A Study of MLN0264 in Participants With Cancer of the Sto... | NCT02202759

ID	Type	Description
U1111-1155-9023	Other Identifier	WHO
2014-000804-88	EudraCT Number
REec-2014-1176	Registry Identifier	REec

Label	Type	Description	Intervention Names
MLN0264 1.8 mg/kg	Experimental	MLN0264 1.8 mg/kg, 30-minute intravenous (IV) infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 14 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264.	Drug: MLN0264

Name	Type	Description	Arm Group Labels	Other Names
MLN0264	Drug	MLN0264 IV infusion	MLN0264 1.8 mg/kg

Measure	Description	Time Frame
Overall Response Rate (ORR) Based on Response Evaluation Criteria in Solid Tumors (RECIST)	ORR is defined as the percentage of participants with complete response (CR) or partial response (PR) as assessed by the investigator 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.	Day 21, every other cycle, starting with Cycle 2 until disease progression, death or study closure (up to 17 months)

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. A serious adverse event (SAE) is defined as any untoward medical occurrence that at any dose results in death, is life-threatening, requires inpatient 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. Relationship of each AE to study drug will be determined by the Investigator.

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Male or female participants 18 years of age or older when written informed consent is obtained.
Histologically confirmed metastatic or advanced inoperable adenocarcinoma of the stomach or gastroesophageal junction with immunohistochemistry (IHC) evidence of guanylyl cyclase C (GCC) expression indicated by an H-score of 10 or greater.
Treatment with 1 or more prior chemotherapies for advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction.
Measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 guidelines. All scans and x-rays used to document measurable disease must be done within 28 days before enrollment (ascites and bone lesions are not considered measureable disease).
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 14 days before enrollment.
Female participants who:
- Are postmenopausal for at least 1 year before the screening visit, OR
- Are surgically sterile, OR
- If they are of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent through 30 days after the last dose of study drug, or
- Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the participant. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods] and withdrawal are not acceptable methods of contraception.)
Male participants, even if surgically sterilized (ie, status postvasectomy), who:
- Agree to practice effective barrier contraception during the entire study treatment period and through 4 months after the last dose of study drug, or
- Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the participant. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods for the female partner] and withdrawal are not acceptable methods of contraception.)
Voluntary written consent must be given before performance of any study-related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the participant at any time without prejudice to future medical care.
Adequate organ and hematological function as evidenced by the following laboratory values within 14 days before enrollment:
- Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L
- Platelet count ≥ 100 x 10^9/L
- Hemoglobin ≥ 9 g/dL
- Activated partial thromboplastin time (aPTT) ≤ 1.5 x the upper limit of the normal range (ULN) per institutional laboratory normal range
- International normalized ratio (INR) ≤ 1.5 x ULN
- Serum creatinine ≤ 1.5 x ULN
- Total bilirubin ≤ 1.5 x ULN
- Albumin ≥ 3g/dL
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN
- Serum lipase ≤ 3 x ULN and serum amylase within the normal range
Resolution of all toxic effects of prior treatments except alopecia to Grade 0 or 1 by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.03.
Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other trial procedures.

Exclusion Criteria:

Radiotherapy within 4 weeks before enrollment.
Concurrent treatment or treatment within 4 weeks of study entry with any other investigational agent or chemotherapy.
Female participants who are lactating and breastfeeding or have a positive pregnancy test during the Screening period.
Uncontrolled, clinically significant, symptomatic cardiovascular disease within 6 months before enrollment, including myocardial infarction, unstable angina, Grade 2 or greater peripheral vascular disease, cerebrovascular accident, transient ischemic attack, congestive heart failure, or arrhythmias not controlled by outpatient medication.
Treatment with any medication that has a clinically relevant potential risk of prolonging the QT interval or inducing torsades de pointes that cannot be discontinued or switched to a different medication before starting study drug.
Participants with electrocardiogram (ECG) abnormalities considered by the investigator to be clinically significant, or repeated baseline prolongation of the rate-corrected QT interval (QTc).
Ongoing or clinically significant active infection as judged by the investigator.
Signs of peripheral neuropathy (PN) ≥ NCI CTCAE Grade 2.
Concomitant chemotherapy, hormonal therapy, immunotherapy, or any other form of cancer treatment.
Use of strong cytochrome P450 (CYP) 3A4 inhibitors within 2 weeks before the first dose of study drug.
Any preexisting medical condition of sufficient severity to prevent full compliance with the study.
History of or current neoplasm other than gastric adenocarcinoma, except for curatively treated nonmelanoma skin cancer or in situ carcinoma of the cervix uteri.
Known diagnosis of human immunodeficiency virus (HIV) infection (testing is not mandatory).
Symptomatic brain metastases.
Ongoing anticoagulant therapy (eg, aspirin, coumadin, heparin).

