Combination Therapy for Melanoma

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Roswell Park Cancer Institute

Must be taking: Anti-PD-1/PD-L1

Must not be taking: Immunosuppressants, Steroids

Disqualifiers: Active infection, CNS metastases, Cardiac events, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 7

Duration: 12 weeks

Trial Summary

Will I have to stop taking my current medications?

The trial requires that you stop taking systemic immunosuppressive agents, including steroids, at least 3 weeks before starting the study, unless they are for endocrine dysfunction and are 10 mg or less of prednisone (or equivalent). Other medications are not specifically mentioned, so it's best to discuss your current medications with the study team.

What data supports the effectiveness of the treatment for melanoma?

Research shows that high-dose interferon alpha-2b (a component of the treatment) can significantly reduce the frequency of melanoma relapse and improve survival rates in high-risk patients. This suggests that the treatment may be effective in managing melanoma. ^{1 2 3 4 5}

Is the combination therapy for melanoma generally safe in humans?

Interferon alpha-2b, a component of the combination therapy, has been shown to have significant toxicity, including flu-like symptoms and fever, but is generally well tolerated with no treatment-related deaths reported. Celecoxib, another component, is commonly used for pain and inflammation and is generally considered safe when used as directed. ^{5 6 7 8 9}

What makes the combination therapy for melanoma unique?

This treatment is unique because it uses alpha-type-1 polarized dendritic cells (aDC1) that are specially designed to boost the immune system's response against melanoma, producing higher levels of a key immune-stimulating protein (IL-12p70) compared to standard methods. It also includes high-dose interferon alfa-2b, which has been shown to reduce melanoma relapse and improve survival rates. ^{5 10 11 12 13}

What is the purpose of this trial?

This phase II trial studies how well polarized dendritic cell (aDC1) based therapy, interferon alpha-2, rintatolimod, and celecoxib work together in treating patients with HLA-A2 positive (+) melanoma that has not responded to previous treatment (refractory). The aDC1 cell-based treatment contains white blood cells (dendritic cells or DCs) that stimulates the immune system. Interferon alpha-2 can improve the body's natural response to infections and other diseases. It can also interfere with the division of cancer cells and slow tumor growth. Rintalolimid may stimulate the immune system. Celecoxib is a drug that reduces pain. This study is being done to find out if the combination of the study cell-based treatment (aDC1 dendritic cells) and interferon alpha-2, rintatolimod, and celecoxib can prevent the growth and/or progression of melanoma.

Research Team

Igor Puzanov

Principal Investigator

Roswell Park Cancer Institute

Eligibility Criteria

This trial is for patients with HLA-A2 positive melanoma that hasn't improved after treatment, including anti PD-1/L1 therapy. They must have a tumor suitable for biopsy and measurable disease, be in fairly good health (ECOG 0-2), and meet specific blood test criteria. Pregnant women or those not using birth control are excluded, as well as individuals with certain heart conditions, active infections, known allergies to study drugs, recent transfusions or immunosuppressive treatments.

Inclusion Criteria

I have a tumor that can be biopsied without affecting response measurement.

I am able to get out of my bed or chair and move around.

I am eligible to restart treatment with anti-PD1/PD-L1 or anti-CTLA4.

Exclusion Criteria

I have a condition that weakens my immune system, like HIV.

I have had allergic reactions to sulfonamides, celecoxib, or nonsteroidal anti-inflammatory drugs.

I have had a recent heart problem or my heart condition severely limits my activities.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive recombinant interferon alpha-2, rintatolimod, and celecoxib, with alpha-type-1 polarized dendritic cells starting from cycle 2. Treatment repeats every 3 weeks for up to 4 cycles.

12 weeks

4 cycles, each with multiple visits

Follow-up

Participants are monitored for safety and effectiveness after treatment completion.

Up to 2 years

Every 3 months

Extension

Participants with progressive disease may switch to ipilimumab with or without a PD-1/PD-L1 inhibitor, and those with a complete response, partial response, or stable disease may switch to a PD-1/PD-L1 inhibitor or best alternative care.

Variable, based on response

Treatment Details

Interventions

• Alpha-type-1 Polarized Dendritic Cells
• Celecoxib
• Recombinant Interferon Alfa-2b
• Rintatolimod

Trial Overview The trial tests a combination of therapies: polarized dendritic cell-based treatment (aDC1) to boost the immune system; interferon alpha-2 to enhance infection defense and slow cancer growth; rintatolimod possibly stimulating immunity; and celecoxib for pain relief. The goal is to see if this mix can stop melanoma from growing or progressing.

