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Yttrium90, Ipilimumab, & Nivolumab for Uveal Melanoma With Liver Metastases

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ClinicalTrials.gov Identifier: NCT02913417
Recruitment Status : Recruiting
First Posted : September 23, 2016
Last Update Posted : May 1, 2019
Sponsor:
Collaborators:
California Pacific Medical Center
Jefferson Medical College of Thomas Jefferson University
University of Chicago
Information provided by (Responsible Party):
David Minor, MD, California Pacific Medical Center Research Institute

Brief Summary:
Reports to date show limited efficacy of immunotherapy for uveal melanoma. Recent experimental and clinical evidence suggests synergy between radiation therapy and immunotherapy. The investigators will explore this synergy with a feasibility study of 26 patients with uveal melanoma and hepatic metastases who will receive SirSpheres Yttrium-90 selective internal hepatic radiation followed by immunotherapy with the combination of ipilimumab and nivolumab.

Condition or disease Intervention/treatment Phase
Uveal Melanoma Hepatic Metastases Device: SIR-Spheres® Yttrium 90 Drug: ipilimumab Drug: nivolumab Phase 1 Phase 2

Detailed Description:

Despite rapid improvements in the treatment of cutaneous melanoma, there has been little advance in therapy for uveal melanoma with hepatic metastases, an fatal orphan disease with no established therapy. Studies by Dr. Sato and others have described some activity for selective internal radiation with Yttrium90 microspheres (SIR-Spheres).There is limited activity as single agents for both the immunotherapy drugs ipilimumab (anti-CTLA-4) and nivolumab (anti-PD-1). In cutaneous melanoma the combination of ipilimumab and nivolumab is clearly synergistic with improvement in response rates and progression-free survival over single agents; however this has yet to be established for uveal melanoma.

Recent experimental and clinical evidence suggests additional synergy between radiation therapy and immunotherapy. This synergy seems most evident when radiation is given through large fraction stereotactic treatments or brachytherapy. The investigators will explore this synergy with a feasibility study of 18 patients who will receive SirSpheres Yttrium-90 selective internal radiation given through the hepatic artery in two treatments followed by immunotherapy with the combination of ipilimumab and nivolumab. The immunotherapy will be given with the dose and schedule that has been established and FDA-approved for cutaneous melanoma. Because of the generally low toxicity of Yttrium-90 selective internal radiation therapy the investigators feel it can be given in full dosage prior to full dosage of immunotherapy.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 26 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Feasibility Study of Sequential Hepatic Internal Radiation and Systemic Ipilimumab and Nivolumab in Patients With Uveal Melanoma Metastatic to Liver.
Study Start Date : October 2016
Estimated Primary Completion Date : January 2020
Estimated Study Completion Date : June 2021


Arm Intervention/treatment
Experimental: hepatic radiation followed by immunotherapy
SIR-Spheres Yttrium 90 will be given by injection into the hepatic artery in two treatments, one for each lobe. 3-5 weeks later patients receive concurrent ipilimumab 1mg/kg q 3 wk x 4 and nivolumab 1mg/kg q 3 weeks x 4, all followed by nivolumab 3mg/kg q 2 weeks until progression or 3 years
Device: SIR-Spheres® Yttrium 90
Patient treatment will consist of three parts: first, selective internal radiation with SIR-Spheres Yttrium-90 microspheres with dosage per package insert reduced to give 35cGymax to normal liver; second, concurrent ipilimumab 1mg/kg and nivolumab 1mg/kg every 3 weeks for 4 doses (immunotherapy part 1); then maintenance nivolumab at 3mg/kg every 2 weeks (immunotherapy part 2) until progression or 3 years

Drug: ipilimumab
ipilimumab 1mg/kg every 3 weeks x 4
Other Name: Yervoy

Drug: nivolumab
nivolumab 1mg/kg every 3 weeks x 4 then 240mg q 2 weeks
Other Name: Opdivo




Primary Outcome Measures :
  1. safety and tolerability of sequential selective internal radiation with Yttrium90 followed by immunotherapy with ipilimumab and nivolumab. [ Time Frame: 3 years ]
    Determine the safety and tolerability of sequential selective internal radiation with Y90 followed by immunotherapy with ipilimumab and nivolumab in patients with uveal melanoma metastatic to the liver. Endpoints are CTAE determined grade 3-5 toxicities.


Secondary Outcome Measures :
  1. Preliminary clinical efficacy [ Time Frame: 2 years ]
    co-endpoints for this measure will be RECIST response rate and PFS

  2. immunological changes [ Time Frame: 2 years ]
    Changes in peripheral blood lymphocyte counts

  3. Correlation of tissue markers and response to immunotherapy [ Time Frame: 2 years ]
    Study of archival tumor tissue for tumor mutations, PDL-1, PDL-2, others

  4. Explore relationship of response to immunotherapy with tumor melanin [ Time Frame: 2 years ]
    Correlate response with tumor production of melanin assessed by tumor density on MRI scans



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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. Histologic diagnosis of metastatic uveal melanoma.
  2. Patients must have measurable disease as defined by RECIST (see Section 6).
  3. Patients must have liver metastasis
  4. Patients must have no more than one prior systemic therapeutic regimen. This includes chemotherapy, biologic therapy, biochemotherapy, or investigational treatment. This does not include any therapies given in the adjuvant setting. No prior anti-CTLA4 therapy. Prior anti PD-1 or anti-PDL-1 antibody therapy is acceptable.
  5. No concomitant therapy with any of the following: IL-2, interferon or other non-study immunotherapy regimens; cytotoxic chemotherapy; immunosuppressive agents; other investigation therapies; or chronic use of systemic corticosteroids.
  6. Patients with prior selective internal radiation are candidates are eligible as long as they are candidates for repeat procedures and they have demonstrated progressive disease.
  7. Age ≥ 18 years.
  8. No known infection with HIV. Due to the mechanism of action of ipilimumab, activity and side effects in an immune compromised patient are unknown.
  9. No active infection with Hepatitis B.
  10. No active infection with Hepatitis C.
  11. ECOG performance status 0 or 1.
  12. Women must not be pregnant or breast-feeding due to unknown effects of treatments on the unborn fetus. All women of childbearing potential must have a blood test within 72 hours prior to randomization to rule out pregnancy. Women of childbearing potential and sexually active males must be strongly advised to use an accepted and effective method of contraception. Women of childbearing potential (WOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study and for up to 12 weeks after the last dose of investigational product, in such a manner that the risk of pregnancy is minimized. Sexually mature females who have not undergone a hysterectomy or who have not been postmenopausal naturally for at least 24 consecutive months (i.e., who have had menses at some time in the preceding 24 consecutive months) are considered to be of childbearing potential. Women who are using oral contraceptives, other hormonal contraceptives (vaginal products, skin patches, or implanted or injectable products), or mechanical products such as an intrauterine device or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy, or are practicing abstinence or where their partner is sterile (e.g.,vasectomy) should be considered to be of childbearing potential.
  13. Patients must have the following lab values obtained < 4 weeks prior to starting treatment:

    • WBC ≥2000/uL
    • ANC ≥1500/mcL
    • Platelets ≥ 100,000/mcL
    • Hemoglobin ≥ 8g/dL
    • Creatinine ≤ 3.0 xULN
    • AST and ALT < 2.5 x ULN
    • Bilirubin ≤ 2.0 x ULN, (except patients with Gilbert's Syndrome, who must have a total bilirubin less than 3.0 mg/dL)
    • Albumin ≥ 3g/dL

Exclusion Criteria

  1. Patients are excluded if they have liver tumor volume > 50%
  2. Patients are excluded if they have active CNS metastases. Patients with history of CNS metastases must have MRI scans that show stability of brain metastases for 8 weeks.
  3. Patients are excluded if they have a history of any other malignancy from which the patient has been disease-free for less than 2 years, with the exception of adequately treated and cured basal or squamous cell skin cancer, superficial bladder cancer or carcinoma in situ of the cervix, or stage 1 or 2 cutaneous melanoma
  4. Patients are excluded if they have a history of autoimmune disease, as follows: Patients with a history of inflammatory bowel disease are excluded from this study as are patients with a history of symptomatic disease (e.g., rheumatoid arthritis, systemic progressive sclerosis [scleroderma], Systemic Lupus Erythematosus, autoimmune vasculitis [e.g., Wegener's Granulomatosis]). Patients with a history of Guillain-Barre Syndrome are excluded but myasthenia gravis or psoriasis is acceptable.
  5. Patients are excluded for any underlying medical or psychiatric condition which, in the opinion of the investigator, will make treatment hazardous or obscure the interpretation of adverse events, such as a condition associated with frequent diarrhea.
  6. Patients are excluded if they have a history of prior treatment with ipilimumab or CTLA-4 inhibitor.
  7. Patients are excluded if they have any concurrent medical condition requiring the use of systemic steroids (the use of inhaled or topical steroids is permitted).
  8. Patients are excluded if they have had prior hepatic arterial embolization therapy

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): NCT02913417


Contacts
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Contact: Kevin B Kim, M.D. 415-885-8600 KimKB@sutterhealth.org
Contact: Laurel Brechtel 415-600-1654 brechtelLA@cpmcri.org

Locations
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United States, California
California Pacific Medical Center Recruiting
San Francisco, California, United States, 94115
Contact: Kevin B Kim, MD    415-885-8600    KimKB@sutterhealth.org   
Contact: Joni Beemsterboer    4156003967    beemj@cpmcri.org   
Principal Investigator: Kevin B Kim, MD         
United States, Illinois
University of Chicago Active, not recruiting
Chicago, Illinois, United States, 60637
United States, Pennsylvania
Jefferson Medical College of Thomas Jefferson University Recruiting
Philadelphia, Pennsylvania, United States, 19107
Contact: Takami Sato, M.D., Ph.D.    215-955-8875    takami.sato@jefferson.edu   
Principal Investigator: Takami Sato, M.D., Ph.D.         
Sponsors and Collaborators
David Minor, MD
California Pacific Medical Center
Jefferson Medical College of Thomas Jefferson University
University of Chicago
Investigators
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Study Chair: David R. Minor, M.D. California Pacific Medical Center Research Institute

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Responsible Party: David Minor, MD, Associate Director Melanoma Center, California Pacific Medical Center Research Institute
ClinicalTrials.gov Identifier: NCT02913417     History of Changes
Other Study ID Numbers: Uveal Melanoma IIP
First Posted: September 23, 2016    Key Record Dates
Last Update Posted: May 1, 2019
Last Verified: April 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Keywords provided by David Minor, MD, California Pacific Medical Center Research Institute:
uveal melanoma
liver metastases

Additional relevant MeSH terms:
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Melanoma
Neoplasm Metastasis
Uveal Neoplasms
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas
Neoplastic Processes
Pathologic Processes
Eye Neoplasms
Neoplasms by Site
Eye Diseases
Uveal Diseases
Nivolumab
Ipilimumab
Antineoplastic Agents, Immunological
Antineoplastic Agents