Name	Affiliation	Role
Medical Director Clinical Science	Millennium Pharmaceuticals, Inc.	Study Director

ID	Title	Description
FG000	MLN0264 1.8 mg/kg (GCC Low)	MLN0264 1.8 mg/kg, 30-minute intravenous (IV) infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 14 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264. Participants with guanylyl cyclase C (GCC) protein expression=Low (combined H-score 10-59). Total H-score 0-600 is the combined score of cytoplasmic staining 0-300 and apical staining 0-300 and is based on the percentage of tumor cells with staining intensity 1+, 2+ and 3+.

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

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

ORR is defined as the percentage of participants with complete response (CR) or partial response (PR) as assessed by the investigator 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 included all participants with measurable disease who received at least 1 dose of MLN0264 and had at least 1 post-baseline response assessment.

Posted

Number

percentage of participants

Day 21, every other cycle, starting with Cycle 2 until disease progression, death or study closure (up to 17 months)

ID	Title	Description
OG000	MLN0264 1.8 mg/kg (GCC Low)	MLN0264 1.8 mg/kg, 30-minute intravenous (IV) infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 14 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264. Participants with guanylyl cyclase C (GCC) protein expression=Low (combined H-score 10-59). Total H-score 0-600 is the combined score of cytoplasmic staining 0-300 and apical staining 0-300 and is based on the percentage of tumor cells with staining intensity 1+, 2+ and 3+.
OG001	MLN0264 1.8 mg/kg (GCC Intermediate)	MLN0264 1.8 mg/kg, 30-minute IV infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 9 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264. Participants with guanylyl cyclase C (GCC) protein expression=Intermediate (combined H-score 60-119). Total H-score 0-600 is the combined score of cytoplasmic staining 0-300 and apical staining 0-300 and is based on the percentage of tumor cells with staining intensity 1+, 2+ and 3+.
OG002	MLN0264 1.8 mg/kg (GCC High)	MLN0264 1.8 mg/kg, 30-minute IV infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 8 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264. Participants with guanylyl cyclase C (GCC) protein expression=Intermediate (combined H-score >120). Total H-score 0-600 is the combined score of cytoplasmic staining 0-300 and apical staining 0-300 and is based on the percentage of tumor cells with staining intensity 1+, 2+ and 3+.

Units	Counts
Participants	OG0009 OG00114 OG00213

Title

Denominators

Categories

Title	Measurements
	OG0000 OG00114 OG0020

Secondary

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. A serious adverse event (SAE) is defined as any untoward medical occurrence that at any dose results in death, is life-threatening, requires inpatient 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. Relationship of each AE to study drug will be determined by the Investigator.

Safety population included all participants who received any amount of MLN0264.

Posted

Number

participants

From the first dose through 30 days after the last dose of study medication (Up to 10.7 months)

ID	Title	Description
OG000	MLN0264 1.8 mg/kg (GCC Low)	MLN0264 1.8 mg/kg, 30-minute intravenous (IV) infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 14 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264. Participants with guanylyl cyclase C (GCC) protein expression=Low (combined H-score 10-59). Total H-score 0-600 is the combined score of cytoplasmic staining 0-300 and apical staining 0-300 and is based on the percentage of tumor cells with staining intensity 1+, 2+ and 3+.
OG001

Secondary

Number of Participants With Potentially Clinically Significant Laboratory Evaluation Findings

Participants with at least one post-baseline potentially clinically significant serum chemistry, hematology, coagulation or urinalysis result. Clinically significant results are those that were assessed by the investigator to be Grade 3 or higher using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE). Grade 3=severe, Grade 4=life threatening or disabling and Grade 5=Death.

