Nivolumab/Ipilimumab Plus Cabozantinib in Patients With Unresectable Advanced Melanoma

• ClinicalTrials.gov Identifier: NCT04091750
• Recruitment Status: Recruiting
• First Posted: September 17, 2019
• Last Update Posted: December 7, 2020
• Sponsor: Georgetown University
• Collaborators: MedStar Franklin Square Medical Center; Hackensack Meridian Health; Exelixis
• Information provided by (Responsible Party): Georgetown University

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Melanoma	Drug: Nivolumab; Drug: Ipilimumab; Drug: Cabozantinib	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 27 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Study of Nivolumab/Ipilimumab Plus Cabozantinib in Patients With Unresectable Advanced Melanoma
• Actual Study Start Date: March 2, 2020
• Estimated Primary Completion Date: March 2022
• Estimated Study Completion Date: March 2023

Arms and Interventions

Arm

Intervention/treatment

Experimental: Single Arm; Induction phase: Nivolumab 3mg/kg IV plus Ipilimumab 1mg/kg IV every 3 weeks x 4 cycles (12 week period) Cabozantinib 40mg PO daily for 12 weeks Maintenance phase: 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 Name: Opdivo; Drug: Ipilimumab; Induction: 1mg/kg IV every 3 weeks x 4 cycles; Other Name: Yervoy; Drug: Cabozantinib; Induction and Maintenance: 40mg PO daily; Other Name: Cabometyx

Outcome Measures

Primary Outcome Measures :

1. The progression free survival (PFS) for nivolumab/ipilimumab plus cabozantinib in patients with unresectable advanced melanoma. [ Time Frame: 1 year ]
   The PFS rate for nivolumab/ipilimumab plus cabozantinib in patients with unresectable advanced melanoma using imRECIST.

Secondary Outcome Measures :

1. The response rate of nivolumab/ipilimumab plus cabozantinib in patients with unresectable advanced melanoma. [ Time Frame: 1 year ]
   The ORR by imRECIST of nivolumab/ipilimumab plus cabozantinib in patients with unresectable advanced melanoma.
2. The overall survival (OS) of patients with unresectable advanced melanoma treated with nivolumab/ipilimumab plus cabozantinib. [ Time Frame: 3 years ]
   The median and 3 year OS rate of patients with unresectable advanced melanoma treated with nivolumab/ipilimumab plus cabozantinib.
3. The incidence of treatment-emergent adverse events of nivolumab/ipilimumab plus cabozantinib in patients with unresectable advanced melanoma. [ Time Frame: 2 years ]
   The rate of all grade and grade 3-5 adverse events and the rate of discontinuation of study drug(s) due to adverse events.

Other Outcome Measures:

1. 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. [ Time Frame: 3 years ]
   Measured in terms of ORR, PFS, and OS.
2. 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. [ Time Frame: 3 years ]
   Measured in terms of ORR, PFS, and OS.
3. On treatment biopsy for evidence of increased immune infiltration, vascularization, and MHC expression to nivolumab/ipilimumab plus cabozantinib in patients with unresectable advanced melanoma. [ Time Frame: 1 year ]
   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.

Eligibility Criteria

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

Criteria

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.

Contacts and Locations

Contacts

Contact: Gayle Cramer, RN, MHS; 202-687-1116; gc604@georgetown.edu

Locations

United States, District of Columbia

Lombardi Comprehensive Cancer Center; Recruiting

Washington, District of Columbia, United States, 20007

Contact: Gayle Cramer, RN, MHS 202-687-1116 gc604@georgetown.edu

United States, Maryland

Medstar Franklin Square Medical Center, Harry and Jeanette Weinberg Cancer Institute; Recruiting

Baltimore, Maryland, United States, 21237

Contact: Amy Avergas 443-777-8876 amy.m.avergas@medstar.net

United States, New Jersey

John Theurer Cancer Center at Hackensack University Medical Center; Recruiting

Hackensack, New Jersey, United States, 07601

Contact: Danielle Blair 551-996-5809 danielle.blair@hackensackmeridian.org

Sponsors and Collaborators

Georgetown University

MedStar Franklin Square Medical Center

Hackensack Meridian Health

Exelixis

Investigators

• Principal Investigator: Geoffrey T Gibney, MD; MedStar Georgetown University Hospital

More Information

• Responsible Party: Georgetown University
• ClinicalTrials.gov Identifier: NCT04091750
• Other Study ID Numbers: STUDY00000904
• First Posted: September 17, 2019
• Last Update Posted: December 7, 2020
• Last Verified: December 2020

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Georgetown University:

melanoma

Additional relevant MeSH terms:

Melanoma; Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Nivolumab; Ipilimumab; Antineoplastic Agents, Immunological; Antineoplastic Agents