Clinical Trials /

Pembrolizumab and Ibrutinib in Treating Patients With Stage III-IV Melanoma That Cannot Be Removed by Surgery

NCT03021460

Description:

This phase II trial studies how well pembrolizumab and ibrutinib work in treating patients with stage III-IV melanoma that cannot be removed by surgery. Monoclonal antibodies, such as pembrolizumab, may interfere with the ability of tumor cells to grow and spread. Ibrutinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving pembrolizumab and ibrutinib may work better in treating patients with melanoma.

Related Conditions:
  • Melanoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Pembrolizumab and Ibrutinib in Treating Patients With Stage III-IV Melanoma That Cannot Be Removed by Surgery
  • Official Title: A Phase II Study of Pembrolizumab in Combination With Ibrutinib in the Treatment of Unresectable or Metastatic Melanoma

Clinical Trial IDs

  • ORG STUDY ID: MC1577
  • SECONDARY ID: NCI-2017-00079
  • SECONDARY ID: MC1577
  • SECONDARY ID: P30CA015083
  • NCT ID: NCT03021460

Conditions

  • Metastatic Melanoma
  • Stage III Skin Melanoma
  • Stage IIIA Skin Melanoma
  • Stage IIIB Skin Melanoma
  • Stage IIIC Skin Melanoma
  • Stage IV Skin Melanoma

Interventions

DrugSynonymsArms
IbrutinibBTK Inhibitor PCI-32765, CRA-032765, Imbruvica, PCI-32765Treatment (ibrutinib, pembrolizumab)
PembrolizumabKeytruda, Lambrolizumab, MK-3475, SCH 900475Treatment (ibrutinib, pembrolizumab)

Purpose

This phase II trial studies how well pembrolizumab and ibrutinib work in treating patients with stage III-IV melanoma that cannot be removed by surgery. Monoclonal antibodies, such as pembrolizumab, may interfere with the ability of tumor cells to grow and spread. Ibrutinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving pembrolizumab and ibrutinib may work better in treating patients with melanoma.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To evaluate the overall response rate (ORR) in patients with advanced melanoma receiving
      ibrutinib and pembrolizumab.

      SECONDARY OBJECTIVES:

      I. To assess the safety and adverse-event profiles of combination of ibrutinib with
      pembrolizumab in patients with advanced melanoma.

      II. To evaluate the progression-free-survival (PFS) in patients advanced melanoma receiving
      ibrutinib and pembrolizumab.

      III. To evaluate the duration of response, overall survival (OS) in patients with advanced
      melanoma receiving ibrutinib and pembrolizumab.

      IV. To assess the effect of treatment with ibrutinib and pembrolizumab on Th1/Th2 immune
      polarity.

      TERTIARY OBJECTIVES:

      I. To assess the CD8 T cell response to multiple melanoma-associated antigens, and to
      correlate CD8 T cell responses with changes in Th1/Th2 immune polarity.

      II. To assess changes in plasma cytokines induced by treatment with ibrutinib and
      pembrolizumab.

      III. To assess the change in potential biomarkers, such as tumor-bound and soluble PD-L1
      levels and tumor-infiltrating lymphocytes, that may correlate with treatment responses.

      OUTLINE:

      Patients receive ibrutinib orally (PO) daily on days 1-28 of course 1 and days 1-21 of
      course 2 and subsequent courses. Patients also receive pembrolizumab intravenously (IV) over
      30 minutes on day 8 of course 1 and day 1 of course 2 and subsequent courses. Course 1
      continues for 28 days and subsequent courses repeat every 21 days in the absence of disease
      progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up every 6 months for 5 years.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (ibrutinib, pembrolizumab)ExperimentalPatients receive ibrutinib PO daily on days 1-28 of course 1 and days 1-21 of course 2 and subsequent courses. Patients also receive pembrolizumab IV over 30 minutes on day 8 of course 1 and day 1 of course 2 and subsequent courses. Course 1 continues for 28 days and subsequent courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
  • Ibrutinib

Eligibility Criteria

        Inclusion Criteria:

          -  Histological or cytologically confirmed diagnosis of unresectable stage III or
             metastatic melanoma (stage IV) not amenable to local therapy

          -  Testing for BRAF V600E or V600K mutation status must be initiated prior to
             registration; (results may be pending at the time of registration)

          -  Willing to undergo a tumor biopsy from a lesion not previously irradiated and
             obtained within 28 days prior to registration

               -  Mandatory unless deemed unsafe by the treating investigator

          -  At least one non-nodal lesion considered measurable by Response Evaluation Criteria
             in Solid Tumors (RECIST) criteria (that is, a lesion whose longest diameter can be
             accurately measured as >= 1.0 cm with computed tomography [CT] scan, CT component of
             a positron emission tomography [PET]/CT, or magnetic resonance imaging [MRI]) or at
             least one malignant lymph node is considered measurable by RECIST criteria (that is,
             its short axis is >= 1.5 cm when assessed by CT scan)

               -  NOTE: Tumor lesions in a previously irradiated area are not considered
                  measurable disease

          -  Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1, or 2

          -  Absolute neutrophil count (ANC) >= 1000/mm^3

          -  Platelet count >= 75,000/mm^3

               -  Criteria must be met without a transfusion within four weeks of registration

          -  Hemoglobin >= 9.0 g/dL

          -  Total bilirubin =< 1.5 x upper limit of normal (ULN); if total bilirubin > 1.5 ULN
             then direct bilirubin =< ULN