Safety population included all participants who received any amount of MLN0264.

Posted

Number

participants

From the first dose through 30 days after the last dose of study medication (Up to 10.7 months)

ID	Title	Description
OG000	MLN0264 1.8 mg/kg	MLN0264 1.8 mg/kg, 30-minute intravenous (IV) infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 14 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264.

Units	Counts
Participants	OG000

Secondary

Number of Participants With Potentially Clinically Significant Vital Signs Findings

Participants with at least one potentially clinically significant post-baseline vital sign finding including measurements of diastolic and systolic blood pressure, heart rate, and oral temperature.

Safety population included all participants who received any amount of MLN0264.

Posted

Number

participants

Day 1 of each 21 day cycle and 30 days after the last dose of study medication (Up to 10.7 months)

ID	Title	Description
OG000	MLN0264 1.8 mg/kg	MLN0264 1.8 mg/kg, 30-minute intravenous (IV) infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 14 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264.

Units	Counts
Participants	OG000

Secondary

Progression Free Survival (PFS)

PFS is defined as the time in days from the date of first study drug administration to the date of first documentation of disease progression or death. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.

Response-Evaluable population included all participants with measurable disease who received at least 1 dose of MLN0264 and had at least 1 post-baseline response assessment.

Posted

Median

Full Range

days

Time Frame: Day 21 of every other 21-day cycle starting with Cycle 2, 30 days after the last dose of study medication, and then every 12 weeks for up to an additional 6 months (Up to 16.7 months)

ID	Title	Description
OG000	MLN0264 1.8 mg/kg (GCC Low)	MLN0264 1.8 mg/kg, 30-minute intravenous (IV) infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 14 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264. Participants with guanylyl cyclase C (GCC) protein expression=Low (combined H-score 10-59). Total H-score 0-600 is the combined score of cytoplasmic staining 0-300 and apical staining 0-300 and is based on the percentage of tumor cells with staining intensity 1+, 2+ and 3+.
OG001	MLN0264 1.8 mg/kg (GCC Intermediate)

Secondary

Duration of Response

Duration of response is defined as the time in days from the date of first documentation of a confirmed response to the date of first documentation of disease progression. Per RECIST v1.1 for target lesions and assessed by magnetic resonance imaging (MRI) - 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.

Participants from the Response-Evaluable population, all participants with measurable disease who received at least 1 dose of MLN0264 and had at least 1 post-baseline response assessment, who had response.

Posted

Median

Full Range

days

From first documented response until disease progression (Up to 16.7 months)

ID	Title	Description
OG000	MLN0264 1.8 mg/kg	MLN0264 1.8 mg/kg, 30-minute intravenous (IV) infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 14 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264.

Units	Counts
Participants

Secondary

Disease Control Rate

Disease control rate is defined as the percentage of participants with complete response (CR) or partial response (PR) or stable disease (SD) with a minimum of 12 weeks' duration. 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 the Longest Diameter (LD) of target lesions, taking as reference the baseline sum LD and no new lesions. SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD) of target lesions, taking as reference the smallest sum LD since the treatment started and no new lesions. Investigator response is based on the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1.

Response-Evaluable population included all participants with measurable disease who received at least 1 dose of MLN0264 and had at least 1 post-baseline response assessment.

Posted

Number

percentage of participants

Day 21 of every other 21-day cycle starting with Cycle 2, 30 days after the last dose of study medication, and then every 12 weeks for up to an additional 6 months (Up to 16.7 months)

ID	Title	Description
OG000	MLN0264 1.8 mg/kg (GCC Low)	MLN0264 1.8 mg/kg, 30-minute intravenous (IV) infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 14 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264. Participants with guanylyl cyclase C (GCC) protein expression=Low (combined H-score 10-59). Total H-score 0-600 is the combined score of cytoplasmic staining 0-300 and apical staining 0-300 and is based on the percentage of tumor cells with staining intensity 1+, 2+ and 3+.

