Trebananib With or Without Bevacizumab, Pazopanib Hydrochloride, Sorafenib Tosylate, or Sunitinib Malate in Treating Patients With Advanced Kidney Cancer

A Randomized Phase 2 Study of AMG 386 With or Without Continued Anti-Vascular Endothelial Growth Factor (VEGF) Therapy in Patients With Renal Cell Carcinoma Who Have Progressed on Bevacizumab, Pazopanib, Sorafenib, or Sunitinib

This randomized phase II trial studies how well trebananib with or without bevacizumab, pazopanib hydrochloride, sorafenib tosylate, or sunitinib malate works in treating patients with kidney cancer that has spread to other places in the body and usually cannot be cured or controlled with treatment (advanced). Trebananib may stop the growth of tumor cells by blocking blood flow to the tumor. Immunotherapy with monoclonal, such as bevacizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Pazopanib hydrochloride, sorafenib tosylate, and sunitinib malate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth or by blocking blood flow to the tumor. It is not yet known whether giving trebananib with or without bevacizumab, pazopanib hydrochloride, sorafenib tosylate, or sunitinib malate is more effective in treating kidney cancer.

Study Overview

• Status: Completed
• Conditions: Advanced Renal Cell Carcinoma; Stage III Renal Cell Cancer AJCC v7; Stage IV Renal Cell Cancer AJCC v7; Advanced Sarcomatoid Renal Cell Carcinoma
• Intervention / Treatment: Drug: Pazopanib Hydrochloride; Biological: Bevacizumab; Drug: Sunitinib Malate; Drug: Sorafenib Tosylate; Biological: Trebananib

Detailed Description

PRIMARY OBJECTIVE:

I. To evaluate the overall response rate (complete response [CR] + partial response [PR]) of trebananib (AMG 386) alone and in combination with continuation of previously administered bevacizumab, pazopanib hydrochloride (pazopanib), sorafenib tosylate (sorafenib), or sunitinib malate (sunitinib) in advanced renal cell carcinoma.

SECONDARY OBJECTIVES:

I. To evaluate progression free survival in each arm. II. To evaluate the tolerance and toxicity of AMG 386 alone and in combination with continuation of the prior VEGF targeted agent.

CORRELATIVE OBJECTIVES:

I. To evaluate the association between pretreatment tumor gene expression levels and response to AMG 386 in combination with continuation of the prior VEGF targeted agent.

II. To evaluate the association between single nucleotide polymorphisms (SNPs) in angiogenic genes and response to AMG 386 in combination with continuation of the prior VEGF targeted agent.

III. To compare changes in circulating angiogenic factors in patients treated with AMG 386 monotherapy to those treated with AMG 386 in combination with VEGF-targeted therapy.

IV. To compare expression of angiogenic genes from archival tumor specimens to the expression in biopsy specimens obtained after progression on anti-VEGF therapy.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive trebananib intravenously (IV) over 30-60 minutes on days 1, 8, 15, 22, 29, and 36. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive trebananib as in Arm I and either bevacizumab IV over 30-90 minutes on days 1, 15, and 29, pazopanib hydrochloride orally (PO) once daily (QD) on days 1-42, sorafenib tosylate PO twice daily (BID) on days 1-42, or sunitinib malate PO QD on days 1-28. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 4-8 weeks.

• Study Type: Interventional
• Enrollment (Actual): 41
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Duarte, California, United States, 91010
      • City of Hope Comprehensive Cancer Center
    • Los Angeles, California, United States, 90033
      • USC / Norris Comprehensive Cancer Center
    • Sacramento, California, United States, 95817
      • University of California Davis Comprehensive Cancer Center
    • South Pasadena, California, United States, 91030
      • City of Hope South Pasadena
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Wayne State University/Karmanos Cancer Institute
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic in Rochester
    • Saint Louis Park, Minnesota, United States, 55416
      • Metro Minnesota Community Oncology Research Consortium
  • New Jersey
    • New Brunswick, New Jersey, United States, 08903
      • Rutgers Cancer Institute of New Jersey
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • UNC Lineberger Comprehensive Cancer Center
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033-0850
      • Penn State Milton S Hershey Medical Center
    • Pittsburgh, Pennsylvania, United States, 15232
      • University of Pittsburgh Cancer Institute (UPCI)
  • Virginia
    • Mechanicsville, Virginia, United States, 23116
      • VCU Massey Cancer Center at Hanover Medical Park

