AMG 386 Phase 2 Open-Label Renal Cell Carcinoma (RCC) Study 1st Line or After Cytokine Failure in Combination With Sunitinib

Study Overview
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Brief Summary
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This phase 2 study is an open-label, multi-center study to determine the safety and tolerability of AMG 386 in combination with sunitinib in the treatment of subjects with metastatic renal cell carcinoma.

Official Title
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Phase 2 Open-Label, Multi-Center Study to Evaluate the Safety and Efficacy of Sunitinib Malate in Combination With AMG 386 as First Line or Second Line Therapy for Subjects With Metastatic Renal Cell Carcinoma

Conditions
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Advanced Renal Cell Carcinoma

Intervention / Treatment
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* Drug: Sunitinib
* Drug: Trebananib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects must have a histologically confirmed metastatic renal cell cancer (RCC) with a clear cell component Low or intermediate risk according to the Memorial Sloan Kettering Cancer Center (MSKCC) prognostic risk classification Measurable disease with at least one unidimensionally measurable lesion per Response Evaluation Criteria in Solid Tumor (RECIST) guidelines with modifications Adequate organ and hematological function as evidenced by laboratory studies conducted at Screening Eastern Cooperative Oncology Group (ECOG) of 0 or 1 Exclusion Criteria: Disease related Known history of central nervous system metastases. Previous treatment (excluding surgery, prior cytokine-based immunotherapy and palliative radiotherapy) for advanced or metastatic renal cell carcinoma Focal radiation therapy for palliation of pain from bony metastases within 14 days of enrollment. Medications Currently or previously treated with sunitinib or other small molecule inhibitors of vascular endothelial growth factor (VEGF) Currently or previously treated with agents that neutralizing VEGF Currently or previously treated with AMG 386, or other molecules that inhibit the angiopoietins or Tie2 receptor Currently or previously treated with agents inhibiting the mammalian target of rapamycin (mTOR) Current or within 30 days prior to enrollment treatment with immune modulators Concomitant or previous use within 30 days prior to enrollment of any strong inducer of CYP3A4 Concomitant or previous use of amiodarone within 6 months prior to enrollment General medical Clinically significant cardiovascular disease within 12 months prior to 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, percutaneous transluminal coronary angioplasty/stent Major surgery within 28 days prior to enrollment or still recovering from prior surgery Uncontrolled hypertension as defined as diastolic > 90 mmHg OR systolic >150 mmHg. The use of anti-hypertensive medications to control hypertension is permitted. Other Other investigational procedures are excluded Subject currently is enrolled in or has not yet completed at least 30 days since ending other investigational device or drug study(s), or subject is receiving other investigational agent(s) Other inclusion/exclusion criteria may apply, per protocol.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Trebananib 10 mg/kg + Sunitinib<br>Trebananib 10 mg/kg intravenously (IV) once weekly (QW) plus sunitinib 50 mg orally (PO) once daily (QD) 4 weeks on/2 weeks off | Drug: Sunitinib<br>* Sunitinib will be administered 50 mg QD and is considered to be the background therapy as it is licensed for treatment of reneal cell cancer (RCC) and will be administered to all participants.<br>* Other names: SUTENT (oral multi-kinase inhibitor);Drug: Trebananib<br>* Administered until a participant develops disease progression, clinical progression, unacceptable toxicity, withdraws consent, or death.<br>* Other names: Angiogenesis inhibitor;|
| Experimental: Trebananib 15 mg/kg + Sunitinib<br>Trebananib 15 mg/kg IV QW plus sunitinib 50 mg PO QD 4 weeks on/2 weeks off | Drug: Sunitinib<br>* Sunitinib will be administered 50 mg QD and is considered to be the background therapy as it is licensed for treatment of reneal cell cancer (RCC) and will be administered to all participants.<br>* Other names: SUTENT (oral multi-kinase inhibitor);Drug: Trebananib<br>* Administered until a participant develops disease progression, clinical progression, unacceptable toxicity, withdraws consent, or death.<br>* Other names: Angiogenesis inhibitor;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Discontinuations (DCs) Due to Adverse Events (AEs) | AE: any untoward medical occurrence that does not necessarily have a causal relationship with treatment. SAE: an AE that: is fatal; is life threatening; requires in-patient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; is an other significant medical hazard. Treatment-emergent AEs (TEAEs) are those that occurred after the first administration of study drug through 30 days after the last study drug administration. Severity was graded according to Common Terminology Criteria (CTCAE) version 3.0, as grade 1 (mild), grade 2 (moderate), grade 3 (severe), grade 4 (life-threatening), grade 5 (death). | From first dose of study drug to 30 days after last dose. Median treatment duration of trebananib and sunitinib was 316 and 315 days, respectively, for Trebananib 10 mg/kg+Sunitinib, and 393 and 358 days, respectively, for Trebananib 15 mg/kg+Sunitinib. | 
