	Investigations	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Blood urine present	Investigations	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Breath sounds abnormal	Investigations	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Lipase increased	Investigations	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Platelet count decreased	Investigations	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0021 affected7 at risk EG003
Platelet count increased	Investigations	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Prothrombin level decreased	Investigations	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Troponin increased	Investigations	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
White blood cell count decreased	Investigations	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
White blood cell count increased	Investigations	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Back pain	Musculoskeletal and connective tissue disorders	20.0	Systematic Assessment	EG0001 affected4 at risk EG0011 affected3 at risk EG0022 affected7 at risk EG003
Myalgia	Musculoskeletal and connective tissue disorders	20.0	Systematic Assessment	EG0002 affected4 at risk EG0010 affected3 at risk EG0021 affected7 at risk EG003
Arthralgia	Musculoskeletal and connective tissue disorders	20.0	Systematic Assessment	EG0002 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Muscle spasms	Musculoskeletal and connective tissue disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0011 affected3 at risk EG0021 affected7 at risk EG003
Flank pain	Musculoskeletal and connective tissue disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0021 affected7 at risk EG003
Groin pain	Musculoskeletal and connective tissue disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Musculoskeletal chest pain	Musculoskeletal and connective tissue disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Neck pain	Musculoskeletal and connective tissue disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Pain in extremity	Musculoskeletal and connective tissue disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Arthropathy	Musculoskeletal and connective tissue disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Bone pain	Musculoskeletal and connective tissue disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Clubbing	Musculoskeletal and connective tissue disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Fibromyalgia	Musculoskeletal and connective tissue disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0011 affected3 at risk EG0020 affected7 at risk EG003
Muscular weakness	Musculoskeletal and connective tissue disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Osteopenia	Musculoskeletal and connective tissue disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Headache	Nervous system disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0011 affected3 at risk EG0021 affected7 at risk EG003
Dizziness	Nervous system disorders	20.0	Systematic Assessment	EG0001 affected4 at risk EG0010 affected3 at risk EG0021 affected7 at risk EG003
Neuropathy peripheral	Nervous system disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0021 affected7 at risk EG003
Peripheral sensory neuropathy	Nervous system disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0021 affected7 at risk EG003
Dysgeusia	Nervous system disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Aphasia	Nervous system disorders	20.0	Systematic Assessment	EG0001 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Lethargy	Nervous system disorders	20.0	Systematic Assessment	EG0001 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Paraesthesia	Nervous system disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Somnolence	Nervous system disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Ataxia	Nervous system disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Hyperaesthesia	Nervous system disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0011 affected3 at risk EG0020 affected7 at risk EG003
Memory impairment	Nervous system disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Motor dysfunction	Nervous system disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0021 affected7 at risk EG003
Neurotoxicity	Nervous system disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Peripheral motor neuropathy	Nervous system disorders	20.0	Systematic Assessment	EG0001 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Peripheral sensorimotor neuropathy	Nervous system disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Restless legs syndrome	Nervous system disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Sciatica	Nervous system disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0021 affected7 at risk EG003
Vocal cord paralysis	Nervous system disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Urinary tract infection	Infections and infestations	20.0	Systematic Assessment	EG0001 affected4 at risk EG0010 affected3 at risk EG0021 affected7 at risk EG003
Upper respiratory tract infection	Infections and infestations	20.0	Systematic Assessment	EG0000 affected4 at risk EG0011 affected3 at risk EG0020 affected7 at risk EG003
Bronchitis	Infections and infestations	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Viral upper respiratory tract infection	Infections and infestations	20.0	Systematic Assessment	EG0000 affected4 at risk EG0011 affected3 at risk EG0021 affected7 at risk EG003