Secondary

Overall Survival (OS)

Overall survival is defined as the time in days from the date of first study drug administration to the date of death.

Response-evaluable population, all participants with measurable disease who received at least 1 dose of MLN0264 and had at least 1 postbaseline response assessment.

Posted

Median

Full Range

days

Until death or 6 months after the last patient completes treatment-whichever occurs first (Up to 17 months)

ID	Title	Description
OG000	MLN0264 1.8 mg/kg (GCC Low)	MLN0264 1.8 mg/kg, 30-minute intravenous (IV) infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 14 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264. Participants with guanylyl cyclase C (GCC) protein expression=Low (combined H-score 10-59). Total H-score 0-600 is the combined score of cytoplasmic staining 0-300 and apical staining 0-300 and is based on the percentage of tumor cells with staining intensity 1+, 2+ and 3+.
OG001	MLN0264 1.8 mg/kg (GCC Intermediate)	MLN0264 1.8 mg/kg, 30-minute IV infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 9 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264. Participants with guanylyl cyclase C (GCC) protein expression=Intermediate (combined H-score 60-119). Total H-score 0-600 is the combined score of cytoplasmic staining 0-300 and apical staining 0-300 and is based on the percentage of tumor cells with staining intensity 1+, 2+ and 3+.

Secondary

Cmax: Maximum Observed Serum Concentration for MLN0264

Maximum observed serum concentration (Cmax) is the peak serum concentration of a drug after administration, obtained directly from the serum concentration-time curve.

Cmax was not a pre-specified secondary outcome measure. No data was collected.

Posted

Cycles 1-3 predose and 10 minutes, 4 hours, and 3, 4, 8 and 15 days postdose. Cycles 4+ predose, 10 minutes, 4 hours, and 4 and 8 days postdose.

ID	Title	Description
OG000	MLN0264 1.8 mg/kg	MLN0264 1.8 mg/kg, 30-minute intravenous (IV) infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 14 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264.

Units	Counts
Participants	OG000

Secondary

MLN0264 Serum Concentrations

Blood samples were collected and sent to a laboratory to be tested for serum concentrations of MLN0264.

Pharmacokinetic (PK)-Evaluable population included all participants who received at least 1 dose of MLN0264 and who had sufficient MLN0264 concentration-time data to permit reliable estimation of MLN0264 exposure. "n" in the categories is the number of participants with data available at the given time-point.

Posted

Mean

Standard Deviation

μg/mL

Cycles 1-3 pre-dose and 10 minutes, 4 hours, and 3, 4, 8 and 15 days post-dose; Cycles 4-9 and 11-14 pre-dose and 10 minutes post-dose; End of Treatment.

ID	Title	Description
OG000	MLN0264 1.8 mg/kg	MLN0264 1.8 mg/kg, 30-minute intravenous (IV) infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 14 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264.

Units	Counts
Participants	OG000

Secondary

Serum Concentration of Total Antibodies (Conjugated and Unconjugated)

Blood samples were collected and sent to a laboratory to be tested for conjugated and unconjugated antibodies.

PK-Evaluable population included all participants who received at least 1 dose of MLN0264 and who had sufficient MLN0264 concentration-time data to permit reliable estimation of MLN0264 exposure. "n" in the categories is the number of participants with data available at the given time-point.

Posted

Mean

Standard Deviation

μg/mL

Cycles 1-3 pre-dose and 10 minutes, 4 hours, and 3, 4, 8 and 15 days post-dose; Cycles 4-9 and 11-14 pre-dose and 10 minutes post-dose; End of Treatment.

ID	Title	Description
OG000	MLN0264 1.8 mg/kg	MLN0264 1.8 mg/kg, 30-minute intravenous (IV) infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 14 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264.

Units	Counts
Participants	OG000

Secondary

Serum Concentration of Monomethyl Auristatin E (MMAE)

Blood samples were collected and sent to a laboratory to be tested for MMAE.