          -  Aspartate transaminase (AST) and alanine transaminase (ALT) =< 2.5 x ULN OR =< 5 x
             ULN for patients with liver metastases

          -  Creatinine =< 1.5 x ULN and creatinine clearance (CrCL) >= 30 ml/min per Cockcroft
             Gault formula

          -  Female patients of childbearing potential, negative urine pregnancy test done =< 7
             days prior to study registration

          -  Provide informed written consent

          -  Patient is willing to undergo treatment and monitoring at the enrolling institution

          -  Willing to provide tissue and blood samples for correlative research purposes

        Exclusion Criteria:

          -  Any of the following:

               -  Pregnant women

               -  Nursing women

               -  Men or women of childbearing potential who are unwilling to employ adequate
                  contraception within the projected duration of the study, starting with the
                  screening visit through 120 days after the last dose of study medication;
                  adequate contraception is defined as 2 methods of birth control (e.g., hormonal
                  contraceptives, intrauterine device, diaphragm with spermicide, cervical cap
                  with spermicide, male condoms, or female condom with spermicide) or prior
                  surgical sterilization, or abstinence from heterosexual activity

          -  Prior treatment with ibrutinib or an anti-PD-1, or PD-L1 or PD-L2 agent or ipilimumab
             in the metastatic setting

          -  Current use of warfarin or other vitamin K antagonists

          -  Current use of a strong cytochrome P450 (CYP) 3A4/5 inhibitor or inducer

          -  Currently participating or has participated in a study of an investigational cancer
             therapy agent or using an investigational device within 28 days prior to study
             registration

          -  Prior chemotherapy, immunotherapy, radioactive, or biological cancer therapy
             (including monoclonal antibody [mAb]) within 28 days prior to study registration

          -  Live vaccines within 28 days prior to study registration

          -  Invasive surgical procedure within 28 days prior to study registration

          -  History of clinically severe (e.g., requires chronic immunosuppressive therapy,
             [e.g., cyclosporine A, tacrolimus]) autoimmune disease (e.g., ulcerative colitis,
             lupus), or history of organ transplant

          -  Known history of human immunodeficiency virus (HIV) infection, active infection with
             hepatitis B virus or hepatitis C virus, or any uncontrolled active systemic infection

          -  Gastrointestinal disease that might inhibit ibrutinib absorption (e.g., malabsorption
             syndrome, resection of the stomach or a large portion of small bowel, or
             partial/complete bowel obstruction), or unable to swallow capsules

          -  Active central nervous system metastases and/or carcinomatous meningitis

               -  Note: Patients with untreated brain metastasis will be excluded; patients with
                  previously treated brain metastases may participate provided they meet the
                  following criteria:

                    -  Inactive (without evidence of progression which is documented by CT or MRI
                       within 90 days prior to registration), AND

                    -  On =< 10 mg/day prednisone or equivalent for at least 28 days prior
                       registration

          -  Co-morbid systemic illnesses or other severe concurrent disease which, in the
             judgment of the investigator, would make the patient inappropriate for entry into
             this study or interfere significantly with the proper assessment of safety and
             toxicity of the prescribed regimens

          -  Clinically significant cardiovascular disease such as unstable angina, myocardial
             infarction, or acute coronary syndrome within =<180 days prior to registration,
             symptomatic or uncontrolled arrhythmia, congestive heart failure, or any class 3 or 4
             cardiac disease as defined by the New York Heart Association Functional
             Classification

          -  Other active malignancy =< 3 years prior to registration; note: if there is a history
             of prior malignancy, the patient must not be receiving other specific treatment for
             cancer

               -  EXCEPTIONS: Non-melanotic skin cancer or carcinoma-in-situ of the cervix

          -  Currently active, clinically significant cardiovascular disease, such as uncontrolled
             arrhythmia or class 3 or 4 congestive heart failure as defined by the New York Heart
             Association Functional Classification; or a history of myocardial infarction,
             unstable angina, or acute coronary syndrome within 6 months prior to randomization

          -  Known bleeding disorders (von Wilebrand's disease or hemophilia)

          -  History of ischemic stroke or intracranial hemorrhage within 180 days prior to
             registration

          -  Currently active, clinically significant hepatic impairment Child-Pugh class B or C
             according to the Child Pugh classification
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Tumor response rate defined as the percentage of patients whose objective disease status meets the criteria for RECIST criteria for partial or complete response on two consecutive disease evaluations at least 6 weeks apart
Time Frame:Up to 5 years
Safety Issue:
Description:Overall response rate (ORR) in patients with advanced melanoma receiving ibrutinib and pembrolizumab.

Secondary Outcome Measures

Measure:Duration of response
Time Frame:Up to 5 years
Safety Issue:
Description:For those patients who disease had a partial or complete response to treatment on two consecutive disease evaluations at least 6 weeks apart, the duration of treatment response is defined as the time from registration to disease progression.
Measure:Incidence of adverse events evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0
Time Frame:Up to 5 years
Safety Issue:
Description:For each type of toxicity reported, the proportion of patients experiencing a severe level of that toxicity will be determined. For each agent, the total dose delivered as a percentage of the starting dose will be determined.
Measure:Overall Survival
Time Frame:From registration to death due to any cause, assessed up to 5 years
Safety Issue:
Description:Will be estimated using the Kaplan-Meier method.
Measure:Progression Free Survival
Time Frame:From registration to documentation of first disease progression or death due to any cause, assessed up to 5 years
Safety Issue:
Description:Will be estimated using the Kaplan-Meier method.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Mayo Clinic

Last Updated

March 21, 2017