Participant Groups

Group I: Treatment (IFNA2, rintatolimod, celecoxib, alphaDC1 cell based treatment) Experimental Treatment 6 Interventions

Patients receive recombinant interferon alpha-2 IV over 30 minutes, rintatolimod IV over 2.5 hours, and celecoxib PO BID on days 1-3. Beginning cycle 2, patients also receive alpha-type-1 polarized dendritic cells ID on day 1. Treatment repeats every 3 weeks up to 4 cycles in the absence of disease progression or unacceptable toxicity. At 12 weeks, patients with progressive disease may switch to ipilimumab with or without a PD-1/PD-L1 inhibitor and patients with a complete response CR, PR, or stable disease SD may switch to a PD-1/PD-L1 inhibitor or best alternative care.

Who Is Running the Clinical Trial?

Roswell Park Cancer Institute

Lead Sponsor

Trials

427

Recruited

40,500+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

A systematic review and meta-analysis of 14 randomized controlled trials involving 8122 patients demonstrated that interferon alpha (IFN-alpha) significantly improves disease-free survival (DFS) in high-risk cutaneous melanoma, with a hazard ratio of 0.82, indicating a reduced risk of disease recurrence.

IFN-alpha also showed a statistically significant improvement in overall survival (OS) in some comparisons, with a hazard ratio of 0.89, suggesting it can help patients live longer, although the optimal dose and treatment duration were not determined.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Interferon alpha adjuvant therapy in patients with high-risk melanoma: a systematic review and meta-analysis. Mocellin, S., Pasquali, S., Rossi, CR., et al.[2022]

Alpha interferons (IFN-alpha) have a long history of use in treating various cancers, including cutaneous melanoma, and while newer targeted therapies have emerged, IFN-alpha remains relevant for specific tumor types.

The exact mechanisms by which IFN-alpha exerts its anticancer effects are still not fully understood, despite extensive research and clinical experience, highlighting the need for further investigation into its action in cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The anticancer face of interferon alpha (IFN-alpha): from biology to clinical results, with a focus on melanoma. Pasquali, S., Mocellin, S.[2019]

Interferon (IFN) alpha-2b is currently the only available adjuvant therapy for high-risk melanoma and has been shown to improve overall and recurrence-free survival based on meta-analyses of clinical trials.

Despite concerns about its toxicity and the need for more research to identify which patients will benefit most, IFN should be recommended for patients at high risk of melanoma recurrence, with specific guidelines based on disease stage provided by an Italian Expert Panel.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Interferon alpha for the adjuvant treatment of melanoma: review of international literature and practical recommendations from an expert panel on the use of interferon. Ascierto, PA., Chiarion-Sileni, V., Muggiano, A., et al.[2015]

This case report presents the first instance of an HIV-positive patient receiving adjuvant interferon (IFN)-alpha therapy for high-risk melanoma after surgery, highlighting a potential treatment avenue for this patient population.

The study emphasizes the need for more data on the safety and efficacy of adjuvant immunotherapy in HIV-infected patients with melanoma, as current information is limited.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adjuvant high-dose interferon-{alpha} for resected melanoma in a patient with HIV infection. Saba, NS., George, TJ., Boulmay, BC.[2021]

High-dose interferon alpha2b (IFN-alpha2b) effectively reverses T cell signaling defects and promotes dendritic cell polarization in melanoma patients, leading to improved immune responses.

Clinical trials have shown that high-dose IFN-alpha2b significantly reduces relapse rates and improves overall survival compared to observation or other treatments, highlighting its efficacy as an adjuvant therapy for high-risk melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical and immunologic basis of interferon therapy in melanoma. Tarhini, AA., Kirkwood, JM.[2021]

Recombinant human interferon-α1b (IFN-α1b) is a well-tolerated treatment for advanced melanoma, with only 7.8% of patients experiencing significant toxicity, primarily fever, and no treatment-related deaths reported.

In a study of 90 patients with stage IV melanoma, IFN-α1b therapy resulted in a median overall survival of 14.1 months, indicating its potential to prolong survival in patients with unresectable metastatic melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Interferon-α1b for the treatment of metastatic melanoma: results of a retrospective study. Shi, Q., Liu, L., Zhang, W., et al.[2022]

High-dose adjuvant interferon alpha-2b (IFN alpha 2b) improves quality-adjusted survival (QAS) for melanoma patients, with 77% of patients in one trial experiencing a benefit, although this was not statistically significant for all.

The effectiveness of IFN alpha 2b on QAS is influenced more by patients' perceptions of its toxicity rather than the fear of melanoma recurrence, indicating that cancer patients may have a higher tolerance for treatment side effects compared to the general population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Quality-of-life-adjusted survival analysis of high-dose adjuvant interferon alpha-2b for high-risk melanoma patients using intergroup clinical trial data. Kilbridge, KL., Cole, BF., Kirkwood, JM., et al.[2018]

High-dose interferon-alpha2b is an FDA-approved treatment for stage III melanoma, but its limited effectiveness and significant side effects make it a controversial choice among patients and doctors.

