A Phase 1 Study Evaluating the Safety, Tolerability and P... | NCT02525536

ID	Type	Description	Link
U1111-1170-0395	Registry Identifier	WHO
JapicCTI-101161	Registry Identifier	JapicCTI

Label	Type	Description	Intervention Names
Trebananib 3 mg/kg	Experimental	Trebananib (AMG 386) 3 milligram/kilogram (mg/kg), 60-minute infusion, intravenously once weekly on Days 1, 8, 15 and 22 and thereafter once weekly starting from Day 36 (Week 6) until intolerance to investigational product, progressive disease, consent withdrawn, or lost to follow-up (up to approximately 249 weeks).	Drug: Trebananib 3 mg/kg
Trebananib 10 mg/kg	Experimental	Trebananib (AMG 386) 10 mg/kg, 60-minute infusion, intravenously once weekly on Days 1, 8, 15 and 22 and thereafter once weekly starting from Day 36 (Week 6) until intolerance to investigational product, progressive disease, consent withdrawn, or lost to follow-up (up to approximately 249 weeks).	Drug: Trebananib 10 mg/kg
Trebananib 30 mg/kg	Experimental	Trebananib (AMG 386) 30 mg/kg, 60-minute infusion, intravenously once weekly on Days 1, 8, 15 and 22 and thereafter once weekly starting from Day 36 (Week 6) until intolerance to investigational product, progressive disease, consent withdrawn, or lost to follow-up (up to approximately 249 weeks).	Drug: Trebananib 30 mg/kg

Name	Type	Description	Arm Group Labels	Other Names
Trebananib 3 mg/kg	Drug	Trebananib (AMG 386) 3 mg/kg, intravenous infusion.	Trebananib 3 mg/kg

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Number of Participants With Dose Limiting Toxicity (DLT)	DLT is defined as any treatment-related, grade 4 or higher hematologic or grade 3 or higher non-hematologic toxicity (according to the Common Terminology Criteria for Adverse Events [CTCAE] version 3.0; hematologic toxicity means any toxicities which are categorized in blood/bone marrow category of CTCAE), except for aspartate aminotransferase (AST), alanine aminotransferase (ALT) and infusion reaction, occurred during the first 28 days after the initial administration (before examination on Study Day 29). DLT also includes AST or ALT: >10*upper limit of normal (ULN) international units per liter (IU/L).	Day 1 up to Day 28
Number of Participants Reporting One or More Treatment-emergent Adverse Events (AEs) and Serious Adverse Event (SAEs)	An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (example, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. Treatment emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug. A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; or congenital anomaly; or a medically important event.	Baseline up to 4 weeks after the last dose of study drug, where last dose was given up to Week 249
Number of Participants With Significant Change From Baseline in Electrocardiogram (ECG)	Change relative to baseline in electrocardiogram measured throughout study. Significant change in ECG observed at any time point was summarized and reported.	Week 1: predose, 1, 6 hours after end of infusion, Week 4: predose, 1 hour after end of infusion, Week 8, 16: predose, thereafter predose of every 8 weeks up to 4 weeks after the last dose of study drug, where last dose was given up to Week 249

Secondary Outcomes

Measure	Description	Time Frame
Number of Participants With Best Overall Response	Best overall response for a participant is the best observed post-baseline disease response as per Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 criteria. Complete Response (CR): disappearance of all target lesions, non-target lesions and normalization of tumor marker level. Partial Response (PR): at least 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum of longest diameter. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the baseline smallest sum of longest diameter; persistence of 1 or more non-target lesion(s) or maintenance of tumor marker level above the normal limits. PD: at least 20% increase in the sum of the longest diameter of target lesions, taking as reference the baseline smallest sum of longest diameter or appearance of 1 or more new lesions or unequivocal progression of existing non-target lesions.

Eligibility Module

Eligibility Criteria

Inclusion Criteria: 1. Histologically or cytologically documented and definitively diagnosed, advanced solid tumor that is refractory to standard treatment or for which no curative therapy is available. 2. Has Eastern Cooperative Oncology Group (ECOG) of 0 or 1 (within 2 weeks prior to enrollment). 3. Men or women, 20 to 74 years old at the time the written informed consent is obtained. 4. Those meeting the following laboratory criteria (within 2 weeks prior to enrollment): A. Hematological function, as follows: • Absolute neutrophil count >=1500 /microliter (mcL) (without granulocyte colony stimulating factor support within 2 weeks of enrollment). • Platelet count >=10*10^4 /mcL (without transfusion within 2 weeks of enrollment). • Hemoglobin >=9 grams per deciliter (g/dL) (without transfusion within 2 weeks of enrollment). B. Renal function, as follows: • Calculated creatinine clearance (CCr) >40 milliliter per minute (mL/min) according to the Cockcroft-Gault formula. • Urinary protein quantitative value of less than or equal to (<=) 30 mg/dL in urinalysis or <=1+ on dipstick, unless quantitative protein is <=1,000 mg in a 24 hour urine sample. C. Hepatic function, as follows: • AST <=2.5*ULN (if liver metastases are present, <=5*ULN). • ALT <=2.5*ULN (if liver metastases are present, <=5*ULN). • Alkaline phosphatase <=2.0*ULN (if bone or liver metastates present <=5*ULN). • Total bilirubin <=2.0*ULN. D. Hemostatic function, as follows: • Prothrombin time (PT) or activated partial thromboplastin time (APTT) <=1.5*ULN. E. ECG • Normal sinus rhythm (no clinical significant 12-lead ECG changes) 5. Life expectancy of 3 months, in the judgment of the investigator. Exclusion Criteria: 1. Has primary central nervous system (CNS) tumors, including any CNS lymphoma. 2. Has history of CNS metastases (including previously treated metastases) (The brain imaging test by CT or MRI will be performed at screening. If the imaging test was performed within 3 months prior to written informed consent, the result can be used to confirm the exclusion criterion.) 3. Has hematological malignancies. 4. Has unresolved toxicities from prior anti-cancer therapy, defined as having not resolved to CTCAE grade 0 or 1, or to levels specified in the inclusion/exclusion criteria with the exception of alopecia. 5. Has clinically significant cardiovascular disease within 1 year prior to enrollment, including myocardial infarction, unstable angina, New York Heart Association class 2 or greater heart failure, peripheral vascular disease, cerebrovascular accident, transient ischemic attack, or arrhythmias not controlled by outpatient medication. 6. Has uncontrolled hypertension [diastolic >90 millimeter of mercury [mmHg]; systolic >150 mmHg]. Participant on antihypertensive medication must meet these parameters on a stable antihypertensive. 7. Has history of arterial or venous (deep vein) thrombosis within 1 year before enrollment. 8. Has presence of ascites or pleural effusion requiring medical intervention (example, drainage.) 9. Has history of bleeding diathesis or clinically significant bleeding including hemoptysis within 6 months of enrollment. 10. Has non-healing wound, ulcer or fracture. 11. With head and neck cancer. 12. Has squamous cell tumor or lung cancer with large central (located adjacent to or within the hilum or mediastinum) tumor lesions >=3 centimeter (cm), regardless of histology. 13. Has positive test for human immunodeficiency virus infection. 14. Has positive test for hepatitis C virus infection (positive hepatitis C virus antibody [HCVAb] or hepatitis B infection (positive hepatitis B virus antigen [HBsAg] or positive hepatitis B virus antibody [HBcAb])). 15. Had major surgery (requiring general anesthesia) within 4 weeks before enrollment. 16. Has minor surgery, placement of central venous catheter, or fine needle aspiration within 7 days prior to enrollment. 17. Is unable to tolerate IV administration, in the judgment of the investigator. 18. Has prior anti-tumor therapies, defined as: •Treatment with tumor directed antibody therapy within 4 weeks prior to Study Day 1, with the exception of bevacizumab and other monoclonal antibodies with a half-life >10 days, which must be discontinued at least 8 weeks prior to Study Day 1. •Anti-cancer therapy including chemotherapy and retinoid therapy within 4 weeks (6 weeks for nitrosoureas or mitomycin) before Study Day 1. •Hormonal anti-tumor therapy within 4 weeks before Study Day 1. Does not include hormones for non-cancer related conditions (example, insulin for diabetes, hormone replacement therapy). •Therapeutic or palliative radiation therapy within 4 weeks before Study Day 1 (participants must have resolution of any significant adverse effects from radiation therapy received prior to 2 weeks before Study Day 1). 19. Has any elective surgeries scheduled during their participation in the study. 20. Has prior radiation to abdomen. 21. Has concurrent or prior (within 4 weeks before Study Day 1) anticoagulation therapy excluding aspirin and anti-platelet agents. The concurrent use of low molecular weight heparin or low dose warfarin (<=1 mg daily) for prophylaxis against thrombosis is acceptable. 22. Has concurrent immunosuppressant therapy (cyclosporine, tacrolimus, or chronic treatment with prednisolone [> 5 mg daily]) within 4 weeks prior to Study Day 1. 23. Currently or previously treated with angiopoietin inhibitors, or inhibitors of Tie-1 or Tie-2 including, but not limited to, AMG 386, XL880, XL820. 24. Is enrolled in the clinical study for other investigational products or devices or within 4 weeks since the last administration at the enrollment. 25. Is pregnant (example, positive human choriogonadotropin [HCG] test) or breastfeeding. 26. Has a childbearing potential, or participant who has a partner of childbearing potential, who is not using adequate contraceptive precautions, and participant unwilling for 6 months after the last AMG 386 infusion. 27. Has any kind of disorder that compromises the ability of the participant to give written informed consent and/or comply with study procedures. 28. Has any co-morbid medical condition that would increase the risk of toxicity, in the judgement of the investigator or the sponsor. 29. The investigator has determined the participant has difficulties that would prevent the participant's ability to participate in the study. 30. Has a history of allergic reactions to bacterially produced proteins. 31. Has a history of severe drug hypersensitivity.