| Number of Participants With Dose Delays Due to Adverse Events | A trebananib dose was considered delayed if it was administered 11 or more days from the previous trebananib infusion. A sunitinib dose was considered delayed if it was administered 3 or more days from the previous dose, except during holidays. | Median treatment duration of trebananib and sunitinib was 316 and 315 days, respectively, for Trebananib 10 mg/kg+Sunitinib, and 393 and 358 days, respectively, for Trebananib 15 mg/kg+Sunitinib. | 
| Number of Participants With Sunitinib Dose Modifications Within 12 Weeks of First Dose | Participants who had a sunitinib dose modification within 12 weeks from their first dose due to adverse event, laboratory toxicity, or laboratory toxicity and adverse event. | first 12 weeks of study treatment | 
| Number of Participants With Worst Post-Baseline Grade 3 or Higher Toxicity in Laboratory Values | Severity was graded according to Common Terminology Criteria (CTCAE) version 3.0, as grade 1 (mild), grade 2 (moderate), grade 3 (severe), grade 4 (life-threatening), grade 5 (death). | From first dose of study drug to 30 days after last dose. Median treatment duration of trebananib and sunitinib was 316 and 315 days, respectively, for Trebananib 10 mg/kg+Sunitinib, and 393 and 358 days, respectively, for Trebananib 15 mg/kg+Sunitinib. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate (ORR) | ORR was defined as the percentage of participants with either a confirmed complete response (CR) or partial response (PR) per modified Response Evaluation Criteria in Solid Tumor (RECIST) criteria (responder). A confirmed CR requires 2 consecutive assessments of CR at least 28 days apart. A confirmed PR requires 2 consecutive assessments at least 28 days apart of PR or CR. All participants who did not meet the criteria for an objective response by the analysis cutoff date were considered non responders. | 48 months after last subject enrolled (LSE) | 
| Kaplan-Meier Estimate: Duration of Response (DOR) | DOR was calculated as the time from the first confirmed objective response to first observed disease progression per modified RECIST v. 1.0 criteria or death due to any cause. DOR was calculated only for participants who had an objective response. Objective response was defined as either a confirmed CR or PR per modified RECIST criteria. A confirmed CR required 2 consecutive assessments of CR at least 28 days apart. A confirmed PR required 2 consecutive assessments at least 28 days apart of PR or CR. Participants not meeting criteria for progression by the analysis data cutoff date were censored at their last evaluable radiographical disease assessment date. | 48 months after LSE | 
| Disease Control Rate (DCR) | DCR was defined as the percentage of participants with confirmed CR or PR or stable disease (SD), as defined by modified RECIST v1.0 criteria. A confirmed CR required 2 consecutive assessments of CR at least 28 days apart. A confirmed PR requires 2 consecutive assessments at least 28 days apart of PR or CR. CR or PR was confirmed at least 28 days after the criteria for response were first met. A response assessment of PR or CR that was not subsequently confirmed at least 4 weeks later were included as SD. | 48 months after LSE | 
| Kaplan-Meier Estimate: Progression Free Survival (PFS) | PFS was defined as the time from enrollment date to date of disease progression (ie, radiographic progression) per modified RECIST v 1.0 criteria or death. Radiological imaging to assess disease status was performed until participants developed disease progression. Events of radiographic progression per modified RECIST 1.0 that occurred after initiation of subsequent anticancer therapy were not considered PFS events. Deaths occurring after initiation of subsequent anticancer therapy were considered PFS events. Participants not meeting criteria for progression by the analysis data cutoff date were censored at their last evaluable disease assessment date. | 48 months after LSE | 
| Kaplan-Meier Estimate: Overall Survival (OS) | The time from enrollment date to date of death. Participants who had not died by the analysis data cutoff date were censored at their last contact date. | 48 months after LSE | 
| Maximum Percent Reduction From Baseline in the Sum of the Longest Diameters (SLD) of Target Lesions From Baseline to Post-Baseline Nadir | Change in tumor burden was evaluated by the maximum percent reduction from baseline in the SLD of target lesions. | Baseline, 48 months after LSE | 
| Pharmacokinetic Parameter: Maximum Observed Concentration (Cmax) for Trebananib Over Time |  | Pre-infusion and up to 10 minutes post-infusion on Weeks 1, 4, 7, 10, 13, 22, 34, 46, 58, 70, 82, 94, 106, and safety follow-up (30 ±7 days after the last dose of study drug) | 
| Pharmacokinetic Parameter: Minimum Observed Concentration (Cmin) for Trebananib Over Time |  | Pre-infusion on Weeks 4, 7, 10, 13, 22, 34, 46, 58, 70, 82, 94, 106, and safety follow-up (30 ±7 days after the last dose of study drug) | 
| Pharmacokinetic Parameter: Cmin for Sunitinib Over Time |  | Pre-infusion on Weeks 4, 7, 10, 16, 22, 34, 46, 58, 70, 82, 94, 106, and safety follow-up (30 ±7 days after the last dose of study drug) | 
| Pharmacokinetic Parameter: Cmin for Sunitinib Metabolite Over Time |  | Pre-infusion on Weeks 4, 7, 10, 16, 22, 34, 46, 58, 70, 82, 94, 106, and safety follow-up (30 ±7 days after the last dose of study drug) | 
| Number of Participants Binding Antibody- or Neutralizing Antibody-Positive Post-Baseline | Transient positive results were defined as a positive post-baseline result followed by a negative result at the participant's last time point tested within the study period. | 48 months after LSE |