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

• ClinicalTrials.gov Identifier: NCT02348008
• Recruitment Status: Completed
• First Posted: January 28, 2015
• Results First Posted: July 31, 2020
• Last Update Posted: September 14, 2022
• Sponsor: Arkadiusz Z. Dudek, MD
• Collaborators: Merck Sharp & Dohme LLC; Big Ten Cancer Research Consortium
• Information provided by (Responsible Party): Arkadiusz Z. Dudek, MD, Big Ten Cancer Research Consortium

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Clear Cell Renal Carcinoma	Drug: MK-3475; Drug: Bevacizumab	Phase 1; Phase 2

Detailed Description:

OUTLINE: This is a multi-center study.

The phase Ib dose escalation study will evaluate MK-3475 in combination with bevacizumab in subjects with metastatic clear cell renal carcinoma after failure of at least one systemic therapy for metastatic disease. The phase II trial will determine the activity of the combination of MK-3475 and bevacizumab in first line therapy for subjects with metastatic clear cell renal carcinoma.

PHASE Ib DOSE ESCALATION INVESTIGATIONAL TREATMENT:

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.

PHASE II INVESTIGATIONAL TREATMENT:

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. Treatment will continue until disease progression, unacceptable toxicity, subject refusal, or subject death either from progression of disease, the therapy itself, or from other causes. Subjects who voluntarily stop the study, have progressive disease, or unacceptable toxicities will be followed for a total of 24 months.

Karnofsky Performance Status (KPS) ≥ 70% within 28 days prior to registration for protocol therapy.

Life Expectancy: 6 months or greater

The following baseline labs must be completed within 28 days prior to registration for protocol therapy:

Hematopoietic:

• Absolute neutrophil count (ANC) ≥ 1.5 × 10 9/L
• Platelets ≥ 100 × 10 9/L
• Hemoglobin (Hgb) ≥ 9.0 g/dL

Renal:

• Serum creatinine ≤ 1.5 × upper limit of normal (ULN)
• OR, if serum creatinine > 1.5 × ULN, estimated glomerular filtration rate (eGFR) ≥ 40 mL/min

Hepatic:

• Total serum bilirubin ≤ 1.5 × ULN
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × ULN
• OR, AST and ALT ≤ 5 × ULN if liver function abnormalities are due to underlying malignancy

Coagulation:

• INR < 1.5 × ULN
• OR for subjects receiving warfarin or LMWH, the subjects must, in the investigator's opinion, be clinically stable with no evidence of active bleeding while receiving anticoagulant therapy. The INR for these subjects may exceed 1.5 × ULN if that is the goal of anticoagulant therapy.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 61 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase Ib and Phase II Studies of Anti-PD-1 Antibody MK-3475 in Combination With Bevacizumab for the Treatment of Metastatic Renal Cell Carcinoma: Big Ten Cancer Research Consortium GU14-003
• Actual Study Start Date: March 2015
• Actual Primary Completion Date: December 5, 2019
• Actual Study Completion Date: December 5, 2019

Arms and Interventions

Arm	Intervention/treatment
Experimental: Arm A - Phase 1b Dose Escalation Cohort; 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; Arm A: Phase 1b Cohort 1: 200mg IV; Arm A: Phase 1b Cohort 2: 200mg IV; Other Name: Pembrolizumab; Drug: Bevacizumab; Arm A: Phase 1b Cohort 1: 10mg IV; Arm A: Phase 1b Cohort 2: 15mg IV; Other Name: Avastin
Arm B - Phase II Investigational Treatment; 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; Arm B: Phase II Treatment: 200mg IV; Other Name: Pembrolizumab; Drug: Bevacizumab; Arm B: Phase II Treatment: administered at the maximum safe dose of 10mg or 15mg as established in the Phase 1b dose escalation cohort study.; Other Name: Avastin

Outcome Measures

Primary Outcome Measures :

1. Phase 1b: Maximum Safe Dose of Treatment Regimen [ Time Frame: Every 21 days while on treatment (estimated 4 months) ]
   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.
2. Overall Response Rate [ Time Frame: Every 6 weeks while on treatment (estimated 10 months) ]

   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

Secondary Outcome Measures :

1. Progression-Free Survival [ Time Frame: Up to two years from enrollment ]

   To determine median progression-free survival (PFS) for this patient population, per 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

2. Overall Survival [ Time Frame: Up to 2 years from registration ]
   To determine if treatment regimen improves overall survival for this patient population. Median overall survival will be calculated up to 2 years from registration.
3. Clinical Benefit Rate [ Time Frame: Every 6 months while on treatment (estimated 4-10 months) ]

   To determine the proportion of subjects with clinical benefit (complete response, partial response, or stable disease) 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

4. Characterize Adverse Events [ Time Frame: Every week while on treatment (estimated 4-10 months) ]
   Characterize adverse effects (AE) of pembrolizumab in combination with bevacizumab in subjects with metastatic RCC after failure of at least one systemic therapy. Toxicity will be assessed using CTCAE version 4. All grade 3 and 4 treatment-related adverse events will be reported.

