Randomized Study of Nivolumab+Ipilimumab+/- SBRT for Metastatic Merkel Cell Carcinoma

• ClinicalTrials.gov Identifier: NCT03071406
• Recruitment Status: Active, not recruiting
• First Posted: March 6, 2017
• Results First Posted: May 19, 2023
• Last Update Posted: February 20, 2024
• Sponsor: H. Lee Moffitt Cancer Center and Research Institute
• Collaborator: Bristol-Myers Squibb
• Information provided by (Responsible Party): H. Lee Moffitt Cancer Center and Research Institute

Tracking Information

• First Submitted Date: March 1, 2017
• First Posted Date: March 6, 2017
• Results First Submitted Date: April 3, 2023
• Results First Posted Date: May 19, 2023
• Last Update Posted Date: February 20, 2024
• Actual Study Start Date: March 14, 2017
• Actual Primary Completion Date: April 6, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 6, 2023)

Best Overall Response [ Time Frame: Up to 18 months ]

Overall response according to Immunotherapy Response Evaluation Criteria in Solid Tumors (iRECIST) including Complete Response (CR) + Partial Response (PR).

Original Primary Outcome Measures (submitted: March 1, 2017)

Overall Response Rate [ Time Frame: 24 weeks ]

Objective-response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1: including Complete Response (CR) rate, Partial Response (PR) rate, and Stable Disease (SD) rate will be calculated through exact binomial distribution with a 2-sided 95% confidence interval among patients who obtain a least one dose of study drug.

Current Secondary Outcome Measures (submitted: April 6, 2023)

• Progression Free Survival (PFS) [ Time Frame: up to 28 months ]
  Median Progression Free Survival with 95% Confidence Interval. Progression is defined as progressive tumor lesions per immune-related Response Evaluation in Solid Tumors (irRECIST) definition, or appearance of one or more new Merkel cell carcinoma lesions, which can be local or distant in location from the irradiated lesions.
• Overall Survival (OS) [ Time Frame: Up to 30 months ]
  Median Overall Survival with 95% Confidence Interval. The length of time from the start of treatment until death from any cause.

Original Secondary Outcome Measures (submitted: March 1, 2017)

• Progression Free Survival (PFS) [ Time Frame: 36 months ]
  Median Progression Free Survival with 95% Confidence Interval. Progression is defined as progressive tumor lesions per immune-related Response Evaluation in Solid Tumors (irRECIST) definition, or appearance of one or more new Merkel cell carcinoma lesions, which can be local or distant in location from the irradiated lesions.
• Overall Survival (OS) [ Time Frame: 24 months ]
  Median Overall Survival with 95% Confidence Interval. The length of time from the start of treatment until death from any cause.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Randomized Study of Nivolumab+Ipilimumab+/- SBRT for Metastatic Merkel Cell Carcinoma
• Official Title: A Phase 2, Randomized, Multi-institutional Study of Nivolumab and Ipilimumab Versus Nivolumab, Ipilimumab and Stereotactic Body Radiation Therapy for Metastatic Merkel Cell Carcinoma
• Brief Summary: The purpose of this study is to test the effectiveness, safety, and tolerability of the drugs nivolumab plus ipilimumab with or without the addition of stereotactic body radiation therapy (SBRT). Nivolumab is an antibody (a type of human protein) that is being tested to see if it will stimulate the body's immune system to work against tumor cells. This study will test an investigational use of nivolumab.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

Participants are randomly assigned in a 1:1 ratio to Arm A (nivolumab + ipilimumab), or Arm B (nivolumab + ipilimumab + SBRT).

Masking: None (Open Label)
Primary Purpose: Treatment

Condition

• Merkel Cell Carcinoma
• Skin Cancer

Intervention

• Drug: Nivolumab
  Nivolumab 240 mg/dose intravenously (IV) every 2 (q2) weeks.
  Other Name: OPDIVO
• Drug: Ipilimumab
  Ipilimumab 1 mg/kg/dose IV q6 weeks.
  Other Name: YERVOY
• Radiation: Stereotactic Body Radiation Therapy (SBRT)
  Stereotactic Body Radiation Therapy 24Gy in 3 fractions.
  Other Name: SBRT

