Naltrexone and Propranolol Combined With Immunotherapy

NCT05968690 | Recruiting Phase 1 DMC FDA Drug

• 3 other identifiers: 092302Pro2023001214NCI-2023-06872
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 1

Brief Summary

Various forms of stress can promote cancer development and growth and negatively impact the immune system's response to tumors. Beta-adrenergic and opioid receptors co-exist in many cells including immune cells and are integral components of the body's response to stress. Pre-clinical studies have demonstrated that dual blockade of these receptors can decrease tumor growth and modulate the anti-tumor immune response. This clinical trial investigates the safety and potential therapeutic benefits of combining a beta-adrenergic blocker (propranolol) and an opioid receptor antagonist (naltrexone) with immune checkpoint inhibitors in patients with advanced melanoma.

Conditions

Advanced Melanoma

Keywords

Melanoma; Metastatic melanoma; Skin cancer; Immune checkpoint inhibitors; Propranolol; Naltrexone; Beta-adrenergic blocker; Opioid receptor antagonist; Tumor microenvironment; NK cells; T-cells; Combination therapy; Immunotherapy; Ipilimumab; Nivolumab

Outcome Measures

Primary Outcomes (3)

• Safety as assessed by Common Terminology Criteria for Adverse Events (CTCAE) v5.0

  initial 28 days of treatment and then for up to 2 years

• Dose-limiting toxicity of naltrexone in combination with propranolol and ipilimumab plus nivolumab

  initial 28 days of treatment

• Recommended phase 2 dose of naltrexone in combination with propranolol and ipilimumab plus nivolumab

  up to 2 years from start of treatment

Secondary Outcomes (3)

• Objective Response Rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1

  up to 2 years from start of treatment

• Progression-Free Survival (PFS)

  up to 2 years from start of treatment

• Overall Survival (OS)

  up to 2 years from start of treatment

Other Outcomes (1)

• Exploratory objectives are to assess the impact of propranolol + naltrexone on the anti-tumor immune response through correlative biomarker studies performed on tumor and blood.

  up to 2 years from start of treatment

Study Arms (4)

Cohort 1 - Propranolol

EXPERIMENTAL

Patients will receive intravenous ipilimumab 3 mg/kg + nivolumab 1 mg/kg every 21 days for up to 4 cycles followed by intravenous nivolumab monotherapy 480 mg every 28 days. Propranolol will be administered as 30 mg orally twice a day, continuously.

Drug: Propranolol

Cohort 2 - Propranolol + Naltrexone 4.5 mg

EXPERIMENTAL

Patients will receive intravenous ipilimumab 3 mg/kg + nivolumab 1 mg/kg every 21 days for up to 4 cycles followed by intravenous nivolumab monotherapy 480 mg every 28 days. Propranolol will be administered as 30 mg orally twice a day, continuously. Naltrexone will be administered as 4.5 mg orally once a day, continuously.

Drug: Propranolol; Drug: Naltrexone

Cohort 3 - Propranolol + Naltrexone 9 mg

EXPERIMENTAL

Patients will receive intravenous ipilimumab 3 mg/kg + nivolumab 1 mg/kg every 21 days for up to 4 cycles followed by intravenous nivolumab monotherapy 480 mg every 28 days. Propranolol will be administered as 30 mg orally twice a day, continuously. Naltrexone will be administered as 9 mg orally once a day, continuously.

Drug: Propranolol; Drug: Naltrexone

Cohort 4 - Propranolol + Naltrexone 25 mg

EXPERIMENTAL

Patients will receive intravenous ipilimumab 3 mg/kg + nivolumab 1 mg/kg every 21 days for up to 4 cycles followed by intravenous nivolumab monotherapy 480 mg every 28 days. Propranolol will be administered as 30 mg orally twice a day, continuously. Naltrexone will be administered as 25 mg orally once a day, continuously.

Drug: Propranolol; Drug: Naltrexone

Interventions

Propranolol DRUG

Propranolol will be administered to patients in all cohorts.

Cohort 1 - Propranolol; Cohort 2 - Propranolol + Naltrexone 4.5 mg; Cohort 3 - Propranolol + Naltrexone 9 mg; Cohort 4 - Propranolol + Naltrexone 25 mg

Naltrexone DRUG

Naltrexone will be administered to patients in cohorts 2, 3, and 4.

Cohort 2 - Propranolol + Naltrexone 4.5 mg; Cohort 3 - Propranolol + Naltrexone 9 mg; Cohort 4 - Propranolol + Naltrexone 25 mg

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age of 18 years or older and able to understand and sign the informed consent form.
• Histologically confirmed diagnosis of unresectable stage III or stage IV melanoma.
• Candidate for standard of care therapy with ipilimumab 3 mg/kg + nivolumab 1 mg/kg.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
• Treatment-naïve or has received any number of prior lines of therapy. Prior targeted therapy is allowed, but small molecule inhibitors must be discontinued within two weeks before starting the study.
• Life expectancy of at least 6 months.
• Presence of at least one accessible site of disease to provide an on-study biopsy for tumor tissue. The biopsy may be waived after discussion with the Principal Investigator (PI) if it is deemed unfeasible. The site may be a target lesion as long as it will not be rendered unmeasurable by the biopsy procedure.
• Willingness to undergo tumor biopsy (if archival tumor is not available) prior to initiation of therapy and while on the study.
• Willingness to provide an archival specimen block, if available, for research purposes.
• Normal organ function, defined as:
• Absolute neutrophil count (ANC) \>1500/mcL
• Platelets \>100,000/mcL
• Hemoglobin (Hb) \>9 g/dL
• Albumin \>2.5 mg/dL
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) \<2.5 times the upper limit of normal (ULN)

You may not qualify if:

• Use of corticosteroids to control immune-related adverse events at enrollment. Participants who previously required corticosteroids for symptom control must be off steroids for at least two weeks. Low-dose steroid use (=10 mg of prednisone or equivalent) as corticosteroid replacement therapy for primary or secondary adrenal insufficiency is allowed.
• Failure to recover (i.e., Grade 1 or at baseline) from adverse events due to prior treatment.
• History of grade 3-4 neurologic or cardiac toxicity or life-threatening liver toxicity poorly responsive to steroids with prior anti-PD-1 therapy.
• Presence of leptomeningeal disease.
• Active autoimmune disease unrelated to the use of immune checkpoint inhibitors that has required systemic treatment in the past year (e.g., use of disease-modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment.
• Contraindications to the use of propranolol, including:
• Cardiogenic shock.
• Sinus bradycardia greater than first-degree block.
• Severe bronchial asthma.
• Known hypersensitivity to propranolol.
• Requirement for current use of an alternative beta-blocker.
• Uncontrolled diabetes.
• Uncontrolled depression.
• Unstable angina or myocardial infarction within 3 months of Day 1 Cycle 1.
• For enrollment into Cohort 2-4 ONLY: Contraindications to the use of naltrexone, including:

Sponsors & Collaborators

• Sarah Weiss: lead

Study Sites (1)

Rutgers Cancer Institute of New Jersey

New Brunswick, New Jersey, 08903, United States

RECRUITING

MeSH Terms

Conditions

Melanoma; Skin Neoplasms

Interventions

Propranolol; Naltrexone

Condition Hierarchy (Ancestors)

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; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Phenoxypropanolamines; Propanolamines; Amino Alcohols; Alcohols; Organic Chemicals; Propanols; Amines; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Polycyclic Compounds; Naloxone; Morphinans; Opiate Alkaloids; Alkaloids; Heterocyclic Compounds; Heterocyclic Compounds, Bridged-Ring; Heterocyclic Compounds, 4 or More Rings; Heterocyclic Compounds, Fused-Ring; Phenanthrenes

Study Officials

• Sarah Weiss, MD

  Rutgers Cancer Institute of New Jersey

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Sarah Weiss, MD

CONTACT

732-235-2465; saweiss@cinj.rutgers.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Associate Professor of Medicine

Model Details: This is an open-label, single institution, phase I study with a 3+3 design of dose escalated naltrexone in combination with propranolol 30 mg bid and ipilimumab 3 mg/kg plus nivolumab 1 mg/kg q3wk for up to 4 doses followed by NIVO monotherapy q4wk in participants with advanced melanoma.

Study Record Dates

• First Submitted: July 18, 2023
• First Posted: August 1, 2023
• Study Start: September 11, 2023
• Primary Completion (Estimated): September 30, 2026
• Study Completion (Estimated): September 30, 2027
• Last Updated: September 18, 2025

Record last verified: 2025-09

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)