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Nivolumab/Ipilimumab Plus Cabozantinib in Patients With Unresectable Advanced Melanoma

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ClinicalTrials.gov Identifier: NCT04091750
Recruitment Status : Not yet recruiting
First Posted : September 17, 2019
Last Update Posted : November 13, 2019
Sponsor:
Collaborators:
MedStar Franklin Square Medical Center
Hackensack Meridian Health
Exelixis
Information provided by (Responsible Party):
Georgetown University

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 27 participants
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
Estimated Study Start Date : December 2019
Estimated Primary Completion Date : March 2022
Estimated Study Completion Date : March 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Melanoma

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




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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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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.
  2. Age > 18 and ECOG Performance Status of 0 or 1.
  3. Measurable disease by RECIST 1.1 and a tumor site amenable for on treatment biopsy.
  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 oral anticoagulants (eg, warfarin, direct thrombin and Factor Xa inhibitors) or platelet inhibitors (eg, clopidogrel).

    Allowed anticoagulants are the following:

    1. Low-dose aspirin for cardioprotection (per local applicable guidelines) is permitted.
    2. Low-dose low molecular weight heparins (LMWH) are permitted.
    3. Anticoagulation with therapeutic doses of LMWH is allowed in subjects without known brain metastases who are on a stable dose of LMWH for at least 6 weeks 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04091750


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

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

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Responsible Party: Georgetown University
ClinicalTrials.gov Identifier: NCT04091750     History of Changes
Other Study ID Numbers: IST83
First Posted: September 17, 2019    Key Record Dates
Last Update Posted: November 13, 2019
Last Verified: November 2019

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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:
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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