Duvelisib + Nivolumab for Melanoma

Overseen By Amy Rose, RN

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: John Kirkwood

Must not be taking: Immunosuppressants, Systemic steroids

Disqualifiers: CNS metastases, Autoimmune disease, Cardiovascular, Pulmonary, others

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

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to evaluate the effectiveness of combining two drugs, duvelisib (a cancer treatment) and nivolumab (an immunotherapy drug), for individuals with advanced melanoma that cannot be surgically removed and has worsened despite previous treatments. The researchers seek to determine the optimal dose of duvelisib to use with nivolumab. This trial suits those who have undergone anti-PD1 treatments for at least three months but have experienced melanoma progression. Participants must have at least one measurable tumor and should not have melanoma in the eye or mucous membranes. As a Phase 1, Phase 2 trial, this research focuses on understanding the treatment's effects in people and assessing its effectiveness in an initial, smaller group.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you should avoid medications or foods that strongly affect a liver enzyme called CYP3A within 2 weeks before starting the study. It's best to discuss your current medications with the study team.

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

Research has shown that using duvelisib and nivolumab together is generally safe for patients with advanced melanoma. In earlier studies, patients did not experience severe side effects that would prevent them from continuing treatment, indicating that the side effects were manageable.

Nivolumab, one of the drugs in this combination, is already used to treat melanoma and is generally considered safe. Common side effects include fatigue and diarrhea, which are usually mild.

Duvelisib is being tested for different types of cancer and has shown promise in treating conditions like chronic lymphocytic leukemia (CLL). The goal of combining it with nivolumab is to assist patients who haven't responded well to other treatments. While more research is needed, current evidence suggests that this combination is safe for many patients. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard of care for melanoma, which often includes treatments like targeted therapies and traditional immunotherapies, the combination of duvelisib and nivolumab offers a unique approach. Duvelisib is an oral inhibitor that targets specific pathways in cancer cells, potentially disrupting their growth and survival. When combined with nivolumab, an immune checkpoint inhibitor that helps the body's immune system recognize and attack cancer cells, this duo may enhance the overall immune response against melanoma. Researchers are excited because this combination could provide a more effective and potentially faster-acting treatment option compared to existing therapies.

What evidence suggests that the combination of duvelisib and nivolumab could be effective for melanoma?

Research has shown that using duvelisib and nivolumab together, as studied in this trial, may help treat advanced melanoma. Early results from studies suggest that this combination is safe for patients whose melanoma hasn't improved with other treatments. Importantly, patients taking both duvelisib and nivolumab lived longer, averaging 20.4 months, compared to 8.8 months with other treatments. They also went about 3 months without their disease worsening. These findings suggest that this combination could effectively manage advanced melanoma. ^{1 2 3 6 7}

Who Is on the Research Team?

John Kirkwood, MD

Principal Investigator

UPMC Hillman Cancer Center

Are You a Good Fit for This Trial?

Adults (18+) with advanced unresectable melanoma that worsened after anti-PD1 therapy can join. They must have measurable disease, be willing to use effective birth control, and have normal organ/bone marrow function. Excluded are those with significant infections, recent treatments, allergies to trial drugs, CNS metastases unless stable, autoimmune diseases except mild ones like type I diabetes or skin disorders not needing systemic treatment.

Inclusion Criteria

I can take care of myself but might not be able to do heavy physical work.

My organs and bone marrow are functioning normally.

Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria

I have had T-vec therapy, but not more than three patients like me can join the Phase II study.

I had a severe immune reaction in my gut but tolerated treatment after anti-CTLA-4 therapy.

I had severe side effects from previous immune therapy, but they are now under control.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase I Treatment

Participants receive duvelisib orally in varying doses and nivolumab intravenously to determine the recommended dose for Phase II

8 weeks

Bi-weekly visits for nivolumab administration

Phase II Treatment

Participants receive the recommended dose of duvelisib and nivolumab for up to 1 year or until disease progression or unacceptable side effects

Up to 1 year

Monthly visits for nivolumab administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

36 months

What Are the Treatments Tested in This Trial?

Interventions

• Duvelisib
• Nivolumab

Trial Overview The study tests a combination of oral duvelisib and intravenous nivolumab in patients with advanced melanoma who didn't respond to previous anti-PD1 therapy. The Phase I part determines the safe dose for Phase II where it's given up to one year or until disease progression or unacceptable side effects occur.

How Is the Trial Designed?

Group I: Duvelisib plus Nivolumab Experimental Treatment 2 Interventions

Phase 1: Duvelisib will be taken orally in doses from 15mg once a day, 25mg once a day or 25mg twice a day, 12 hours a part, to determine the recommended dose for the Phase II study when combined with nivolumab. Nivolumab, 240mg, IV, every 2 weeks for the first four cycles; thereafter it may be switched to 480mg, IV, once every 4 weeks if deemed appropriate by the study doctor. Phase II: The Recommended Phase II dosage of duvelisib administered will not be determined until Phase I is completed. Nivolumab, 480mg, IV, every 4 weeks, for up to 1 year.