Name	Affiliation	Role
Medical Director	Takeda	Study Director

PubMed Identifier	Type	Citation	Retractions
23124648	Result	Doi T, Ohtsu A, Fuse N, Yoshino T, Tahara M, Shibayama K, Takubo T, Weinreich DM. Phase 1 study of trebananib (AMG 386), an angiogenesis targeting angiopoietin-1/2 antagonist, in Japanese patients with advanced solid tumors. Cancer Chemother Pharmacol. 2013 Jan;71(1):227-35. doi: 10.1007/s00280-012-2000-1. Epub 2012 Nov 3.

ID	Title	Description
FG000	Trebananib 3 mg/kg	Trebananib (AMG 386) 3 mg/kg, 60-minute infusion, intravenously once weekly on Days 1, 8, 15 and 22 and thereafter once weekly starting from Day 36 (Week 6) until intolerance to investigational product, progressive disease, consent withdrawn, or lost to follow-up (up to approximately 249 weeks).
FG001

ID	Title	Description
BG000	Trebananib 3 mg/kg	Trebananib (AMG 386) 3 mg/kg, 60-minute infusion, intravenously once weekly on Days 1, 8, 15 and 22 and thereafter once weekly starting from Day 36 (Week 6) until intolerance to investigational product, progressive disease, consent withdrawn, or lost to follow-up (up to approximately 249 weeks).
BG001	Trebananib 10 mg/kg	Trebananib (AMG 386) 10 mg/kg, 60-minute infusion, intravenously once weekly on Days 1, 8, 15 and 22 and thereafter once weekly starting from Day 36 (Week 6) until intolerance to investigational product, progressive disease, consent withdrawn, or lost to follow-up (up to approximately 249 weeks).
BG002	Trebananib 30 mg/kg	Trebananib (AMG 386) 30 mg/kg, 60-minute infusion, intravenously once weekly on Days 1, 8, 15 and 22 and thereafter once weekly starting from Day 36 (Week 6) until intolerance to investigational product, progressive disease, consent withdrawn, or lost to follow-up (up to approximately 249 weeks).
BG003	Total	Total of all reporting groups

Units	Counts
Participants	BG0006 BG0016 BG0026 BG00318

Baseline Measures

Title

Description

Population Description

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Denominator Units Selected

Denominators

Classes

Age, Continuous

Mean

Standard Deviation

years

Title

Denominators

Categories

Title	Measurements
	BG00057.7± 10.41 BG00155.3± 7.71 BG00260.7± 6.71 BG003

Age, Customized

Number

participants

Title

Denominators

Categories

Less than (<) 65 years

Title	Measurements
	BG0004 BG0015 BG002

Sex: Female, Male

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
Female	BG0002 BG0013 BG002

Height

Mean

Standard Deviation

centimeter

Title

Denominators

Categories

Title	Measurements
	BG000162.28± 6.233 BG001161.08± 12.788 BG002

Weight

Mean

Standard Deviation

kilogram

Title

Denominators

Categories

Title	Measurements
	BG00052.80± 10.208 BG00164.03± 10.623 BG002

Medical and surgical history

Number

participants

Title

Denominators

Categories

With medical and surgical history

Title	Measurements
	BG0006 BG0014 BG002

Primary Tumor Type

Number

participants

Title

Denominators

Categories

Neoplasm, stomach

Title	Measurements
	BG0003 BG0010 BG002

Prior Radiotherapy

Number

participants

Title

Denominators

Categories

With prior radiotherapy

Title	Measurements
	BG0000 BG0012 BG002

Prior Other Cancer Medication

Number

participants

Title

Denominators

Categories

With prior other cancer medication

Title	Measurements
	BG0006 BG0016 BG002

Eastern Cooperative Oncology Group (ECOG) Performance Status

ECOG Performance status was defined as: 0 = fully active, able to carry on all pre-disease performance without restriction; 1 = Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature (example, light house work, office work); 2 = Ambulatory and capable of all self-care but unable to carry out work activities. Up and about >50% of waking hours; 3 = Capable of only limited self-care, confined to bed or chair >50% of waking hours; 4 = completely disabled. Cannot carry on any self-care. Totally confined to bed or chair; or 5 = Dead.

Number

participants

Title

Denominators

Categories

ECOG performance status 0

Title	Measurements
	BG0006 BG001

Method of Tumor Assessment

Number

participants

Title

Denominators

Categories

Computed Tomography (CT)

Title	Measurements
	BG0006 BG0016 BG002

Number of Target Lesions

Number

participants

Title

Denominators

Categories

1 Target Lesion

Title	Measurements
	BG0000 BG0011 BG002

Sum of the Longest Diameter of Target Lesions

Mean

Standard Deviation

millimeters

Title

Denominators

Categories

Title	Measurements
	BG000112.3± 98.70 BG001179.3± 99.23 BG002

Presence of Non-Target Lesions

Number

participants

Title

Denominators

Categories

With Non-Target Lesions

Title	Measurements
	BG0006 BG0016 BG002

Region of Enrollment

Enrollment in Japan is reported in this measure.

