Phase Ib and Phase II Studies of MK-3475 in Combination + for Renal Cell Carcinoma:

NCT02348008 | Completed Phase 1 Results DMC

• 1 other identifier: BTCRC GU14-003
• Study Type: interventional
• Target: 61
• Locations: 1 country
• Sites: 9

Brief Summary

This is an open label, multi-institutional, single arm study of dose escalation phase Ib cohort, followed by a phase II cohort of anti-PD-1 antibody MK-3475 in combination with bevacizumab. No randomization or blinding is involved.

Conditions

Clear Cell Renal Carcinoma

Keywords

MK-3475; Pembrolizumab; Bevacizumab

Outcome Measures

Primary Outcomes (2)

• Phase 1b: Maximum Safe Dose of Treatment Regimen

  To establish the maximum tested safe dose of bevacizumab in combination with 200mg of MK-3475(pembrolizumab) for subjects with metastatic clear cell renal carcinoma after failure of at least one systemic therapy for metastatic disease.

  Every 21 days while on treatment (estimated 4 months)

• Overall Response Rate

  To determine the activity of combination of MK-3475 and bevacizumab in first line therapy for subjects with treatment naïve metastatic clear cell RCC as assessed by response rates (complete or partial response) By calculating the proportion of subjects with a response (CR, PR) based on RECIST 1.1 where: Complete Response (CR): Disappearance of all target lesions Partial Response (PR): At least a 30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LD Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started

  Every 6 weeks while on treatment (estimated 10 months)

Secondary Outcomes (4)

• Progression-Free Survival

  Up to two years from enrollment

• Overall Survival

  Up to 2 years from registration

• Clinical Benefit Rate

  Every 6 months while on treatment (estimated 4-10 months)

• Characterize Adverse Events

  Every week while on treatment (estimated 4-10 months)

Study Arms (2)

Arm A - Phase 1b Dose Escalation Cohort

EXPERIMENTAL

Cohort 1 will consist of 3-6 patients who will receive MK-3475 200mg and bevacizumab 10mg on day 1 of the 21-day cycle. The drugs are administered 15-30 minutes apart in separate intravenous infusions. Cohort 2 will consist of 3-9 patients who will receive MK-3475 200mg and bevacizumab 15mg on day 1 of the 21-day cycle. The drugs are administered 15-30 minutes apart in separate intravenous infusions. If none of the 3 subjects experience a dose limiting toxicity (DLT) during the first cycle of therapy, an additional 3 subjects will be enrolled at dose level 2. If all three subjects in dose level 2 complete the first cycle of therapy without DLT, 3 more subjects will be enrolled to ensure only 0-1 of 6 subjects have a DLT. There will be no further escalation beyond dose level 2.

Drug: MK-3475; Drug: Bevacizumab

Arm B - Phase II Investigational Treatment

OTHER

The maximum safe dose of MK-3475 in combination bevacizumab (as determined in the phase 1b cohort) will be given on day 1 of each 21 day cycle.

Drug: MK-3475; Drug: Bevacizumab

Interventions

MK-3475 DRUG

Arm A: Phase 1b Cohort 1: 200mg IV; Arm A: Phase 1b Cohort 2: 200mg IV

Also known as: Pembrolizumab

Arm A - Phase 1b Dose Escalation Cohort

Bevacizumab DRUG

Arm A: Phase 1b Cohort 1: 10mg IV; Arm A: Phase 1b Cohort 2: 15mg IV

Also known as: Avastin

Arm A - Phase 1b Dose Escalation Cohort

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or female ≥ 18 years of age at time of consent.
• Phase Ib dose escalation cohort study: subjects with histologically assessed metastatic clear cell RCC (defined as more than 50% clear cell component) after failure of at least one systemic therapy for metastatic disease (including, but not limited to prior therapy with interleukin 2, interferon, bevacizumab, VEGF TKI, and mTOR) for metastatic disease. NOTE: A biopsy to prove metastatic disease is not required.
• Phase II study: subjects with treatment-naïve histologically assessed metastatic clear cell RCC (defined as more than 50% clear cell component) and who are candidates for standard first-line therapy. NOTE: A biopsy to prove metastatic disease is not required.
• Measurable disease, defined as at least 1 tumor that fulfills the criteria for a target lesion according to RECIST 1.1, and obtained by imaging within 28 days prior to registration for protocol therapy.
• Karnofsky Performance Status ≥ 70% within 28 days prior to registration for protocol therapy.
• Life expectancy of 6 months or greater as determined by the treating physician.
• Adequate hepatic function within 28 days prior to registration for protocol therapy defined as meeting all of the following criteria:
• total bilirubin ≤ 1.5 × upper limit of normal (ULN) OR direct bilirubin ≤ ULN for subjects with total bilirubin levels \> 1.5 x ULN
• and aspartate aminotransferase (AST) ≤ 2.5 × ULN or ≤ 5 × ULN for subjects with known hepatic metastases
• and alanine aminotransferase (ALT) ≤ 2.5 × ULN or ≤ 5 × ULN for subjects with known hepatic metastases
• Adequate renal function within 28 days prior to registration for protocol therapy defined by either of the following criteria:
• serum creatinine ≤ 3 mg/dL
• OR if serum creatinine \> 3 mg/dL, estimated glomerular filtration rate (GFR) ≥ 20 mL/min
• Adequate hematologic function within 28 days prior to registration for protocol therapy defined as meeting all of the following criteria:
• hemoglobin ≥ 9 g/dL

