Sequential Treatment of Cabozantinib or Cabozantinib With Nivolumab for Advanced Renal Cell Carcinoma (RCC)

Overview

The goal of this clinical trial is to learn about the effects of a higher dose of cabozantinib or the effects of cabozantinib-nivolumab combination in patients with advanced renal cell carcinoma who have progressed on or after receiving cabozantinib treatment. The study will have two parts or "cohorts".

• Cohort 1: cabozantinib 80mg daily
• Cohort 2: cabozantinib 40mg daily with nivolumab The cohort assignment will be determined by investigator, based on how much cabozantinib the participant is able to safely receive.

Description

This is a multi-center, open-label, 2 cohort, phase II study to assess the efficacy of cabozantinib dose escalation and cabozantinib/nivolumab combination at the time of progression on/after cabozantinib monotherapy. The study will enroll subjects with advanced RCC (defined as locally advanced, unresectable or metastatic) who have disease progression on/after cabozantinib monotherapy in any line of treatment

Eligibility

Inclusion Criteria:

1. Patients with advanced RCC (defined as locally advanced unresectable or metastatic) of any histology who progressed on/after cabozantinib monotherapy in any line of treatment. Patient must have cabozantinib sensitive disease (prior treatment with cabozantinib >6 months)
2. Ability to tolerate prior cabozantinib at 60mg PO daily (for Cohort 1) or 40mg PO daily (for Cohort 2) with manageable toxicity profile at the respective doses, at investigator discretion
3. Prior PD-1 inhibitor/PD-L1 inhibitor allowed
4. Evidence of measurable disease per RECIST 1.1
5. For up to 5 patients opting into on-treatment biopsy in each cohort, one of the following must be met:
   1. Archival tissue confirmed to be available and obtained within 30 days of informed consent as well as willingness to undergo an on-treatment biopsy at 12 weeks (+/- 7 days).

      OR

   2. Willingness to undergo a baseline biopsy prior to Cycle 1 Day1, as well as an on-treatment biopsy at 12 weeks (+/- 7 days).
6. Age ≥ 18 at time of consent
7. ECOG performance status ≤ 2
8. Capable of understanding and complying with the protocol requirements and must have signed the informed consent document
9. Minimum of 2 weeks washout for cabozantinib and minimum of 44 weeks or 4 half-lives washout, whichever is shorter, for other standard or experimental anti-cancer therapies.
10. Recovery to baseline or ≤ Grade 1 National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5 from toxicities related to any prior treatments, unless AE(s) are clinically nonsignificant and/or stable on supportive therapy
11. Adequate organ and marrow function, based upon meeting all of the following laboratory criteria within 14 days before first dose of study treatment:
    1. Absolute neutrophil count (ANC) ≥ 1500/µL without granulocyte colony-stimulating factor (G-CSF) support
    2. White blood cell (WBC) count ≥ 2500/µL
    3. Platelets ≥ 100,000/µL without transfusion
    4. Hemoglobin ≥ 9 g/dL (≥ 90 g/L) (transfusion acceptable per investigator discretion)
    5. Alanine transaminase (ALT), AST and alkaline phosphatase (ALP) ≤ 3 x ULN. ALP ≤ 5x ULN with documented bone metastases
    6. Total bilirubin ≤ 1.5 x ULN (for subjects with Gilbert's disease ≤ 3x ULN)
    7. Serum albumin ≥ 2.8 g/dl
    8. Prothrombin (PT)/international normalized ratio (INR) or partial thromboplastin time (PTT) test < 1.3x the laboratory ULN
    9. Serum creatinine ≤ 1.5x ULN or calculated creatinine clearance ≥ 40mL/min (≥ 0.675mL/sec) using the Cockcroft-Gault equation:
       • Males: (140 - age) x weight (kg)/(serum creatinine [mg/dL] × 72)
       • Females: [(140 - age) x weight (kg)/(serum creatinine [mg/dL] × 72)] × 0.85
    10. Urine protein/creatinine ratio (UPCR) ≤1 mg/mg (≤113.2 mg/mmol), or 24h urine

        protein ≤1 g

12. Sexually active fertile subjects and their partners must agree to use medically

    accepted methods of contraception (e.g., barrier methods, including male condom, female condom, or diaphragm with spermicidal gel) during the course of the study and for 4 months after the last dose of cabozantinib and 5 months after the last dose of nivolumab.

