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

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ClinicalTrials.gov Identifier: NCT03021460
Recruitment Status : Recruiting
First Posted : January 16, 2017
Last Update Posted : December 30, 2019
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Mayo Clinic

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Metastatic Melanoma Stage III Skin Melanoma Stage IIIA Skin Melanoma Stage IIIB Skin Melanoma Stage IIIC Skin Melanoma Stage IV Skin Melanoma Drug: Ibrutinib Other: Laboratory Biomarker Analysis Biological: Pembrolizumab Phase 2

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 51 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Study of Pembrolizumab in Combination With Ibrutinib in the Treatment of Unresectable or Metastatic Melanoma
Actual Study Start Date : January 31, 2017
Estimated Primary Completion Date : February 1, 2021
Estimated Study Completion Date : February 1, 2021


Arm Intervention/treatment
Experimental: Treatment (ibrutinib, pembrolizumab)
Patients 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.
Drug: Ibrutinib
Given PO
Other Names:
  • BTK Inhibitor PCI-32765
  • CRA-032765
  • Imbruvica
  • PCI-32765

Other: Laboratory Biomarker Analysis
Correlative studies

Biological: Pembrolizumab
Given IV
Other Names:
  • Keytruda
  • Lambrolizumab
  • MK-3475
  • SCH 900475




Primary Outcome Measures :
  1. Tumor response rate defined as the percentage of patients whose objective disease status meets the criteria for Response Evaluation Criteria in Solid criteria for partial or complete response on two consecutive disease evaluations at least 6 weeks apart [ Time Frame: Up to 5 years ]
    Tumor response rate will be assessed patients treated with pembrolizumab and ibrutinib.


Secondary Outcome Measures :
  1. Duration of response [ Time Frame: Up to 5 years ]
    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.

  2. 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 ]
    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.

  3. Overall survival [ Time Frame: From registration to death due to any cause, assessed up to 5 years ]
    Will be estimated using the Kaplan-Meier method.

  4. Progression free survival [ Time Frame: From registration to documentation of first disease progression or death due to any cause, assessed up to 5 years ]
    Will be estimated using the Kaplan-Meier method.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
  • 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 X 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

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 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
  • 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 Wilebrand?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 B or C according to the Child Pugh classification
  • 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]) within 28 days prior to registration

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03021460


Locations
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United States, Minnesota
Mayo Clinic Recruiting
Rochester, Minnesota, United States, 55905
Contact: Clinical Trials Referral Office    855-776-0015      
Principal Investigator: Matthew S. Block         
Sponsors and Collaborators
Mayo Clinic
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Matthew Block Mayo Clinic

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Responsible Party: Mayo Clinic
ClinicalTrials.gov Identifier: NCT03021460    
Other Study ID Numbers: MC1577
NCI-2017-00079 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
MC1577 ( Other Identifier: Mayo Clinic )
P30CA015083 ( U.S. NIH Grant/Contract )
First Posted: January 16, 2017    Key Record Dates
Last Update Posted: December 30, 2019
Last Verified: December 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Melanoma
Skin Neoplasms
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas
Neoplasms by Site
Skin Diseases
Pembrolizumab
Antineoplastic Agents, Immunological
Antineoplastic Agents