Clinical Trials /

Nivolumab and Radiation Therapy or Ipilimumab as Adjuvant Therapy in Treating Patients With Merkel Cell Cancer

NCT03798639

Description:

This phase I trial studies the side effects and how well nivolumab works when given together with radiation therapy or ipilimumab as adjuvant therapy in treating patients with Merkel cell cancer. 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. Radiation therapy uses high energy x-rays, gamma rays, neutrons, protons or other sources to kill tumor cells and shrink tumors. Giving nivolumab with radiation therapy or ipilimumab after surgery may kill any remaining tumor cells.

Related Conditions:
  • Merkel Cell Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Nivolumab and Radiation Therapy or Ipilimumab as Adjuvant Therapy in Treating Patients With Merkel Cell Cancer
  • Official Title: Randomized, Multi-Institutional Pilot Study of Nivolumab and Radiation Therapy Versus Nivolumab and Ipilimumab as Adjuvant Therapy for Merkel Cell Carcinoma

Clinical Trial IDs

  • ORG STUDY ID: OSU-18231
  • SECONDARY ID: NCI-2018-03329
  • SECONDARY ID: P30CA016058
  • NCT ID: NCT03798639

Conditions

  • Merkel Cell Carcinoma
  • Pathologic Stage IIIA Merkel Cell Carcinoma AJCC v8
  • Pathologic Stage IIIB Merkel Cell Carcinoma AJCC v8

Interventions

DrugSynonymsArms
IpilimumabAnti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody, BMS-734016, MDX-010, MDX-CTLA4, YervoyArm II (nivolumab, ipilimumab)
NivolumabBMS-936558, MDX-1106, NIVO, ONO-4538, OpdivoArm I (nivolumab, radiation therapy)

Purpose

This phase I trial studies the side effects and how well nivolumab works when given together with radiation therapy or ipilimumab as adjuvant therapy in treating patients with Merkel cell cancer. 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. Radiation therapy uses high energy x-rays, gamma rays, neutrons, protons or other sources to kill tumor cells and shrink tumors. Giving nivolumab with radiation therapy or ipilimumab after surgery may kill any remaining tumor cells.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To assess the tolerability of two different experimental immunotherapy regimens in the
      adjuvant setting in patients with Merkel cell carcinoma (MCC).

      SECONDARY OBJECTIVES:

      I. To assess the safety and tolerability profile of each of the treatment using Common
      Terminology Criteria for Adverse Events (CTCAE) version 5.0.

      II. To assess the efficacy of each of the treatment arms according to recurrence-free
      survival (RFS) at one and half years, defined as the time between the date of randomization
      and the date of first progression (local, regional or distant metastasis) or death (whatever
      the cause), whichever occurs first.

      III. To assess the efficacy of each of the treatment arms according to overall survival (OS)
      at three years, defined from the time of randomization and the date of death, compared to
      historical registry control.

      EXPLORATORY OBJECTIVES:

      I. To explore potential biomarkers, next generation T cell receptor (TCR) sequencing will be
      performed to identify and longitudinally track individual T cell clones thus granting a
      comprehensive insight into immunological changes that occur within the tumor and peripheral
      blood throughout the course of the disease.

      OUTLINE: Patients are randomized to 1 of 2 arms.

      ARM A: Patients receive nivolumab intravenously (IV) over 30 minutes at week 0. Treatments
      repeat every 4 weeks for 1 year in the absence of disease progression or unacceptable
      toxicity. Beginning week 2, patients also receive radiation therapy on Monday-Friday or 5
      days per week for 6 weeks in the absence of disease progression or unacceptable toxicity.

      ARM B: Patients receive nivolumab IV over 30 minutes and ipilimumab IV over 30 minutes at
      week 0. Treatments repeat every 2 weeks for nivolumab and 6 weeks for ipilimumab for up to 1
      year in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up every 3 months for 2 years and
      then every 6 months for 1 year.
    

Trial Arms

NameTypeDescriptionInterventions
Arm I (nivolumab, radiation therapy)ExperimentalPatients receive nivolumab IV over 30 minutes at week 0. Treatments repeat every 4 weeks for 1 year in the absence of disease progression or unacceptable toxicity. Beginning week 2, patients also receive radiation therapy on Monday-Friday or 5 days per week for 6 weeks in the absence of disease progression or unacceptable toxicity.
  • Nivolumab
Arm II (nivolumab, ipilimumab)Active ComparatorPatients receive nivolumab IV over 30 minutes and ipilimumab IV over 30 minutes at week 0. Treatments repeat every 2 weeks for nivolumab and 6 weeks for ipilimumab for up to 1 year in the absence of disease progression or unacceptable toxicity.
  • Ipilimumab
  • Nivolumab

Eligibility Criteria

        Inclusion Criteria:

          -  Be willing and able to understand and give written informed consent and comply with
             all study related procedures

          -  All patients should undergo definitive surgical resection, including when possible
             sentinel lymph node dissection

          -  Patients must have recovered after any recent surgery and be ambulatory

          -  Have node positive disease (stage pIIIA or pIIIB) +/- extracapsular extension

          -  Have node negative disease and any of the following high risk features

               -  Tumor size >= 2 cm

               -  Margins =< 1-2 cm and re-resection is not possible

               -  Evidence of perineural or lymphovascular invasion

          -  Human immunodeficiency virus (HIV) patients with undetectable viral load and CD4+
             T-cell counts >= 350 cells/uL

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0-2

          -  Absolute neutrophil count (ANC) >= 1,500/mcL (performed within 16 days of treatment
             initiation)

          -  Platelets >= 100,000/mcL in the absence of transfusion support within 7 days of
             determining eligibility (performed within 16 days of treatment initiation)

          -  Hemoglobin >= 8 g/dL (performed within 16 days of treatment initiation)

          -  Serum creatinine =< 1.5 x upper limit of normal (ULN) OR Measured or calculated
             creatinine clearance >= 40 mL/min creatinine clearance (performed within 16 days of
             treatment initiation) (Glomerular filtration rate [GFR] can also be used in place of
             creatinine or creatinine clearance [CrCl])

               -  Creatinine clearance should be calculated per institutional standard

          -  Serum total bilirubin =< 1.5 x ULN OR Except subjects with Gilbert Syndrome, who can
             have total bilirubin < 3.0 x ULN (performed within 16 days of treatment initiation)

          -  Aspartate aminotransferase (AST)(serum glutamic-oxaloacetic transaminase [SGOT]) and
             alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x
             ULN (performed within 16 days of treatment initiation)

          -  Female subject of childbearing potential should have a negative urine or serum
             pregnancy at screening and within 24 hours prior to receiving the first dose of study
             medication and then every 4 weeks while on treatment. If the urine test is positive or
             cannot be confirmed as negative, a serum pregnancy test will be required

          -  Female subjects of childbearing potential should be willing to use 2 methods of birth
             control or be surgically sterile, or abstain from heterosexual activity for the course
             of the study through 5 months after the last dose of study medication. Subjects should
             agree to ongoing pregnancy testing during the course of the study and after the end of
             study therapy. Female subjects of childbearing potential are those who have not been
             surgically sterilized or have not been free from menses for > 1 year

          -  Male subjects should agree to use an adequate method of contraception starting with
             the first dose of study therapy through 7 months after the last dose of study therapy.
             Males must refrain from donating sperm during study participation and for 7 months
             after the last dose of study medication. Female subject should agree to use an
             adequate method of contraception starting with the first dose of study therapy through
             5 months after the last dose of study therapy

        Exclusion Criteria:

          -  Has known distant metastatic MCC

          -  Has a known history of active TB (Bacillus tuberculosis)

          -  Hypersensitivity to any study agents

          -  Have received prior immunotherapy with any PD-1/PDL-1 inhibitors or CTLA-4 antibodies
             at any time in the past

          -  Has had prior chemotherapy or radiation therapy for treatment of MCC

          -  Has a clinically significant medical condition, which in the judgment of the attending
             physician would contraindicate immunotherapy or radiotherapy, such as serious
             autoimmune disease, hypersensitivity to investigational product or any component in
             its formulations, per Food and Drug Administration (FDA) prescription notice

          -  Subjects with prior history of non-Merkel cell carcinoma malignancies are excluded
             except

               -  Adequately treated basal cell, squamous cell skin cancer, chronic lymphocytic
                  leukemia (CLL) or other indolent malignancies not requiring therapy (ie. active
                  surveillance)

               -  Adequately treated malignancies and patient has been in complete remission for at
                  least two years

               -  Patients with history of breast cancer and no evidence of disease on hormonal
                  therapy to prevent recurrence

               -  Patients with prostate cancer on adjuvant hormonal therapy with undetectable PSA
                  are eligible

          -  Has active autoimmune disease that has required systemic treatment in the past 2 years
             (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive
             drugs). Replacement therapy (thyroxine, insulin, or physiologic corticosteroid
             replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
             form of systemic treatment

          -  Subjects with a condition requiring systemic treatment with either corticosteroids (>
             10 mg daily prednisone equivalent) or other immunosuppressive medications within 14
             days of randomization will be excluded. Inhaled or topical steroids are permitted in
             the absence of active autoimmune disease

          -  Has an active infection requiring intravenous systemic therapy

          -  Solid organ transplant recipients and patients with concurrent hematological
             malignancies including thymomas, leukemias (other than CLL) and lymphomas actively
             undergoing treatment or completed < 5 years prior

          -  Clinically significant cardiovascular disease with uncontrolled arrhythmia, New York
             Association class 3 or 4 congestive heart failure, history of myocardial infarction
             within 6 months, or prolonged corrected QT (QTc) > 500 msec

          -  Is pregnant or breastfeeding, or expecting to conceive or father children within the
             projected duration of the trial, starting with the pre-screening or screening visit
             through 120 days after the last dose of trial treatment

          -  Has known active hepatitis B (e.g., hepatitis B virus surface antigen [HBsAg]
             reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA]
             [qualitative] is detected)
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Percentage of patients completing 12 months of treatment
Time Frame:Up to 12 months
Safety Issue:
Description:Will be estimated along with the 95% confidence interval for each arm based on the binomial distribution.

Secondary Outcome Measures

Measure:Recurrence-free survival (RFS) one and half years
Time Frame:Time between the date of randomization and the date of first progression (local, regional or distant metastasis) or death (whatever the cause), assessed up to one and half years.
Safety Issue:
Description:Kaplan-Meier curves will be generated to summarize the secondary outcomes, RFS and overall survival (OS), for each arm; the differences between groups in terms of hazard ratio for OS/RFS will also be estimated.
Measure:Overall survival at three years
Time Frame:Time from randomization to the date of death, assessed up to 3 years
Safety Issue:
Description:Kaplan-Meier curves will be generated to summarize the secondary outcomes, RFS and OS, for each arm; the differences between groups in terms of hazard ratio for OS/RFS will also be estimated.
Measure:Incidence of adverse events (AEs)
Time Frame:Up to 3 years post treatment
Safety Issue:
Description:Adverse experiences will be graded and recorded throughout the study and during the follow-up period according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Side effects will be summarized by each treatment group.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Hiral Shah

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