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Stage IIIC Cutaneous Melanoma AJCC v7Phase 1/2NCT03384836

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

A Phase 1/2 study testing Laboratory Biomarker Analysis, Pembrolizumab and Propranolol Hydrochloride in people with Stage IIIC Cutaneous Melanoma AJCC v7 and Stage IV Cutaneous Melanoma AJCC v6 and v7, run by Roswell Park Cancer Institute at 4 sites in United States.

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Official record

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Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Laboratory Biomarker Analysis, Pembrolizumab and Propranolol Hydrochloride
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
47 participants
Where
4 sitesUnited States
Study dates
31 Jan 2018to 31 May 2027
Phase
Phase 1/2

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
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  • 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 or plasma (based on site's SOP) 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 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

Who cannot join

  • 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 that are already on non-selective B-AR blockers for various indications. Patients on selective beta-blockers are considered eligible for enrollment with a caveat that their clinician prescribing the beta-blocker is willing to discontinue their selective beta-blocker in order to transition to propranolol at the specified protocol dose.
  • 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
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  • 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), bradycardia (resting heart rate <55bpm), 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 non-selective beta-blockers or non-dihydropyridine calcium channel blockers. Patients on selective beta blockers will be eligible for enrollment only under the condition that their prescribing clinician is willing to discontinue their selective beta blocker in order to begin propranolol and only at the specified dose (after which time the patient is not to be started on any non-selective beta-blockers or non-dihydropyridine 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
  • Has received a live vaccine or live-attenuated vaccine 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. Administration of killed vaccines is allowed.

Trial locations and contacts

4 sites in 1 country.

United States4 sites

  • Emory University Hospital/ Winship Cancer Institute

    Atlanta, Georgia, 30322

  • Roswell Park Cancer Institute

    Buffalo, New York, 14263

  • Cleveland Clinic Cancer Center

    Cleveland, Ohio, 44195

  • Penn State Milton S. Hershy Medical Center Cancer Institute

    Hershey, Pennsylvania, 17033

Other trials in United States

About this study

Official title: A Phase Ib/II Study of Propranolol With Fixed-Dose Pembrolizumab in Patients With Unresectable Stage III and Stage IV Melanoma

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.

Read the detailed description

PRIMARY OBJECTIVES:

  1. 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:

  1. 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:

  1. 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.

Being tested
Laboratory Biomarker Analysis, Pembrolizumab, Propranolol Hydrochloride
Keywords
Melanoma, Immune Checkpoint Inhibitors, Beta Adrenergic Blockers
Medical subject headings
Melanoma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Laboratory Biomarker AnalysisOther

    Correlative studies

  • PembrolizumabBiological

    Also called Keytruda, Lambrolizumab, MK-3475, SCH 900475

    Given IV

  • Propranolol HydrochlorideDrug

    Also called Inderal, Innopran XL

    Given PO

Study groups in NCT03384836
Study groupRoleWhat they receive
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.
Receives: Other: Laboratory Biomarker Analysis; Biological: Pembrolizumab; Drug: Propranolol Hydrochloride

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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)

    Adverse events and toxicities will be summarized by dose level using frequencies and relative frequencies.

    Measured: Up to 12 weeks

  2. Overall response rate (ORR) per immune-related Response Evaluation Criteria in Solid Tumors (irRECIST) version 1.1 (Phase II)

    ORR is defined as partial or complete response within 6 months of initiating combination therapy.

    Measured: Up to 6 months

Secondary outcomes (3)

  1. Overall survival (OS) (Phase II)

    Will be summarized using standard Kaplan-Meier methods and rates will be obtained with 90% confidence intervals.

    Measured: From treatment initiation until death due to any cause (event) or last follow-up, assessed up to 2 years

  2. PFS (Phase II)

    Will summarized using standard Kaplan-Meier methods and rates will be obtained with 90% confidence intervals.

    Measured: From treatment initiation until disease progression, death due to disease (events), or last follow-up, assessed up to 2 years

  3. Progression free survival (PFS) (Phase II)

    Will be summarized using standard Kaplan-Meier methods and rates will be obtained with 90% confidence intervals.

    Measured: At 1 year

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted27 Dec 2017
  2. Study start31 Jan 2018
  3. Primary completion31 May 2027 (estimated)
  4. Study completion31 May 2027 (estimated)

Why it stopped: interim Analysis

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
47 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03384836
Sponsor's protocol ID
I 53217
Other IDs
NCI-2017-02210, I 53217
Status last verified
Jul 2026
First submitted
12 Dec 2017
Last updated
15 Jul 2026
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No

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