Clinical Trials /

Propranolol Hydrochloride and Pembrolizumab in Treating Patients With Stage IIIC-IV Melanoma That Cannot Be Removed by Surgery

NCT03384836

Description:

This phase Ib/II trial studies the side effects and best dose of propranolol hydrochloride when given together with pembrolizumab and how well they work in treating patients with stage IIIC-IV melanoma that cannot be removed by surgery. Pembrolizumab is a monoclonal antibody that ?takes the brakes off the immune system? and thus allows for anti-tumor immune responses. Propranolol hydrochloride is a beta adrenergic blocking agent that can enhance immune cell responses when under stress. Giving propranolol hydrochloride and pembrolizumab may work better in treating patients with melanoma.

Related Conditions:
  • Melanoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Propranolol Hydrochloride and Pembrolizumab in Treating Patients With Stage IIIC-IV Melanoma That Cannot Be Removed by Surgery
  • Official Title: A Phase Ib/II Study of Propranolol With Fixed-Dose Pembrolizumab in Patients With Unresectable Stage III and Stage IV Melanoma

Clinical Trial IDs

  • ORG STUDY ID: I 53217
  • SECONDARY ID: NCI-2017-02210
  • SECONDARY ID: I 53217
  • SECONDARY ID: P30CA016056
  • NCT ID: NCT03384836

Conditions

  • Stage IIIC Cutaneous Melanoma AJCC v7
  • Stage IV Cutaneous Melanoma AJCC v6 and v7

Interventions

DrugSynonymsArms
PembrolizumabKeytruda, Lambrolizumab, MK-3475, SCH 900475Treatment (propranolol hydrochloride, pembrolizumab)
Propranolol HydrochlorideInderal, Innopran XLTreatment (propranolol hydrochloride, pembrolizumab)

Purpose

This phase Ib/II trial studies the side effects and best dose of propranolol hydrochloride when given together with pembrolizumab and how well they work in treating patients with stage IIIC-IV melanoma that cannot be removed by surgery. Pembrolizumab is a monoclonal antibody that ?takes the brakes off the immune system? and thus allows for anti-tumor immune responses. Propranolol hydrochloride is a beta adrenergic blocking agent that can enhance immune cell responses when under stress. Giving propranolol hydrochloride and pembrolizumab may work better in treating patients with melanoma.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine dose limiting toxicities (DLT) of propranolol hydrochloride (propranolol) in
      combination with fixed dose pembrolizumab in the treatment of melanoma.

      II. To evaluate the efficacy of pembrolizumab in combination with propranolol in patients
      with melanoma, as determined by overall response rate (ORR) per immune-modified Response
      Evaluation Criteria in Solid Tumors (RECIST) (1).

      SECONDARY OBJECTIVES:

      I. To evaluate the efficacy of pembrolizumab in combination with propranolol in patients with
      melanoma, as determined by secondary measures of efficacy, including: progression free
      survival (PFS) and overall survival (OS).

      TERTIARY OBJECTIVES:

      I. To correlate baseline or changes in the levels of biomarkers, like, peripheral T-cell
      subsets/myeloid derived suppressor cells (MDSC)/cytokines/urinary catecholamine and perceived
      stress scale (PSS) with efficacy (ORR, PFS, OS) in melanoma patients treated with
      pembrolizumab and propranolol.

      OUTLINE: This is a phase Ib, dose-escalation study of propranolol hydrochloride followed by a
      phase II study.

      Patients receive propranolol hydrochloride orally (PO) twice daily (BID) and pembrolizumab
      intravenously (IV) over 30 minutes of day 1. Courses repeat every 3 weeks for up to 2 years
      in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up at 30 days, every 3 months for
      6 months, and then every 6 months thereafter.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (propranolol hydrochloride, pembrolizumab)ExperimentalPatients receive propranolol hydrochloride PO BID and pembrolizumab IV over 30 minutes of day 1. Courses repeat every 3 weeks for up to 2 years in the absence of disease progression or unacceptable toxicity.
  • Pembrolizumab
  • Propranolol Hydrochloride

Eligibility Criteria

        Inclusion Criteria:

          -  Participants must be newly diagnosed, treatment-naive with histologically confirmed
             stage IIIC unresectable melanoma or stage IV melanoma

          -  Have an Eastern Cooperative Oncology Group (ECOG) performance status 0-1

          -  Available archival formalin-fixed paraffin-embedded (FFPE) from a prior biopsy or,
             participant must be willing to have a tissue biopsy taken at a clinic visit prior to
             start of study treatment

