Study of Pembrolizumab and Cabozantinib in Patients With Metastatic Renal Cell Carcinoma

Study Overview
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Brief Summary
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This is a phase I/II open-label study designed to evaluate the combination of pembrolizumab and cabozantinib in subjects with locally advanced, recurrent, or metastatic renal cell carcinoma. Sequential dose escalation of cabozantinib with standard dose pembrolizumab will occur in the phase I dose escalation part of the study to determine the recommended phase 2 dose (RP2D). Subsequently, subjects will receive cabozantinib at the RP2D in combination with pembrolizumab in the phase II dose expansion part of the study.

Detailed Description
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Primary Objectives To determine the efficacy based on objective response rate [ORR = complete response (CR) + partial response (PR)] of pembrolizumab and cabozantinib when administered in combination in subjects with locally advanced or metastatic renal cell carcinoma.. Secondary Objectives To characterize dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), and recommended phase 2 dose (RP2D) for the combination. To assess other measures of anti-tumor activity of the combination of pembrolizumab and cabozantinib in subjects with locally advanced or metastatic renal cell carcinoma.

Official Title
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Phase I/II Study of Pembrolizumab and Cabozantinib in Patients With Metastatic Renal Cell Carcinoma

Conditions
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Metastatic Renal Cell Carcinoma

