Nivolumab/Ipilimumab Plus Cabozantinib in Patients With Unresectable Advanced Melanoma

Phase II Study of Nivolumab/Ipilimumab Plus Cabozantinib in Patients With Unresectable Advanced Melanoma

In this phase II advanced melanoma study, all patients will receive treatment with nivolumab/ipilimumab plus cabozantinib for a 12 week induction period followed by nivolumab plus cabozantinib maintanence to complete up to 2 years of therapy unless disease progression, dose limiting toxicity, provider/patient decision or patient withdrawal of consent occurs. The primary endpoint is the one year PFS rate. Patients will have staging scans at baseline and every 12 weeks during the first 2 years on study. Safety evaluations including labs, EKG and history and physical will occur at each visit. Baseline tumor sample is required and on treatment biopsy will be optional of superficial tumor in the skin, subcutaneous tissue or lymph node that is palpable.

Study Overview

• Status: Active, not recruiting
• Conditions: Melanoma
• Intervention / Treatment: Drug: Nivolumab; Drug: Ipilimumab; Drug: Cabozantinib

Detailed Description

Subjects will receive nivolumab, ipilimumab and cabozantinib until either disease progression, the occurrence of unacceptable drug-related toxicity or for other reason(s) for subject withdrawal. Treatment will continue for up to 2 years unless there is disease progression, drug intolerance or other reason for discontinuation discussed with the principal investigator (PI). Patients with ongoing complete or partial response may discontinue therapy after 1 year on treatment at the discretion of the treating investigator.

• Study Type: Interventional
• Enrollment (Actual): 14
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • District of Columbia
    • Washington D.C., District of Columbia, United States, 20007
      • Lombardi Comprehensive Cancer Center
  • Maryland
    • Baltimore, Maryland, United States, 21237
      • Medstar Franklin Square Medical Center, Harry and Jeanette Weinberg Cancer Institute
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • John Theurer Cancer Center at Hackensack University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. All patients must have unresectable stage IIIb-IIId or IV melanoma by AJCC 8th edition. Note: Patients with uveal melanoma are excluded from this study.
2. Age > 18 and ECOG Performance Status of 0 or 1.
3. Measurable disease by RECIST 1.1
4. Baseline tumor specimen available.
5. Recovery to baseline or ≤ Grade 1 CTCAE v4 from toxicities related to any prior treatments, unless AE(s) are clinically nonsignificant and/or stable on supportive therapy.
6. Adequate organ and marrow function.
7. Capable of understanding and complying with the protocol requirements and must have signed the informed consent document.
8. Sexually active fertile subjects and their partners must agree to use medically accepted methods of contraception (eg, 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 study treatment.
9. Female subjects of childbearing potential must not be pregnant at screening.

Exclusion Criteria:

1. Prior treatment with anti-PD-1/PD-L1 therapy, anti-CTLA-4 therapy or cabozantinib. Prior adjuvant anti-PD-1 and/or anti-CTLA-4 therapy is allowed if relapse is greater than 6 months from last dose.
2. Receipt of any type of small molecule kinase inhibitor (including investigational kinase inhibitor) within 2 weeks before first dose of study treatment.
3. Receipt of any type of cytotoxic, biologic or other systemic anticancer therapy (including investigational) within 4 weeks before first dose of study treatment.
4. Radiation therapy for bone metastasis or brain metastasis within 2 weeks, any other radiation therapy within 4 weeks before first dose of study treatment. Systemic treatment with radionuclides within 6 weeks before the first dose of study treatment.
5. Known brain metastases that are >10mm or cranial epidural disease unless adequately treated with radiosurgery and/or surgery (including radiosurgery). Eligible subjects must be neurologically asymptomatic and without corticosteroid requirement. Dexamethasone < 2mg daily (or equivalent) will be allowed if discontinuation of corticosteroids is not feasible due to post-radiation effects and patient is asymptomatic. Patients with active, asymptomatic brain metastases that are <10mm and no corticosteroid requirement will be allowed without radiosurgery or surgery.
6. History of active autoimmune disorder requiring immunosuppressive agents. Patients with autoimmune disorders considered low risk, such as vitiligo and thyroiditis, will be allowed.