Number

participants

Title

Denominators

Categories

Title	Measurements
	BG0006 BG0016 BG002

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 Dose Limiting Toxicity (DLT)

DLT is defined as any treatment-related, grade 4 or higher hematologic or grade 3 or higher non-hematologic toxicity (according to the Common Terminology Criteria for Adverse Events [CTCAE] version 3.0; hematologic toxicity means any toxicities which are categorized in blood/bone marrow category of CTCAE), except for aspartate aminotransferase (AST), alanine aminotransferase (ALT) and infusion reaction, occurred during the first 28 days after the initial administration (before examination on Study Day 29). DLT also includes AST or ALT: >10*upper limit of normal (ULN) international units per liter (IU/L).

DLT analysis set: all participants who experience at least 1 DLT in the first 28 days of treatment, or who received all planned AMG 386 dose and are followed until the day before the treatment on Study Day 29.

Posted

Number

participants

Day 1 up to Day 28

ID	Title	Description
OG000	Trebananib 3 mg/kg	Trebananib (AMG 386) 3 mg/kg, 60-minute infusion, intravenously once weekly on Days 1, 8, 15 and 22 and thereafter once weekly starting from Day 36 (Week 6) until intolerance to investigational product, progressive disease, consent withdrawn, or lost to follow-up (up to approximately 249 weeks).
OG001	Trebananib 10 mg/kg	Trebananib (AMG 386) 10 mg/kg, 60-minute infusion, intravenously once weekly on Days 1, 8, 15 and 22 and thereafter once weekly starting from Day 36 (Week 6) until intolerance to investigational product, progressive disease, consent withdrawn, or lost to follow-up (up to approximately 249 weeks).
OG002	Trebananib 30 mg/kg	Trebananib (AMG 386) 30 mg/kg, 60-minute infusion, intravenously once weekly on Days 1, 8, 15 and 22 and thereafter once weekly starting from Day 36 (Week 6) until intolerance to investigational product, progressive disease, consent withdrawn, or lost to follow-up (up to approximately 249 weeks).

Units	Counts
Participants	OG0006 OG0016 OG0026

Title

Denominators

Categories

Title	Measurements
	OG0000 OG0010 OG0020

Primary

Number of Participants Reporting One or More Treatment-emergent Adverse Events (AEs) and Serious Adverse Event (SAEs)

An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (example, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. Treatment emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug. A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; or congenital anomaly; or a medically important event.

Safety analysis set: all participants who received at least 1 dose of AMG 386.

Posted

Number

participants

Baseline up to 4 weeks after the last dose of study drug, where last dose was given up to Week 249

ID	Title	Description
OG000	Trebananib 3 mg/kg	Trebananib (AMG 386) 3 mg/kg, 60-minute infusion, intravenously once weekly on Days 1, 8, 15 and 22 and thereafter once weekly starting from Day 36 (Week 6) until intolerance to investigational product, progressive disease, consent withdrawn, or lost to follow-up (up to approximately 249 weeks).
OG001

Primary

Number of Participants With Significant Change From Baseline in Electrocardiogram (ECG)

Change relative to baseline in electrocardiogram measured throughout study. Significant change in ECG observed at any time point was summarized and reported.

Safety analysis set: all participants who received at least 1 dose of AMG 386.

Posted

Number

participants

Week 1: predose, 1, 6 hours after end of infusion, Week 4: predose, 1 hour after end of infusion, Week 8, 16: predose, thereafter predose of every 8 weeks up to 4 weeks after the last dose of study drug, where last dose was given up to Week 249

ID	Title	Description
OG000	Trebananib 3 mg/kg	Trebananib (AMG 386) 3 mg/kg, 60-minute infusion, intravenously once weekly on Days 1, 8, 15 and 22 and thereafter once weekly starting from Day 36 (Week 6) until intolerance to investigational product, progressive disease, consent withdrawn, or lost to follow-up (up to approximately 249 weeks).
OG001	Trebananib 10 mg/kg	Trebananib (AMG 386) 10 mg/kg, 60-minute infusion, intravenously once weekly on Days 1, 8, 15 and 22 and thereafter once weekly starting from Day 36 (Week 6) until intolerance to investigational product, progressive disease, consent withdrawn, or lost to follow-up (up to approximately 249 weeks).
OG002	Trebananib 30 mg/kg

Primary

Number of Participants With Clinically Significant Change From Baseline in Vital Signs

Vital signs included body temperature, diastolic and systolic blood pressure, and pulse (beats per minutes). clinically significant change in vital signs observed at any time point was summarized and reported.

Safety analysis set: all participants who received at least 1 dose of AMG 386.

Posted

Number

participants

Week 1: predose, 1, 2, 6, 24, 48 and 96 hours after infusion end, Week 2, 3, 4: predose and 1 hour after infusion end, thereafter predose of every 4 weeks starting from Week 8 up to 4 weeks after the last dose of study drug (last dose=Week 249)

ID	Title	Description
OG000	Trebananib 3 mg/kg	Trebananib (AMG 386) 3 mg/kg, 60-minute infusion, intravenously once weekly on Days 1, 8, 15 and 22 and thereafter once weekly starting from Day 36 (Week 6) until intolerance to investigational product, progressive disease, consent withdrawn, or lost to follow-up (up to approximately 249 weeks).
OG001	Trebananib 10 mg/kg	Trebananib (AMG 386) 10 mg/kg, 60-minute infusion, intravenously once weekly on Days 1, 8, 15 and 22 and thereafter once weekly starting from Day 36 (Week 6) until intolerance to investigational product, progressive disease, consent withdrawn, or lost to follow-up (up to approximately 249 weeks).
OG002

Primary

Number of Participants With Abnormal Laboratory Values

The number of participants with any abnormal standard safety laboratory values collected throughout study. Parameters assessed were hematology, chemistry, coagulation and urinalysis. Abnormal laboratory values observed at any time point was summarized and reported.

Safety analysis set: all participants who received at least 1 dose of AMG 386.

Posted

Number

participants

Week 1: predose, 24, 48 and 96 hours after infusion end, Week 2 and 3: predose, Week 4: predose and 1 hour after infusion end, thereafter every 4 weeks starting from Week 8 up to 4 weeks after the last dose of study drug (last dose=Week 249)

ID	Title	Description
OG000	Trebananib 3 mg/kg	Trebananib (AMG 386) 3 mg/kg, 60-minute infusion, intravenously once weekly on Days 1, 8, 15 and 22 and thereafter once weekly starting from Day 36 (Week 6) until intolerance to investigational product, progressive disease, consent withdrawn, or lost to follow-up (up to approximately 249 weeks).
OG001	Trebananib 10 mg/kg	Trebananib (AMG 386) 10 mg/kg, 60-minute infusion, intravenously once weekly on Days 1, 8, 15 and 22 and thereafter once weekly starting from Day 36 (Week 6) until intolerance to investigational product, progressive disease, consent withdrawn, or lost to follow-up (up to approximately 249 weeks).
OG002

Primary

Cmax: Maximum Observed Serum Concentration for AMG 386 After Week 1 Dose

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

Pharmacokinetic analysis set: all participants who had at least 1 evaluable serum concentrations, received at least 1 dose of AMG 386, and had Week 1 assessment available.

