NeoVax + Immunotherapy for Melanoma

Overseen By Patrick Ott, MD, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Dana-Farber Cancer Institute

Must not be taking: Immunosuppressants, Methotrexate, Chloroquine, others

Disqualifiers: Active brain metastases, Autoimmune disease, HIV, others

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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 14

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new vaccine, NeoVax, combined with the drugs Montanide, Ipilimumab (Yervoy), and Nivolumab (Opdivo), to treat advanced skin cancer known as cutaneous melanoma. The researchers aim to determine if this combination can more effectively treat the cancer by boosting the body's immune response. People with stage III or IV cutaneous melanoma that cannot be surgically removed, but with at least one tumor that can be biopsied, might be suitable candidates. 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 new treatment.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot take any anti-cancer or immunosuppressive agents within six months of joining the study. It's best to discuss your specific medications with the study team.

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

Research shows that the combination of Nivolumab, NeoVax with Montanide, and Ipilimumab is generally well-tolerated by patients with advanced melanoma. Past studies have demonstrated positive safety results for patients taking Nivolumab and Ipilimumab together over long periods. For instance, after 6.5 years, patients experienced lasting survival benefits.

The personalized vaccine NeoVax, when combined with Montanide and Ipilimumab, is currently being tested for safety in melanoma patients. Although this combination remains under study, the treatments have shown manageable safety in other contexts.

Ipilimumab and Nivolumab are already approved for treating melanoma, indicating a proven safety record. However, because NeoVax is personalized, each patient's experience may differ. Patients should always consult their healthcare provider to understand the risks and benefits. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combined use of NeoVax, Montanide, and Ipilimumab with Nivolumab in treating melanoma because this approach aims to boost the body's immune response more effectively. Unlike the standard of care, which typically involves either checkpoint inhibitors like Ipilimumab and Nivolumab or personalized vaccines separately, this trial combines them to potentially enhance their efficacy. NeoVax is a personalized cancer vaccine designed to target specific mutations in a patient's tumor, which could lead to a more precise immune response. Additionally, Montanide serves as an adjuvant to enhance the vaccine's effectiveness, making this combination approach particularly promising in its ability to tailor and amplify the immune system's attack on melanoma cells.

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

Research shows that using Nivolumab and Ipilimumab together effectively treats advanced melanoma. In previous studies, about 43% of patients who received this combination survived ten years, indicating a lasting benefit. In this trial, participants will receive Nivolumab and Ipilimumab with the personalized vaccine NeoVax, designed to help the immune system target cancer cells more precisely. NeoVax is used with Montanide to enhance its effectiveness. These treatments aim to strengthen the immune response against melanoma, potentially improving survival chances. ^{1 6 7 8 9}

Who Is on the Research Team?

Patrick Ott, MD, PhD

Principal Investigator

Dana-Farber Cancer Institute

Are You a Good Fit for This Trial?

Adults over 18 with advanced melanoma that can't be removed by surgery or is stage III/IV. They must have normal organ/marrow function, no HIV/AIDS, and not be pregnant/nursing. Participants should agree to use contraception and have recovered from previous treatments.

Inclusion Criteria

Women who could become pregnant should have a negative pregnancy test within 24 hours before starting Nivolumab.

I agree to use birth control from the start of the study until 31 weeks after the last dose.

Participant is willing and able to give written informed consent

Exclusion Criteria

I do not have any unmanaged ongoing illnesses.

I haven't taken steroids or immune-weakening drugs in the last 2 weeks.

I have not received vaccines for infectious diseases in the last 4 weeks.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Initial Treatment

Participants receive Nivolumab every 4 weeks for 12 weeks while NeoVax is prepared

12 weeks

3 visits (in-person)

Vaccine Administration

Participants receive NeoVax plus Montanide and Ipilimumab on weeks 12, 15, 18, and 21

9 weeks

4 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

26 weeks

6 visits (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Ipilimumab
• NeoVax plus Montanide
• Nivolumab

Trial Overview The trial tests a personalized neoantigen vaccine (NeoVax) plus Montanide with Ipilimumab (Yervoy) and Nivolumab (Opdivo). It aims to see if this combination helps treat unresectable or stage III/IV melanoma more effectively than current methods.