Intervention / Treatment
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* Drug: Cabozantinib
* Drug: Pembrolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects must have histological or cytological documentation of renal cell carcinoma Subjects must have locally advanced, recurrent, or metastatic disease. Be willing and able to provide written informed consent/assent for the trial. Stated willingness to complywith all study procedures and be available for the duration of the trial. Be ≥ 18 years of age on day of signing informed consent. Have measurable or evaluable disease based on RECIST 1.1. Recovery to baseline or ≤ Grade 1 CTCAE v.4.0 from toxicities related to any prior treatments, unless AE(s) are clinically non-significant and/or stable on supportive therapy. Confirmed availability of representative archival tumor specimens in paraffin blocks (preferred) or ≥ 10 unstained slides, with an associated pathology report. Acceptable samples include core needle biopsies for deep tumor tissue or excisional, incisional, or punch biopsies for cutaneous, subcutaneous, or mucosal lesions. Tumor tissue from bone metastases is not evaluable for PD-L1 expression and is therefore not acceptable. A subject with insufficient or unavailable archival tissue may be eligible, upon discussion with the Principal Investigator, if the subject is willing to consent to undergo a pretreatment core, punch, or excisional/incisional biopsy sample collection of the tumor. Have a performance status of 0 or 1 on the ECOG Performance Scale. Demonstrate adequate organ function as defined by desired lab values. Female subject of childbearing potential should have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. Female subjects of childbearing potential (Section 5.7.2) must be willing to use an adequate method of contraception as outlined in Section 5.7.2 - Contraception, for the course of the study through 120 days after the last dose of study medication. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject. Male subjects of childbearing potential (Section 5.7.1) must agree to use an adequate method of contraception as outlined in Section 5.7.1- Contraception, starting with the first dose of study therapy through 120 days after the last dose of study therapy. Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject. Exclusion Criteria: Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment. Has a diagnosis of immunodeficiency or is receiving systemic steroiderapy equivalent to ≥ 10 mg/day of prednisone, or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. Has a known history of active TB (Bacillus Tuberculosis) Has had prior treatment with pembrolizumab. Has had prior treatment with cabozantinib. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents administered more than 4 weeks earlier. - Note: Subjects with stable, treated hypothyroidism or adrenal insufficiency may qualify for the study Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered agent. Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study. Subjects with hypertension managed with medication are an exception to this criterion and may qualify for the study. Subjects with ≤ Grade 2 endocrinopathy (e.g. hypothyroidism or adrenal insufficiency managed with medication) are an exception to this criterion and may qualify for the study. Has had major surgery within 4 weeks or minor surgery within 2 weeks prior to study Day 1. Subjects must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy. Prior treatment with immune checkpoint inhibitors is allowed, provided that no treatment-related Grade ≥ 3 adverse events (other than Grade 3 endocrinopathy managed with replacement therapy) were observed and at least a minimum of 28 days have elapsed between the last dose of prior treatment and the proposed Cycle 1 Day 1. Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer, carcinoma in situ or superficial bladder cancer, low-grade prostate cancer, intraductal papillary mucinous neoplasm (IPMN), and other low grade cancers that is suitable for active surveillance in the opinion of the investigator. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Active CNS metastases will be defined as brain lesions that 1) require intervention with surgery, stereotactic radiosurgery (SRS), or whole brain radiotherapy (WBRT) or 2) require anti-epileptic therapy, systemic steroid treatment, or intrathecal therapy. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks after completion of focal therapy for brain metastases 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 trial treatment. This exception does not include carcinomatous meningitis, which is excluded regardless of clinical stability. 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). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is allowed. Has history of solid organ transplantation. Has history of osteonecrosis of the jaw. Has history of reversible posterior leukoencephalopathy syndrome. Has history of wound dehiscence or complications requiring medical intervention within 6 months of study entry. Has history of (non-infectious) pneumonitis that required steroids or active, non- infectious pneumonitis. Has an active infection requiring systemic therapy with IV antibiotics. Has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions: Cardiovascular disorders: Symptomatic congestive heart failure, unstable angina pectoris, serious cardiac arrhythmias. Uncontrolled hypertension defined as sustained BP > 150 mm Hg systolic or > 100 mm Hg diastolic despite optimal antihypertensive treatment. Stroke (including TIA), myocardial infarction, or other ischemic event, or thromboembolic event (e.g., deep venous thrombosis, pulmonary embolism) within 3 months before randomization. Gastrointestinal (GI) disorders including those associated with a high risk of perforation or fistula formation: Tumors invading the GI-tract, active peptic ulcer disease, inflammatory bowel disease, diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis or acute obstruction of the pancreatic or biliary duct, or gastric outlet obstruction. Abdominal fistula, gastrointestinal perforation, bowel obstruction, or intra-abdominal abscess within 6 months before randomization. Complete healing of an intra-abdominal abscess must be confirmed before study initiation. Has clinically significant hematuria, hematemesis, or hemoptysis of > 0.5 teaspoon within 3 months before randomization. Known endobronchial disease manifestation. Patients with suspected endobronchial disease on imaging who have no evidence of endobronchial disease on bronchoscopy are allowed. Patients with treated endobronchial disease are also allowed provided they are stable. Lesions invading major pulmonary blood vessels. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment. Has an inability to swallow tablets or capsules. Has a previously identified allergy or hypersensitivity to components of the study treatment formulations. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected). Has received a live vaccine within 30 days of planned start of study therapy. Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1: Pembrolizumab 200 mg plus Cabozantinib 40mg<br>Pembrolizumab 200 mg intravenous (IV) infusion on day 1 of each 21-day cycle in combination with cabozantinib 40 mg orally once daily until disease progression, unacceptable toxicity, or consent withdrawal. | Drug: Cabozantinib<br>* Pharmaceutical form: tablets Route of administration: oral<br>* Other names: Cabometyx;Drug: Pembrolizumab<br>* Pharmaceutical form: solution Route of administration: injection<br>* Other names: Keytruda;|
| Experimental: Phase 1: Pembrolizumab 200 mg plus Cabozantinib 60mg<br>Pembrolizumab 200 mg intravenous (IV) infusion on day 1 of each 21-day cycle in combination with cabozantinib 60 mg orally once daily until disease progression, unacceptable toxicity, or consent withdrawal. | Drug: Cabozantinib<br>* Pharmaceutical form: tablets Route of administration: oral<br>* Other names: Cabometyx;Drug: Pembrolizumab<br>* Pharmaceutical form: solution Route of administration: injection<br>* Other names: Keytruda;|
| Experimental: Phase 2: Pembrolizumab 200 mg plus Cabozantinib at the RP2D<br>Pembrolizumab 200 mg intravenous (IV) infusion on day 1 of each 21-day cycle in combination with cabozantinib at the RP2D orally once daily for up to 35 cycles, until disease progression, unacceptable toxicity, or consent withdrawal. All participants who stop pembrolizumab after 35 cycles with SD or better may be eligible for up to an additional 17 cycles (approximately 1 year) of pembrolizumab treatment if they progress after stopping pembrolizumab from the initial treatment phase. | Drug: Cabozantinib<br>* Pharmaceutical form: tablets Route of administration: oral<br>* Other names: Cabometyx;Drug: Pembrolizumab<br>* Pharmaceutical form: solution Route of administration: injection<br>* Other names: Keytruda;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy of Pembrolizumab and Cabozantinib Based on Objective Response Rate | Measured through the complete response (CR) + partial response (PR)] of pembrolizumab and cabozantinib when administered in combination in subjects with locally advanced or metastatic renal cell carcinoma. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. | Beginning of study to end of study, up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximally Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) | The MTD is defined as the highest dose level with no more than 1 DLT reported in 6 DLT-evaluable subjects. The Recommended Phase 2 Dose (RP2D) of cabozantinib will be selected based on the clinical data and will not exceed the MTD. If < 2/6 subjects experience a DLT at 60 mg daily during dose escalation, then 60 mg daily will be considered the RP2D. If ≥ 2/6 subjects experience DLTs at 60 mg daily, and ≤ 1/6 subjects experience a DLT at 40 mg daily, then 40 mg daily will be considered the RP2D. The dose of pembrolizumab will be constant at 200 mg IV every 3 weeks. | Throughout Cycle 1, up to 21 days | 
| Dose Limiting Toxicities | Assessed through Common Terminology Criteria for Adverse Events (CTCAE) v 4.0. Dose Limiting Toxicity (DLT) was defined as any of the following events occurring during the DLT assessment window (21 days) and is assessed by the investigator to be likely related to study treatment (pembrolizumab and/or cabozantinib). Grade ≥ 3 non-hematologic, non-hepatic adverse events Grade 3 nausea, vomiting, or diarrhea lasting >72 hours despite maximal medical therapy. Grade ≥ 4 neutropenia (ANC < 500 cells/μL) lasting > 7 days Grade ≥ 3 febrile neutropenia Grade ≥ 4 anemia Grade ≥ 4 thrombocytopenia, or Grade 3 thrombocytopenia associated with clinically significant bleeding Grade ≥ 3 elevation of serum hepatic transaminase (ALT or AST). Grade ≥ 3 elevation of serum total bilirubin. ALT or AST > 3 × upper limit of normal (ULN) AND total bilirubin >2 × ULN will require permanent treatment discontinuation. | Throughout Cycle 1, up to 21 days | 
| Progression-Free Survival | Measured as the time it takes for an occurrence of documented disease progression. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. | Beginning of study to end of study, or death, whichever comes first, up to 5 years | 
| Overall Survival | Measured as the time it takes for an occurrence of death due to any cause | Beginning of study to end of study, or death, whichever comes first, up to 5 years | 
| Disease Control Rate (DCR), AKA Clinical Benefit Rate (CBR) | DCR is the sum of the complete response, partial response, and stable disease rates | Beginning of study to end of study, or death, whichever comes first, up to 5 years | 
| Duration of Response | Duration of time that patients maintain RECIST response to treatment | Time of first response as measured by RECIST 1.1 to time of progression or death, whichever comes first, up to 5 years |