Posted

Mean

Standard Deviation

microgram per milliliter (mcg/mL)

Week 1: predose, 1, 2, 6, 24, 48 and 96 hours after end of infusion, Week 2: predose

ID	Title	Description
OG000	Trebananib 3 mg/kg	Trebananib (AMG 386) 3 mg/kg, 60-minute infusion, intravenously once weekly on Days 1, 8, 15 and 22 and thereafter once weekly starting from Day 36 (Week 6) until intolerance to investigational product, progressive disease, consent withdrawn, or lost to follow-up (up to approximately 249 weeks).
OG001	Trebananib 10 mg/kg	Trebananib (AMG 386) 10 mg/kg, 60-minute infusion, intravenously once weekly on Days 1, 8, 15 and 22 and thereafter once weekly starting from Day 36 (Week 6) until intolerance to investigational product, progressive disease, consent withdrawn, or lost to follow-up (up to approximately 249 weeks).
OG002	Trebananib 30 mg/kg

Primary

Cmax: Maximum Observed Serum Concentration for AMG 386 After Week 4 Dose

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

Pharmacokinetic analysis set: all participants who had at least 1 evaluable serum concentrations, received at least 1 dose of AMG 386, and had Week 4 assessment available.

Posted

Mean

Standard Deviation

mcg/mL

Week 4: predose, 1, 2, 6, 24, 48, 96, 168 and 264 hours after end of infusion

ID	Title	Description
OG000	Trebananib 3 mg/kg	Trebananib (AMG 386) 3 mg/kg, 60-minute infusion, intravenously once weekly on Days 1, 8, 15 and 22 and thereafter once weekly starting from Day 36 (Week 6) until intolerance to investigational product, progressive disease, consent withdrawn, or lost to follow-up (up to approximately 249 weeks).
OG001	Trebananib 10 mg/kg	Trebananib (AMG 386) 10 mg/kg, 60-minute infusion, intravenously once weekly on Days 1, 8, 15 and 22 and thereafter once weekly starting from Day 36 (Week 6) until intolerance to investigational product, progressive disease, consent withdrawn, or lost to follow-up (up to approximately 249 weeks).
OG002	Trebananib 30 mg/kg	Trebananib (AMG 386) 30 mg/kg, 60-minute infusion, intravenously once weekly on Days 1, 8, 15 and 22 and thereafter once weekly starting from Day 36 (Week 6) until intolerance to investigational product, progressive disease, consent withdrawn, or lost to follow-up (up to approximately 249 weeks).

Primary

Tmax: Time to Reach the Maximum Serum Concentration (Cmax) for AMG 386 After Week 1 Dose

Tmax is the time to reach the maximum serum concentration (Cmax), equal to time (hours) to Cmax.

Pharmacokinetic analysis set: all participants who had at least 1 evaluable serum concentrations, received at least 1 dose of AMG 386, and had Week 1 assessment available.

Posted

Median

Full Range

hour (hr)

Week 1: predose, 1, 2, 6, 24, 48 and 96 hours after end of infusion, Week 2: predose

ID	Title	Description
OG000	Trebananib 3 mg/kg	Trebananib (AMG 386) 3 mg/kg, 60-minute infusion, intravenously once weekly on Days 1, 8, 15 and 22 and thereafter once weekly starting from Day 36 (Week 6) until intolerance to investigational product, progressive disease, consent withdrawn, or lost to follow-up (up to approximately 249 weeks).
OG001	Trebananib 10 mg/kg	Trebananib (AMG 386) 10 mg/kg, 60-minute infusion, intravenously once weekly on Days 1, 8, 15 and 22 and thereafter once weekly starting from Day 36 (Week 6) until intolerance to investigational product, progressive disease, consent withdrawn, or lost to follow-up (up to approximately 249 weeks).
OG002	Trebananib 30 mg/kg	Trebananib (AMG 386) 30 mg/kg, 60-minute infusion, intravenously once weekly on Days 1, 8, 15 and 22 and thereafter once weekly starting from Day 36 (Week 6) until intolerance to investigational product, progressive disease, consent withdrawn, or lost to follow-up (up to approximately 249 weeks).

Primary

Tmax: Time to Reach the Maximum Serum Concentration (Cmax) for AMG 386 After Week 4 Dose

Tmax is the time to reach the maximum serum concentration (Cmax), equal to time (hours) to Cmax.

Pharmacokinetic analysis set: all participants who had at least 1 evaluable serum concentrations, received at least 1 dose of AMG 386, and had Week 4 assessment available.

Posted

Median

Full Range

Week 4: predose, 1, 2, 6, 24, 48, 96, 168 and 264 hours after end of infusion

ID	Title	Description
OG000	Trebananib 3 mg/kg	Trebananib (AMG 386) 3 mg/kg, 60-minute infusion, intravenously once weekly on Days 1, 8, 15 and 22 and thereafter once weekly starting from Day 36 (Week 6) until intolerance to investigational product, progressive disease, consent withdrawn, or lost to follow-up (up to approximately 249 weeks).
OG001	Trebananib 10 mg/kg	Trebananib (AMG 386) 10 mg/kg, 60-minute infusion, intravenously once weekly on Days 1, 8, 15 and 22 and thereafter once weekly starting from Day 36 (Week 6) until intolerance to investigational product, progressive disease, consent withdrawn, or lost to follow-up (up to approximately 249 weeks).
OG002	Trebananib 30 mg/kg	Trebananib (AMG 386) 30 mg/kg, 60-minute infusion, intravenously once weekly on Days 1, 8, 15 and 22 and thereafter once weekly starting from Day 36 (Week 6) until intolerance to investigational product, progressive disease, consent withdrawn, or lost to follow-up (up to approximately 249 weeks).

Secondary

Number of Participants With Best Overall Response

Best overall response for a participant is the best observed post-baseline disease response as per Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 criteria. Complete Response (CR): disappearance of all target lesions, non-target lesions and normalization of tumor marker level. Partial Response (PR): at least 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum of longest diameter. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the baseline smallest sum of longest diameter; persistence of 1 or more non-target lesion(s) or maintenance of tumor marker level above the normal limits. PD: at least 20% increase in the sum of the longest diameter of target lesions, taking as reference the baseline smallest sum of longest diameter or appearance of 1 or more new lesions or unequivocal progression of existing non-target lesions.

Response evaluable analysis set: a subset of participants in the full analysis set (FAS) with at least 1 measurable lesion at baseline using the RECIST 1.0. FAS consisted of all participants who had evaluable data and received at least 1 dose of AMG 386.

Posted

Number

participants

Baseline, assessed every 8 weeks up to 4 weeks after the last dose of study drug, where last dose was given up to Week 249

ID	Title	Description
OG000	Trebananib 3 mg/kg	Trebananib (AMG 386) 3 mg/kg, 60-minute infusion, intravenously once weekly on Days 1, 8, 15 and 22 and thereafter once weekly starting from Day 36 (Week 6) until intolerance to investigational product, progressive disease, consent withdrawn, or lost to follow-up (up to approximately 249 weeks).

Secondary

Percentage of Participants With Objective Response

Objective response rate defined as the rate of participants with CR or PR based on RECIST 1.0 criteria. CR: disappearance of all target lesions, non-target lesions and normalization of tumor marker level. PR: at least 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum of longest diameter.

Response evaluable analysis set: a subset of participants in the FAS with at least 1 measurable lesion at baseline using the RECIST 1.0. FAS consisted of all participants who had evaluable data and received at least 1 dose of AMG 386.