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Patients must have histologically or cytologically confirmed renal cell carcinoma except medullary or collecting duct subtypes; sarcomatoid differentiation will be allowed
• Patients must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >= 20 mm with conventional techniques or as >= 10 mm with spiral computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam
• Patients must have documented radiologic or clinical progressive disease following at least one prior anti-VEGF regimen administered either as a single agent or in combination with other agents for at least 8 weeks; the prior anti-VEGF treatment regimen must have included bevacizumab, pazopanib, sorafenib or sunitinib administered not more than 12 weeks before study entry; Note: enrollment not more than 8 weeks after the last dose of anti-VEGF therapy is encouraged; nevertheless, intercurrent therapy with an mTOR inhibitor (everolimus or temsirolimus) will be allowed if progression on that treatment is observed within 12 weeks of the prior anti-VEGF therapy
• Any number of prior regimens is allowed; prior investigational therapy is allowed
• Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%)
• Life expectancy of greater than 3 months
• Leukocytes >= 3,000/mcL
• Absolute neutrophil count >= 1,500/mcL
• Platelets >= 100,000/mcL
• Total bilirubin =< institutional upper limits of normal
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal
• Partial thromboplastin time (PTT) or activated partial thromboplastin time (aPTT) =< upper limit of normal (ULN) per institutional laboratory range
• International normalized ratio (INR) =< 1.5
• Creatinine within normal institutional limits OR creatinine clearance > 40 mL/min per 24 hour (h) urine collection or calculated according to the Cockcroft-Gault formula
• Urinary protein =< 100 mg/dL in urinalysis or =< 1+ on dipstick, unless quantitative protein is < 1000 mg in a 24 h urine sample
• Generally well-controlled blood pressure with systolic blood pressure =< 140 mmHg AND diastolic blood pressure =< 90 mmHg prior to enrollment; the use of anti-hypertensive medications to control hypertension is permitted
• Patients must have a tumor site amenable to biopsy as determined by the treating investigator; any questions regarding suitability of a site for biopsy will be adjudicated by the principal investigator
• Patients must be willing to consent to tumor biopsy for research purposes
• Patients should have archival tumor tissue (either unstained slides or tumor blocks) available for retrieval
• The effects of AMG 386 are known to be detrimental to fetal development; for this reason and because inhibitors of angiogenesis as well as other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and 6 months after completion of AMG 386; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately; men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 6 months after completion of AMG 386 and bevacizumab, pazopanib, sunitinib, or sorafenib administration
• Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

• Intolerance of prior treatment with bevacizumab, pazopanib, sorafenib, or sunitinib; Note: subjects who required a dose reduction of pazopanib, sorafenib, or sunitinib during prior therapy MAY be eligible if they tolerated the agent after dose level reduction (to a minimum of dose level -2 as defined in this protocol)
• Central nervous system metastases unless: (1) metastases have been treated and have remained controlled for at least two weeks following treatment, AND (2) patient has no residual neurological dysfunction off corticosteroids for at least one week; a CT or MRI to evaluate for central nervous system (CNS) disease is required for symptomatic patients only
• History of venous or arterial thromboembolism within 12 months prior to enrollment/randomization
• History of clinically significant bleeding within 6 months of enrollment/randomization
• Unresolved toxicities from prior systemic therapy that are Common Terminology Criteria in Adverse Events (CTCAE) version 3.0 or 4.0 >= grade 2 in severity except alopecia
• Currently or previously treated with AMG 386, or other molecules that inhibit the angiopoietins or Tie2 receptor
• Clinically significant cardiovascular disease within 12 months prior to enrollment/randomization, 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 or placement of percutaneous transluminal coronary angioplasty/stent
• Major surgery within 28 days prior to enrollment or still recovering from prior surgery
• Minor surgical procedures except placement of tunneled central venous access device within 3 days prior to enrollment
• Non-healing wound, ulcer (including gastrointestinal), or fracture
• Subject not consenting to the use of highly effective contraceptive precautions (e.g., double barrier method [i.e., condom plus diaphragm]) during the course of the study and for 6 months after administration of the last study medication
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to AMG 386 or the anti-VEGF agent used in study
• History of allergic reactions to bacterially-produced proteins
• Patients who have had anti-VEGFR tyrosine kinase inhibitor within 1 week, mTOR inhibitor within 1 week or anti-VEGF antibody therapy within 3 weeks prior to entering the study; patients who have had other forms of chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier
• Patients who have not yet completed at least 21 days (30 days for prior monoclonal antibody therapy) since ending other investigational device or drug trials, or who are currently receiving other investigational treatments
• Patients receiving any medications or substances that are strong inhibitors or inducers of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP450 3A4) are ineligible; caution is advised for patients requiring weak or moderate CYP450 3A4 inhibitors or inducers; specifically prohibited medicines include indinavir, nelfinavir, ritonavir, clarithromycin, itraconazole, ketoconazole, nefazodone, carbamazepine, phenobarbital, phenytoin, pioglitazone, rifabutin, rifampin, St. John's wort, and troglitazone
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• Pregnant women are excluded from this study because AMG 386, bevacizumab, pazopanib, sorafenib, and sunitinib are inhibitors of angiogenesis with the potential for teratogenic or abortifacient effects; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with AMG 386, breastfeeding must be discontinued if the mother is treated with AMG 386
• Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with pazopanib, sorafenib, or sunitinib; in addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy; appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated
• Inability to take oral medications on a continuous basis; patients who are to take pazopanib, sorafenib, or sunitinib and are unable to swallow pills whole are ineligible (the pills cannot be crushed or broken)
• Any condition which in the investigator's opinion makes the subject unsuitable for study participation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm I (trebananib monotherapy); Patients receive trebananib IV over 30-60 minutes on days 1, 8, 15, 22, 29, and 36. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity.	Biological: Trebananib; Given IV; Other Names: AMG 386; AMG386; Angiopoietin 1/2-Neutralizing Peptibody AMG 386
Experimental: Arm II (trebananib and anti-VEGF therapy); Patients receive trebananib as in Arm I and either bevacizumab IV over 30-90 minutes on days 1, 15, and 29, pazopanib hydrochloride PO QD on days 1-42, sorafenib tosylate PO BID on days 1-42, or sunitinib malate PO QD on days 1-28. Cycles repeat every 42 days in the absence of disease progression or unacceptable toxicity.	Drug: Pazopanib Hydrochloride; Given PO; Other Names: GW786034B; Votrient; Biological: Bevacizumab; Given IV; Other Names: Avastin; Anti-VEGF; Anti-VEGF Humanized Monoclonal Antibody; Anti-VEGF rhuMAb; Bevacizumab awwb; Bevacizumab Biosimilar BEVZ92; Bevacizumab Biosimilar BI 695502; Bevacizumab Biosimilar CBT 124; Bevacizumab Biosimilar CT-P16; Bevacizumab Biosimilar FKB238; Bevacizumab Biosimilar GB-222; Bevacizumab Biosimilar HD204; Bevacizumab Biosimilar HLX04; Bevacizumab Biosimilar IBI305; Bevacizumab Biosimilar LY01008; Bevacizumab Biosimilar MIL60; Bevacizumab Biosimilar QL 1101; Bevacizumab Biosimilar RPH-001; Bevacizumab Biosimilar SCT501; BP102; BP102 Biosimilar; HD204; Immunoglobulin G1 (Human-Mouse Monoclonal rhuMab-VEGF Gamma-Chain Anti-Human Vascular Endothelial Growth Factor), Disulfide With Human-Mouse Monoclonal rhuMab-VEGF Light Chain, Dimer; Recombinant Humanized Anti-VEGF Monoclonal Antibody; rhuMab-VEGF; SCT501; Drug: Sunitinib Malate; Given PO; Other Names: Sutent; SU011248; SU11248; sunitinib; Drug: Sorafenib Tosylate; Given PO; Other Names: BAY 54-9085; Nexavar; BAY 43-9006 Tosylate; sorafenib; Biological: Trebananib; Given IV; Other Names: AMG 386; AMG386; Angiopoietin 1/2-Neutralizing Peptibody AMG 386

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Observed Response Rate	Defined as the total number of efficacy-evaluable patients who achieve a complete or partial response by RECIST version 1.1 criteria, assessed by MRI: Complete Response (CR), Disappearance of all target lesions: any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm; Partial Response (PR), >= 30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. Best response will be listed for each patient and summarized using standard descriptive methods-point estimate and associated confidence intervals.	Up to 8 weeks
Tumor Response	Tumor Response Classification	at 8 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival (PFS)	Time to reach Kaplan-Meier median survival (outcome being death or progression) (95% Confidence Interval) is reported. Progressive Disease is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered a progression.)	From start of treatment to time of progression or death, whichever occurs first, assessed up to 8 weeks
Number of Participants With Grade 3, 4, 5 Toxicities Related to the Treatment Drugs	Adverse events were graded using CTCAE version 5.0. Grades 3, 4, 5 (on a scale of 1 to 5, 5 being the worst grade - death) toxicities related ('Possibly', 'Probably', or 'Definitely') to the treatment drugs (AMG 386 alone or in combination with prior VEGF targeted agent).	8 weeks for adverse events. Until removal from the study or to death for late adverse events, up to 12 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in Circulating Angiogenic Factors	Analyzed as continuous variables (most likely after transformation). The gene expression results from the pretreatment tumor biopsies are expressed as ratios between that of the gene of interest and the internal reference gene beta-actin and can be analyzed as continuous variables - generally after log transformation.	Baseline to up to 8 weeks

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Thomas J Semrad, City of Hope Comprehensive Cancer Center

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2012
• Primary Completion (Actual): December 7, 2020
• Study Completion (Actual): December 7, 2020

Study Registration Dates

• First Submitted: August 10, 2012
• First Submitted That Met QC Criteria: August 10, 2012
• First Posted (Estimate): August 14, 2012

Study Record Updates

• Last Update Posted (Actual): June 7, 2022
• Last Update Submitted That Met QC Criteria: May 17, 2022
• Last Verified: May 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Kidney Diseases; Urologic Diseases; Adenocarcinoma; Neoplasms, Glandular and Epithelial; Kidney Neoplasms; Carcinoma, Renal Cell; Carcinoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Immunologic Factors; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Protein Kinase Inhibitors; Antibodies; Sorafenib; Sunitinib; Immunoglobulins; Bevacizumab; Antibodies, Monoclonal; Antineoplastic Agents, Immunological; Immunoglobulin G; Endothelial Growth Factors; Trebananib
• Other Study ID Numbers: NCI-2012-01289 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); P30CA033572 (U.S. NIH Grant/Contract); N01CM00038 (U.S. NIH Grant/Contract); PHII-122; P9048_A12PAMDREVW01; CDR0000738785; 9048 (CTEP)