You may not qualify if:

• Phase Ib: Received prior monoclonal antibody therapy other than bevacizumab within 4 weeks of study registration or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events of such agents administered more than 4 weeks earlier.
• Phase II: has had prior therapy for metastatic renal cell carcinoma.
• Surgery within 4 weeks prior to study treatment except for minor procedures: NOTES: Hepatic biliary stent placement is allowed. Subject must have adequately recovered from the toxicity and/or complications of major surgery prior to study registration, as determined by the treating physician.
• Known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with neurological symptoms must undergo a head CT scan or brain MRI to exclude brain metastasis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to study registration. This exception does not include carcinomatous meningitis, which is excluded regardless of clinical stability.
• Previously received an organ or allogeneic progenitor/stem cell transplant.
• Received a live vaccine within 30 days prior to the first dose of trial treatment: Examples of live vaccines include, but are not limited to: measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG, and typhoid (oral) vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g. Flu-Mist®) are live attenuated vaccines and are not allowed.
• History of blood clots, pulmonary embolism, or deep vein thrombosis unless controlled by anticoagulant treatment.
• Known history of human immunodeficiency virus \[(HIV) HIV 1/2 antibodies\].
• Known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA \[qualitative\] is detected).
• Diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to study registration.
• Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs).
• NOTE: Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
• Received prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study registration or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events from previously administered agents. NOTE: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and can still be considered for the study.
• Any clinically significant infection defined as any acute viral, bacterial, or fungal infection that requires specific treatment. NOTE: Anti-infective treatment must be completed ≥ 7 days prior to study registration.
• Evidence of interstitial lung disease, history of (non-infectious) pneumonitis that required steroids, or current pneumonitis.

Sponsors & Collaborators

• Arkadiusz Z. Dudek, MD: lead
• Merck Sharp & Dohme LLC: collaborator
• Big Ten Cancer Research Consortium: collaborator

Study Sites (9)

Northwestern University, Robert H. Lurie Cancer Center

Chicago, Illinois, 60611, United States

Location

University of Illinois Cancer Center

Chicago, Illinois, 60612, United States

Location

University of Iowa, Holden Comprehensive Cancer Center

Iowa City, Iowa, 52242, United States

Location

University of Michigan Comprehensive Cancer Center

Ann Arbor, Michigan, 48109, United States

Location

Michigan State University, Breslin Cancer Center

Lansing, Michigan, 48910, United States

Location

University of Minnesota: Masonic Cancer Center

Minneapolis, Minnesota, 55455, United States

Location

University of Nebraska, Fred and Pamela Buffet Cancer Center

Omaha, Nebraska, 68198, United States

Location

Rutgers Cancer Institute of New Jersey

New Brunswick, New Jersey, 08903, United States

Location

Penn State Hershey Cancer Institute

Hershey, Pennsylvania, 17033, United States

Location

Related Publications (1)

• Dudek AZ, Liu LC, Gupta S, Logan TF, Singer EA, Joshi M, Zakharia YN, Lang JM, Schwarz JK, Al-Janadi A, Alva AS. Phase Ib/II Clinical Trial of Pembrolizumab With Bevacizumab for Metastatic Renal Cell Carcinoma: BTCRC-GU14-003. J Clin Oncol. 2020 Apr 10;38(11):1138-1145. doi: 10.1200/JCO.19.02394. Epub 2020 Feb 25.

  PMID: 32097091 DERIVED

Related Links

• Big Ten Cancer Research Consortium Website

MeSH Terms

Conditions

Carcinoma, Renal Cell

Interventions

pembrolizumab; Bevacizumab

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Kidney Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Kidney Diseases; Urologic Diseases; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Results Point of Contact

• Title: Clinicaltrials.gov Results Coordinator
• Organization: Hoosier Cancer Research Network

jsmith@hoosiercancer.org

317-921-2050

Study Officials

• Arkadiusz Z Dudek, M.D., Ph.D.

  Big Ten Cancer Research Consortium

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Sponsor-Investigator

Study Record Dates

• First Submitted: January 16, 2015
• First Posted: January 28, 2015
• Study Start: March 1, 2015
• Primary Completion: December 5, 2019
• Study Completion: December 5, 2019
• Last Updated: September 14, 2022
• Results First Posted: July 31, 2020

Record last verified: 2022-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (9)