Posted

Number

95% Confidence Interval

Percentage of participants

Baseline, assessed every 8 weeks up to 4 weeks after the last dose of study drug, where last dose was given up to Week 249

ID	Title	Description
OG000	Trebananib 3 mg/kg	Trebananib (AMG 386) 3 mg/kg, 60-minute infusion, intravenously once weekly on Days 1, 8, 15 and 22 and thereafter once weekly starting from Day 36 (Week 6) until intolerance to investigational product, progressive disease, consent withdrawn, or lost to follow-up (up to approximately 249 weeks).
OG001	Trebananib 10 mg/kg	Trebananib (AMG 386) 10 mg/kg, 60-minute infusion, intravenously once weekly on Days 1, 8, 15 and 22 and thereafter once weekly starting from Day 36 (Week 6) until intolerance to investigational product, progressive disease, consent withdrawn, or lost to follow-up (up to approximately 249 weeks).

Secondary

Time to Progression (TTP)

TTP is defined as the time from the date of first administration of study treatment to the date of first documentation of PD or death caused by progression. For participants who did not have a documented PD or died owing to causes other than progression, TTP was censored at the time of last response assessment. PD is defined as at least 20% increase in the sum of the longest diameter of target lesions, taking as reference the baseline smallest sum of longest diameter or appearance of 1 or more new lesions or unequivocal progression of existing non-target lesions.

Posted

Median

Full Range

Days

Baseline, assessed every 8 weeks up to 4 weeks after the last dose of study drug, where last dose was given up to Week 249

ID	Title	Description
OG000	Trebananib 3 mg/kg	Trebananib (AMG 386) 3 mg/kg, 60-minute infusion, intravenously once weekly on Days 1, 8, 15 and 22 and thereafter once weekly starting from Day 36 (Week 6) until intolerance to investigational product, progressive disease, consent withdrawn, or lost to follow-up (up to approximately 249 weeks).
OG001	Trebananib 10 mg/kg	Trebananib (AMG 386) 10 mg/kg, 60-minute infusion, intravenously once weekly on Days 1, 8, 15 and 22 and thereafter once weekly starting from Day 36 (Week 6) until intolerance to investigational product, progressive disease, consent withdrawn, or lost to follow-up (up to approximately 249 weeks).

Secondary

Percent Change From Baseline to Post-baseline in the Sum of the Longest Diameters of Tumor

The percent change from baseline to post-baseline is the largest percent reduction from baseline among all post-dose measures of the sum of the longest diameter of the tumor burden.

Response evaluable analysis set: a subset of participants in the FAS with at least 1 measurable lesion at baseline using the RECIST 1.0 and valid post-baseline tumor lesion assessment available. FAS consisted of all participants who had evaluable data and received at least 1 dose of AMG 386.

Posted

Mean

Standard Deviation

percent change

Baseline, assessed every 8 weeks up to 4 weeks after the last dose of study drug, where last dose was given up to Week 249

ID	Title	Description
OG000	Trebananib 3 mg/kg	Trebananib (AMG 386) 3 mg/kg, 60-minute infusion, intravenously once weekly on Days 1, 8, 15 and 22 and thereafter once weekly starting from Day 36 (Week 6) until intolerance to investigational product, progressive disease, consent withdrawn, or lost to follow-up (up to approximately 249 weeks).
OG001	Trebananib 10 mg/kg	Trebananib (AMG 386) 10 mg/kg, 60-minute infusion, intravenously once weekly on Days 1, 8, 15 and 22 and thereafter once weekly starting from Day 36 (Week 6) until intolerance to investigational product, progressive disease, consent withdrawn, or lost to follow-up (up to approximately 249 weeks).

Secondary

Number of Participant With Anti-AMG 386 Antibody

The immunogenicity of AMG 386 was evaluated with an immunoassay that detects anti-AMG 386 binding antibodies. Antibody formation reported at any of the time points was summarized.

Safety analysis set: all participants who received at least 1 dose of AMG 386.

Posted

Number

participants

Week 1: predose,1,2,6,24,48 and 98 hours after infusion end, Week 3: predose, Week 4: predose, 1,2,6,24,48,96,168 and 264 hours after infusion end, thereafter predose every 4 weeks starting from Week 8 up to 8 weeks after last dose (last dose=Week 249)

ID	Title	Description
OG000	Trebananib 3 mg/kg	Trebananib (AMG 386) 3 mg/kg, 60-minute infusion, intravenously once weekly on Days 1, 8, 15 and 22 and thereafter once weekly starting from Day 36 (Week 6) until intolerance to investigational product, progressive disease, consent withdrawn, or lost to follow-up (up to approximately 249 weeks).
OG001	Trebananib 10 mg/kg	Trebananib (AMG 386) 10 mg/kg, 60-minute infusion, intravenously once weekly on Days 1, 8, 15 and 22 and thereafter once weekly starting from Day 36 (Week 6) until intolerance to investigational product, progressive disease, consent withdrawn, or lost to follow-up (up to approximately 249 weeks).
OG002	Trebananib 30 mg/kg

Primary

AUC (0-tau): Area Under the Serum Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval for AMG 386 After Week 1 Dose

AUC (0-tau) is the area under the serum concentration-time curve during a dosing interval, where tau is the length of the dosing interval (168 hours for once weekly regimen).

Pharmacokinetic analysis set: all participants who had at least 1 evaluable serum concentrations, received at least 1 dose of AMG 386, and had Week 1 assessment available.

Posted

Mean

Standard Deviation

microgram*hour/milliliter (mcg*hr/mL)

Week 1: predose, 1, 2, 6, 24, 48 and 96 hours after end of infusion, Week 2: predose

ID	Title	Description
OG000	Trebananib 3 mg/kg	Trebananib (AMG 386) 3 mg/kg, 60-minute infusion, intravenously once weekly on Days 1, 8, 15 and 22 and thereafter once weekly starting from Day 36 (Week 6) until intolerance to investigational product, progressive disease, consent withdrawn, or lost to follow-up (up to approximately 249 weeks).
OG001	Trebananib 10 mg/kg	Trebananib (AMG 386) 10 mg/kg, 60-minute infusion, intravenously once weekly on Days 1, 8, 15 and 22 and thereafter once weekly starting from Day 36 (Week 6) until intolerance to investigational product, progressive disease, consent withdrawn, or lost to follow-up (up to approximately 249 weeks).
OG002

Primary

AUC (0-tau): Area Under the Serum Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval for AMG 386 After Week 4 Dose

AUC (0-tau) is the area under the serum concentration-time curve during a dosing interval, where tau is the length of the dosing interval (168 hours for once weekly regimen).

Pharmacokinetic analysis set: all participants who had at least 1 evaluable serum concentrations, received at least 1 dose of AMG 386, and had Week 4 assessment available.

Posted

Mean

Standard Deviation

mcg*hr/mL

Week 4: predose, 1, 2, 6, 24, 48, 96, and 168 hours after end of infusion

ID	Title	Description
OG000	Trebananib 3 mg/kg	Trebananib (AMG 386) 3 mg/kg, 60-minute infusion, intravenously once weekly on Days 1, 8, 15 and 22 and thereafter once weekly starting from Day 36 (Week 6) until intolerance to investigational product, progressive disease, consent withdrawn, or lost to follow-up (up to approximately 249 weeks).
OG001	Trebananib 10 mg/kg	Trebananib (AMG 386) 10 mg/kg, 60-minute infusion, intravenously once weekly on Days 1, 8, 15 and 22 and thereafter once weekly starting from Day 36 (Week 6) until intolerance to investigational product, progressive disease, consent withdrawn, or lost to follow-up (up to approximately 249 weeks).
OG002	Trebananib 30 mg/kg

Primary

Cmin: Minimum Observed Serum Trough Concentration for AMG 386 After Week 1 Dose

Cmin was the observed serum concentration at 168 hours postdose.