          -  Have measurable disease per irRECIST v1.1

          -  Ability to swallow and retain oral medication

          -  Absolute neutrophil count (ANC) >= 1500/uL

          -  Hemoglobin (Hb) >= 9 g/dL

          -  Platelet count >= 100, 000/uL

          -  Total bilirubin =< 1.5 x ULN (upper limit of normal) - unless patient has Gilbert's
             syndrome

          -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2 x ULN

          -  If the patient has liver metastasis AST and ALT less than or greater to 5x ULN

          -  Serum creatinine < 2 x ULN

          -  Participants of child-bearing potential must have a negative pregnancy test at study
             entry and then agree to use adequate contraceptive methods (e.g., hormonal or barrier
             method of birth control; abstinence) prior to study entry; should a woman become
             pregnant or suspect she is pregnant while she or her partner is participating in this
             study, she should inform her treating physician immediately

          -  Participant or legal representative must understand the investigational nature of this
             study and sign an Independent Ethics Committee/Institutional Review Board approved
             written informed consent form prior to receiving any study related procedure

        Exclusion Criteria:

          -  Participants who have received previous immunotherapy for any cancer (excluding
             melanoma) including PD-1/PD-L1 inhibitors but not interferons and CTLA-4 inhibitors

          -  Participants with chronic autoimmune diseases

          -  Participants with symptomatic known brain metastases < 4 weeks from radiation
             treatment should be excluded from this clinical trial

          -  Other invasive cancers diagnosed < 3 years back that required systemic treatment. If
             diagnosed with other invasive cancer >=3 years, should have complete recovery from all
             systemic toxicity except neuropathy and alopecia

          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
             arrhythmia, or psychiatric illness/social situations that would limit compliance with
             study requirements

          -  Pregnant or nursing female participants, where pregnancy is defined as the state of a
             female after conception and until the termination of gestation, confirmed by a
             positive human chorionic gonadotropin (hCG) laboratory test

          -  Unwilling or unable to follow protocol requirements

          -  Any condition which in the investigator's opinion deems the participant an unsuitable
             candidate to receive study drug

          -  Other active non-melanoma metastatic cancers

          -  Contraindications to the use of beta-blockers, like, uncontrolled depression, unstable
             angina pectoris, uncontrolled heart failure (grade III or IV), hypotension (systolic
             blood pressure < 100 mmHg), severe asthma or chronic obstructive pulmonary disease
             (COPD), uncontrolled type I or type II diabetes mellitus (glycosylated hemoglobin
             [HbA1C] > 8.5 or fasting plasma glucose > 160 mg/dl at screening), symptomatic
             peripheral arterial disease or Raynaud?s syndrome, untreated pheochromocytoma, current
             use or past use in the last two years of beta-blockers or calcium channel blockers

          -  Patient is currently receiving or has received systemic corticosteroids (=< 2 weeks
             prior to starting study drug, or who have not fully recovered from side effects of
             such treatment)

          -  Diagnosis of immunodeficiency or receiving systemic steroid therapy or any other form
             of immunosuppressive therapy within 14 days prior to the first dose of the study drug

          -  Live vaccines within 30 days prior to the first dose of trial treatment and while
             participating in the trial. Examples of live vaccines include, but are not limited to,
             the following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, BCG,
             and typhoid vaccine.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Dose limiting toxicities (DLT) defined as any grade 3 or higher hematological or non-hematological toxicity that is probably or definitely related to treatment according to Common Terminology Criteria for Adverse Events version 4.03 (Phase Ib)
Time Frame:Up to 12 weeks
Safety Issue:
Description:Adverse events and toxicities will be summarized by dose level using frequencies and relative frequencies.

Secondary Outcome Measures

Measure:Overall survival (OS) (Phase II)
Time Frame:From treatment initiation until death due to any cause (event) or last follow-up, assessed up to 2 years
Safety Issue:
Description:Will be summarized using standard Kaplan-Meier methods and rates will be obtained with 90% confidence intervals.
Measure:PFS (Phase II)
Time Frame:From treatment initiation until disease progression, death due to disease (events), or last follow-up, assessed up to 2 years
Safety Issue:
Description:Will summarized using standard Kaplan-Meier methods and rates will be obtained with 90% confidence intervals.
Measure:Progression free survival (PFS) (Phase II)
Time Frame:At 1 year
Safety Issue:
Description:Will be summarized using standard Kaplan-Meier methods and rates will be obtained with 90% confidence intervals.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Roswell Park Cancer Institute

Trial Keywords

  • Melanoma
  • Immune Checkpoint Inhibitors
  • Beta Adrenergic Blockers

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