7. Concomitant anticoagulation with coumarin agents (e.g., warfarin), direct thrombin inhibitors (e.g. dabigatran), betrixaban, or platelet inhibitors (eg, 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) are permitted.
   2. Anticoagulation with therapeutic doses of LMWH or anticoagulation with direct factor Xa inhibitors rivaroxaban, edoxaban, or apixaban is allowed in subjects without known brain metastases who are on a stable dose of LMWH anticoagulant for at least 6 weeks 1week before first dose of study treatment, and who have had no clinically significant hemorrhagic complications from the anticoagulation regimen or the tumor.
8. The subject has prothrombin time (PT)/INR or partial thromboplastin time (PTT) test ≥ 1.3 x the laboratory ULN within 7 days before the first dose of study treatment.
9. The subject has uncontrolled, significant intercurrent or recent illness.
10. Major surgery (eg, GI surgery, removal or biopsy of brain metastasis) within 8 weeks before first dose of study treatment.
11. Corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms per electrocardiogram (ECG) within 28 days before first dose of study treatment.
12. Pregnant or lactating females.
13. Inability to swallow tablets.
14. Previously identified allergy or hypersensitivity to components of the study treatment formulations.
15. Diagnosis of another malignancy within 2 years before first dose of study treatment, except for superficial skin cancers, or localized, low grade tumors deemed cured and not treated with systemic therapy.
16. Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Single Arm; Nivolumab 3mg/kg IV plus Ipilimumab 1mg/kg IV every 3 weeks x 4 cycles with Cabozantinib 40mg PO daily for 12 weeks (Induction); Followed by Maintenance therapy: Nivolumab 480mg IV every 4 weeks for up to 92 weeks; Cabozantinib 40mg PO daily for up to 92 weeks; Maintenance therapy will continue for up to 92 weeks to complete 2 years total of treatment if tolerating therapy well and disease is controlled.

Drug: Nivolumab; Induction: 3mg/kg IV every 3 weeks x 4 cycles Maintenance: 480mg IV every 4 weeks for up to 92 weeks; Other Names: Opdivo; Drug: Ipilimumab; Induction: 1mg/kg IV every 3 weeks x 4 cycles; Other Names: Yervoy; Drug: Cabozantinib; Induction and Maintenance: 40mg PO daily; Other Names: Cabometyx

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Progression Free Survival (PFS) for Nivolumab/Ipilimumab Plus Cabozantinib in Patients With Unresectable Advanced Melanoma.	The PFS rate for nivolumab/ipilimumab plus cabozantinib in patients with unresectable advanced melanoma using imRECIST.	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Response Rate of Nivolumab/Ipilimumab Plus Cabozantinib in Patients With Unresectable Advanced Melanoma.	The ORR by imRECIST of nivolumab/ipilimumab plus cabozantinib in patients with unresectable advanced melanoma.	1 year
The Overall Survival (OS) of Patients With Unresectable Advanced Melanoma Treated With Nivolumab/Ipilimumab Plus Cabozantinib.	The median and 3 year OS rate of patients with unresectable advanced melanoma treated with nivolumab/ipilimumab plus cabozantinib.	3 years
The Incidence of Treatment-emergent Adverse Events of Nivolumab/Ipilimumab Plus Cabozantinib in Patients With Unresectable Advanced Melanoma.	The rate of all grade and grade 3-5 adverse events and the rate of discontinuation of study drug(s) due to adverse events.	2 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Associations Between Baseline Tumor Mutational Burden (TMB), Angiogenesis Pathways, and Immunophenotyping With Clinical Activity of Nivolumab/Ipilimumab Plus Cabozantinib in Patients With Unresectable Advanced Melanoma.	Measured in terms of ORR, PFS, and OS.	3 years
Associations Between Baseline Mutations in Genes Regulating Anti-tumor Immunity With Tumor Immunophenotype and Clinical Activity of Nivolumab/Ipilimumab Plus Cabozantinib in Patients With Unresectable Advanced Melanoma.	Measured in terms of ORR, PFS, and OS.	3 years
On Treatment Biopsy for Evidence of Increased Immune Infiltration, Vascularization, and MHC Expression to Nivolumab/Ipilimumab Plus Cabozantinib in Patients With Unresectable Advanced Melanoma.	Measured by the change in immune cell populations, CD31 vascularization, and MHC class I expression by multiplex immunofluorescense (IF) between baseline and on treatment tumor specimens.	1 year

Collaborators and Investigators

• Sponsor: Georgetown University
• Collaborators: Exelixis; Hackensack Meridian Health; MedStar Franklin Square Medical Center
• Investigators: Principal Investigator: Geoffrey T Gibney, MD, MedStar Georgetown University Hospital

Study record dates

Study Major Dates

• Study Start (Actual): March 2, 2020
• Primary Completion (Actual): August 8, 2023
• Study Completion (Estimated): December 1, 2026

Study Registration Dates

• First Submitted: September 13, 2019
• First Submitted That Met QC Criteria: September 13, 2019
• First Posted (Actual): September 17, 2019

Study Record Updates

• Last Update Posted (Actual): March 3, 2026
• Last Update Submitted That Met QC Criteria: February 10, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: melanoma
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Skin Diseases; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Skin Neoplasms; Skin and Connective Tissue Diseases; Melanoma; Amino Acids, Peptides, and Proteins; Proteins; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Nivolumab; Ipilimumab; cabozantinib
• Other Study ID Numbers: STUDY00000904

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No