Influenza	Infections and infestations	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Lung infection	Infections and infestations	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Rash pustular	Infections and infestations	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Breast abscess	Infections and infestations	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Conjunctivitis viral	Infections and infestations	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Furuncle	Infections and infestations	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Gastroenteritis viral	Infections and infestations	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Herpes zoster	Infections and infestations	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Infective exacerbation of chronic obstructive airways disease	Infections and infestations	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Laryngitis	Infections and infestations	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Nail infection	Infections and infestations	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Oral fungal infection	Infections and infestations	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Paronychia	Infections and infestations	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Pneumonia	Infections and infestations	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Pyelonephritis	Infections and infestations	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Sinusitis	Infections and infestations	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Tongue fungal infection	Infections and infestations	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Hypotension	Vascular disorders	20.0	Systematic Assessment	EG0002 affected4 at risk EG0010 affected3 at risk EG0021 affected7 at risk EG003
Flushing	Vascular disorders	20.0	Systematic Assessment	EG0001 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Hot flush	Vascular disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0011 affected3 at risk EG0020 affected7 at risk EG003
Haematoma	Vascular disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Hypertension	Vascular disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Pallor	Vascular disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Vena cava thrombosis	Vascular disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Vision blurred	Eye disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Eyelid oedema	Eye disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Dry eye	Eye disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Eye haemorrhage	Eye disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Eye pain	Eye disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Cataract	Eye disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0021 affected7 at risk EG003
Eye inflammation	Eye disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Ocular hyperaemia	Eye disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Periorbital oedema	Eye disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Retinal haemorrhage	Eye disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Atrial fibrillation	Cardiac disorders	20.0	Systematic Assessment	EG0001 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Palpitations	Cardiac disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Tachycardia	Cardiac disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0011 affected3 at risk EG0020 affected7 at risk EG003
Atrial flutter	Cardiac disorders	20.0	Systematic Assessment	EG0001 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Atrial tachycardia	Cardiac disorders	20.0	Systematic Assessment	EG0001 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Atrial thrombosis	Cardiac disorders	20.0	Systematic Assessment	EG0001 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Left ventricular dysfunction	Cardiac disorders	20.0	Systematic Assessment	EG0001 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Pericardial effusion	Cardiac disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Arrhythmia	Cardiac disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Sinus Tachycardia	Cardiac disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Ventricular fibrillation	Cardiac disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Acute kidney injury	Renal and urinary disorders	20.0	Systematic Assessment	EG0001 affected4 at risk EG0010 affected3 at risk EG0021 affected7 at risk EG003
Dysuria	Renal and urinary disorders	20.0	Systematic Assessment	EG0001 affected4 at risk EG0010 affected3 at risk EG0021 affected7 at risk EG003
Haematuria	Renal and urinary disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Hydronephrosis	Renal and urinary disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Pollakiuria	Renal and urinary disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Proteinuria	Renal and urinary disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0011 affected3 at risk EG0020 affected7 at risk EG003
Renal hypertension	Renal and urinary disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Urinary incontinence	Renal and urinary disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Urinary tract obstruction	Renal and urinary disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0011 affected3 at risk EG0020 affected7 at risk EG003
Insomnia	Psychiatric disorders	20.0	Systematic Assessment	EG0003 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Depression	Psychiatric disorders	20.0	Systematic Assessment	EG0001 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Confusional state	Psychiatric disorders	20.0	Systematic Assessment	EG0001 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Anxiety	Psychiatric disorders	20.0	Systematic Assessment	EG0001 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Melanocytic naevus	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	20.0	Systematic Assessment	EG0000 affected4 at risk EG0011 affected3 at risk EG0020 affected7 at risk EG003
Tumour pain	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Cancer pain	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Metastases to skin	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Seborrhoeic keratosis	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Hyperbilirubinaemia	Hepatobiliary disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Cholestasis	Hepatobiliary disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Hepatocellular injury	Hepatobiliary disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Hyperthyroidism	Endocrine disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Adrenal insufficiency	Endocrine disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Hypopituitarism	Endocrine disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Hypothyroidism	Endocrine disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Thyroiditis	Endocrine disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0011 affected3 at risk EG0020 affected7 at risk EG003
