Clinical Trials /

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

NCT03021460

Description:

This phase I trial studies the best dose of ibrutinib when given together with pembrolizumab in treating patients with stage III-IV melanoma that cannot be removed by surgery. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and 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 1

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: Phase I 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 Cutaneous Melanoma AJCC v7
  • Stage IIIA Cutaneous Melanoma AJCC v7
  • Stage IIIB Cutaneous Melanoma AJCC v7
  • Stage IIIC Cutaneous Melanoma AJCC v7
  • Stage IV Cutaneous Melanoma AJCC v6 and v7
  • Unresectable 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 I trial studies the best dose of ibrutinib when given together with pembrolizumab in treating patients with stage III-IV melanoma that cannot be removed by surgery. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and 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 determine the maximum tolerated dose of ibrutinib in combination with pembrolizumab in
      patients with advanced melanoma. (Phase I) II. To estimate the overall response rate treated
      at the maximum tolerated dose of ibrutinib in combination with pembrolizumab in patients with
      advanced melanoma. (Dose expansion cohort)

      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 overall response rate (ORR) in patients advanced melanoma receiving
      ibrutinib and pembrolizumab.

      III. To evaluate the duration of response, progression-free survival (PFS), and 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.

      EXPLORATORY 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: This is a dose-escalation study of ibrutinib.

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

Eligibility Criteria

        Inclusion Criteria:

          -  PRE-REGISTRATION- INCLUSION CRITERIA

          -  Diagnosis of unresectable stage III or metastatic melanoma (stage IV) not amenable to
             local therapy

          -  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

          -  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

          -  REGISTRATION- INCLUSION CRITERIA

          -  Histologic or cytologic confirmation of unresectable stage III or metastatic melanoma
             (stage IV) not amenable to local therapy

          -  Previous exposure to anti-PD-1 or anti-PD-L1 therapy is allowed, if 1) patients have
             disease progression on or within 6 months after anti-PD-1/anti-PD-L1 therapy in the
             metastatic setting, or 2) patients have disease progression within 6 months after the
             last dose of adjuvant/neoadjuvant anti-PD-1/anti-PD-L1 treatment

          -  Absolute neutrophil count (ANC) >= 1000/mm^3 (obtained =< 14 days prior to
             registration)

          -  Platelet count >= 75,000/mm^3 (obtained =< 14 days prior to registration)

               -  Criteria must be met without a transfusion =< four weeks prior to registration

          -  Hemoglobin >= 9.0 g/dL (obtained =< 14 days prior to registration)

          -  Total bilirubin =< 1.5 X upper limit of normal (ULN); if total bilirubin > 1.5 X ULN
             then direct bilirubin =< ULN (obtained =< 14 days prior to registration)

          -  Aspartate aminotransferase (aspartate transaminase [AST]) and alanine aminotransferase
             (alanine transaminase [ALT]) =< 2.5 x ULN OR =< 5 X ULN for patients with liver
             metastases (obtained =< 14 days prior to registration)

          -  Creatinine =< 1.5 X ULN and creatinine clearance (CrCL) >= 30 ml/min per Cockcroft
             Gault formula (obtained =< 14 days prior to registration)

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

        Exclusion Criteria:

          -  PRE-REGISTRATION 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 prior exposure to BTK inhibitors

          -  Uveal melanoma

          -  Current use of warfarin or other vitamin K antagonists

          -  Require continuous treatment with a strong CYP3A inhibitor

          -  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

          -  Live vaccines within 28 days prior to study pre-registration

          -  Invasive surgical procedure within 28 days prior to study pre-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
                       pre-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 pre-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 =< 6 months prior to pre-randomization

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

          -  History of ischemic stroke or intracranial hemorrhage =< 180 days prior to
             pre-registration

          -  Currently active, clinically significant hepatic impairment Child-Pugh class A, B or C
             according to the Child Pugh classification

          -  Unresolved toxicities from prior anti-cancer therapy, defined as not resolved to
             Common Terminology Criteria for Adverse Events (CTCAE, version [v]4.0) grade 0 or 1,
             or to the levels dictated in the inclusion/exclusion criteria with the exceptions of
             alopecia and peripheral neuropathy

          -  REGISTRATION- EXCLUSION

          -  Failure to confirm histologically or cytologically unresectable stage III or
             metastatic melanoma (stage IV) not amenable to local therapy

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

          -  Received a strong cytochrome P450 (CYP) 3A inhibitor =< 7 days prior to registration

          -  Concurrent systemic immunosuppressant therapy =< 21 days prior to registration

          -  Recent infection requiring systemic antibiotic treatment that was completed =< 14
             prior to registration
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose (Phase I)
Time Frame:Up to start of second course of treatment
Safety Issue:
Description:Will be defined as the highest dose level among those tested where at most one out of 6 patients develops a dose limiting toxicity prior to the start of their second course of treatment. The maximum grade of each type of toxicity will be recorded for each patient. For each toxicity reported by dose level, the percentage of patients developing any degree of that toxicity as well as the percentage of patients developing a severe degree (grade 3 or higher) will be determined.

Secondary Outcome Measures

Measure:Tumor response evaluated according to Response Evaluation Criteria in Solid criteria (RECIST)
Time Frame:Up to 5 years
Safety Issue:
Description:A patient whose tumor has met the RECIST criteria for complete response or partial response on two consecutive evaluations at least 8 weeks apart is considered to have had a tumor response.
Measure:Progression-free survival
Time Frame:From study entry to the documentation of disease progression, assessed up to 5 years
Safety Issue:
Description:Will be examined in an exploratory and hypothesis-generating fashion.
Measure:Overall survival
Time Frame:From study entry to death due to any cause, assessed up to 5 years
Safety Issue:
Description:Will be examined in an exploratory and hypothesis-generating fashion.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Mayo Clinic

Last Updated

April 8, 2021