Naltrexone + Propranolol Combined With Immunotherapy for Melanoma

Overseen By Sarah Weiss, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Sarah Weiss

Must be taking: Beta-blockers, Opioid antagonists

Must not be taking: Opioids, Corticosteroids

Disqualifiers: Brain metastases, Autoimmune disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 0

Duration: 12-16 weeks

12 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial tests a new treatment for patients with advanced melanoma. The treatment combines drugs that block stress signals with drugs that help the immune system fight cancer. Researchers want to see if this combination is safe and effective.

Do I need to stop my current medications to join the trial?

The trial requires that small molecule inhibitors be stopped two weeks before starting. If you're on corticosteroids, you must be off them for at least two weeks, unless it's a low-dose replacement therapy. Other medications are not specifically mentioned, so it's best to discuss with the trial team.

What evidence supports the effectiveness of the drug combination of Naltrexone and Propranolol with Immunotherapy for treating melanoma?

Research suggests that propranolol, a beta-blocker, may help slow down melanoma progression by affecting tumor growth and immune response. Additionally, a study on breast cancer showed that combining propranolol with naltrexone, an opioid blocker, had strong anti-tumor effects, indicating potential benefits for melanoma treatment as well. ^{1 2 3 4 5}

Is the combination of Naltrexone and Propranolol safe for use in humans?

Research on the combination of Naltrexone and Propranolol in a preclinical model of breast cancer showed promising antitumor effects, but specific safety data for humans is not provided. Propranolol has been studied in combination with other treatments for melanoma, showing potential benefits, but detailed safety information for the combination with Naltrexone in humans is not available. ^{3 4 5 6 7}

How does the drug combination of Naltrexone and Propranolol with Immunotherapy differ from other melanoma treatments?

This treatment is unique because it combines Naltrexone and Propranolol, which are typically used for other conditions, with immunotherapy to potentially enhance the immune response against melanoma. Propranolol, a beta-blocker, may improve the tumor environment for immunotherapy by reducing stress-related signals that suppress the immune system, while Naltrexone, an opioid receptor antagonist, may further support immune activation. ^{1 3 4 5 7}

Research Team

Sarah Weiss, MD

Principal Investigator

Rutgers Cancer Institute of New Jersey

Eligibility Criteria

Adults with advanced melanoma, either treatment-naïve or previously treated, can join this trial. They must have measurable cancer lesions and normal organ function. Women of childbearing age should use effective contraception or abstain from sex for six months post-treatment; men also need to agree to contraception use. Participants cannot have other active cancers, untreated brain metastases, severe past reactions to anti-PD-1 therapy, certain infections like hepatitis B/C, or be on steroids at enrollment.

Inclusion Criteria

My melanoma is at an advanced stage and cannot be surgically removed.

I am 18 or older and can understand and sign a consent form.

I am fully active or have some restrictions but can still care for myself.

Exclusion Criteria

I have no other cancers except for skin cancer.

I am not using opioids, not opioid-dependent, not pregnant, and not breastfeeding.

I have small, symptom-free brain metastases not requiring immediate treatment.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive propranolol and naltrexone in combination with ipilimumab and nivolumab. Ipilimumab and nivolumab are administered every 21 days for up to 4 cycles, followed by nivolumab monotherapy every 28 days.

12-16 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Naltrexone
• Propranolol

Trial Overview The trial tests the combination of propranolol (a beta-blocker) and naltrexone (an opioid blocker) with standard immunotherapy in patients with melanoma. It aims to see if stress receptor blockade enhances immune response against tumors. Patients will receive these medications alongside immune checkpoint inhibitors ipilimumab and nivolumab.

Participant Groups

Group I: Cohort 4 - Propranolol + Naltrexone 25 mg Experimental Treatment 2 Interventions

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.

Group II: Cohort 3 - Propranolol + Naltrexone 9 mg Experimental Treatment 2 Interventions

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.

Group III: Cohort 2 - Propranolol + Naltrexone 4.5 mg Experimental Treatment 2 Interventions

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.

Group IV: Cohort 1 - Propranolol Experimental Treatment 1 Intervention

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.

Who Is Running the Clinical Trial?

Sarah Weiss

Lead Sponsor

Trials

1

Recruited

10+

Ryan Stephenson

Lead Sponsor

Trials

1

Recruited

10+

Rutgers, The State University of New Jersey

Lead Sponsor

Trials

471

Recruited

81,700+

Findings from Research

Preclinical studies suggest that β-adrenoceptors play a significant role in the progression of melanoma, indicating that targeting these receptors could be a potential therapeutic strategy.

Retrospective and prospective observational studies indicate that β-blockers, particularly propranolol, may delay melanoma progression, highlighting the need for further clinical trials to confirm their efficacy as an antitumor treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Role of β-Blockers in Melanoma. De Giorgi, V., Geppetti, P., Lupi, C., et al.[2021]

Propranolol, a beta-adrenergic receptor antagonist, effectively delays tumor growth and metastasis in a mouse model of melanoma by reducing cell proliferation and blood vessel density in tumors.

