Working…
COVID-19 is an emerging, rapidly evolving situation.
Get the latest public health information from CDC: https://www.coronavirus.gov.

Get the latest research information from NIH: https://www.nih.gov/coronavirus.
ClinicalTrials.gov
ClinicalTrials.gov Menu

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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03149822
Recruitment Status : Recruiting
First Posted : May 11, 2017
Last Update Posted : March 12, 2020
Sponsor:
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
University of Colorado, Denver

Tracking Information
First Submitted Date  ICMJE April 28, 2017
First Posted Date  ICMJE May 11, 2017
Last Update Posted Date March 12, 2020
Actual Study Start Date  ICMJE September 28, 2017
Estimated Primary Completion Date June 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 2, 2018)
Efficacy of Pembrolizumab and Cabozantinib Based on Objective Response Rate [ Time Frame: Beginning of study to end of study, up to 5 years ]
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.
Original Primary Outcome Measures  ICMJE
 (submitted: May 10, 2017)
Objective Response Rate [ Time Frame: 5 years ]
Objective response is defined as a complete or partial response, as determined by investigator assessment using RECIST and irRC. Subjects with missing or no response assessments will be classified as non-responders.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 2, 2018)
  • Maximally Tolerated Dose (MTD) [ Time Frame: Throughout Cycle 1, up to 21 days ]
    MTD is defined as the highest dose level with no more than 1 DLT reported in 6 DLT-evaluable subjects.
  • Recommended Phase 2 Dose [ Time Frame: Throughout Cycle 1, up to 21 days ]
    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.
  • Dose Limiting Toxicities [ Time Frame: Throughout Cycle 1, up to 21 days ]
    Assessed through Common Terminology Criteria for Adverse Events (CTCAE) v 4.0
  • Progression-Free Survival [ Time Frame: Beginning of study to end of study, or death, whichever comes first, up to 5 years ]
    Measured as the time it takes for an occurrence of documented disease progression
  • Progression of Overall Disease [ Time Frame: Beginning of study to end of study, or death, whichever comes first, up to 5 years ]
    Measured according to RECIST 1.1 and irRECIST
  • 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 ]
    Measured according to RECIST 1.1 and irRECIST
  • Clinical Benefit Rate [ Time Frame: Beginning of study to end of study, or death, whichever comes first, up to 5 years ]
    Measured as complete response (CR) + partial response (PR) + stable disease (SD)
  • Duration of Disease Stability [ Time Frame: Beginning of study to end of study, or death, whichever comes first, up to 5 years ]
    Measured according to RECIST 1.1 and irRECIST
  • 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 ]
    Measured according to RECIST 1.1 and irRECIST
Original Secondary Outcome Measures  ICMJE
 (submitted: May 10, 2017)
  • Maximally Tolerated Dose (MTD) of pembrolizumab and cabozantinib pembrolizumab and cabozantinib [ Time Frame: Up to Cycle 2 of Phase 1 (21 days) ]
    MTD is defined as the highest dose level with no more than 1 DLT reported in 6 DLT-evaluable subjects.
  • MTD is defined as the highest dose level with no more than 1 DLT reported in 6 DLT-evaluable subjects. [ Time Frame: 6 months ]
    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.
  • Progression-Free Survival [ Time Frame: 5 years ]
    Progression-free survival (PFS) will be defined as the time from study treatment initiation (Cycle 1, Day 1) to the first occurrence of documented disease progression or death from any cause during the study, whichever occurs first. For subjects who do not have documented progressive disease or death during the study, PFS will be censored at the day of the last tumor assessment.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study of Pembrolizumab and Cabozantinib in Patients With Metastatic Renal Cell Carcinoma
Official Title  ICMJE Phase I/II Study of Pembrolizumab and Cabozantinib in Patients With Metastatic Renal Cell Carcinoma
Brief Summary 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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Masking Description:
Open-Label
Primary Purpose: Treatment
Condition  ICMJE Metastatic Renal Cell Carcinoma
Intervention  ICMJE
  • Drug: Cabozantinib
    Pharmaceutical form: tablets Route of administration: oral
    Other Name: Cabometyx
  • Drug: Pembrolizumab
    Pharmaceutical form: solution Route of administration: injection
    Other Names:
    • MK-3475
    • Keytruda
Study Arms  ICMJE
  • Experimental: Phase 1: Pembrolizumab 200 mg plus Cabozantinib 40mg
    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.
    Interventions:
    • Drug: Cabozantinib
    • Drug: Pembrolizumab
  • Experimental: Phase 1: Pembrolizumab 200 mg plus Cabozantinib 60mg
    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.
    Interventions:
    • Drug: Cabozantinib
    • Drug: Pembrolizumab
  • Experimental: Phase 2: Pembrolizumab 200 mg plus Cabozantinib at the RP2D
    Pembrolizumab 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.
    Interventions:
    • Drug: Cabozantinib
    • Drug: Pembrolizumab
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: May 10, 2017)
55
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE June 2020
Estimated Primary Completion Date June 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.

    - Note: Subjects with stable, treated hypothyroidism or adrenal insufficiency may qualify for the study

  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 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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 100 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Mary Anduha 720-848-0659 mary.anduha@ucdenver.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03149822
Other Study ID Numbers  ICMJE 16-2300.cc
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party University of Colorado, Denver
Study Sponsor  ICMJE University of Colorado, Denver
Collaborators  ICMJE Merck Sharp & Dohme Corp.
Investigators  ICMJE
Principal Investigator: Elaine Lam, MD University of Colorado, Denver
PRS Account University of Colorado, Denver
Verification Date March 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP