Nivolumab and Ipilimumab with or without Stereotactic Body Radiation Therapy in Treating Patients with Recurrent or Stage IV Merkel Cell Cancer
This randomized phase II trial studies how well nivolumab and ipilimumab with or without stereotactic body radiation therapy work in treating patients with Merkel cell cancer that has come back or is stage IV. Immunotherapy with monoclonal antibodies, such as nivolumab and ipilimumab, may help the body’s immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Stereotactic body radiation therapy uses special equipment to position a patient and deliver radiation to tumors with high precision. This method can kill tumor cells with fewer doses over a shorter period and cause less damage to normal tissue. Giving nivolumab and ipilimumab with or without stereotactic body radiation therapy may work better in treating patients with Merkel cell cancer.
- Subjects must have signed and dated an Institutional Review Board/Independent Ethics Committee (IRB/IEC) approved written informed consent form in accordance with regulatory and institutional guidelines; this must be obtained before the performance of any protocol related procedures that are not part of normal subject care
- Subjects must be willing and able to comply with scheduled visits, treatment schedule, laboratory tests, tumor biopsies, and other requirements of the study
- All subjects must be either recurrent or stage IV American Joint Committee on Cancer (AJCC) (7th edition) and have histologically confirmed Merkel cell carcinoma with confirmed pathology in order to be eligible
- Eastern Cooperative Oncology Group performance status (ECOG PS) < 2
- Active disease measurable by computed tomography (CT) or magnetic resonance imaging (MRI)
- 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
- All subjects must have at least 2 distinct lesions as documented by a complete physical examination and imaging studies within 4 weeks prior to randomization; imaging studies must include a 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; prior surgery that required general anesthesia must be completed at least 4 weeks before study drug administration; surgery requiring local/epidural anesthesia must be completed at least 72 hours before study drug administration
- Prior surgery that required general anesthesia must be completed at least 4 weeks before study drug administration; surgery requiring local/epidural anesthesia must be completed at least 72 hours before study drug administration
- White blood cells (WBCs) >= 2000/uL (should be obtained within 14 days of randomization)
- Neutrophils >= 1500/uL (should be obtained within 14 days of randomization)
- Platelets >= 100 x 10^3/uL (should be obtained within 14 days of randomization)
- Hemoglobin >= 9.0 g/dL (should be obtained within 14 days of randomization)
- Creatinine serum creatinine =< 1.5 x upper limit of normal (ULN) or creatinine clearance > 40 mL/minute (using Cockcroft/Gault formula) (should be obtained within 14 days of randomization)
- Aspartate aminotransferase (AST) =< 3 x ULN (should be obtained within 14 days of randomization)
- Alanine aminotransferase (ALT) =< 3 x ULN (should be obtained within 14 days of randomization)
- Total bilirubin =< 1.5 x ULN (except subjects with Gilbert Syndrome who must have total bilirubin < 3.0 mg/dL) (should be obtained within 14 days of randomization)
- Subject re-enrollment: this study permits the re-enrollment of a subject that has discontinued the study as a screen failure (ie, subject has not been randomized / has not been treated); if re-enrolled, the subject must be re-consented
- Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) within 24 hours prior to the start of study drug
- Women must not be breastfeeding
- WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug(s) plus 5 half-lives of study drug plus 30 days (duration of ovulatory cycle); the half-life of nivolumab and ipilimumab is up to 25 days and 18 days, respectively; WOCBP should therefore use an adequate method to avoid pregnancy for a total of 23 weeks post-treatment completion
- Men who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment with study drug(s) plus 5 half-lives of the study drug(s) plus 90 days (duration of sperm turnover); the half-life of nivolumab and ipilimumab is up to 25 days and 18 days, respectively; men should therefore use an adequate method of contraception for a total of 31 weeks post-treatment completion
- Azoospermic males and WOCBP who are continuously not heterosexually active are exempt from contraceptive requirements; however, they must still undergo pregnancy testing as described in this section
- Subjects with brain metastases
- Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of study drug administration; inhaled or topical steroids are permitted in the absence of active autoimmune disease
- Subjects requiring palliative radiation therapy at presentation
- Subjects with history of grade 3 toxicity or use of infliximab with prior immunotherapy
- Subjects with active, known, or suspected autoimmune disease; subjects 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; for any cases of uncertainty, it is recommended that the medical monitor be consulted prior to signing informed consent
- Subjects 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
- Subjects with 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
- Any serious or uncontrolled medical disorder or active infection that, in the opinion of the investigator, may increase the risk associated with study participation, study drug administration, or would impair the ability of the subject to receive protocol therapy
- Positive test for hepatitis B virus surface antigen (HBVsAg) or hepatitis C virus ribonucleic acid (HCV RNA) indicating acute or chronic infection
- Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)
- History of grade 3 or higher allergy to humanized monoclonal antibodies
- Prisoners or subjects who are involuntarily incarcerated
- Subjects who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness
- Pregnant or nursing women
- Psychological, familial, sociological, or geographical conditions that potentially hamper compliance with the study protocol and follow-up schedule; those conditions should be discussed with the subject before registration in the trial
Locations & Contacts
Trial Objectives and Outline
I. To compare the efficacy, as measured by objective response rate (ORR), provided by nivolumab and ipilimumab versus stereotactic body radiation therapy (SBRT) plus nivolumab and ipilimumab in subjects with metastatic Merkel cell carcinoma.
I. To compare the progression free survival (PFS) of nivolumab and ipilimumab versus SBRT plus nivolumab and ipilimumab in subjects with metastatic Merkel cell carcinoma.
II. To compare the overall survival (OS) of nivolumab and ipilimumab versus SBRT plus nivolumab and ipilimumab in subjects with metastatic Merkel cell carcinoma.
III. To evaluate the local control of irradiated tumor provided by SBRT in combination with nivolumab and ipilimumab.
IV. To assess the overall safety and tolerability of nivolumab and ipilimumab versus SBRT plus nivolumab and ipilimumab in subjects with metastatic Merkel cell carcinoma.
V. To evaluate whether PD-L1 expression is a predictive biomarker for ORR.
VI. To evaluate the Health Related Quality of Life (HRQoL) as assessed by European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30).
I. To evaluate associations between Merkel polyomavirus expression status and clinical efficacy (ORR, PFS and overall survival [OS]).
II. To explore potential biomarkers associated with clinical efficacy (ORR, PFS, and OS) and/or incidence of adverse events by analyzing biomarker measures within the tumor microenvironment and periphery (eg, blood, serum, plasma and peripheral blood mononuclear cells [PBMCs]) in comparison to clinical outcomes.
III. To assess changes in health status and work and activity impairment in treatment groups using the EuroQol five dimensions questionnaire (EQ-5D) and the Work Productivity and Activity Impairment questionnaire (WPAI:GH), respectively.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM A: Patients receive nivolumab intravenously (IV) over 30 minutes once (Q) every 2 weeks and ipilimumab IV over 30 minutes Q6 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity.
ARM B: Patients receive nivolumab IV over 30 minutes Q2 weeks and ipilimumab IV over 30 minutes Q6 weeks. Treatment continues in the absence of disease progression or unacceptable toxicity. Beginning in week 2, patients undergo SBRT on 3 consecutive days or every other day during weeks 2-3 for a total of 3 fractions.
After completion of study treatment, patients are followed up at 30, 84, and 114 days, every 12 weeks for 24 months, and then every 6 months for up to 5 years.
Trial Phase & Type
Moffitt Cancer Center
Secondary IDs NCI-2017-00427
Clinicaltrials.gov ID NCT03071406