Wound	Injury, poisoning and procedural complications	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Fall	Injury, poisoning and procedural complications	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0021 affected7 at risk EG003
Incision site pain	Injury, poisoning and procedural complications	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0021 affected7 at risk EG003
Infusion related reaction	Injury, poisoning and procedural complications	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Stoma site haemorrhage	Injury, poisoning and procedural complications	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Vaginal haemorrhage	Reproductive system and breast disorders	20.0	Systematic Assessment	EG0001 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Female genital tract fistula	Reproductive system and breast disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Vaginal discharge	Reproductive system and breast disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Vulvovaginal discomfort	Reproductive system and breast disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Drug hypersensitivity	Immune system disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Food allergy	Immune system disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Sarcoidosis	Immune system disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Deafness unilateral	Ear and labyrinth disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Ear pain	Ear and labyrinth disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Device occlusion	Product Issues	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0020 affected7 at risk EG003
Blood creatine phosphokinase increased	Investigations	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0021 affected7 at risk EG003
Musculoskeletal pain	Musculoskeletal and connective tissue disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0010 affected3 at risk EG0021 affected7 at risk EG003
Malnutrition	Metabolism and nutrition disorders	20.0	Systematic Assessment	EG0000 affected4 at risk EG0011 affected3 at risk EG0020 affected7 at risk EG003

ID	Term
C000626518	tovorafenib
C572449	sapanisertib
C550258	MLN 8237
D017239	Paclitaxel
D000068818	Cetuximab
D000077146	Irinotecan

ID	Term
D043823	Taxoids
D043822	Cyclodecanes
D003516	Cycloparaffins
D006840	Hydrocarbons, Alicyclic
D006844	Hydrocarbons, Cyclic
D006838	Hydrocarbons
D009930	Organic Chemicals
D004224	Diterpenes
D013729	Terpenes
D061067	Antibodies, Monoclonal, Humanized
D000911	Antibodies, Monoclonal
D000906	Antibodies
D007136	Immunoglobulins
D007162	Immunoproteins
D001798	Blood Proteins
D011506	Proteins
D000602	Amino Acids, Peptides, and Proteins
D012712	Serum Globulins
D005916	Globulins
D002166	Camptothecin
D000470	Alkaloids
D006571	Heterocyclic Compounds

ID	Title	Description
BG000	MLN2480 100 mg + MLN0128 2 mg	Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and MLN0128 2 mg, capsules, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles.
BG001	MLN2480 100 mg + Alisertib 30 mg	Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30 mg, tablets, orally, twice daily (BID) on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle.
BG002	MLN2480 160 mg + Alisertib 30 mg	Dose Escalation Phase: MLN2480 160 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30 mg, tablets, orally, twice daily (BID) on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle.
BG003	MLN2480 200 mg + Alisertib 30 mg	Dose Escalation Phase: MLN2480 200 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30 mg, tablets, orally, BID on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle.
BG004	MLN2480 100 mg + Alisertib 40 mg	Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 40 mg, tablets, orally, BID on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle.
BG005	MLN2480 100 mg + Paclitaxel 80 mg/m^2	Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 milligram per square meter (mg/m^2), intravenous (IV) infusion, once weekly (QW) for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care.
BG006	MLN2480 160 mg + Paclitaxel 80 mg/m^2	Dose Escalation Phase: MLN2480 160 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care.
BG007	MLN2480 200 mg + Paclitaxel 80 mg/m^2	Dose Escalation Phase: MLN2480 200 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care.
BG008	MLN2480 400 mg + Paclitaxel 80 mg/m^2	Dose Escalation Phase: MLN2480 400 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care.
BG009	MLN2480 600 mg + Paclitaxel 80 mg/m^2	Dose Escalation Phase: MLN2480 600 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care.
BG010	MLN2480 400 mg + Cetuximab 250 mg/m^2	Dose Escalation Phase: MLN2480 400 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and cetuximab administered intravenously at a loading dose of 400 mg/m^2 (cycle 1 Day 1), then at 250 mg/m^2 QW on Days 8, 15, and 22 of cycle 1 and Days 1, 8, 15, and 22 in each additional 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in cetuximab dose was based on the standard of care.
BG011	MLN2480 600 mg + Cetuximab 250 mg/m^2	Dose Escalation Phase: MLN2480 600 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and cetuximab administered intravenously at a loading dose of 400 mg/m^2 (cycle 1 Day 1), then at 250 mg/m^2 QW on Days 8, 15, and 22 of cycle 1 and Days 1, 8, 15, and 22 in each additional 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in cetuximab dose was based on the standard of care.
BG012	ML2480 300 mg + Irinotecan 180 mg/m^2	Dose Escalation Phase: MLN2480 300 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and irinotecan 180 mg/m^2, IV infusion over 90 minutes, every other week (Q2W) for 2 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in irinotecan dose was based on the standard of care.
BG013	ML2480 400 mg + Irinotecan 180 mg/m^2	Dose Escalation Phase: MLN2480 400 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and irinotecan 180 mg/m^2, IV infusion over 90 minutes, every other week (Q2W) for 2 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in irinotecan dose was based on the standard of care.
