Clinical Trials /

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

NCT03149822

Description:

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.

Related Conditions:
  • Renal Cell Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: 16-2300.cc
  • NCT ID: NCT03149822

Conditions

  • Metastatic Renal Cell Carcinoma

Interventions

DrugSynonymsArms
CabozantinibCabometyxPhase 1: Pembrolizumab 200 mg plus Cabozantinib 40mg
PembrolizumabMK-3475, KeytrudaPhase 1: Pembrolizumab 200 mg plus Cabozantinib 40mg

Purpose

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

      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.
    

Trial Arms

NameTypeDescriptionInterventions
Phase 1: Pembrolizumab 200 mg plus Cabozantinib 40mgExperimentalPembrolizumab 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.
  • Cabozantinib
  • Pembrolizumab
Phase 1: Pembrolizumab 200 mg plus Cabozantinib 60mgExperimentalPembrolizumab 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.
  • Cabozantinib
  • Pembrolizumab
Phase 2: Pembrolizumab 200 mg plus Cabozantinib at the RP2DExperimentalPembrolizumab 200 mg intravenous (IV) infusion on day 1 of each 21-day cycle in combination with cabozantinib at the RP2D orally once daily until disease progression, unacceptable toxicity, or consent withdrawal.
  • Cabozantinib
  • Pembrolizumab

Eligibility Criteria

        Inclusion Criteria:

          1. Subjects must have histological or cytological documentation of locally advanced,
             recurrent, or metastatic renal cell carcinoma.

          2. Be willing and able to provide written informed consent/assent for the trial.

          3. Stated willingness to complywith all study procedures and be available for the
             duration of the trial.

          4. Be ≥ 18 years of age on day of signing informed consent.

          5. Have measurable or evaluable disease based on RECIST 1.1.

          6. 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.

          7. 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.

          8. Have a performance status of 0 or 1 on the ECOG Performance Scale.

          9. Demonstrate adequate organ function as defined by desired lab values.

         10. 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.

         11. 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.

         12. 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:

          1. 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.

          2. 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.

          3. Has a known history of active TB (Bacillus Tuberculosis)

          4. Has had prior treatment with pembrolizumab.

          5. Has had prior treatment with cabozantinib.

          6. 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.

          7. 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 ≤ Grade 2 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.

          8. 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.

          9. 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.

         10. 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.

         11. 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.

         12. 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.

         13. Has history of solid organ transplantation.

         14. Has history of osteonecrosis of the jaw.

         15. Has history of reversible posterior leukoencephalopathy syndrome.

         16. Has history of wound dehiscence or complications requiring medical intervention within
             6 months of study entry.

         17. Has history of (non-infectious) pneumonitis that required steroids or active, non-
             infectious pneumonitis.

         18. Has an active infection requiring systemic therapy with IV antibiotics.

         19. Has uncontrolled, significant intercurrent or recent illness including, but not
             limited to, the following conditions:

               1. 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.

               2. 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.

               3. Has clinically significant hematuria, hematemesis, or hemoptysis of > 0.5
                  teaspoon within 3 months before randomization.

               4. 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.

               5. Lesions invading major pulmonary blood vessels.

         20. 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.

         21. Has known psychiatric or substance abuse disorders that would interfere with
             cooperation with the requirements of the trial.

         22. 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.

         23. Has an inability to swallow tablets or capsules.

         24. Has a previously identified allergy or hypersensitivity to components of the study
             treatment formulations.

         25. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).

         26. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA
             [qualitative] is detected).

         27. 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.
      
Maximum Eligible Age:100 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Efficacy of Pembrolizumab and Cabozantinib Based on Objective Response Rate
Time Frame:Beginning of study to end of study, up to 5 years
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Maximally Tolerated Dose (MTD)
Time Frame:Throughout Cycle 1, up to 21 days
Safety Issue:
Description:MTD is defined as the highest dose level with no more than 1 DLT reported in 6 DLT-evaluable subjects.
Measure:Recommended Phase 2 Dose
Time Frame:Throughout Cycle 1, up to 21 days
Safety Issue:
Description: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.
Measure:Dose Limiting Toxicities
Time Frame:Throughout Cycle 1, up to 21 days
Safety Issue:
Description:Assessed through Common Terminology Criteria for Adverse Events (CTCAE) v 4.0
Measure:Progression-Free Survival
Time Frame:Beginning of study to end of study, or death, whichever comes first, up to 5 years
Safety Issue:
Description:Measured as the time it takes for an occurrence of documented disease progression
Measure:Progression of Overall Disease
Time Frame:Beginning of study to end of study, or death, whichever comes first, up to 5 years
Safety Issue:
Description:Measured according to RECIST 1.1 and irRECIST
Measure:Progression of Bone Metastasis or Skeletal Related Event (SRE)
Time Frame:Beginning of study to end of study, or death, whichever comes first, up to 5 years
Safety Issue:
Description:Measured according to RECIST 1.1 and irRECIST
Measure:Clinical Benefit Rate
Time Frame:Beginning of study to end of study, or death, whichever comes first, up to 5 years
Safety Issue:
Description:Measured as complete response (CR) + partial response (PR) + stable disease (SD)
Measure:Duration of Disease Stability
Time Frame:Beginning of study to end of study, or death, whichever comes first, up to 5 years
Safety Issue:
Description:Measured according to RECIST 1.1 and irRECIST
Measure:Duration on Treatment in Subjects Beyond Treatment Progression
Time Frame:Beginning of study to end of study, or death, whichever comes first, up to 5 years
Safety Issue:
Description:Measured according to RECIST 1.1 and irRECIST

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University of Colorado, Denver

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