Naltrexone and Propranolol Combined With Immunotherapy

• ClinicalTrials.gov Identifier: NCT05968690
• Recruitment Status: Recruiting
• First Posted: August 1, 2023
• Last Update Posted: November 15, 2023
• Sponsor: Ryan Stephenson
• Information provided by (Responsible Party): Ryan Stephenson, Rutgers, The State University of New Jersey

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Advanced Melanoma	Drug: Propranolol; Drug: Naltrexone	Phase 1

Detailed Description:

This is an open-label, single institution, phase I clinical trial to investigate the safety, tolerability, and preliminary efficacy of dose-escalated naltrexone (NTX) in combination with propranolol (PRO), ipilimumab (IPI), and nivolumab (NIVO) in patients with advanced melanoma.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 12 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Intervention Model Description: 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.
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I Study to Evaluate the Safety of Naltrexone and Propranolol in Combination With Standard of Care Ipilimumab and Nivolumab in Patients With Advanced Melanoma
• Actual Study Start Date: September 11, 2023
• Estimated Primary Completion Date: September 30, 2025
• Estimated Study Completion Date: September 30, 2025

Arms and Interventions

Arm	Intervention/treatment
Experimental: Cohort 1 - Propranolol; 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; Propranolol will be administered to patients in all cohorts.
Experimental: Cohort 2 - Propranolol + Naltrexone 4.5 mg; 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; Propranolol will be administered to patients in all cohorts.; Drug: Naltrexone; Naltrexone will be administered to patients in cohorts 2, 3, and 4.
Experimental: Cohort 3 - Propranolol + Naltrexone 9 mg; 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; Propranolol will be administered to patients in all cohorts.; Drug: Naltrexone; Naltrexone will be administered to patients in cohorts 2, 3, and 4.
Experimental: Cohort 4 - Propranolol + Naltrexone 25 mg; 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; Propranolol will be administered to patients in all cohorts.; Drug: Naltrexone; Naltrexone will be administered to patients in cohorts 2, 3, and 4.

Outcome Measures

Primary Outcome Measures :

1. Safety as assessed by Common Terminology Criteria for Adverse Events (CTCAE) v5.0 [ Time Frame: initial 28 days of treatment and then for up to 2 years ]
2. Dose-limiting toxicity of naltrexone in combination with propranolol and ipilimumab plus nivolumab [ Time Frame: initial 28 days of treatment ]
3. Recommended phase 2 dose of naltrexone in combination with propranolol and ipilimumab plus nivolumab [ Time Frame: up to 2 years from start of treatment ]

Secondary Outcome Measures :

1. Objective Response Rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 [ Time Frame: up to 2 years from start of treatment ]
2. Progression-Free Survival (PFS) [ Time Frame: up to 2 years from start of treatment ]
3. Overall Survival (OS) [ Time Frame: up to 2 years from start of treatment ]

Other Outcome Measures:

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. [ Time Frame: up to 2 years from start of treatment ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• 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:

  1. Absolute neutrophil count (ANC) >1500/mcL
  2. Platelets >100,000/mcL
  3. Hemoglobin (Hb) >9 g/dL
  4. Albumin >2.5 mg/dL
  5. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <2.5 times the upper limit of normal (ULN)
  6. Serum total bilirubin <1.5 times ULN or direct bilirubin < ULN for subjects with total bilirubin levels >1.5 times ULN.
• Female participants of childbearing potential should have a negative serum pregnancy test within 72 hours prior to receiving the first dose of study medication.
• Female participants of childbearing potential should be willing to use a highly effective form of contraception (hormonal or intrauterine device) along with a condom in their male partner, or be surgically sterile, or abstain from heterosexual activity for a period of at least six months after the last dose of study medication.
• Male participants should agree to use an adequate method of contraception starting with the first dose of study therapy through at least six months after the last dose of study drug.
• Participants must have at least one measurable lesion at baseline by computed tomography (CT) or magnetic resonance imaging (MRI) as per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria. Tumor sites situated in a previously irradiated area or in an area subjected to other loco-regional therapy are not considered measurable unless there has been demonstrated progression in the lesion.
• Prior focal radiotherapy is allowed.

Exclusion Criteria:

• Presence of untreated brain metastases, unless discussed with the Principal Investigator (PI) and meet specific criteria for inclusion (treatment-naïve patients with brain metastases <10 mm, asymptomatic, without significant edema, hemorrhage, shift, or requirement for steroids or anti-seizure medications, and not in eloquent areas). These patients may potentially forego initial local treatment of the brain metastases and have them reassessed after consultation with the Neurosurgery and Radiation Oncology teams.
• 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:

  1. Cardiogenic shock.
  2. Sinus bradycardia greater than first-degree block.
  3. Severe bronchial asthma.
  4. Known hypersensitivity to propranolol.
  5. Requirement for current use of an alternative beta-blocker.
  6. Uncontrolled diabetes.
  7. Uncontrolled depression.
  8. 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:

  1. Participants currently receiving opioid analgesics or anticipated to require opioid analgesics in the near future.
  2. Participants currently dependent on opioids, including those currently maintained on opiate agonists (e.g., methadone) or partial agonists (e.g., buprenorphine).
  3. Participants in acute opioid withdrawal.
  4. Individuals with a history of sensitivity to naltrexone.
• Pregnancy or breastfeeding. If a woman becomes pregnant or suspects she is pregnant while participating in this study, she should inform her treating physician immediately. Breastfeeding must be discontinued if the mother is enrolled in this trial due to the potential risk for adverse events in nursing infants.
• Receipt of any other investigational agents or participation in a study of an investigational agent or use of an investigational device within four weeks of the first dose of treatment.
• Concurrent condition (including medical illness, active infection requiring treatment with intravenous antibiotics, or presence of laboratory abnormalities) or history of a prior condition that places the patient at unacceptable risk if treated with the study drug or confounds the ability to interpret data from the study.
• Concurrent, active malignancies in addition to those being studied, except for cutaneous squamous cell carcinoma or basal cell carcinoma.
• Active (non-infectious) pneumonitis.
• Hepatitis B (HBV) or Hepatitis C (HCV) acute or chronic infection.
• Receipt of a live vaccine

Contacts and Locations

Contacts

Contact: Sarah Weiss, MD; 732-235-2465; saweiss@cinj.rutgers.edu

Locations

United States, New Jersey

Rutgers Cancer Institute of New Jersey; Recruiting

New Brunswick, New Jersey, United States, 08903

Contact: Sarah Weiss, MD 732-235-2465 saweiss@cinj.rutgers.edu

Sponsors and Collaborators

Ryan Stephenson

Investigators

• Principal Investigator: Sarah Weiss, MD; Rutgers Cancer Institute of New Jersey

More Information

• Responsible Party: Ryan Stephenson, Associate Professor of Medicine, Rutgers, The State University of New Jersey
• ClinicalTrials.gov Identifier: NCT05968690
• Other Study ID Numbers: 092302; Pro2023001214 ( Other Identifier: Rutgers, The State University of New Jersey ); NCI-2023-06872 ( Other Identifier: NCI CTRP (Clinical Trial Reporting Program) )
• First Posted: August 1, 2023
• Last Update Posted: November 15, 2023
• Last Verified: November 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• 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

Keywords provided by Ryan Stephenson, Rutgers, The State University of New Jersey:

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

Additional relevant MeSH terms:

Melanoma; Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Propranolol; Naltrexone; Alcohol Deterrents; Narcotic Antagonists; Physiological Effects of Drugs; Sensory System Agents; Peripheral Nervous System Agents; Adrenergic beta-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Antihypertensive Agents; Vasodilator Agents