Duvelisib + Nivolumab for Skin Cancer

Not currently recruiting at 21 trial locations

Overseen By Jia Ruan

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: National Cancer Institute (NCI)

Must not be taking: CYP3A4 inhibitors, CYP3A4 inducers

Disqualifiers: Autoimmune disease, Hepatitis B/C, others

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

Compensation: Varies

Number of Visits: 6

Duration: Up to 2 years

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores the combination of two drugs, duvelisib (a type of targeted therapy) and nivolumab (an immunotherapy), to determine their effectiveness in treating advanced stages of mycosis fungoides and Sezary syndrome, types of skin cancer. Duvelisib blocks certain enzymes to stop cancer cell growth, while nivolumab helps the immune system attack cancer cells. The trial aims to find the best dose and understand any potential benefits or side effects of using these drugs together. Individuals with stages IIB-IVB mycosis fungoides or Sezary syndrome, who have undergone at least one previous systemic treatment, might be suitable for this trial. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to be among the first to receive this new combination therapy.

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

The trial protocol does not specify if you must stop all current medications, but there are some restrictions. You cannot be on strong inhibitors or inducers of CYP3A4, and you must stop any systemic therapy for MF/SS with specific washout periods: 8 weeks for low-dose total skin electron beam therapy, 4 weeks for systemic cytotoxic agents or tumor-targeting monoclonal antibodies (except alemtuzumab, which is 16 weeks), 2 weeks or 5 half-lives for systemic retinoids and other specified agents, 2 weeks for local radiation, and 1 week for topical retinoids and other specified topical treatments. You can continue using inhaled steroids and certain topical steroids if stable for at least 4 weeks. Please consult with the trial team for guidance on your specific medications.

Will I have to stop taking my current medications?

The trial does not specify if you must stop all current medications, but you cannot take certain medications like strong inhibitors or inducers of CYP3A4, and some immunosuppressive drugs. There are specific 'washout' periods for certain treatments, such as 4 weeks for some anticancer agents and 1 week for topical treatments.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that the combination of duvelisib and nivolumab is generally safe for patients. In a study involving individuals with advanced melanoma, this treatment did not cause severe side effects. Duvelisib, a drug approved by the FDA for other uses, may help stop cancer cells from growing. Nivolumab is an immunotherapy that aids the body's immune system in fighting cancer. Previous studies have used these drugs together safely. While side effects can occur, past research found them manageable, suggesting this combination is safe for further testing. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of duvelisib and nivolumab for skin cancer because it targets the disease in a novel way. Unlike most treatments that focus solely on one pathway, duvelisib is a dual inhibitor that targets both PI3K-delta and PI3K-gamma, which are enzymes linked to cancer cell growth. Meanwhile, nivolumab is an immune checkpoint inhibitor that helps the immune system recognize and attack cancer cells. This dual-action approach could potentially enhance the effectiveness of treatment by both directly inhibiting cancer cell proliferation and boosting the body's immune response against the tumor.

What evidence suggests that this treatment might be an effective treatment for skin cancer?

Research has shown that nivolumab, one of the drugs in this trial, effectively treats various cancers, such as melanoma and head and neck cancer. It aids the immune system in attacking cancer cells. Duvelisib, also included in this trial, inhibits certain enzymes that promote cancer cell growth. Although no direct study has examined the combination of duvelisib and nivolumab for mycosis fungoides and Sezary syndrome, the trial aims to enhance their cancer-fighting effects when used together. The goal is for the combination to be more effective than each drug alone. Early results suggest potential benefits, but further research is needed to confirm this for the specific conditions in the trial. ^{6 7 8 9 10}

Who Is on the Research Team?

Neha Mehta-Shah

Principal Investigator

Yale University Cancer Center LAO

Are You a Good Fit for This Trial?

Adults over 18 with stage IIB-IVB mycosis fungoides or Sezary syndrome who've had prior systemic therapy can join this trial. They must have certain levels of blood cells, kidney and liver function, and controlled brain metastases if present. Heart disease patients need a specific risk assessment. Participants must use effective contraception and not be pregnant or breastfeeding.

