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

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ClinicalTrials.gov Identifier: NCT03384836
Recruitment Status : Recruiting
First Posted : December 27, 2017
Last Update Posted : January 13, 2021
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Roswell Park Cancer Institute

Tracking Information
First Submitted Date  ICMJE December 12, 2017
First Posted Date  ICMJE December 27, 2017
Last Update Posted Date January 13, 2021
Actual Study Start Date  ICMJE January 31, 2018
Estimated Primary Completion Date January 31, 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 26, 2017)
  • 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 ]
    Adverse events and toxicities will be summarized by dose level using frequencies and relative frequencies.
  • Overall response rate (ORR) per immune-related Response Evaluation Criteria in Solid Tumors (irRECIST) version 1.1 (Phase II) [ Time Frame: Up to 6 months ]
    ORR is defined as partial or complete response within 6 months of initiating combination therapy.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 26, 2017)
  • 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 ]
    Will be summarized using standard Kaplan-Meier methods and rates will be obtained with 90% confidence intervals.
  • 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 ]
    Will summarized using standard Kaplan-Meier methods and rates will be obtained with 90% confidence intervals.
  • Progression free survival (PFS) (Phase II) [ Time Frame: At 1 year ]
    Will be summarized using standard Kaplan-Meier methods and rates will be obtained with 90% confidence intervals.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: December 26, 2017)
Changes in the levels of biomarkers [ Time Frame: Baseline up to 2 years ]
to correlate baseline or changes in levels of biomarkers with efficacy in melanoma patients treated with pembrolizumab and propranolol.
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Propranolol Hydrochloride and Pembrolizumab in Treating Patients With Stage IIIC-IV Melanoma That Cannot Be Removed by Surgery
Official Title  ICMJE A Phase Ib/II Study of Propranolol With Fixed-Dose Pembrolizumab in Patients With Unresectable Stage III and Stage IV Melanoma
Brief Summary 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Stage IIIC Cutaneous Melanoma AJCC v7
  • Stage IV Cutaneous Melanoma AJCC v6 and v7
Intervention  ICMJE
  • Other: Laboratory Biomarker Analysis
    Correlative studies
  • Biological: Pembrolizumab
    Given IV
    Other Names:
    • Keytruda
    • Lambrolizumab
    • MK-3475
    • SCH 900475
  • Drug: Propranolol Hydrochloride
    Given PO
    Other Names:
    • Inderal
    • Innopran XL
Study Arms  ICMJE Experimental: Treatment (propranolol hydrochloride, pembrolizumab)
Patients 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.
Interventions:
  • Other: Laboratory Biomarker Analysis
  • Biological: Pembrolizumab
  • Drug: Propranolol Hydrochloride
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: December 26, 2017)
47
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE January 31, 2024
Estimated Primary Completion Date January 31, 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03384836
Other Study ID Numbers  ICMJE I 53217
NCI-2017-02210 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
I 53217 ( Other Identifier: Roswell Park Cancer Institute )
P30CA016056 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Roswell Park Cancer Institute
Study Sponsor  ICMJE Roswell Park Cancer Institute
Collaborators  ICMJE National Cancer Institute (NCI)
Investigators  ICMJE
Principal Investigator: Shipra Gandhi, MD Roswell Park Cancer Institute
PRS Account Roswell Park Cancer Institute
Verification Date January 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP