Trial of an Alternative Cabozantinib Dosing Schedule in Metastatic Renal Cell Carcinoma and Neuroendocrine Tumors

NCT05263050 | Recruiting Phase 2 DMC FDA Drug

• 2 other identifiers: 21-1020GU-187
• Study Type: interventional
• Target: 111
• Locations: 1 country
• Sites: 1

Brief Summary

This is a multi-site, three-cohort phase II trial of cabozantinib for IMDC all-risk frontline metastatic renal cell carcinoma (mRCC) patients OR any line mRCC patients who have not previously been treated with cabozantinib, and patients with pancreatic or extra-pancreatic neuroendocrine tumors.

Conditions

Carcinoid Tumor; Metastatic Renal Cell Carcinoma; Clear-cell Metastatic Renal Cell Carcinoma; Neuroendocrine Tumors

Outcome Measures

Primary Outcomes (3)

• Cohort A: Average daily dose of cabozantinib > 42.8 mg in at least 70% of patients

  To show that alternative cabozantinib dosing can improve average daily dose compared to historical controls

  2 years

• Cohort B: 75% of patients alive and progression free at 12 months

  Cohort B: To show that alternative cabozantinib dosing + nivolumab (standard dose) can improve 12-month rate of progression-free survival over standard dose cabozantinib + nivolumab

  1 year

• Cohort C: Decreased rate of grade ≥ 3 adverse events compared to 75% reported in CABINET trial

  Cohort C: To show that alternative cabozantinib dosing can improve rates of grade \> 3 adverse events compared to the grade 3-5 adverse events reported in the CABINET trial

  2 years

Secondary Outcomes (10)

• Cohort A: Decreased grade ≥ 3 adverse events compared to historical controls (METEOR trial)

  2 years

• Cohort A: Improved median duration of time on drug compared to historical controls

  2 years

• Cohort A: Objective response rate per RECIST 1.1 criteria of all patients treated

  2 years

• Cohort B: Decreased grade ≥ 3 adverse events compared to historical comparison from the CheckMate 9ER trial

  2 years

• Cohort B: Improved median duration on the drug (as defined by time from initiation of therapy to time of cessation of therapy) compared to historical comparison to the CheckMate 9ER trial

  2 years

Study Arms (2)

Cabozantinib

EXPERIMENTAL

Cabozantinib treatment will start at 40 mg of cabozantinib daily and dose escalate or de-escalate based on pre-specified criteria and at set dosing schedules to allow for smaller median dose changes between adjustments. The de-escalation would be fine-tuned and adjustments would be made in 10 mg average daily dosing increments by utilizing alternate day dosing schedules (e.g 60 mg/40 mg every other day) rather than decreasing by 20 mg. The maximum dose of cabozantinib is 60 mg daily. Cycles would be 28 days, with weekly follow-up for cycle 1 and bi-weekly follow-up for cycle 2 to allow for prompt dose adjustments, and then monthly. At each check-in, patients that have met the established protocol criteria and were not yet at the maximum dose of 60 mg daily would be eligible for dose-escalation. Patients would also be dose de-escalated as determined by the investigator. Patients who de-escalate may be allowed to re-escalate in the future.

Drug: Cabozantinib

Cabozantinib and nivolumab

EXPERIMENTAL

Cabozantinib treatment will receive monthly fix-dosed nivolumab infusions, and start at 40 mg of cabozantinib daily and dose escalate or de-escalate based on pre-specified criteria and at set dosing schedules to allow for smaller median dose changes between adjustments. The de-escalation would be fine-tuned and adjustments would be made in 10 mg average daily dosing increments by utilizing alternate day dosing schedules (e.g 60 mg/40 mg every other day) rather than decreasing by 20 mg. The maximum dose of cabozantinib is 60 mg daily. Cycles would be 28 days, with weekly follow-up for cycle 1 and bi-weekly follow-up for cycle 2 to allow for prompt dose adjustments, and then monthly. At each check-in, patients that have met established protocol criteria and were not yet at the maximum dose of 60 mg daily would be eligible for dose-escalation. Patients would also be dose de-escalated as determined by the investigator. Patients who de-escalate may be allowed to re-escalate in the future.

Drug: Cabozantinib; Drug: Nivolumab

Interventions

Cabozantinib DRUG

Cabozantinib initiated at 40 mg daily. Dose-escalate or de-escalate based on pre-specified criteria and at set dosing schedules

Also known as: XL184

Cabozantinib; Cabozantinib and nivolumab

Nivolumab DRUG

Nivolumab injection is to be administered as an IV infusion at a dose of 480 mg on day 1 of each cycle

Also known as: Opdivo

Cabozantinib and nivolumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Cohorts A and B: Histologically or cytologically confirmed advanced RCC with any clear cell or non-clear cell component. 100% sarcomatoid is permissible.
• Cohorts A and B: Patient may have had any number of prior therapies for Cohort A, but for Cohort B patients must not have received any systemic therapy in the metastatic setting
• Patients who have received prior (neo)adjuvant immunotherapy with pembrolizumab or similar are eligible for Cohort B IF they completed the adjuvant therapy \> 12 months from start of trial therapy
• Treatment naïve patients may be treated in Cohort A if deemed not candidates for nivolumab or if felt single agent cabozantinib most appropriate by the treating clinician
• Cohort C: Well differentiated NET, grades 1-3 (any primary site) who have progressed on or are not eligible for somatostatin analogs per treating physician discretion
• Cohort C: Disease progression within prior 12 months
• Cohort C: Prior or concurrent treatment with somatostatin analogue allowed but no limit on lines of therapy (stable dose of somatostatin for 2 months)
• All Cohorts:
• At least one measurable lesion as defined by RECIST version 1.1
• No evidence of pre-existing uncontrolled hypertension as assessed by investigator. Patients may undergo adjustments or additions to their antihypertensive regimen before or during screening to achieve optimal BP control.
• Age \> 18 years.
• ECOG performance status 0 - 2
• Patients must have normal organ and marrow function as defined below
• Leukocytes, \> 2,000/mcL
• Absolute neutrophil count, \> 1,500/mcL

You may not qualify if:

• Patients who have had systemic anti-cancer therapy or radiotherapy within 14 days or five half-lives, whichever is shorter, prior to entering the study.
• Radiation therapy for bone metastases within 2 weeks, any other radiation therapy within 4 weeks, or systemic treatment with radionuclides within 6 weeks before first dose of study treatment. Ongoing clinically relevant complications from prior radiation therapy would preclude eligibility.
• Patients with prior therapy with cabozantinib.
• Prior systemic therapy directed at advanced RCC is not allowed for patients enrolled to Cohort B (treatment-naïve group).
• Cohort B only: Active, known or suspected autoimmune disease. Subjects are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger
• Cohort B only: Patients have a condition requiring systemic treatment with either corticosteroids (\> 10 mg daily prednisone or equivalent) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses \> 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
• Patients may not be receiving any other investigational agents
• History of allergic reactions or hypersensitivity attributed to compound of similar chemical or biologic composition to the agent(s) used in this study
• Current use or anticipated need for treatment with drugs or foods that are known strong CYP3A4 inhibitors and inducers. Refer to Section 5.3.2 for detailed information. The topical use of these medications (if applicable), such as 2% ketoconazole cream, is allowed.
• 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:
• Prophylactic use of low-dose aspirin for cardio-protection (per local applicable guidelines) and low-dose low molecular weight heparins (LMWH).
• 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.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Cardiovascular disorders:
• Congestive heart failure New York Heart Association Class 3 or 4, unstable angina pectoris, serious cardiac arrhythmias.

Sponsors & Collaborators

• Fox Chase Cancer Center: lead
• Exelixis: collaborator

Study Sites (1)

Fox Chase Cancer Center

Philadelphia, Pennsylvania, 19111, United States

RECRUITING

MeSH Terms

Conditions

Carcinoma, Renal Cell; Clear-cell metastatic renal cell carcinoma; Neuroendocrine Tumors; Carcinoid Tumor

Interventions

cabozantinib; Nivolumab

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Kidney Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Kidney Diseases; Urologic Diseases; Male Urogenital Diseases; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Matthew Zibelman, MD

  Fox Chase Cancer Center

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Ryan Romasko, MBA

CONTACT

215-728-4097; ryan.romasko@fccc.edu

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Patients will start at 40 mg of cabozantinib daily and dose escalate or de-escalate based on pre-specified criteria and at set dosing schedules to allow for smaller median dose changes between adjustments. Patients in cohorts A and C will be treated with the same cabozantinib alternative dosing schema and schedule, with the exception of Cohort B patients also receiving monthly fix-dosed nivolumab infusions.

Study Record Dates

• First Submitted: February 21, 2022
• First Posted: March 2, 2022
• Study Start: January 21, 2022
• Primary Completion: February 1, 2026
• Study Completion (Estimated): February 1, 2027
• Last Updated: December 3, 2025

Record last verified: 2025-12

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)