RECRUITING

Naltrexone and Propranolol Combined With Immunotherapy

Conditions

Advanced Melanoma 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

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Study Overview

This clinical trial focuses on testing the efficacy of different digital interventions to promote re-engagement in cancer-related long-term follow-up care for adolescent and young adult (AYA) survivors of childhood cancer.

Description

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.

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

Quick Facts

Study Start:2023-09-11

Study Completion:2025-09-30

Study Type:Not specified

Phase:Not Applicable

Enrollment:Not specified

Status:RECRUITING

Study ID

NCT05968690

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Ages Eligible for Study:18 Years

Sexes Eligible for Study:ALL

Accepts Healthy Volunteers:No

Standard Ages:ADULT, OLDER_ADULT

Inclusion Criteria	Exclusion 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.	* 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

Inclusion Criteria

Exclusion 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.

* 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

Study Contact

Sarah Weiss, MD

CONTACT

732-235-2465

saweiss@cinj.rutgers.edu

Principal Investigator

Sarah Weiss, MD

PRINCIPAL_INVESTIGATOR

Rutgers Cancer Institute of New Jersey

Study Locations (Sites)

Rutgers Cancer Institute of New Jersey

New Brunswick, New Jersey, 08903

United States

Collaborators and Investigators

Sponsor: Ryan Stephenson

Sarah Weiss, MD, PRINCIPAL_INVESTIGATOR, Rutgers Cancer Institute of New Jersey

Study Record Dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates

Study Start Date2023-09-11

Study Completion Date2025-09-30

Study Record Updates

Study Start Date2023-09-11

Study Completion Date2025-09-30

Terms related to this study

Keywords Provided by Researchers

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

Advanced Melanoma