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: Unknown

Duration: 12-16 weeks

12 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines how combining two stress-related drugs, propranolol and naltrexone, with standard cancer treatment might benefit people with advanced melanoma. The goal is to determine if blocking certain stress responses can slow cancer growth and enhance the immune system's ability to fight tumors. Individuals with advanced melanoma that cannot be surgically removed and who qualify for standard cancer treatment may be suitable candidates for this study. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this innovative approach.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that using propranolol and naltrexone together can affect tumor growth and the body's immune response, primarily observed in early research. Propranolol, commonly used for high blood pressure and heart issues, may slow melanoma growth, a type of skin cancer. Naltrexone, typically used for addiction treatment, might also aid in fighting cancer when taken in low doses.

A study on the combination of propranolol and naltrexone found encouraging results in reducing tumor growth in a breast cancer model. This suggests the combination could be safe and effective for humans as well.

However, this trial remains in its early stages, so researchers are carefully monitoring safety. While propranolol and naltrexone are generally safe for their usual purposes, more research is needed to understand their combined effects on cancer. Researchers continue to learn about possible side effects and the best doses to use. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about this treatment approach for melanoma because it combines naltrexone and propranolol with existing immunotherapy drugs, potentially enhancing their effectiveness. While standard treatments like ipilimumab and nivolumab work by stimulating the immune system to attack cancer cells, the addition of propranolol, a beta-blocker, and naltrexone, typically used for addiction, could modulate the body's stress response and immune function, respectively. This combination might improve patient outcomes by addressing tumor growth from multiple angles, offering a more comprehensive attack on the cancer cells compared to current options.

What evidence suggests that this trial's treatments could be effective for melanoma?

Research suggests that combining propranolol and naltrexone might help treat melanoma, a type of skin cancer. Early studies show that this combination can slow tumor growth and alter the immune system's response to cancer. In this trial, participants will join different cohorts to receive varying doses of naltrexone with propranolol, or propranolol alone. Propranolol, commonly used for heart issues, has been linked to slowing melanoma progression and improving survival rates. Specifically, studies found that fewer patients taking propranolol experienced disease progression compared to those who did not. Naltrexone, typically given in low doses, has shown promise as an additional cancer treatment. Together, these drugs target stress-related pathways that can aid cancer growth, potentially making them effective against melanoma. ^{6 7 8 9 10}

Who Is on the Research Team?

Sarah Weiss, MD

Principal Investigator

Rutgers Cancer Institute of New Jersey

Are You a Good Fit for This Trial?

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

I have or haven't had cancer treatment before, but I stopped any small molecule inhibitors two weeks ago.

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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