        Should a woman become pregnant or suspect she is pregnant while participating in this
        study, she should inform her treating physician immediately.
          1. Female subjects are considered to be of childbearing potential unless one of the
             following criteria is met:
               -  documented permanent sterilization (hysterectomy, bilateral salpingectomy, or
                  bilateral oophorectomy), or
               -  documented postmenopausal status (defined as 12 months of amenorrhea in a woman >
                  45 years-of-age in the absence of other biological or physiological causes.
          2. In addition, females < 55 years-of-age must have a serum follicle stimulating hormone
             (FSH) level > 40 mIU/mL to confirm menopause.
        Exclusion Criteria:
          1. For Cohort 2 only, Prior prior treatment with concurrent cabozantinib/nivolumab (not
             an exclusion for cohort 1).
          2. Radiation therapy for bone metastasis within 2 weeks or any other radiation therapy
             within 4 weeks before first dose of study treatment. Systemic treatment with
             radionuclides within 6 weeks before first dose of study treatment. Subjects with
             clinically relevant ongoing complications from prior radiation therapy are not
             eligible
          3. Known brain metastases or cranial epidural disease unless adequately treated with
             radiotherapy and/or surgery (including radiosurgery) and stable for 1) at least 2
             weeks after radiotherapy or 2) at least 4 weeks after major surgery (e.g., removal or
             biopsy of brain metastasis) prior to first dose of study treatment. Subjects must have
             complete wound healing from major surgery or minor surgery before first dose of study
             treatment. Eligible subjects must be neurologically asymptomatic and without
             corticosteroid treatment for the brain metastasis at the time of first dose of study
             treatment
          4. Concomitant anticoagulation with coumarin agents (e.g., warfarin), direct thrombin
             inhibitors (e.g., dabigatran), direct factor Xa inhibitor betrixaban, or platelet
             inhibitors (e.g., clopidogrel). Allowed anticoagulants are the following: 1)
             prophylactic use of low-dose aspirin for cardio-protection (per local applicable
             guidelines) and low-dose low molecular weight heparins (LMWH). 2) Therapeutic doses of
             LMWH or anticoagulation with direct factor Xa inhibitors rivaroxaban, edoxaban, or
             apixaban in subjects without known brain metastases who are on a stable dose of the
             anticoagulant for at least 1 week before first dose of study treatment without
             clinically significant hemorrhagic complications from the anticoagulation regimen or
             the tumor
          5. Administration of a live, attenuated vaccine within 30 days before first dose of study
             treatment
          6. The subject has uncontrolled, significant intercurrent or recent illness including,
             but not limited to, the following conditions:
               1. Cardiovascular disorders: 1) congestive heart failure New York Heart Association
                  Class 3 or 4, unstable angina pectoris, serious cardiac arrhythmias; 2)
                  uncontrolled hypertension defined as sustained blood pressure (BP) > 140 mm Hg
                  systolic or > 90 mm Hg diastolic despite optimal antihypertensive treatment
                  within 1 week of treatment; 3) stroke (including transient ischemic attack
                  [TIA]), myocardial infarction (MI), or other ischemic event, or thromboembolic
                  event (e.g., deep venous thrombosis [DVT], pulmonary embolism [PE]) within 6
                  months before first dose of study treatment. Note: subjects with a diagnosis of
                  incidental, subsegmental PE or DVT within 6 months are allowed if stable,
                  asymptomatic, and treated with a stable dose of permitted anticoagulation (see
                  exclusion criterion #3.2.4) for at least 1 week before first dose of study
                  treatment
               2. Gastrointestinal (GI) disorders including those associated with a high risk of
                  perforation or fistula formation, including 1) the subject has evidence of tumor
                  invading the GI tract, active peptic ulcer disease, inflammatory bowel disease
                  (e.g., Crohn's disease), diverticulitis, cholecystitis, symptomatic cholangitis
                  or appendicitis, acute pancreatitis, acute obstruction of the pancreatic duct or
                  common bile duct, or gastric outlet obstruction; 2) abdominal fistula, GI
                  perforation, bowel obstruction, or intra-abdominal abscess within 6 months before
                  first dose of study treatment. Note: Complete healing of an intra-abdominal