How Is the Trial Designed?

Group I: Cohort 2: Nivolumab, NeoVax + Montanide, Ipilimumab 5.0 mg per injection site Experimental Treatment 3 Interventions

* Patients will receive Nivolumab at a 480 mg flat dose I.V. infusion every 4 weeks (28 days) * Patients will receive NeoVax plus Montanide injection on weeks 12, 15, 18, and 21 * Patients will receive concurrent Ipilimumab (5.0 mg per injection site) on weeks 12, 15, 18, and 21

Group II: Cohort 1: Nivolumab, NeoVax + Montanide, Ipilimumab 2.5 mg per injection site Experimental Treatment 3 Interventions

* Patients will receive Nivolumab at a 480 mg flat dose I.V. infusion every 4 weeks (28 days) * Patients will receive NeoVax plus Montanide injection on weeks 12, 15, 18, and 21 * Patients will receive concurrent Ipilimumab (2.5 mg per injection site) on weeks 12, 15, 18, and 21

Ipilimumab is already approved in United States, European Union for the following indications:

Approved in United States as Yervoy for:

• Advanced melanoma
• Stage III unresectable melanoma
• Stage IV metastatic melanoma

Approved in European Union as Yervoy for:

• Advanced melanoma
• Stage III unresectable melanoma
• Stage IV metastatic melanoma

Who Is Running the Clinical Trial?

Dana-Farber Cancer Institute

Lead Sponsor

Trials

1,128

Recruited

382,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

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]

In a phase 1 trial involving 53 patients with advanced melanoma, the combination of nivolumab and ipilimumab resulted in a 40% objective response rate, with 65% of patients showing clinical activity, indicating significant effectiveness in tumor reduction.

The concurrent treatment had a manageable safety profile, with 53% of patients experiencing grade 3 or 4 adverse events, which were similar to those seen with monotherapy and generally reversible, suggesting that this combination therapy is a viable option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab plus ipilimumab in advanced melanoma. Wolchok, JD., Kluger, H., Callahan, MK., et al.[2022]

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]

Ipilimumab has shown a positive impact on overall survival in patients with stage IV melanoma, with long-term follow-up indicating its effectiveness compared to conventional treatments.

While 84.8% of patients experience drug-related adverse events, most are mild to moderate; however, severe reactions can occur, necessitating careful monitoring and management, especially when combined with other therapies like vemurafenib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

CTLA-4 blockade with ipilimumab: biology, safety, efficacy, and future considerations. Camacho, LH.[2022]

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]

Nivolumab (OPDIVO) received accelerated FDA approval for treating unresectable or metastatic melanoma based on a 31.7% objective response rate in a study of 120 patients, showing promising efficacy after prior treatments.

The treatment demonstrated durable responses, with 87% of responding patients maintaining their response for at least 6 months, although it carries risks of immune-mediated adverse reactions that were monitored in a safety assessment of 268 patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

U.S. FDA Approval Summary: Nivolumab for Treatment of Unresectable or Metastatic Melanoma Following Progression on Ipilimumab. Hazarika, M., Chuk, MK., Theoret, MR., et al.[2023]

Ipilimumab showed a best overall response rate (BORR) of 5.8% and a disease control rate (DCR) of 27% in patients with advanced melanoma, indicating some level of efficacy in this challenging population.

The treatment resulted in promising long-term survival rates, with 1- and 2-year survival rates of 47.2% and 32.8%, respectively, and a median overall survival of 10.2 months, while adverse events were primarily immune-related but manageable.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of ipilimumab monotherapy in patients with pretreated advanced melanoma: a multicenter single-arm phase II study. O'Day, SJ., Maio, M., Chiarion-Sileni, V., et al.[2022]

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]

In a real-world study of 709 patients with advanced melanoma treated with ipilimumab plus nivolumab, 50.7% experienced severe treatment-related adverse events, highlighting the need for careful monitoring during therapy.

