Naltrexone + Propranolol Combined With Immunotherapy for Melanoma
Recruiting in Palo Alto (17 mi)
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
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
Breakthrough Therapy
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.12345
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.34567
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.13457
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.
See 12 more
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.
See 11 more
Trial 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 (Opioid Receptor Antagonist)
- Propranolol (Beta-adrenergic Blocker)
Trial OverviewThe 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
4Treatment groups
Experimental Treatment
Group I: Cohort 4 - Propranolol + Naltrexone 25 mgExperimental Treatment2 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 mgExperimental Treatment2 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 mgExperimental Treatment2 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 - PropranololExperimental Treatment1 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.
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Rutgers Cancer Institute of New JerseyNew Brunswick, NJ
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Who Is Running the Clinical Trial?
Sarah WeissLead Sponsor
Ryan StephensonLead Sponsor
Rutgers, The State University of New JerseyLead Sponsor
References
The Role of β-Blockers in Melanoma. [2021]Melanoma is one of the most aggressive and less chemotherapy-responsive human cancers, representing a major public health issue worldwide. The early diagnosis still represents the best approach in order to reduce mortality, especially in advanced stages. Preclinical evidence, collected through several in vitro and in vivo models, has been accumulating about the pathophysiological involvement of β-adrenoceptors in melanoma progression. This involvement has been paralleled by the evidence that drugs blocking β-adrenoceptors (β-blockers) may have a relevant role in the treatment of melanoma and in the prevention of its progression. β-blockers are a class of drugs extensively used in clinical practice, not limited to cardiovascular therapeutics. Evidence collected through retrospective and prospective observational studies suggests that treatment with β-blockers, mainly propranolol, is able to delay melanoma progression. Although conclusive evidence is still lacking, current knowledge proposes β-blockers as an opportunity for antitumor treatment in melanoma. Clinical trials are needed in order to prove their claimed efficacy. Graphical Abstract.
Propranolol induces a favourable shift of anti-tumor immunity in a murine spontaneous model of melanoma. [2022]In a previous study on a xenograft model of melanoma, we showed that the beta-adrenergic receptor antagonist propranolol inhibits melanoma development by modulating angiogenesis, proliferation and cell survival. Stress hormones can influence tumor development in different ways and norepinephrine was shown to downregulate antitumor immune responses by favoring the accumulation of immunosuppressive cells, impairing the function of lymphocytes. We assessed the effect of propranolol on antitumor immune response in the MT/Ret mouse model of melanoma. Propranolol treatment delayed primary tumor growth and metastases development in MT/Ret mice. Consistent with our previous observations in human melanoma xenografts, propranolol induces a decrease in cell proliferation and vessel density in the primary tumors and in metastases. In this immunocompetent model, propranolol significantly reduced the infiltration of myeloid cells, particularly neutrophils, in the primary tumor. Inversely, cytotoxic tumor infiltrating lymphocytes were more frequent in the tumor stroma of treated mice. In a consistent manner, we observed the same shift in the proportions of infiltrating leukocytes in the metastases of treated mice. Our results suggest that propranolol, by decreasing the infiltration of immunosuppressive myeloid cells in the tumor microenvironment, restores a better control of the tumor by cytotoxic cells.
Biphasic effects of propranolol on tumour growth in B16F10 melanoma-bearing mice. [2021]Propranolol is a vasoactive drug that shows antiangiogenic and antitumour activities in melanoma. However, it is unknown whether these activities are dose-dependent and whether there is a relationship between systemic vascular effects of propranolol and anti-melanoma activity.
Drug repurposing and rediscovery: Design, synthesis and preliminary biological evaluation of 1-arylamino-3-aryloxypropan-2-ols as anti-melanoma agents. [2021]Malignant melanoma (MM) presents as the highest morbidity and mortality type in skin cancer. Herein, inspired by the previously reported anti-melanoma effect of propranolol, a widely applied β adrenergic receptor antagonist as cardiovascular drug, we set out to exploit its potential as anti-melanoma therapy based on the drug repurposing strategy. Structural optimization of propranolol yielded 5m, which exhibits dramatically improved potency on human melanoma cell growth (1.98-3.70 μM), compared to propranolol (59.5-75.8 μM). Further investigation demonstrated that 5m could inhibit colony formation of melanoma cell line (completely abolished at 2 μM for 5m, partially inhibited at 50 μM for propranolol), induce cell apoptosis and cell cycle arrest in the G2/M phase (both observed at 1 μM). Preliminary mechanism study indicated that 5m could disrupt the cellular microtubule network, which suggested tubulin as a potential target. Docking study provided a structural insight into the interaction between 5m and tubulin. In summary, our study presents a drug repurposing case that redirects a cardiovascular agent to an anti-melanoma agent.
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]Cancer progression is known to be promoted by increased body stress caused by elevated beta-adrenergic and opioidergic nervous system activities. The effects of β2-adrenergic blocker propranolol (PRO) and μ-opioid receptor antagonist naltrexone (NTX) were tested using a preclinical model of human breast cancer. These drugs, individually, and more potently when combined, inhibited the cell growth and progression of breast cancer cells in vitro in cultures, and in vivo in rat xenografts. The antitumor activities of these drugs were associated with direct cell intrinsic effects, including increased cell growth arrest, elevated levels of apoptotic proteins, and reduced production of epithelial-mesenchymal transition factors by the tumor cells, as well as effects on innate immune activation and reduced inflammatory cytokine levels in plasma. These data suggest that the combined treatments of PRO and NTX produce impressive antitumor effects in the preclinical breast cancer model, and thereby may provide a new combinatorial treatment strategy with more clinical treatment modalities.
Can propranolol prevent progression of melanoma? [2020]The worldwide incidence of melanoma has risen rapidly in the past 50 years and is a considerable public health burden in the United States, with significant financial implications. Studies have demonstrated the potential anticarcinogenic effects of antihypertensive agents, specifically beta-blockers, in patients with prostate cancer, breast cancer, and lately cutaneous malignant melanoma. This article explores the empirical clinical evidence of propranolol's anticarcinogenic effects on melanoma and the chemoprotective mechanisms of beta-blockers and other agents that have been used to modify melanoma progression.
Phase I Clinical Trial of Combination Propranolol and Pembrolizumab in Locally Advanced and Metastatic Melanoma: Safety, Tolerability, and Preliminary Evidence of Antitumor Activity. [2022]Increased β-adrenergic receptor (β-AR) signaling has been shown to promote the creation of an immunosuppressive tumor microenvironment (TME). Preclinical studies have shown that abrogation of this signaling pathway, particularly β2-AR, provides a more favorable TME that enhances the activity of anti-PD-1 checkpoint inhibitors. We hypothesize that blocking stress-related immunosuppressive pathways would improve tumor response to immune checkpoint inhibitors in patients. Here, we report the results of dose escalation of a nonselective β-blocker (propranolol) with pembrolizumab in patients with metastatic melanoma.