The treatment enhances the antitumor immune response by decreasing the infiltration of immunosuppressive myeloid cells and increasing the presence of cytotoxic lymphocytes, suggesting a mechanism that improves tumor control.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Propranolol induces a favourable shift of anti-tumor immunity in a murine spontaneous model of melanoma. Jean Wrobel, L., Bod, L., Lengagne, R., et al.[2022]

Propranolol demonstrates a U-shaped biphasic dose-response in inhibiting melanoma growth, where low doses (10 and 20 mg·kg-1·day-1) effectively reduce tumor size, while higher doses become less effective and can even stimulate tumor arteriogenesis.

The study suggests a direct relationship between systemic vascular resistance (SVR) and anti-melanoma activity, indicating that propranolol's effects on tumor growth are influenced by its dose-dependent impact on blood vessel behavior.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biphasic effects of propranolol on tumour growth in B16F10 melanoma-bearing mice. Maccari, S., Buoncervello, M., Rampin, A., et al.[2021]

A new compound derived from propranolol, called 5m, shows significantly improved potency against human melanoma cells, with effective concentrations ranging from 1.98 to 3.70 μM, compared to propranolol's 59.5 to 75.8 μM.

5m not only inhibits melanoma cell growth but also induces cell apoptosis and causes cell cycle arrest at low concentrations, suggesting it disrupts the microtubule network and targets tubulin, making it a promising candidate for anti-melanoma therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Drug repurposing and rediscovery: Design, synthesis and preliminary biological evaluation of 1-arylamino-3-aryloxypropan-2-ols as anti-melanoma agents. Chang, Q., Long, J., Hu, L., et al.[2021]

The combination of the β2-adrenergic blocker propranolol and the μ-opioid receptor antagonist naltrexone significantly inhibited breast cancer cell growth in both laboratory cultures and in rat models, suggesting a potent antitumor effect.

The antitumor activity was linked to mechanisms such as increased cell growth arrest, higher levels of apoptotic proteins, and reduced inflammatory responses, indicating that this combination therapy could be a promising new strategy for breast cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Beta 2 Adrenergic Receptor Antagonist Propranolol and Opioidergic Receptor Antagonist Naltrexone Produce Synergistic Effects on Breast Cancer Growth Prevention by Acting on Cancer Cells and Immune Environment in a Preclinical Model of Breast Cancer. Murugan, S., Rousseau, B., Sarkar, DK.[2023]

Propranolol, a beta-blocker, may have potential anticarcinogenic effects against melanoma, as suggested by emerging clinical evidence.

The article discusses the mechanisms by which beta-blockers and other agents could help slow down the progression of melanoma, highlighting their possible role in cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Can propranolol prevent progression of melanoma? Kao, J., Luu, B.[2020]

The combination of the nonselective β-blocker propranolol with the immune checkpoint inhibitor pembrolizumab was found to be safe for patients with metastatic melanoma, with no dose-limiting toxicities reported during the study.

The treatment showed a high objective response rate of 78%, suggesting that blocking β-adrenergic signaling may enhance the effectiveness of immune therapies in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I Clinical Trial of Combination Propranolol and Pembrolizumab in Locally Advanced and Metastatic Melanoma: Safety, Tolerability, and Preliminary Evidence of Antitumor Activity. Gandhi, S., Pandey, MR., Attwood, K., et al.[2022]

References

1. United States pubmed.ncbi.nlm.nih.gov

The Role of β-Blockers in Melanoma. [2021]

2. United States pubmed.ncbi.nlm.nih.gov

Propranolol induces a favourable shift of anti-tumor immunity in a murine spontaneous model of melanoma. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Biphasic effects of propranolol on tumour growth in B16F10 melanoma-bearing mice. [2021]

4. England pubmed.ncbi.nlm.nih.gov

Drug repurposing and rediscovery: Design, synthesis and preliminary biological evaluation of 1-arylamino-3-aryloxypropan-2-ols as anti-melanoma agents. [2021]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Beta 2 Adrenergic Receptor Antagonist Propranolol and Opioidergic Receptor Antagonist Naltrexone Produce Synergistic Effects on Breast Cancer Growth Prevention by Acting on Cancer Cells and Immune Environment in a Preclinical Model of Breast Cancer. [2023]

6. United States pubmed.ncbi.nlm.nih.gov

Can propranolol prevent progression of melanoma? [2020]

7. United States pubmed.ncbi.nlm.nih.gov

Phase I Clinical Trial of Combination Propranolol and Pembrolizumab in Locally Advanced and Metastatic Melanoma: Safety, Tolerability, and Preliminary Evidence of Antitumor Activity. [2022]