Pharmacokinetic analysis set: all participants who had at least 1 evaluable serum concentrations, received at least 1 dose of AMG 386, and had Week 1 assessment available.

Posted

Mean

Standard Deviation

mcg/mL

Week 2: predose

ID	Title	Description
OG000	Trebananib 3 mg/kg	Trebananib (AMG 386) 3 mg/kg, 60-minute infusion, intravenously once weekly on Days 1, 8, 15 and 22 and thereafter once weekly starting from Day 36 (Week 6) until intolerance to investigational product, progressive disease, consent withdrawn, or lost to follow-up (up to approximately 249 weeks).
OG001	Trebananib 10 mg/kg	Trebananib (AMG 386) 10 mg/kg, 60-minute infusion, intravenously once weekly on Days 1, 8, 15 and 22 and thereafter once weekly starting from Day 36 (Week 6) until intolerance to investigational product, progressive disease, consent withdrawn, or lost to follow-up (up to approximately 249 weeks).
OG002	Trebananib 30 mg/kg	Trebananib (AMG 386) 30 mg/kg, 60-minute infusion, intravenously once weekly on Days 1, 8, 15 and 22 and thereafter once weekly starting from Day 36 (Week 6) until intolerance to investigational product, progressive disease, consent withdrawn, or lost to follow-up (up to approximately 249 weeks).

Primary

Cmin: Minimum Observed Serum Trough Concentration for AMG 386 After Week 4 Dose

Cmin was the observed serum concentration at 168 hours postdose.

Pharmacokinetic analysis set: all participants who had at least 1 evaluable serum concentrations, received at least 1 dose of AMG 386, and had Week 4 assessment available.

Posted

Mean

Standard Deviation

mcg/mL

Week 4: 168 hours after end of infusion

ID	Title	Description
OG000	Trebananib 3 mg/kg	Trebananib (AMG 386) 3 mg/kg, 60-minute infusion, intravenously once weekly on Days 1, 8, 15 and 22 and thereafter once weekly starting from Day 36 (Week 6) until intolerance to investigational product, progressive disease, consent withdrawn, or lost to follow-up (up to approximately 249 weeks).
OG001	Trebananib 10 mg/kg	Trebananib (AMG 386) 10 mg/kg, 60-minute infusion, intravenously once weekly on Days 1, 8, 15 and 22 and thereafter once weekly starting from Day 36 (Week 6) until intolerance to investigational product, progressive disease, consent withdrawn, or lost to follow-up (up to approximately 249 weeks).
OG002	Trebananib 30 mg/kg	Trebananib (AMG 386) 30 mg/kg, 60-minute infusion, intravenously once weekly on Days 1, 8, 15 and 22 and thereafter once weekly starting from Day 36 (Week 6) until intolerance to investigational product, progressive disease, consent withdrawn, or lost to follow-up (up to approximately 249 weeks).

Primary

Vss: Volume of Distribution at Steady State for AMG 386

Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. Vss is the apparent volume of distribution at steady-state, estimated as: Vss = MRTinf *CLss, where MRTinf is mean residence time of drug extrapolated to infinity and CLss is the systemic clearance at the steady state. Vss was normalized to participant's body weight.

Pharmacokinetic analysis set: all participants who had at least 1 evaluable serum concentrations, received at least 1 dose of AMG 386, and had Week 4 assessment available.

Posted

Mean

Standard Deviation

milliliter per kilogram (mL/kg)

Week 4: predose, 1, 2, 6, 24, 48, 96, 168 and 264 hours after end of infusion

ID	Title	Description
OG000	Trebananib 3 mg/kg	Trebananib (AMG 386) 3 mg/kg, 60-minute infusion, intravenously once weekly on Days 1, 8, 15 and 22 and thereafter once weekly starting from Day 36 (Week 6) until intolerance to investigational product, progressive disease, consent withdrawn, or lost to follow-up (up to approximately 249 weeks).
OG001	Trebananib 10 mg/kg	Trebananib (AMG 386) 10 mg/kg, 60-minute infusion, intravenously once weekly on Days 1, 8, 15 and 22 and thereafter once weekly starting from Day 36 (Week 6) until intolerance to investigational product, progressive disease, consent withdrawn, or lost to follow-up (up to approximately 249 weeks).

Primary

Terminal Phase Elimination Half-life (T1/2) for AMG 386

Terminal phase elimination half-life (T1/2) is the time required for half of the drug to be eliminated from the serum.

Pharmacokinetic analysis set: all participants who had at least 1 evaluable serum concentrations, received at least 1 dose of AMG 386, and had Week 4 assessment available.

Posted

Mean

Standard Deviation

Week 4: predose, 1, 2, 6, 24, 48, 96, 168 and 264 hours after end of infusion

ID	Title	Description
OG000	Trebananib 3 mg/kg	Trebananib (AMG 386) 3 mg/kg, 60-minute infusion, intravenously once weekly on Days 1, 8, 15 and 22 and thereafter once weekly starting from Day 36 (Week 6) until intolerance to investigational product, progressive disease, consent withdrawn, or lost to follow-up (up to approximately 249 weeks).
OG001	Trebananib 10 mg/kg	Trebananib (AMG 386) 10 mg/kg, 60-minute infusion, intravenously once weekly on Days 1, 8, 15 and 22 and thereafter once weekly starting from Day 36 (Week 6) until intolerance to investigational product, progressive disease, consent withdrawn, or lost to follow-up (up to approximately 249 weeks).
OG002	Trebananib 30 mg/kg	Trebananib (AMG 386) 30 mg/kg, 60-minute infusion, intravenously once weekly on Days 1, 8, 15 and 22 and thereafter once weekly starting from Day 36 (Week 6) until intolerance to investigational product, progressive disease, consent withdrawn, or lost to follow-up (up to approximately 249 weeks).

Primary

Systemic Clearance at Steady State (CLss) for AMG 386

CL is a quantitative measure of the rate at which a drug substance is removed from the body. Systemic clearance at steady state (CLss) was calculated as the ratio of dose administered to AUC (0 - tau), where AUC (0 - tau) is the area under the serum concentration-time curve during a dosing interval, where tau is the length of the dosing interval (168 hours for once weekly regimen). CLss was normalized to participant's body weight.

Pharmacokinetic analysis set: all participants who had at least 1 evaluable serum concentrations, received at least 1 dose of AMG 386, and had Week 4 assessment available.

Posted

Mean

Standard Deviation

milliliter/hour/kilogram(mL/hr/kg)

Week 4: predose, 1, 2, 6, 24, 48, 96 and 168 hours after end of infusion

ID	Title	Description
OG000	Trebananib 3 mg/kg	Trebananib (AMG 386) 3 mg/kg, 60-minute infusion, intravenously once weekly on Days 1, 8, 15 and 22 and thereafter once weekly starting from Day 36 (Week 6) until intolerance to investigational product, progressive disease, consent withdrawn, or lost to follow-up (up to approximately 249 weeks).
OG001	Trebananib 10 mg/kg	Trebananib (AMG 386) 10 mg/kg, 60-minute infusion, intravenously once weekly on Days 1, 8, 15 and 22 and thereafter once weekly starting from Day 36 (Week 6) until intolerance to investigational product, progressive disease, consent withdrawn, or lost to follow-up (up to approximately 249 weeks).