                  abscess must be confirmed before first dose of study treatment
          7. Clinically significant hematuria, hematemesis, hemoptysis, or other history of
             significant bleeding (e.g., pulmonary hemorrhage) within 6 weeks before first dose of
             study treatment. (Clinically significant hematuria defined by needing transfusion;
             clinically significant hematemesis or hemoptysis defined by needing hospital
             admission)
          8. Cavitating pulmonary lesion(s) or known endotracheal or endobronchial disease
             manifestation
          9. Lesions invading or encasing any major blood vessels
         10. Other clinically significant disorders that would preclude safe study participation
               1. Any active, known or suspected autoimmune disease will be excluded, with the
                  following exceptions: type 1 diabetes mellitus, hypothyroidism only requiring
                  hormone replacement, skin disorders (e.g., vitiligo, psoriasis, or alopecia) not
                  requiring systemic treatment, conditions not expected to recur in the absence of
                  an external trigger
               2. Any condition requiring systemic treatment with either corticosteroids (> 10 mg
                  daily prednisone equivalent) or other immunosuppressive medications within 14
                  days before first dose of study treatment. Note: Inhaled, intranasal,
                  intra-articular, or topical steroids are permitted. Adrenal replacement steroid
                  doses > 10 mg daily prednisone equivalent are permitted. Transient short-term use
                  of systemic corticosteroids for allergic conditions (e.g., contrast allergy) is
                  also allowed
               3. Active infection requiring systemic treatment. Acute or chronic hepatitis B or C
                  infection, known human immunodeficiency virus (HIV) or acquired immunodeficiency
                  syndrome (AIDS)-related illness, or known positive test for tuberculosis
                  infection where there is clinical or radiographic evidence of active
                  mycobacterial infection
               4. History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced
                  pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on
                  screening chest CT scan
               5. Serious non-healing wound/ulcer/bone fracture
               6. Malabsorption syndrome
               7. Uncompensated/symptomatic hypothyroidism
               8. Moderate to severe hepatic impairment (Child-Pugh B or C).
               9. Requirement for hemodialysis or peritoneal dialysis
              10. History of solid organ or allogenic stem cell transplant
              11. Acute COVID-19 infection - clinical recovery from COVID-19 infection at least 14
                  days prior to enrollment allowed.
         11. Major surgery (e.g., laparoscopic nephrectomy, GI surgery, removal or biopsy of brain
             metastasis) within 2 weeks before first dose of study treatment. Minor surgeries
             within 10 days before first dose of study treatment. Subjects must have complete wound
             healing from major surgery or minor surgery before first dose of study treatment.
             Subjects with clinically relevant ongoing complications from prior surgery are not
             eligible
         12. Corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms per
             electrocardiogram (ECG) within 14 days before first dose of study treatment.
             Furthermore, subjects with a history of additional risk factors for torsades de
             pointes (e.g., long QT syndrome) are also excluded. Note: If a single ECG shows a QTcF
             with an absolute value > 500 ms, two additional ECGs at intervals of approximately 3
             min must be performed within 30 min after the initial ECG, and the average of these
             three consecutive results for QTcF will be used to determine eligibility.
         13. Pregnant or lactating females
         14. Inability to swallow tablets
         15. Cohort 2: Unwillingness or inability to receive intravenous (IV) administration
         16. Previously identified allergy or hypersensitivity to components of the study treatment
             formulations or history of severe infusion-related reactions to monoclonal antibodies.
             Subjects with rare hereditary problems of galactose intolerance, the Lapp lactase
             deficiency or glucose-galactose malabsorption are also excluded
         17. Another malignancy within 2 years prior to first dose of study treatment that requires
             active treatment, except for locally curable cancers that have been apparently cured,
             such as basal or squamous cell skin cancer, superficial bladder cancer, Gleason 6
             prostate cancer, or carcinoma in situ of cervix or breast