Posted

Mean

Standard Deviation

ng/mL

Cycles 1-3 pre-dose and 10 minutes, 4 hours, and 3, 4, 8 and 15 days post-dose; Cycles 4-9 and 11-14 pre-dose and 10 minutes post-dose; End of Treatment.

ID	Title	Description
OG000	MLN0264 1.8 mg/kg	MLN0264 1.8 mg/kg, 30-minute intravenous (IV) infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 14 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264.

Units	Counts
Participants	OG000

Secondary

Number of Participants With Reduction From Baseline in Tumor Size

The number of participants with the best percentage of tumor reduction from baseline in the sum of the diameter was calculated.

Response-Evaluable Population was defined as all participants with measurable disease who receive at least 1 dose of MLN0264 and have at least 1 postbaseline response assessment.

Posted

Number

participants

Day 21 of every other 21-day cycle starting with Cycle 2, 30 days after the last dose of study medication, and then every 12 weeks for up to an additional 6 months (Up to 16.7 months)

ID	Title	Description
OG000	MLN0264 1.8 mg/kg (GCC Low)	MLN0264 1.8 mg/kg, 30-minute intravenous (IV) infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 14 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264. Participants with guanylyl cyclase C (GCC) protein expression=Low (combined H-score 10-59). Total H-score 0-600 is the combined score of cytoplasmic staining 0-300 and apical staining 0-300 and is based on the percentage of tumor cells with staining intensity 1+, 2+ and 3+.
OG001	MLN0264 1.8 mg/kg (GCC Intermediate)	MLN0264 1.8 mg/kg, 30-minute IV infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 9 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264. Participants with guanylyl cyclase C (GCC) protein expression=Intermediate (combined H-score 60-119). Total H-score 0-600 is the combined score of cytoplasmic staining 0-300 and apical staining 0-300 and is based on the percentage of tumor cells with staining intensity 1+, 2+ and 3+.

Secondary

Guanylyl Cyclase C (GCC) H-score Assessed by Immunohistochemistry (IHC)

Analysis of GCC protein expression levels in tumor tissue (fresh biopsy pretreatment and whenever a biopsy is considered medically safe and technically feasible) was performed using a semiquantitative immunohistochemistry (IHC) assay and the total GCC H-Score was determined. GCC H-score is based on the sum of the 0 to 300 H-score for cytoplasmic staining and the 0 to 300 H-score for apical staining for a total possible H-score 0 to 600. Separate consent was required to obtain archival tumor specimens for GCC expression assessment prior to screening.

Safety population included all participants who received any amount of MLN0264.

Posted

Mean

Full Range

scores on a scale

Approximately 20 months

ID	Title	Description
OG000	MLN0264 1.8 mg/kg (GCC Low)	MLN0264 1.8 mg/kg, 30-minute intravenous (IV) infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 14 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264. Participants with guanylyl cyclase C (GCC) protein expression=Low (combined H-score 10-59). Total H-score 0-600 is the combined score of cytoplasmic staining 0-300 and apical staining 0-300 and is based on the percentage of tumor cells with staining intensity 1+, 2+ and 3+.
OG001	MLN0264 1.8 mg/kg (GCC Intermediate)

Secondary

Number of Participants With Antitherapeutic Antibodies (ATA)

Blood samples were collected to assess the immunogenicity of MLN0264 (ATA development) using a laboratory test. Neutralizing ATA assessment was performed for ATA-positive samples only.

Safety Population included all participant who received any amount of MLN0264.

Posted

Number

participants

Pre-dose of each 21 day cycle and 30 days after last dose of study medication (Up to 10.7 months)

ID	Title	Description
OG000	MLN0264 1.8 mg/kg (GCC Low)	MLN0264 1.8 mg/kg, 30-minute intravenous (IV) infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 14 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264. Participants with guanylyl cyclase C (GCC) protein expression=Low (combined H-score 10-59). Total H-score 0-600 is the combined score of cytoplasmic staining 0-300 and apical staining 0-300 and is based on the percentage of tumor cells with staining intensity 1+, 2+ and 3+.
OG001	MLN0264 1.8 mg/kg (GCC Intermediate)	MLN0264 1.8 mg/kg, 30-minute IV infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 9 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264. Participants with guanylyl cyclase C (GCC) protein expression=Intermediate (combined H-score 60-119). Total H-score 0-600 is the combined score of cytoplasmic staining 0-300 and apical staining 0-300 and is based on the percentage of tumor cells with staining intensity 1+, 2+ and 3+.

