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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.
Full 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:
Renal:
Hepatic:
Coagulation:
Enrollment
Sex
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Volunteers
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:
Adequate renal function within 28 days prior to registration for protocol therapy defined by either of the following criteria:
Adequate hematologic function within 28 days prior to registration for protocol therapy defined as meeting all of the following criteria:
Adequate coagulation functioning within 28 days prior to registration for protocol therapy defined by either of the following criteria:
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
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:
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.
Primary purpose
Allocation
Interventional model
Masking
61 participants in 2 patient groups
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Data sourced from clinicaltrials.gov
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