Inclusion Criteria

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

Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) or =< 5 x institutional ULN if with history of Gilbert's syndrome

I can understand and am willing to sign the consent form, or I have someone who can do it for me.

Exclusion Criteria

I do not have an active or history of severe autoimmune disease.

I have previously been treated with drugs that boost the immune system.

I have been treated with a PI3K inhibitor before.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive duvelisib orally and nivolumab intravenously in 28-day cycles

Up to 2 years

Monthly visits for each cycle

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 years

Every 6 months

What Are the Treatments Tested in This Trial?

Interventions

• Duvelisib
• Nivolumab

Trial Overview The trial is testing the combination of duvelisib (which blocks enzymes for cell growth) with nivolumab (an immunotherapy that helps the immune system attack cancer). It aims to find the best dose, benefits, and side effects compared to usual treatments for these skin cancers.

How Is the Trial Designed?

Group I: Treatment (duvelisib, nivolumab) Experimental Treatment 6 Interventions

Patients receive duvelisib PO QD or BID on days 1-28 or days 1-14 and nivolumab IV over 30 minutes on day 1 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo PET-CT or CT scan at baseline. Patients also undergo punch biopsy and collection of blood samples throughout the trial.

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?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

The combination of durvalumab and tremelimumab in cancer treatment is associated with a higher incidence of severe adverse events (32.6%) compared to durvalumab alone (23.8%), indicating increased safety concerns with the combination therapy.

Patients receiving the combination therapy also experienced higher rates of specific side effects such as diarrhea (15.6% vs. 8.1%), rash (11.1% vs. 6.5%), and treatment discontinuation (18% vs. 3%), highlighting the need for careful monitoring and patient counseling regarding these risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse Events and Tolerability of Combined Durvalumab and Tremelimumab versus Durvalumab Alone in Solid Cancers: A Systematic Review and Meta-Analysis. Fahmy, O., Ahmed, OAA., Khairul-Asri, MG., et al.[2023]

A review of 29 articles identified specific dermatological adverse events (AEs) associated with various immunotherapy combinations, highlighting that combinations like nivolumab/ipilimumab and lenvatinib/pembrolizumab had the highest incidence of rash.

Understanding these dermatological AEs, such as pruritus and alopecia, is crucial for optimizing treatment plans and improving patient monitoring during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dermatological adverse events associated with immune checkpoint inhibitor-based combinations of anticancer therapies: a systematic review. Salloum, A., Habre, M., Chebl, JA., et al.[2022]

Nivolumab, a PD-1 inhibitor used for advanced lung adenocarcinoma, can cause significant skin toxicity, as observed in a 60-year-old male patient who developed worsening skin rashes after treatment.

Early detection and treatment of immune-related skin toxicity with steroids led to alleviation of symptoms, suggesting that prompt management can improve patient outcomes while maintaining stable lung disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Treatment-related Skin Toxicity Caused by Programmed Death-1 Inhibitor Nivolumab: A Case Report]. Gao, L., Yu, Y., Lu, S.[2020]

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]

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]

In a pooled analysis of 1332 patients with advanced non-small-cell lung cancer (NSCLC), the combination of nivolumab and ipilimumab showed a median overall survival (OS) of 18.6 months and a 3-year OS rate of 35%, indicating significant long-term survival benefits compared to traditional chemotherapy.

The study found that patients who responded to treatment at 6 months had markedly better survival rates, with a 3-year OS of 66% for responders, highlighting the importance of early response in predicting long-term outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term survival with first-line nivolumab plus ipilimumab in patients with advanced non-small-cell lung cancer: a pooled analysis. Borghaei, H., Ciuleanu, TE., Lee, JS., et al.[2023]

Nivolumab, a PD-1 inhibitor, has been FDA-approved for treating recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) after platinum-based therapy, but treatment options remain limited for these patients.