BG014	Dose Expansion: MLN2480 600 mg + Paclitaxel 80 mg/m^2	Dose Expansion Phase: MLN2480 600 mg, tablets, orally, once per week on Days 2, 9, 16 and 23 of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, once on 1, 8, and 15 of a 28-day cycle for up to 12 cycles.
BG015	Total	Total of all reporting groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	MLN2480 100 mg + MLN0128 2 mg	Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and MLN0128 2 mg, capsules, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles.	0	4	2	4	4	4
EG001	MLN2480 100 mg + Alisertib 30 mg	Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30 mg, tablets, orally, twice daily (BID) on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle.	0	3	1	3	3	3
EG002	MLN2480 160 mg + Alisertib 30 mg	Dose Escalation Phase: MLN2480 160 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30 mg, tablets, orally, twice daily (BID) on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle.	2	7	5	7	7	7
EG003	MLN2480 200 mg + Alisertib 30 mg	Dose Escalation Phase: MLN2480 200 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 30 mg, tablets, orally, BID on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle.	0	3	1	3	3	3
EG004	MLN2480 100 mg + Alisertib 40 mg	Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and alisertib 40 mg, tablets, orally, BID on protocol specified days of a 28-day cycle for up to 12 cycles. The doses of MLN2480 and alisertib were modified during this phase based on tolerability during each 28-day cycle.	1	8	3	8	8	8
EG005	MLN2480 100 mg + Paclitaxel 80 mg/m^2	Dose Escalation Phase: MLN2480 100 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 milligram per square meter (mg/m^2), intravenous (IV) infusion, once weekly (QW) for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care.	0	4	1	4	4	4
EG006	MLN2480 160 mg + Paclitaxel 80 mg/m^2	Dose Escalation Phase: MLN2480 160 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care.	0	3	1	3	3	3
EG007	MLN2480 200 mg + Paclitaxel 80 mg/m^2	Dose Escalation Phase: MLN2480 200 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care.	0	4	2	4	4	4
EG008	MLN2480 400 mg + Paclitaxel 80 mg/m^2	Dose Escalation Phase: MLN2480 400 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care.	0	6	3	6	6	6
EG009	MLN2480 600 mg + Paclitaxel 80 mg/m^2	Dose Escalation Phase: MLN2480 600 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, QW for 3 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in paclitaxel dose was based on the standard of care.	0	8	4	8	8	8
EG010	MLN2480 400 mg + Cetuximab 250 mg/m^2	Dose Escalation Phase: MLN2480 400 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and cetuximab administered intravenously at a loading dose of 400 mg/m^2 (cycle 1 Day 1), then at 250 mg/m^2 QW on Days 8, 15, and 22 of cycle 1 and Days 1, 8, 15, and 22 in each additional 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in cetuximab dose was based on the standard of care.	2	6	2	6	6	6
EG011	MLN2480 600 mg + Cetuximab 250 mg/m^2	Dose Escalation Phase: MLN2480 600 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and cetuximab administered intravenously at a loading dose of 400 mg/m^2 (cycle 1 Day 1), then at 250 mg/m^2 QW on Days 8, 15, and 22 of cycle 1 and Days 1, 8, 15, and 22 in each additional 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in cetuximab dose was based on the standard of care.	2	7	3	7	7	7
EG012	ML2480 300 mg + Irinotecan 180 mg/m^2	Dose Escalation Phase: MLN2480 300 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and irinotecan 180 mg/m^2, IV infusion over 90 minutes, every other week (Q2W) for 2 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in irinotecan dose was based on the standard of care.	0	1	0	1	1	1
EG013	ML2480 400 mg + Irinotecan 180 mg/m^2	Dose Escalation Phase: MLN2480 400 mg, tablets, orally, once on protocol specified days of a 28-day cycle for up to 12 cycles, and irinotecan 180 mg/m^2, IV infusion over 90 minutes, every other week (Q2W) for 2 weeks in each 28-day cycle for up to 12 cycles. The dose of MLN2480 was modified during this phase based on tolerability during each 28-day cycle. Any changes in irinotecan dose was based on the standard of care.	0	7	4	7	7	7
EG014	Dose Expansion: MLN2480 600 mg + Paclitaxel 80 mg/m^2	Dose Expansion Phase: MLN2480 600 mg, tablets, orally, once per week on Days 2, 9, 16 and 23 of a 28-day cycle for up to 12 cycles, and paclitaxel 80 mg/m^2, IV infusion, once on 1, 8, and 15 of a 28-day cycle for up to 12 cycles.	2	10	7	10	10	10