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Anaemia	Blood and lymphatic system disorders	MedDRA, Version 18.0	Systematic Assessment	EG0006 affected38 at risk
Neutropenia	Blood and lymphatic system disorders	MedDRA, Version 18.0	Systematic Assessment	EG0005 affected38 at risk
Abdominal pain	Gastrointestinal disorders	MedDRA, Version 18.0	Systematic Assessment	EG0004 affected38 at risk
Ascites	Gastrointestinal disorders	MedDRA, Version 18.0	Systematic Assessment	EG0002 affected38 at risk
Constipation	Gastrointestinal disorders	MedDRA, Version 18.0	Systematic Assessment	EG0009 affected38 at risk
Diarrhoea	Gastrointestinal disorders	MedDRA, Version 18.0	Systematic Assessment	EG0006 affected38 at risk
Dysphagia	Gastrointestinal disorders	MedDRA, Version 18.0	Systematic Assessment	EG0003 affected38 at risk
Gastrooesophageal reflux disease	Gastrointestinal disorders	MedDRA, Version 18.0	Systematic Assessment	EG0002 affected38 at risk
Nausea	Gastrointestinal disorders	MedDRA, Version 18.0	Systematic Assessment	EG00020 affected38 at risk
Stomatitis	Gastrointestinal disorders	MedDRA, Version 18.0	Systematic Assessment	EG0003 affected38 at risk
Vomiting	Gastrointestinal disorders	MedDRA, Version 18.0	Systematic Assessment	EG00010 affected38 at risk
Asthenia	General disorders	MedDRA, Version 18.0	Systematic Assessment	EG00010 affected38 at risk
Fatigue	General disorders	MedDRA, Version 18.0	Systematic Assessment	EG00012 affected38 at risk
Oedema peripheral	General disorders	MedDRA, Version 18.0	Systematic Assessment	EG0007 affected38 at risk
Pain	General disorders	MedDRA, Version 18.0	Systematic Assessment	EG0002 affected38 at risk
Pyrexia	General disorders	MedDRA, Version 18.0	Systematic Assessment	EG0004 affected38 at risk
Urinary tract infection	Infections and infestations	MedDRA, Version 18.0	Systematic Assessment	EG0002 affected38 at risk
Fall	Injury, poisoning and procedural complications	MedDRA, Version 18.0	Systematic Assessment	EG0002 affected38 at risk
Blood alkaline phosphatase increased	Investigations	MedDRA, Version 18.0	Systematic Assessment	EG0004 affected38 at risk
Gamma-glutamyltransferase increased	Investigations	MedDRA, Version 18.0	Systematic Assessment	EG0004 affected38 at risk
Neutrophil count decreased	Investigations	MedDRA, Version 18.0	Systematic Assessment	EG0004 affected38 at risk
Weight decreased	Investigations	MedDRA, Version 18.0	Systematic Assessment	EG0003 affected38 at risk
Decreased appetite	Metabolism and nutrition disorders	MedDRA, Version 18.0	Systematic Assessment	EG00011 affected38 at risk
Dehydration	Metabolism and nutrition disorders	MedDRA, Version 18.0	Systematic Assessment	EG0003 affected38 at risk
Hyperglycaemia	Metabolism and nutrition disorders	MedDRA, Version 18.0	Systematic Assessment	EG0003 affected38 at risk
Hypoalbuminaemia	Metabolism and nutrition disorders	MedDRA, Version 18.0	Systematic Assessment	EG0004 affected38 at risk
Hypocalcaemia	Metabolism and nutrition disorders	MedDRA, Version 18.0	Systematic Assessment	EG0004 affected38 at risk
Hypokalaemia	Metabolism and nutrition disorders	MedDRA, Version 18.0	Systematic Assessment	EG0002 affected38 at risk
Hypomagnesaemia	Metabolism and nutrition disorders	MedDRA, Version 18.0	Systematic Assessment	EG0002 affected38 at risk
Hyponatraemia	Metabolism and nutrition disorders	MedDRA, Version 18.0	Systematic Assessment	EG0002 affected38 at risk
Back pain	Musculoskeletal and connective tissue disorders	MedDRA, Version 18.0	Systematic Assessment	EG0004 affected38 at risk
Musculoskeletal pain	Musculoskeletal and connective tissue disorders	MedDRA, Version 18.0	Systematic Assessment	EG0003 affected38 at risk
Myalgia	Musculoskeletal and connective tissue disorders	MedDRA, Version 18.0	Systematic Assessment	EG0002 affected38 at risk
Pain in extremity	Musculoskeletal and connective tissue disorders	MedDRA, Version 18.0	Systematic Assessment	EG0004 affected38 at risk
Dizziness	Nervous system disorders	MedDRA, Version 18.0	Systematic Assessment	EG0002 affected38 at risk
Hypoaesthesia	Nervous system disorders	MedDRA, Version 18.0	Systematic Assessment	EG0002 affected38 at risk
Neuropathy peripheral	Nervous system disorders	MedDRA, Version 18.0	Systematic Assessment	EG0004 affected38 at risk
Tremor	Nervous system disorders	MedDRA, Version 18.0	Systematic Assessment	EG0002 affected38 at risk
Confusional state	Psychiatric disorders	MedDRA, Version 18.0	Systematic Assessment	EG0002 affected38 at risk
Depression	Psychiatric disorders	MedDRA, Version 18.0	Systematic Assessment	EG0002 affected38 at risk
Proteinuria	Renal and urinary disorders	MedDRA, Version 18.0	Systematic Assessment	EG0002 affected38 at risk
Dyspnoea	Respiratory, thoracic and mediastinal disorders	MedDRA, Version 18.0	Systematic Assessment	EG0004 affected38 at risk
Orthopnoea	Respiratory, thoracic and mediastinal disorders	MedDRA, Version 18.0	Systematic Assessment	EG0002 affected38 at risk
Alopecia	Skin and subcutaneous tissue disorders	MedDRA, Version 18.0	Systematic Assessment	EG0005 affected38 at risk
Deep vein thrombosis	Vascular disorders	MedDRA, Version 18.0	Systematic Assessment	EG0002 affected38 at risk

Facility	Status	City	State	ZIP	Country	Contacts
		Aurora	Colorado		United States

ID	Title	Description
BG000	MLN0264 1.8 mg/kg (GCC Low)	MLN0264 1.8 mg/kg, 30-minute intravenous (IV) infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 14 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264. Participants with guanylyl cyclase C (GCC) protein expression=Low (combined H-score 10-59). Total H-score 0-600 is the combined score of cytoplasmic staining 0-300 and apical staining 0-300 and is based on the percentage of tumor cells with staining intensity 1+, 2+ and 3+.
BG001	MLN0264 1.8 mg/kg (GCC Intermediate)	MLN0264 1.8 mg/kg, 30-minute IV infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 9 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264. Participants with guanylyl cyclase C (GCC) protein expression=Intermediate (combined H-score 60-119). Total H-score 0-600 is the combined score of cytoplasmic staining 0-300 and apical staining 0-300 and is based on the percentage of tumor cells with staining intensity 1+, 2+ and 3+.
BG002	MLN0264 1.8 mg/kg (GCC High)	MLN0264 1.8 mg/kg, 30-minute IV infusion, Day 1 of each 21-day cycle, for up to 1 year or until disease progression or unacceptable toxicity occurs (Up to 8 cycles). The dose may be decreased, delayed or discontinued in participants who develop treatment-associated nonhematologic and hematologic toxicity to MLN0264. Participants with guanylyl cyclase C (GCC) protein expression=Intermediate (combined H-score >120). Total H-score 0-600 is the combined score of cytoplasmic staining 0-300 and apical staining 0-300 and is based on the percentage of tumor cells with staining intensity 1+, 2+ and 3+.
BG003	Total	Total of all reporting groups