Study Arms

• Active Comparator: Arm A: Nivolumab + Ipilimumab
  Nivolumab every 2 weeks and Ipilimumab every 6 weeks until progression or unacceptable toxicity.
  Interventions:

  • Drug: Nivolumab
  • Drug: Ipilimumab
• Active Comparator: Arm B: Nivolumab + Ipilimumab + SBRT
  Nivolumab every 2 weeks and Ipilimumab every 6 weeks until progression or unacceptable toxicity. Stereotactic Body Radiation Therapy (SBRT) to be given at the start of week 2.
  Interventions:

  • Drug: Nivolumab
  • Drug: Ipilimumab
  • Radiation: Stereotactic Body Radiation Therapy (SBRT)

• Publications *: Kim S, Wuthrick E, Blakaj D, Eroglu Z, Verschraegen C, Thapa R, Mills M, Dibs K, Liveringhouse C, Russell J, Caudell JJ, Tarhini A, Markowitz J, Kendra K, Wu R, Chen DT, Berglund A, Michael L, Aoki M, Wang MH, Hamaidi I, Cheng P, de la Iglesia J, Slebos RJ, Chung CH, Knepper TC, Moran-Segura CM, Nguyen JV, Perez BA, Rose T, Harrison L, Messina JL, Sondak VK, Tsai KY, Khushalani NI, Brohl AS. Combined nivolumab and ipilimumab with or without stereotactic body radiation therapy for advanced Merkel cell carcinoma: a randomised, open label, phase 2 trial. Lancet. 2022 Sep 24;400(10357):1008-1019. doi: 10.1016/S0140-6736(22)01659-2. Epub 2022 Sep 12.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: March 1, 2017): 50
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: July 2024
• Actual Primary Completion Date: April 6, 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• At least 18 years of age
• Eastern Cooperative Oncology Group (ECOG) Performance Status less than 2
• Active disease measurable by CT, MRI or clinical exam.
• Prior chemotherapy or immunotherapy will be allowed if new or persistent measurable site(s) of disease are present.
• Prior radiation therapy will be allowed if there is active measurable disease burden.
• Must be either recurrent, unresectable or Stage IV American Joint Committee on Cancer (AJCC) (7th edition) and have histologically confirmed Merkel cell carcinoma with at least 2 distinct lesions in order to be eligible.
• Must have at least 2 distinct lesions as documented by a complete physical examination or imaging studies within 4 weeks prior to randomization. Imaging studies must include a diagnostic CT scan of the involved disease sites and all known sites of resected disease and brain magnetic resonance (MRI) or CT (brain CT allowable if MRI is contraindicated or if there is no known history of resected brain lesions).
• Tumor tissue from the core biopsy or resected site of disease must be provided for biomarker analyses.

Exclusion Criteria:

• History of Grade 3 toxicity or use of infliximab with prior immunotherapy
• Patients with active brain metastasis.
• Active, known, or suspected autoimmune disease. Potential participants with type I diabetes mellitus, residual hypothyroidism due to autoimmune thyroiditis only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment are permitted to enroll.
• Patients with prior history of non-Merkel cell carcinoma malignancies are excluded except adequately treated basal cell, squamous cell skin cancer, chronic lymphocytic leukemia or other indolent diseases not requiring therapy; adequately treated, with curative intent, cancer from which the patient is currently in complete remission per investigator's judgment; or patients with history of breast cancer and no evidence of disease on hormonal therapy to prevent recurrence and patients with prostate cancer on adjuvant hormonal therapy with undetectable PSA are eligible.
• A condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of randomization. Inhaled or topical steroids are permitted in the absence of active autoimmune disease.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03071406
• Other Study ID Numbers: MCC-18786; CA209-737 ( Other Identifier: Bristol-Myers Squibb )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: H. Lee Moffitt Cancer Center and Research Institute
• Original Responsible Party: Same as current
• Current Study Sponsor: H. Lee Moffitt Cancer Center and Research Institute
• Original Study Sponsor: Same as current
• Collaborators: Bristol-Myers Squibb

Investigators

• Principal Investigator: Evan Wuthrick, M.D; H. Lee Moffitt Cancer Center and Research Institute

• PRS Account: H. Lee Moffitt Cancer Center and Research Institute
• Verification Date: February 2024