Duvelisib is already approved in United States for the following indications:

Approved in United States as Copiktra for:

• Relapsed or refractory chronic lymphocytic leukemia (CLL)
• Relapsed or refractory small lymphocytic lymphoma (SLL)

Who Is Running the Clinical Trial?

John Kirkwood

Lead Sponsor

Trials

6

Recruited

130+

Secura Bio, Inc.

Industry Sponsor

Trials

9

Recruited

200+

Bristol-Myers Squibb

Industry Sponsor

Trials

2,731

Recruited

4,127,000+

Headquarters

New York City, USA

Known For

Oncology & Cardiovascular

Top Products

Eliquis, Opdivo, Revlimid, Orencia

Christopher Boerner

Bristol-Myers Squibb

Chief Executive Officer since 2023

PhD in Business Administration from the Haas School of Business, University of California, Berkeley; BA in Economics and History from Washington University in St. Louis

Deepak L. Bhatt

Bristol-Myers Squibb

Chief Medical Officer since 2024

MD from Yale University; MSc in Clinical Epidemiology from the University of Pennsylvania

Published Research Related to This Trial

In a study of 945 patients with untreated metastatic melanoma, the combination of nivolumab and ipilimumab significantly improved progression-free survival to a median of 11.5 months compared to just 2.9 months with ipilimumab alone.

For patients with PD-L1-negative tumors, the combination therapy was particularly effective, showing a progression-free survival of 11.2 months compared to 5.3 months with nivolumab alone, highlighting the potential of dual checkpoint inhibition in this subgroup.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. Larkin, J., Chiarion-Sileni, V., Gonzalez, R., et al.[2023]

Nivolumab (Opdivo) monotherapy led to complete regression of local recurrence and multiple lung metastases in a patient with recurrent skin melanoma and a positive BRAF mutation, demonstrating its efficacy as a treatment option.

After 5 courses of nivolumab, the patient experienced significant improvement in her condition, achieving an ECOG performance status of 0, indicating a return to an active lifestyle without pain, and normal serum LDH levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[EVALUATION OF THE EFFICASY OF THE DRUG OPDIVO (NIVOLUMAB) IN A PATIENT DIAGNOSED WITH UNRESECTABLE SKIN MELANOMA, POSITIVE BRAF MUTATION AND DISEASE DISSEMINATION (CASE REPORT)]. Samsonia, M., Kandelaki, M., Gibradze, O., et al.[2021]

In a study of 355 patients with metastatic melanoma resistant to anti-PD-(L)1 therapy, combining ipilimumab with anti-PD-1 (either pembrolizumab or nivolumab) resulted in a significantly higher objective response rate (31%) compared to ipilimumab alone (13%).

Patients receiving the combination therapy also experienced longer overall survival (20.4 months vs. 8.8 months) and longer progression-free survival (3.0 months vs. 2.6 months), while the rates of severe adverse events were similar between the two treatment groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ipilimumab alone or ipilimumab plus anti-PD-1 therapy in patients with metastatic melanoma resistant to anti-PD-(L)1 monotherapy: a multicentre, retrospective, cohort study. Pires da Silva, I., Ahmed, T., Reijers, ILM., et al.[2021]

In a cohort of 64 adults with advanced melanoma treated with nivolumab and ipilimumab, 91% experienced clinically significant immune-related adverse events (AEs), highlighting the treatment's potential for serious side effects.

Despite the high incidence of AEs, most patients did not complete all 4 doses of the treatment, suggesting that fewer doses may still provide clinical benefits without the need for extensive immunosuppression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Measuring Toxic Effects and Time to Treatment Failure for Nivolumab Plus Ipilimumab in Melanoma. Shoushtari, AN., Friedman, CF., Navid-Azarbaijani, P., et al.[2023]

Nivolumab significantly improved overall survival and progression-free survival in patients with unresectable or metastatic melanoma compared to dacarbazine, with hazard ratios of 0.42 and 0.43 respectively, based on a trial involving 418 patients.

The most common side effects of nivolumab included fatigue, diarrhea, and rash, but it was still considered to have a favorable benefit-risk profile compared to dacarbazine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval of Nivolumab for the First-Line Treatment of Patients with BRAFV600 Wild-Type Unresectable or Metastatic Melanoma. Beaver, JA., Theoret, MR., Mushti, S., et al.[2018]

In the Asian subpopulation with advanced non-small cell lung cancer (NSCLC) and PD-L1 expression ≥1%, patients treated with nivolumab plus ipilimumab showed significantly improved overall survival (OS) and progression-free survival (PFS) compared to those receiving chemotherapy, with a 3-year OS rate of 53% versus 37%.

The safety profile of nivolumab plus ipilimumab was manageable, with grade 3-4 treatment-related adverse events occurring in 40% of patients, similar to the 36% in the chemotherapy group, indicating no new safety concerns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-line nivolumab + ipilimumab in advanced NSCLC: CheckMate 227 subpopulation analyses in Asian patients. O'Byrne, KJ., Lee, KH., Kim, SW., et al.[2022]

Nivolumab is shown to be the most cost-effective treatment option for advanced melanoma patients in England, with incremental cost-effectiveness ratios of £24,483 for BRAF mutation-negative and £17,362 for mutation-positive patients.