Eligibility Criteria

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

Criteria

Inclusion Criteria:

• 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
  • and absolute neutrophil count (ANC) ≥ 1.5 × 10^9/L
  • and platelet count ≥ 100 × 10^9/L

• Adequate coagulation functioning within 28 days prior to registration for protocol therapy defined by either of the following criteria:

  • INR < 1.5 × ULN
  • OR for subjects receiving warfarin or LMWH, the subjects must, in the investigator's opinion, be clinically stable with no evidence of active bleeding while receiving anticoagulant therapy. The INR for these subjects may exceed 1.5 × ULN if that is the goal of anticoagulant therapy.
• Provided written informed consent and HIPAA authorization for release of personal health information, approved by an Institutional Review Board/Independent Ethics Committee (IRB/IEC).
• Women of childbearing potential (WOCP) must not be pregnant or breast-feeding. A negative serum or urine pregnancy test is required within 72 hours of study registration. If the urine test cannot be confirmed as negative, a serum pregnancy test will be required.
• Women of childbearing potential (WOCP) must be willing to use two effective methods of birth control such as an oral, implantable, injectable, or transdermal hormonal contraceptive, an intrauterine device (IUD), use of a double barrier method (condoms, sponge, diaphragm, or vaginal ring with spermicidal jellies or cream), or total abstinence for the course of the study until 120 days after the last dose of study drug.
• Men who are not surgically sterile (vasectomy) must agree to use an acceptable method of contraception. Male subjects with female sexual partners who are pregnant, possibly pregnant, or who could become pregnant during the study must agree to use condoms from the first dose of study drug through at least 120 days after the last dose of study drug. Total abstinence for the same study period is an acceptable alternative.
• Availability of tissue if applicable (from the primary tumor or metastases) for correlative studies.
• Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures.

Exclusion Criteria:

• 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.
• Known history of active tuberculosis.
• Any other severe, uncontrolled medical condition, including uncontrolled diabetes mellitus or unstable congestive heart failure.
• Known allergy to pembrolizumab or any of its excipients.
• Known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies.

• Any condition that, in the opinion of the treating physician, would exclude the subject from receiving bevacizumab. Examples may include but are not limited to:

  • Hemoptysis (defined as > ½ teaspoon of blood)
  • Pre-existing bleeding diathesis, coagulopathy or hemorrhage
  • Myocardial infarction or cerebrovascular accident within 6 months prior to study registration
  • Any drugs or supplements that interfere with blood clotting can raise the risk of bleeding during treatment with bevacizumab. These drugs include vitamin E, non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen (Advil, Motrin), and naproxen (Aleve, Naprosyn), warfarin (Coumadin), ticlopidine (Ticlid), and clopidogrel (Plavix).These agents should be used with caution.
• Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for enrollment in this study.
• Presence of any non-healing wound, fracture, or ulcer within 28 days prior to study registration.
• Any condition that, in the opinion of the investigator, might jeopardize the safety of the subject or interfere with protocol compliance.
• Any mental or medical condition that prevents the subject from giving informed consent or participating in the trial.
• No prior malignancy is allowed except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, Gleason ≤ grade 7 prostate cancers, or other cancer for which the subject has been disease-free for at least 5 years.
• Received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways).
• Treatment with any investigational agent within 28 days prior to registration for protocol therapy and the subject must have recovered from the acute toxic effects of the regimen.

Contacts and Locations

Locations

United States, Illinois

Northwestern University, Robert H. Lurie Cancer Center

Chicago, Illinois, United States, 60611

University of Illinois Cancer Center

Chicago, Illinois, United States, 60612

United States, Iowa

University of Iowa, Holden Comprehensive Cancer Center

Iowa City, Iowa, United States, 52242

United States, Michigan

University of Michigan Comprehensive Cancer Center

Ann Arbor, Michigan, United States, 48109

Michigan State University, Breslin Cancer Center

Lansing, Michigan, United States, 48910

United States, Minnesota

University of Minnesota: Masonic Cancer Center

Minneapolis, Minnesota, United States, 55455

United States, Nebraska

University of Nebraska, Fred and Pamela Buffet Cancer Center

Omaha, Nebraska, United States, 68198

United States, New Jersey

Rutgers Cancer Institute of New Jersey

New Brunswick, New Jersey, United States, 08903

United States, Pennsylvania

Penn State Hershey Cancer Institute

Hershey, Pennsylvania, United States, 17033

Sponsors and Collaborators

Arkadiusz Z. Dudek, MD

Merck Sharp & Dohme LLC

Big Ten Cancer Research Consortium

Investigators

• Study Chair: Arkadiusz Z Dudek, M.D., Ph.D.; Big Ten Cancer Research Consortium

  Study Documents (Full-Text)

Documents provided by Arkadiusz Z. Dudek, MD, Big Ten Cancer Research Consortium:

Study Protocol and Statistical Analysis Plan  [PDF] October 11, 2018

More Information

Additional Information:

Big Ten Cancer Research Consortium Website 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Arkadiusz Z. Dudek, MD, Sponsor-Investigator, Big Ten Cancer Research Consortium
• ClinicalTrials.gov Identifier: NCT02348008
• Other Study ID Numbers: BTCRC GU14-003
• First Posted: January 28, 2015
• Results First Posted: July 31, 2020
• Last Update Posted: September 14, 2022
• Last Verified: August 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

Keywords provided by Arkadiusz Z. Dudek, MD, Big Ten Cancer Research Consortium:

MK-3475; Pembrolizumab; Bevacizumab

Additional relevant MeSH terms:

Carcinoma; Carcinoma, Renal Cell; Kidney Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Adenocarcinoma; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Kidney Diseases; Urologic Diseases; Bevacizumab; Pembrolizumab; Antineoplastic Agents, Immunological; Antineoplastic Agents; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Physiological Effects of Drugs; Growth Inhibitors