This paper aims to assess the benefits and risks of high-dose interferon-alpha2b, providing a framework to help oncologists support patients in making informed treatment decisions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Helping melanoma patients decide whether to choose adjuvant high-dose interferon-alpha2b. Hurley, KE., Chapman, PB.[2018]

In a pilot study involving 21 patients with metastatic malignant melanoma, recombinant alpha-2b interferon showed limited efficacy, achieving a 14.3% partial response rate and stable disease in 9 patients.

While the treatment demonstrated some activity, it also caused significant side effects, including flu-like symptoms and fatigue, highlighting the need for careful consideration of toxicity in future trials, especially when combined with other therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II trial of recombinant alpha-2b interferon in the treatment of metastatic skin melanoma. Sertoli, MR., Bernengo, MG., Ardizzoni, A., et al.[2018]

In a study involving 11 metastatic melanoma patients, lower doses of IFN-alpha-2b (5 megaunits/m²) were found to be as effective as higher doses (10 megaunits/m²) in activating immune cells, specifically in phosphorylating STAT1.

The research indicates that increasing the dose to 10 megaunits/m² did not enhance the induction of interferon-stimulated genes (ISGs) and led to higher levels of inhibitors of IFN-alpha signaling, suggesting that lower doses may be sufficient for therapeutic effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

IFN-alpha-2b-induced signal transduction and gene regulation in patient peripheral blood mononuclear cells is not enhanced by a dose increase from 5 to 10 megaunits/m2. Zimmerer, JM., Lehman, AM., Ruppert, AS., et al.[2018]

Interferon-alpha, commonly used in cancer treatment for conditions like melanoma, can trigger psoriasis flare-ups in some patients, highlighting a potential side effect of this therapy.

This case illustrates the importance of monitoring patients for skin conditions when administering interferon-alpha, as immune modulation can lead to unexpected exacerbations of pre-existing conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Exacerbation of psoriasis induced by interferon-alpha treatment for melanoma. Tas, F., Atsu, N.[2016]

A new method for generating human dendritic cells (DCs) has been developed, producing fully mature type-1 polarized DCs (alphaDC1) that are highly effective in inducing type-1 immunity, particularly in cancer treatment.

These alphaDC1 cells show significantly higher production of interleukin-12p70 and can generate up to 40-fold more long-lived cytotoxic T lymphocytes (CTLs) against melanoma antigens compared to the current standard DCs, suggesting a promising advancement for cancer vaccines.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

alpha-type-1 polarized dendritic cells: a novel immunization tool with optimized CTL-inducing activity. Mailliard, RB., Wankowicz-Kalinska, A., Cai, Q., et al.[2021]

In a study involving 138 patients with advanced metastatic melanoma, the addition of cisplatin (CDDP) to a treatment regimen of interferon alfa-2a and high-dose interleukin-2 significantly increased the objective response rate from 18% to 33%.

While CDDP improved progression-free survival from 53 days to 92 days, it did not affect overall survival, which remained at a median of 9 months for all patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Interferon alfa-2a and interleukin-2 with or without cisplatin in metastatic melanoma: a randomized trial of the European Organization for Research and Treatment of Cancer Melanoma Cooperative Group. Keilholz, U., Goey, SH., Punt, CJ., et al.[2021]

References

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

Interferon alpha adjuvant therapy in patients with high-risk melanoma: a systematic review and meta-analysis. [2022]

2. United Arab Emirates pubmed.ncbi.nlm.nih.gov

The anticancer face of interferon alpha (IFN-alpha): from biology to clinical results, with a focus on melanoma. [2019]

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

Interferon alpha for the adjuvant treatment of melanoma: review of international literature and practical recommendations from an expert panel on the use of interferon. [2015]

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

Adjuvant high-dose interferon-{alpha} for resected melanoma in a patient with HIV infection. [2021]

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

Clinical and immunologic basis of interferon therapy in melanoma. [2021]

6. England pubmed.ncbi.nlm.nih.gov

Interferon-α1b for the treatment of metastatic melanoma: results of a retrospective study. [2022]

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

Quality-of-life-adjusted survival analysis of high-dose adjuvant interferon alpha-2b for high-risk melanoma patients using intergroup clinical trial data. [2018]

8. England pubmed.ncbi.nlm.nih.gov

Helping melanoma patients decide whether to choose adjuvant high-dose interferon-alpha2b. [2018]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Phase II trial of recombinant alpha-2b interferon in the treatment of metastatic skin melanoma. [2018]

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

IFN-alpha-2b-induced signal transduction and gene regulation in patient peripheral blood mononuclear cells is not enhanced by a dose increase from 5 to 10 megaunits/m2. [2018]

11. England pubmed.ncbi.nlm.nih.gov

Exacerbation of psoriasis induced by interferon-alpha treatment for melanoma. [2016]

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

alpha-type-1 polarized dendritic cells: a novel immunization tool with optimized CTL-inducing activity. [2021]

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

Interferon alfa-2a and interleukin-2 with or without cisplatin in metastatic melanoma: a randomized trial of the European Organization for Research and Treatment of Cancer Melanoma Cooperative Group. [2021]