The analysis utilized a Markov state-transition model based on patient-level data from clinical trials, indicating that nivolumab provides long-term survival benefits while being economically favorable compared to other treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The cost-effectiveness of nivolumab monotherapy for the treatment of advanced melanoma patients in England. Meng, Y., Hertel, N., Ellis, J., et al.[2020]

In a phase 2 trial involving 142 patients with untreated advanced melanoma, the combination of nivolumab and ipilimumab resulted in a 2-year overall survival rate of 63.8%, compared to 53.6% for those receiving ipilimumab alone, suggesting improved survival outcomes with the combination therapy.

However, the combination treatment was associated with a higher incidence of severe side effects, with 54% of patients experiencing grade 3-4 adverse events compared to 20% in the ipilimumab-only group, indicating a trade-off between efficacy and safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combined nivolumab and ipilimumab versus ipilimumab alone in patients with advanced melanoma: 2-year overall survival outcomes in a multicentre, randomised, controlled, phase 2 trial. Hodi, FS., Chesney, J., Pavlick, AC., et al.[2022]

Nivolumab, a monoclonal antibody targeting the programmed death receptor-1, has shown promising efficacy in treating advanced malignant melanoma, with nearly 25% of patients achieving a partial tumor response in a phase II trial involving previously treated stage III/IV patients.

The treatment demonstrated a durable clinical benefit, with a median progression-free survival of 172 days and an acceptable safety profile, as less than 18% of patients experienced severe adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab: a review of its use in patients with malignant melanoma. Deeks, ED.[2021]

Nivolumab, an immune checkpoint inhibitor, can lead to serious endocrine side effects, such as primary hypothyroidism, as seen in a case study of a young melanoma patient who developed symptoms after 12 weeks of treatment.

The patient's hypothyroidism was effectively managed with hormone replacement therapy, allowing him to continue nivolumab treatment safely, which underscores the importance of recognizing and managing endocrine-related adverse events to maintain patient safety and treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab-induced hypothyoidism with consequent hypothyroid related myopathy. Johnson, ED., Kerrigan, K., Butler, K., et al.[2020]

In a phase 3 trial involving 405 patients with advanced melanoma, nivolumab resulted in a significantly higher objective response rate (31.7%) compared to investigator's choice of chemotherapy (10.6%), indicating its superior efficacy as a treatment option.

Nivolumab was associated with fewer severe adverse effects compared to chemotherapy, with only 5% of patients experiencing serious drug-related side effects, suggesting it is a safer alternative for patients who have progressed after previous treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Weber, JS., D'Angelo, SP., Minor, D., et al.[2022]

Durvalumab, a PD-L1 inhibitor, has been shown to be safe for patients with various solid tumors, with common side effects including pruritus and fatigue, based on a meta-analysis of 17 studies involving 1,529 patients.

Higher levels of PD-L1 expression in tumors are linked to better treatment responses to durvalumab, indicating that PD-L1 could serve as a useful biomarker for predicting the drug's efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of durvalumab (MEDI4736) in various solid tumors. Yang, H., Shen, K., Zhu, C., et al.[2022]

Citations

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Interim results from a phase I/II study of duvelisib PI3Kδγ ... Conclusions: The combination of duvelisib and nivolumab was well-tolerated in patients with advanced unresectable melanoma refractory to ICI ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT04688658

NCT04688658 | Duvelisib in Combination With Nivolumab ... This trial is a Phase I/II study in which a combination of duvelisib and nivolumab will be used to treat a total of patients diagnosed with advanced ...

3. withpower.com withpower.com/trial/phase-2-melanoma-6-2021-6bd09

Duvelisib + Nivolumab for Melanoma · Info for Participants Patients receiving the combination therapy also experienced longer overall survival (20.4 months vs. 8.8 months) and longer progression-free survival (3.0 ...

4. researchgate.net researchgate.net/publication/371300889_Interim_results_from_a_phase_III_study_of_duvelisib_PI3Kdg_inhibitor_and_nivolumab_in_patients_with_advanced_unresectable_melanoma_who_have_progressed_on_anti-PD1_therapy

Interim results from a phase I/II study of duvelisib PI3Kδγ ... Interim results from a phase I/II study of duvelisib PI3Kδγ inhibitor and nivolumab in patients with advanced unresectable melanoma who have progressed on anti- ...

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Final, 10-Year Outcomes with Nivolumab plus Ipilimumab in ... Among patients who had been alive and progression-free at 3 years, 10-year melanoma-specific survival was 96% with nivolumab plus ipilimumab, 97 ...

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Duvelisib and Nivolumab for the Treatment of Stage IIB-IVB ... This phase I trial assesses the safety and efficacy of duvelisib in combination with nivolumab in treating advanced stage mycosis fungoides and Sezary syndrome.

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11443371/

The phase III DUO trial of PI3K inhibitor duvelisib versus ... Results from DUO suggest that duvelisib monotherapy may offer an effective treatment for CLL/SLL patients in need of additional therapeutic options.