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

Study Overview
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Brief Summary
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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.

Detailed Description
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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

Official Title
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Phase 2, Open-label, Two Cohort, Multicenter Trial for Sequential Treatment of High Dose Cabozantinib or Cabozantinib Plus Nivolumab on/After Progression on Cabozantinib Monotherapy in Advanced Renal Cell Carcinoma (Seq-Cabo)

Conditions
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RCC, Renal Cell Carcinoma

Intervention / Treatment
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* Drug: Cabozantinib 80 MG
* Drug: Cabozantinib 40Mg Tab
* Drug: Nivolumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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) 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 Prior PD-1 inhibitor/PD-L1 inhibitor allowed Evidence of measurable disease per RECIST 1.1 For up to 5 patients opting into on-treatment biopsy in each cohort, one of the following must be met: 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 Willingness to undergo a baseline biopsy prior to Cycle 1 Day1, as well as an on-treatment biopsy at 12 weeks (+/- 7 days). Age ≥ 18 at time of consent ECOG performance status ≤ 2 Capable of understanding and complying with the protocol requirements and must have signed the informed consent document Minimum of 4 weeks from any other experimental anti-cancer therapies 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 Adequate organ and marrow function, based upon meeting all of the following laboratory criteria within 14 days before first dose of study treatment: Absolute neutrophil count (ANC) ≥ 1500/µL without granulocyte colony-stimulating factor (G-CSF) support White blood cell (WBC) count ≥ 2500/µL Platelets ≥ 100,000/µL without transfusion Hemoglobin ≥ 9 g/dL (≥ 90 g/L) (transfusion acceptable per investigator discretion) Alanine transaminase (ALT), AST and alkaline phosphatase (ALP) ≤ 3 x ULN. ALP ≤ 5x ULN with documented bone metastases Total bilirubin ≤ 1.5 x ULN (for subjects with Gilbert's disease ≤ 3x ULN) Serum albumin ≥ 2.8 g/dl Prothrombin (PT)/international normalized ratio (INR) or partial thromboplastin time (PTT) test < 1.3x the laboratory ULN 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 Urine protein/creatinine ratio (UPCR) ≤1 mg/mg (≤113.2 mg/mmol), or 24h urine protein ≤1 g 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. 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. In addition, females < 55 years-of-age must have a serum follicle stimulating hormone (FSH) level > 40 mIU/mL to confirm menopause. Exclusion Criteria: Prior treatment with concurrent cabozantinib/nivolumab 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 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 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 Administration of a live, attenuated vaccine within 30 days before first dose of study treatment The subject has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions: 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 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 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) Cavitating pulmonary lesion(s) or known endotracheal or endobronchial disease manifestation Lesions invading or encasing any major blood vessels Other clinically significant disorders that would preclude safe study participation 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 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 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 History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan Serious non-healing wound/ulcer/bone fracture Malabsorption syndrome Uncompensated/symptomatic hypothyroidism Moderate to severe hepatic impairment (Child-Pugh B or C). Requirement for hemodialysis or peritoneal dialysis History of solid organ or allogenic stem cell transplant Acute COVID-19 infection - clinical recovery from COVID-19 infection at least 14 days prior to enrollment allowed. 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 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. Pregnant or lactating females Inability to swallow tablets Cohort 2: Unwillingness or inability to receive intravenous (IV) administration 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 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

Ages Eligible for Study
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Minimum Age: 18 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: Cohort 1: Cabozantinib Dose Escalation<br>cabozantinib 80mg PO daily | Drug: Cabozantinib 80 MG<br>* cabozantinib 80mg daily<br>|
| Experimental: Cohort 2: cabozantinib + nivolumab<br>cabozantinib 40mg PO daily + nivolumab 480 mg IV every 4 weeks (q4w) | Drug: Cabozantinib 40Mg Tab<br>* cabozantinib 40mg daily<br>Drug: Nivolumab<br>* nivolumab 480 mg IV every 4 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival of cabozantinib or cabozantinib-nivolumab combination | Progression free survival (PFS) will be evaluated in this study using the new international criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST v 1.1) | From time of enrollment/treatment until disease progression, unacceptable toxicity, death, or discontinuation from the study treatment for any other reason up to 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective Response Rate of cabozantinib or cabozantinib-nivolumab combination | To determine the Objective Response Rate (including stable disease/partial response/complete response) of of cabozantinib or cabozantinib-nivolumab combination assessed by RECIST (version 1.1) | Follow up until disease progression, up to 24 months. | 
| Disease Control Rate of of cabozantinib or cabozantinib-nivolumab combination | To determine the disease control rate (including stable disease/partial response/complete response) of of cabozantinib or cabozantinib-nivolumab combination assessed by RECIST (version 1.1) | Follow up until disease progression, up to 24 months. | 
| Duration of response of of cabozantinib or cabozantinib-nivolumab combination | To determine the duration of response of of cabozantinib or cabozantinib-nivolumab combination compared to historical controls assessed by RECIST (version 1.1) | Follow up until disease progression, up to 24 months. | 
| Overall survival of of cabozantinib or cabozantinib-nivolumab combination | To determine the overall survival rate of response of of cabozantinib or cabozantinib-nivolumab combination compared to historical controls assessed by RECIST (version 1.1) | Follow up until death or withdrawal, up to 36 months. |