Despite the high rate of adverse events, the combination therapy showed promising long-term survival outcomes, with a median overall survival of 28.7 months and a 4-year overall survival rate of 50% for patients similar to those in the CheckMate-067 trial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world Outcomes of Ipilimumab Plus Nivolumab Combination Therapy in a Nation-wide Cohort of Advanced Melanoma Patients in the Netherlands. van Zeijl, MCT., van Breeschoten, J., de Wreede, LC., et al.[2023]

Nivolumab plus ipilimumab showed durable and long-term efficacy in treating advanced non-small cell lung cancer (NSCLC) compared to chemotherapy, regardless of tumor PD-L1 expression levels.

These findings are based on updated results from part 1 of the phase 3 CheckMate 227 trial, indicating that this combination therapy could be a more effective frontline treatment option for NSCLC patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab/Ipilimumab Combo Yields Durable Efficacy in Advanced NSCLC. Kahl, KL.[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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12080919/

Final, 10-Year Outcomes with Nivolumab plus Ipilimumab in ... Among these patients, 10-year overall survival rates were 86% with nivolumab-plus-ipilimumab, 85% with nivolumab, and 79% with ipilimumab ( ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT03929029?term=NCT03929029&rank=1

Neoantigen Vaccine Plus Locally Administered Ipilimumab ... This research study is investigating a new type of personalized neoantigen vaccine, NeoVax, plus Montanide® in combination with Ipilimumab (Yervoy™) and ...

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

Advanced Melanoma Skin Cancer | Clinical Trial Results OPDIVO + YERVOY is FDA approved to treat advanced melanoma regardless of your test results. More people given OPDIVO + YERVOY were alive compared to YERVOY ...

4. news.bms.com news.bms.com/news/details/2024/Bristol-Myers-Squibb-Presents-Landmark-10-Year-Follow-Up-Data-from-CheckMate--067-Which-Showed-Continued-Durable-Long-Term-Survival-Benefit-with-Opdivo-plus-Yervoy-in-Advanced-Melanoma/default.aspx

067 Which Showed Continued Durable Long-Term ... “Remarkably, 43% of patients treated with nivolumab and ipilimumab are alive ten years later and many did not need subsequent therapy.” In ...

5. opdivohcp.com opdivohcp.com/efficacy/melanoma/opdivo-yervoy

OPDIVO® (nivolumab) + YERVOY® (ipilimumab) Efficacy in ... In melanoma patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, infusion-related reactions occurred in 2.5% (10/407) of patients. In HCC ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/37103470/

Real-world Outcomes of Ipilimumab Plus Nivolumab ... Here, we report real-world safety and survival outcomes of ipilimumab plus nivolumab for advanced melanoma. Patients with advanced melanoma ...

7. news.bms.com news.bms.com/news/details/2021/Six-and-a-Half-Year-Outcomes-for-Opdivo-nivolumab-in-Combination-with-Yervoy-ipilimumab-Continue-to-Demonstrate-Durable-Long-Term-Survival-Benefits-in-Patients-with-Advanced-Melanoma/default.aspx

Six-and-a-Half-Year Outcomes for Opdivo (nivolumab) in ... With a minimum follow-up of 6.5 years, median overall survival (OS) was 72.1 months with Opdivo plus Yervoy (95% CI: 38.2-NR), the longest ...

8. mycancergenome.org mycancergenome.org/content/clinical_trials/NCT03929029/

Clinical Trial: NCT03929029 The purpose of this study is to determine if it is possible to administer safely a personalized neoantigen vaccine (NeoVax) + Montanide in ...

9. dana-farber.org dana-farber.org/clinical-trials/18-279

A Phase Ib study of NeoVax plus Montanide in combination ... This research study is investigating a new type of personalized neoantigen vaccine, NeoVax, plus Montanide® in combination with Ipilimumab (Yervoy™) and ...