Phase Ib and Phase II Studies of MK-3475 in Combination + for Renal Cell Carcinoma:
This trial is active, not recruiting.
|Condition||clear cell renal carcinoma|
|Phase||phase 1/phase 2|
|Sponsor||Arkadiusz Z. Dudek, MD|
|Collaborator||Hoosier Cancer Research Network|
|Start date||March 2015|
|End date||March 2017|
|Trial size||61 participants|
|Trial identifier||NCT02348008, BTCRC GU14-003|
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.
|United States||No locations recruiting|
|Other Countries||No locations recruiting|
|Endpoint classification||safety/efficacy study|
|Intervention model||single group assignment|
Phase 1b: Maximum Safe Dose of Treatment Regimen
time frame: Every 21 days while on treatment (estimated 4 months)
Phase II: Efficacy of Treatment Regimen
time frame: Every 6 weeks while on treatment (estimated 10 months)
time frame: 6 months following end of treatment
Clinical Benefit Rate
time frame: Every 6 months while on treatment (estimated 4-10 months)
time frame: Up to 2 years from registration
Characterize Adverse Events
time frame: Every week while on treatment (estimated 4-10 months)
Male or female participants at least 18 years old.
Inclusion Criteria: - Age ≥ 18 years - Written informed consent and HIPAA authorization for release of personal health information. - 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. - 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. A subject with prior brain metastasis may be considered for study if they have completed their treatment for brain metastasis, no longer require corticosteroids, and are asymptomatic. - 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. - Active autoimmune disease requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease, or a syndrome that requires systemic steroids or immunosuppressive agents. NOTE: The following subjects will not be excluded from the study: Subjects with vitiligo or resolved childhood asthma/atopy; Subjects that require intermittent use of bronchodilators or local steroid injections; Subjects with hypothyroidism stable on hormone replacement or Sjögren's syndrome. - 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 or active, non-infectious pneumonitis. - Known history of 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; 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.
|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|
|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 5mg 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 10mg 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.|
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