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

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.

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 disease 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.