Advanced MelanomaPhase 1NCT05968690
Naltrexone and Propranolol Combined With Immunotherapy
A Phase 1 study testing Propranolol and Naltrexone in people with Advanced Melanoma, run by Sarah Weiss at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Advanced Melanoma
- What is being tested?
- Propranolol and Naltrexone
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 12 participants
- Where
- 1 siteUnited States
- Study dates
- 11 Sep 2023to 30 Sep 2027
- Phase
- Phase 1
- Are there results?
- Not yet: the study is under way
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
- 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.
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- 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)
- 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.
Who cannot join
- 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.
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- 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:
- Participants currently receiving opioid analgesics or anticipated to require opioid analgesics in the near future.
- Participants currently dependent on opioids, including those currently maintained on opiate agonists (e.g., methadone) or partial agonists (e.g., buprenorphine).
- Participants in acute opioid withdrawal.
- 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
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
United States1 site, 1 recruiting
- Recruiting
Rutgers Cancer Institute of New Jersey
New Brunswick, New Jersey, 08903
Sarah Weiss, MD, 732-235-2465, saweiss@cinj.rutgers.edu
About this study
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
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.
Read the 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.
- Conditions
- Advanced Melanoma
- Being tested
- Propranolol, Naltrexone
- 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
- Medical subject headings
- Melanoma, Skin Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PropranololDrug
Propranolol will be administered to patients in all cohorts.
NaltrexoneDrug
Naltrexone will be administered to patients in cohorts 2, 3, and 4.
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: 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. Receives: 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. Receives: Drug: Propranolol; Drug: Naltrexone |
What is being measured
The primary outcome is the main question the study is designed to answer.
Safety as assessed by Common Terminology Criteria for Adverse Events (CTCAE) v5.0
Measured: 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
Measured: initial 28 days of treatment
Recommended phase 2 dose of naltrexone in combination with propranolol and ipilimumab plus nivolumab
Measured: 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
Measured: up to 2 years from start of treatment
Progression-Free Survival (PFS)
Measured: up to 2 years from start of treatment
Overall Survival (OS)
Measured: up to 2 years from start of treatment
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted1 Aug 2023
- Study start11 Sep 2023
- Primary completion30 Sep 2026 (estimated)
- Study completion30 Sep 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Advanced MelanomaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
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
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- 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)
- Enrolment
- 12 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Sarah Weiss
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor-investigator, Sarah Weiss, Rutgers, The State University of New Jersey
- Investigators
- Sarah Weiss, MD, Principal investigator, Rutgers Cancer Institute of New Jersey
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05968690
- Sponsor's protocol ID
- 092302
- Other IDs
- Pro2023001214, NCI-2023-06872
- Status last verified
- Sep 2025
- First submitted
- 18 Jul 2023
- Last updated
- 18 Sep 2025
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 18 Sep 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT05968690
- Acronym / sponsor ID
- 092302
- Conditions
- Advanced Melanoma
- Keywords
- Melanoma, Metastatic melanoma, Skin cancer, Immune checkpoint inhibitors, Propranolol, Naltrexone, Beta-adrenergic blocker, Opioid receptor antagonist
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 12 participants (estimated)
- Lead sponsor
- Sarah WeissUniversity, hospital or other
- Study start
- 11 Sep 2023 (actual)
- Primary completion
- 30 Sep 2026 (estimated)
- Study completion
- 30 Sep 2027 (estimated)
- First posted
- 1 Aug 2023 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Number of arms
- 4
- 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.
| Arm | Type | Receives |
|---|---|---|
| Cohort 1 - Propranolol | Experimental | Drug: PropranololPatients 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. |
| Cohort 2 - Propranolol + Naltrexone 4.5 mg | Experimental | Drug: Propranolol, Drug: NaltrexonePatients 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. |
| Cohort 3 - Propranolol + Naltrexone 9 mg | Experimental | Drug: Propranolol, Drug: NaltrexonePatients 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. |
| Cohort 4 - Propranolol + Naltrexone 25 mg | Experimental | Drug: Propranolol, Drug: NaltrexonePatients 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. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (21 listed)
- 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.
Key exclusion criteria (27 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| PropranololPropranolol will be administered to patients in all cohorts. | Drug | Cohort 1 - Propranolol, Cohort 2 - Propranolol + Naltrexone 4.5 mg, Cohort 3 - Propranolol + Naltrexone 9 mg, Cohort 4 - Propranolol + Naltrexone 25 mg |
| NaltrexoneNaltrexone will be administered to patients in cohorts 2, 3, and 4. | Drug | Cohort 2 - Propranolol + Naltrexone 4.5 mg, Cohort 3 - Propranolol + Naltrexone 9 mg, Cohort 4 - Propranolol + Naltrexone 25 mg |
Primary outcome
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
Dose-limiting toxicity of naltrexone in combination with propranolol and ipilimumab plus nivolumab
Time frame: initial 28 days of treatment
Recommended phase 2 dose of naltrexone in combination with propranolol and ipilimumab plus nivolumab
Time frame: up to 2 years from start of treatment
3 secondary outcomes
Objective Response Rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
Time frame: up to 2 years from start of treatment
Progression-Free Survival (PFS)
Time frame: up to 2 years from start of treatment
Overall Survival (OS)
Time frame: up to 2 years from start of treatment
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 18 Sep 2025.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Sarah Weiss, MD principal investigator
Rutgers Cancer Institute of New Jersey
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Propranolol and Naltrexone in people with Advanced Melanoma, run by Sarah Weiss at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 21 inclusion and 27 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 18 Sep 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Sarah Weiss, MD (732-235-2465, saweiss@cinj.rutgers.edu), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Sep 2025.