Primary

Accumulation Ratio (AR) for AMG 386

Accumulation ratio (AR) was calculated by dividing the individual AUC (0-tau) value at Week 4 by the corresponding individual AUC (0-tau) value at Week 1.

Pharmacokinetic analysis set: all participants who had at least 1 evaluable serum concentrations, received at least 1 dose of AMG 386, and had Week 4 assessment available.

Posted

Mean

Standard Deviation

ratio

Week 1: predose, 1, 2, 6, 24, 48 and 96 hours after end of infusion, Week 2: predose, Week 4: predose, 1, 2, 6, 24, 48, 96, and 168 hours after end of infusion

ID	Title	Description
OG000	Trebananib 3 mg/kg	Trebananib (AMG 386) 3 mg/kg, 60-minute infusion, intravenously once weekly on Days 1, 8, 15 and 22 and thereafter once weekly starting from Day 36 (Week 6) until intolerance to investigational product, progressive disease, consent withdrawn, or lost to follow-up (up to approximately 249 weeks).
OG001	Trebananib 10 mg/kg	Trebananib (AMG 386) 10 mg/kg, 60-minute infusion, intravenously once weekly on Days 1, 8, 15 and 22 and thereafter once weekly starting from Day 36 (Week 6) until intolerance to investigational product, progressive disease, consent withdrawn, or lost to follow-up (up to approximately 249 weeks).
OG002	Trebananib 30 mg/kg