A case study of a 46-year-old male with refractory HNSCC showed successful treatment using a combination of nivolumab and ipilimumab, suggesting potential efficacy for this combination therapy in HNSCC, similar to its success in metastatic melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Successful Treatment of Refractory Squamous Cell Cancer of the Head and Neck with Nivolumab and Ipilimumab. Schwab, KS., Kristiansen, G., Schild, HH., et al.[2022]

This phase I/II clinical trial is investigating the safety and efficacy of a combination treatment involving selumetinib, tremelimumab, and durvalumab in 40 patients with previously treated, unresectable non-small-cell lung cancer (NSCLC).

The study aims to determine the maximum tolerated dose and progression-free survival, while also exploring biomarkers of response and resistance, which could help tailor future treatments for NSCLC patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase I/II Trial of Immunotherapy With Durvalumab and Tremelimumab With Continuous or Intermittent MEK Inhibitor Selumetinib in NSCLC: Early Trial Report. Gaudreau, PO., Lee, JJ., Heymach, JV., et al.[2021]

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 study of 81 patients with unresectable locally advanced non-small cell lung cancer (NSCLC), those with high tumor mutational burden (TMB-high) showed significantly better outcomes, including lower local-regional failure rates (9% vs 51%) and improved progression-free survival (66% vs 27%) compared to TMB-low patients.

The study suggests that TMB status could be a valuable biomarker for personalizing treatment strategies, as it was the only factor significantly associated with local-regional failure and progression-free survival after treatment with chemoradiation and adjuvant durvalumab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Analysis of Tumor Mutational Burden, Progression-Free Survival, and Local-Regional Control in Patents with Locally Advanced Non-Small Cell Lung Cancer Treated With Chemoradiation and Durvalumab. Lebow, ES., Shepherd, A., Eichholz, JE., et al.[2023]

Nivolumab, an immune checkpoint inhibitor, significantly improved overall survival and progression-free survival compared to docetaxel in patients with advanced squamous non-small cell lung cancer (NSCLC) in the CheckMate 017 trial.

Nivolumab was better tolerated than docetaxel, with manageable adverse effects, making it a promising treatment option for patients who have already undergone chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab: a review in advanced squamous non-small cell lung cancer. Keating, GM.[2022]

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]

Citations

1. opdivo.com opdivo.com/melanoma/clinical-trial-results

Melanoma Skin Cancer | Clinical Trial Results OPDIVO® (nivolumab) is a prescription medicine used to treat adults with head and neck cancer (squamous cell carcinoma) that has come back or spread and you ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11831104/

Duvelisib with Docetaxel for Patients with Anti–PD-1 ... This phase 2 trial evaluated dual, selective PI3Kδ/γ inhibition with docetaxel in patients with anti–PD-1 refractory recurrent, metastatic HNSCC.

3. opdivo.com opdivo.com/melanoma/clinical-trial-results/advanced-immunotherapy-combination

Advanced Melanoma Skin Cancer | Clinical Trial Results OPDIVO® (nivolumab) is a prescription medicine used to treat adults with head and neck cancer (squamous cell carcinoma) that has come back or spread and you ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4665056/

Opdivo (Nivolumab): Second PD-1 Inhibitor Receives FDA ... Based on an interim analysis of phase 3 clinical data, this novel agent is an effective and safe alternative for patients with unresectable or metastatic ...

5. opdivohcp.com opdivohcp.com/efficacy/melanoma

Efficacy Data for Melanoma | OPDIVO® (nivolumab) Find efficacy information for OPDIVO® (nivolumab) for certain types of melanoma. Please see Indications and Important Safety Information.

6. ascopubs.org ascopubs.org/doi/10.1200/JCO.2023.41.16_suppl.9540

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 ...

7. 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- ...

8. 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 ...

9. 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.

10. cdn.clinicaltrials.gov cdn.clinicaltrials.gov/large-docs/44/NCT03892044/ICF_000.pdf

The Ohio State University Combined Consent to Participate ... Nivolumab is designed to allow the immune system to better recognize cancer cells and act against these cancer cells. Duvelisib has been approved by the United ...