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Lymphopenia	Blood and lymphatic system disorders	MedDRA (15.1)	Systematic Assessment	EG0001 affected6 at risk EG0010 affected6 at risk EG0020 affected6 at risk
Ventricular extrasystoles	Cardiac disorders	MedDRA (15.1)	Systematic Assessment	EG0000 affected6 at risk EG0010 affected6 at risk EG0021 affected6 at risk
Tinnitus	Ear and labyrinth disorders	MedDRA (15.1)	Systematic Assessment	EG0001 affected6 at risk EG0010 affected6 at risk EG0020 affected6 at risk
Conjunctivitis allergic	Eye disorders	MedDRA (15.1)	Systematic Assessment	EG0001 affected6 at risk EG0010 affected6 at risk EG0021 affected6 at risk
Abnormal sensation in eye	Eye disorders	MedDRA (15.1)	Systematic Assessment	EG0000 affected6 at risk EG0010 affected6 at risk EG0021 affected6 at risk
Conjunctival haemorrhage	Eye disorders	MedDRA (15.1)	Systematic Assessment	EG0000 affected6 at risk EG0010 affected6 at risk EG0021 affected6 at risk
Conjunctivitis	Eye disorders	MedDRA (15.1)	Systematic Assessment	EG0000 affected6 at risk EG0010 affected6 at risk EG0021 affected6 at risk
Corneal erosion	Eye disorders	MedDRA (15.1)	Systematic Assessment	EG0000 affected6 at risk EG0011 affected6 at risk EG0020 affected6 at risk
Eyelid oedema	Eye disorders	MedDRA (15.1)	Systematic Assessment	EG0001 affected6 at risk EG0010 affected6 at risk EG0020 affected6 at risk
Constipation	Gastrointestinal disorders	MedDRA (15.1)	Systematic Assessment	EG0002 affected6 at risk EG0011 affected6 at risk EG0022 affected6 at risk
Diarrhoea	Gastrointestinal disorders	MedDRA (15.1)	Systematic Assessment	EG0001 affected6 at risk EG0011 affected6 at risk EG0022 affected6 at risk
Abdominal distension	Gastrointestinal disorders	MedDRA (15.1)	Systematic Assessment	EG0002 affected6 at risk EG0010 affected6 at risk EG0021 affected6 at risk
Nausea	Gastrointestinal disorders	MedDRA (15.1)	Systematic Assessment	EG0001 affected6 at risk EG0010 affected6 at risk EG0022 affected6 at risk
Stomatitis	Gastrointestinal disorders	MedDRA (15.1)	Systematic Assessment	EG0001 affected6 at risk EG0010 affected6 at risk EG0022 affected6 at risk
Abdominal pain	Gastrointestinal disorders	MedDRA (15.1)	Systematic Assessment	EG0000 affected6 at risk EG0011 affected6 at risk EG0021 affected6 at risk
Ascites	Gastrointestinal disorders	MedDRA (15.1)	Systematic Assessment	EG0001 affected6 at risk EG0010 affected6 at risk EG0021 affected6 at risk
Abdominal discomfort	Gastrointestinal disorders	MedDRA (15.1)	Systematic Assessment	EG0000 affected6 at risk EG0011 affected6 at risk EG0020 affected6 at risk
Abdominal pain upper	Gastrointestinal disorders	MedDRA (15.1)	Systematic Assessment	EG0001 affected6 at risk EG0010 affected6 at risk EG0020 affected6 at risk
Cheilitis	Gastrointestinal disorders	MedDRA (15.1)	Systematic Assessment	EG0001 affected6 at risk EG0010 affected6 at risk EG0020 affected6 at risk
Vomiting	Gastrointestinal disorders	MedDRA (15.1)	Systematic Assessment	EG0000 affected6 at risk EG0010 affected6 at risk EG0021 affected6 at risk
Oedema peripheral	General disorders	MedDRA (15.1)	Systematic Assessment	EG0002 affected6 at risk EG0012 affected6 at risk EG0023 affected6 at risk
Fatigue	General disorders	MedDRA (15.1)	Systematic Assessment	EG0003 affected6 at risk EG0011 affected6 at risk EG0021 affected6 at risk
Pyrexia	General disorders	MedDRA (15.1)	Systematic Assessment	EG0002 affected6 at risk EG0011 affected6 at risk EG0022 affected6 at risk
Influenza like illness	General disorders	MedDRA (15.1)	Systematic Assessment	EG0001 affected6 at risk EG0011 affected6 at risk EG0020 affected6 at risk
Chest pain	General disorders	MedDRA (15.1)	Systematic Assessment	EG0001 affected6 at risk EG0010 affected6 at risk EG0020 affected6 at risk
Face oedema	General disorders	MedDRA (15.1)	Systematic Assessment	EG0001 affected6 at risk EG0010 affected6 at risk EG0020 affected6 at risk
Fungal infection	Infections and infestations	MedDRA (15.1)	Systematic Assessment	EG0001 affected6 at risk EG0010 affected6 at risk EG0020 affected6 at risk
Gastroenteritis	Infections and infestations	MedDRA (15.1)	Systematic Assessment	EG0000 affected6 at risk EG0010 affected6 at risk EG0021 affected6 at risk
Gingivitis	Infections and infestations	MedDRA (15.1)	Systematic Assessment	EG0001 affected6 at risk EG0010 affected6 at risk EG0020 affected6 at risk
Ovarian infection	Infections and infestations	MedDRA (15.1)	Systematic Assessment	EG0000 affected6 at risk EG0011 affected6 at risk EG0020 affected6 at risk
Urinary tract infection	Infections and infestations	MedDRA (15.1)	Systematic Assessment	EG0000 affected6 at risk EG0010 affected6 at risk EG0021 affected6 at risk
Infusion related reaction	Injury, poisoning and procedural complications	MedDRA (15.1)	Systematic Assessment	EG0000 affected6 at risk EG0010 affected6 at risk EG0021 affected6 at risk
Eastern Cooperative Oncology Group performance status worsened	Investigations	MedDRA (15.1)	Systematic Assessment	EG0003 affected6 at risk EG0010 affected6 at risk EG0021 affected6 at risk
Gamma-glutamyltransferase increased	Investigations	MedDRA (15.1)	Systematic Assessment	EG0001 affected6 at risk EG0011 affected6 at risk EG0022 affected6 at risk
Alanine aminotransferase increased	Investigations	MedDRA (15.1)	Systematic Assessment	EG0001 affected6 at risk EG0010 affected6 at risk EG0021 affected6 at risk
Aspartate aminotransferase increased	Investigations	MedDRA (15.1)	Systematic Assessment	EG0001 affected6 at risk EG0010 affected6 at risk EG0021 affected6 at risk
Blood alkaline phosphatase increased	Investigations	MedDRA (15.1)	Systematic Assessment	EG0000 affected6 at risk EG0010 affected6 at risk EG0022 affected6 at risk
Blood creatine phosphokinase increased	Investigations	MedDRA (15.1)	Systematic Assessment	EG0001 affected6 at risk EG0010 affected6 at risk EG0020 affected6 at risk
Electrocardiogram QT prolonged	Investigations	MedDRA (15.1)	Systematic Assessment	EG0000 affected6 at risk EG0010 affected6 at risk EG0021 affected6 at risk
White blood cell count increased	Investigations	MedDRA (15.1)	Systematic Assessment	EG0001 affected6 at risk EG0010 affected6 at risk EG0020 affected6 at risk
Decreased appetite	Metabolism and nutrition disorders	MedDRA (15.1)	Systematic Assessment	EG0002 affected6 at risk EG0010 affected6 at risk EG0021 affected6 at risk
Hypoalbuminaemia	Metabolism and nutrition disorders	MedDRA (15.1)	Systematic Assessment	EG0002 affected6 at risk EG0010 affected6 at risk EG0020 affected6 at risk
Dehydration	Metabolism and nutrition disorders	MedDRA (15.1)	Systematic Assessment	EG0001 affected6 at risk EG0010 affected6 at risk EG0020 affected6 at risk
Hyperglycaemia	Metabolism and nutrition disorders	MedDRA (15.1)	Systematic Assessment	EG0000 affected6 at risk EG0010 affected6 at risk EG0021 affected6 at risk
Arthralgia	Musculoskeletal and connective tissue disorders	MedDRA (15.1)	Systematic Assessment	EG0001 affected6 at risk EG0010 affected6 at risk EG0021 affected6 at risk
Musculoskeletal stiffness	Musculoskeletal and connective tissue disorders	MedDRA (15.1)	Systematic Assessment	EG0000 affected6 at risk EG0010 affected6 at risk EG0021 affected6 at risk
Myositis	Musculoskeletal and connective tissue disorders	MedDRA (15.1)	Systematic Assessment	EG0001 affected6 at risk EG0010 affected6 at risk EG0020 affected6 at risk
Cancer pain	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (15.1)	Systematic Assessment	EG0001 affected6 at risk EG0011 affected6 at risk EG0021 affected6 at risk
Headache	Nervous system disorders	MedDRA (15.1)	Systematic Assessment	EG0000 affected6 at risk EG0011 affected6 at risk EG0020 affected6 at risk
Insomnia	Psychiatric disorders	MedDRA (15.1)	Systematic Assessment	EG0000 affected6 at risk EG0010 affected6 at risk EG0021 affected6 at risk
Mood altered	Psychiatric disorders	MedDRA (15.1)	Systematic Assessment	EG0001 affected6 at risk EG0010 affected6 at risk EG0020 affected6 at risk
Dysuria	Renal and urinary disorders	MedDRA (15.1)	Systematic Assessment	EG0000 affected6 at risk EG0011 affected6 at risk EG0020 affected6 at risk
Hydronephrosis	Renal and urinary disorders	MedDRA (15.1)	Systematic Assessment	EG0000 affected6 at risk EG0011 affected6 at risk EG0020 affected6 at risk
Balanitis	Reproductive system and breast disorders	MedDRA (15.1)	Systematic Assessment	EG0000 affected6 at risk EG0010 affected6 at risk EG0021 affected6 at risk
Benign prostatic hyperplasia	Reproductive system and breast disorders	MedDRA (15.1)	Systematic Assessment	EG0001 affected6 at risk EG0010 affected6 at risk EG0020 affected6 at risk
Upper respiratory tract inflammation	Respiratory, thoracic and mediastinal disorders	MedDRA (15.1)	Systematic Assessment	EG0001 affected6 at risk EG0010 affected6 at risk EG0021 affected6 at risk
Dysphonia	Respiratory, thoracic and mediastinal disorders	MedDRA (15.1)	Systematic Assessment	EG0000 affected6 at risk EG0010 affected6 at risk EG0021 affected6 at risk
Dyspnoea	Respiratory, thoracic and mediastinal disorders	MedDRA (15.1)	Systematic Assessment	EG0001 affected6 at risk EG0010 affected6 at risk EG0020 affected6 at risk
Rash	Skin and subcutaneous tissue disorders	MedDRA (15.1)	Systematic Assessment	EG0001 affected6 at risk EG0011 affected6 at risk EG0021 affected6 at risk
Dermal cyst	Skin and subcutaneous tissue disorders	MedDRA (15.1)	Systematic Assessment	EG0000 affected6 at risk EG0010 affected6 at risk EG0021 affected6 at risk
Palmar-plantar erythrodysaesthesia syndrome	Skin and subcutaneous tissue disorders	MedDRA (15.1)	Systematic Assessment	EG0001 affected6 at risk EG0010 affected6 at risk EG0020 affected6 at risk
Petechiae	Skin and subcutaneous tissue disorders	MedDRA (15.1)	Systematic Assessment	EG0000 affected6 at risk EG0010 affected6 at risk EG0021 affected6 at risk
Pruritus	Skin and subcutaneous tissue disorders	MedDRA (15.1)	Systematic Assessment	EG0001 affected6 at risk EG0010 affected6 at risk EG0020 affected6 at risk
Skin fissures	Skin and subcutaneous tissue disorders	MedDRA (15.1)	Systematic Assessment	EG0001 affected6 at risk EG0010 affected6 at risk EG0020 affected6 at risk
Hypertension	Vascular disorders	MedDRA (15.1)	Systematic Assessment	EG0001 affected6 at risk EG0012 affected6 at risk EG0022 affected6 at risk

ID	Title	Description	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Trebananib 3 mg/kg	Trebananib (AMG 386) 3 mg/kg, 60-minute infusion, intravenously once weekly on Days 1, 8, 15 and 22 and thereafter once weekly starting from Day 36 (Week 6) until intolerance to investigational product, progressive disease, consent withdrawn, or lost to follow-up (up to approximately 249 weeks).	2	6	6	6
EG001	Trebananib 10 mg/kg	Trebananib (AMG 386) 10 mg/kg, 60-minute infusion, intravenously once weekly on Days 1, 8, 15 and 22 and thereafter once weekly starting from Day 36 (Week 6) until intolerance to investigational product, progressive disease, consent withdrawn, or lost to follow-up (up to approximately 249 weeks).	0	6	6	6
EG002	Trebananib 30 mg/kg	Trebananib (AMG 386) 30 mg/kg, 60-minute infusion, intravenously once weekly on Days 1, 8, 15 and 22 and thereafter once weekly starting from Day 36 (Week 6) until intolerance to investigational product, progressive disease, consent withdrawn, or lost to follow-up (up to approximately 249 weeks).	1	6	6	6