Nivolumab + Ipilimumab for Neurofibrosarcoma

Overseen By Amber Michalik

Age: Any Age

Sex: Any

Trial Phase: Phase 1

Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Must not be taking: Systemic steroids, Immunosuppressives

Disqualifiers: HIV, Active infection, Autoimmune disease, others

Stay on Your Current Meds You can continue your current medications while participating

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: 2

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if combining two immunotherapy drugs, nivolumab and ipilimumab, is safe and feasible before standard treatments like surgery, chemotherapy, or radiation for individuals with Neurofibromatosis Type 1 (NF1) who have specific nerve tumors. These tumors, known as malignant peripheral nerve sheath tumors, can be pre-cancerous or cancerous. The trial seeks participants diagnosed with these tumors through a biopsy and who have not required treatment for other tumors in the past year. Participants should be willing to adhere to the trial rules and must not have received previous treatments with similar medications. 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 does not specify if you need to stop your current medications. However, if you are on systemic steroids or immunosuppressive medications, you may need to stop them at least 14 days before starting the study drugs. It's best to discuss your specific medications with the trial team.

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

Research has shown that the combination of nivolumab and ipilimumab treats conditions like melanoma and lung cancer. However, these treatments can cause serious side effects. This combination is currently being tested in early trials for neurofibrosarcoma, so detailed safety information for this specific condition is still being collected.

In past treatments for other conditions, common side effects included tiredness, skin rash, and diarrhea. More serious side effects might involve inflammation in parts of the body, such as the lungs or liver. While these side effects can be difficult, medical care usually manages them.

Since this trial is in an early stage, the main goal is to assess how patients handle these drugs when used together. This step is crucial to ensure participant safety before further testing. Prospective participants should consult a healthcare provider to understand the potential risks and benefits. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Researchers are excited about Nivolumab and Ipilimumab for neurofibrosarcoma because these drugs harness the power of the immune system to fight cancer. Unlike traditional treatments like surgery, radiation, or chemotherapy, which directly target and kill cancer cells, Nivolumab and Ipilimumab are immunotherapies. They work by blocking proteins that prevent immune cells from attacking cancer cells, effectively enabling the body's natural defenses to join the fight. This innovative approach offers hope for improved outcomes, particularly for patients who may not respond well to standard treatments.

What evidence suggests that nivolumab and ipilimumab might be an effective treatment for neurofibrosarcoma?

Studies have shown that nivolumab and ipilimumab can be promising for certain cancers by helping the immune system fight tumors. These drugs enable the body's defense system to recognize and attack cancer cells more effectively. Research on other cancer types has demonstrated that this combination can shrink tumors and increase survival rates. In this trial, participants will receive nivolumab and ipilimumab to evaluate their effectiveness for malignant peripheral nerve sheath tumors (MPNSTs), which are rare and difficult to treat. Current treatments like chemotherapy often prove ineffective and have high recurrence rates. The hope is that these immunotherapy drugs can provide better results by directly targeting cancer cells. ^{1 6 7 8 9}

Who Is on the Research Team?

Jaishri Blakeley, MD

Principal Investigator

Johns Hopkins University

Are You a Good Fit for This Trial?

This trial is for individuals with Neurofibromatosis Type 1 (NF1) and newly diagnosed nerve sheath tumors who can undergo surgery. Participants must have good physical function, no contraindications to the study drugs, stable tumors not requiring treatment within a year, measurable disease, normal organ/marrow function, and not be pregnant or breastfeeding. Those with active infections, severe medical conditions, autoimmune diseases or recent immunosuppressant use are excluded.

Inclusion Criteria

You have a detectable disease according to specific guidelines at least in one part of the body.

I can care for myself but may need occasional help.

I have a stable tumor that hasn't needed treatment for the past year and likely won't need it in the coming year.

Exclusion Criteria

I do not have an active infection needing treatment, including Hepatitis B or C.

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

Prisoners or subjects who are compulsorily detained for treatment of either a psychiatric or physical illness

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Neoadjuvant Treatment

Participants receive neoadjuvant nivolumab plus ipilimumab prior to standard therapy

6 weeks

2 visits (in-person) every 3 weeks

Standard Therapy

Participants undergo standard therapy which may include surgery, chemotherapy, or radiation therapy

Varies

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 2 years

What Are the Treatments Tested in This Trial?

Interventions

• Nivolumab and Ipilimumab

Trial Overview The trial tests Nivolumab plus Ipilimumab given before standard treatments like surgery in patients with malignant peripheral nerve sheath tumors related to NF1. The goal is to assess the safety and feasibility of this combination therapy as an initial step before any other therapeutic procedures.

How Is the Trial Designed?

Group I: Immunotherapy with Nivolumab and Ipilimumab Experimental Treatment 2 Interventions

Nivolumab 4.5 mg/kg every 3 weeks (Q3W) x 2 Ipilimumab 1 mg/kg Q3W x 2 Nivolumab monotherapy 4.5mg/kg Q3W concurrent with standard therapy Nivolumab monotherapy should be held for at least 2 weeks before and 2 weeks after surgery

Who Is Running the Clinical Trial?

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Lead Sponsor

Trials

578

Recruited

33,600+

Department of Defense / Congressionally Mandated Research Program (CDMRP)

Collaborator

Trials

1

Recruited

120+

NF Clinical Trials Consortium

Collaborator

Congressionally Directed Medical Research Programs

Collaborator

Trials

59

Recruited

10,600+

Cancer Research and Biostatistics Clinical Trials Consortium

Collaborator

Trials

3

Recruited

120+

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

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]

In a national case series of 19 children with neurofibromatosis type 1-associated plexiform neurofibromas, treatment with selumetinib led to symptom improvement or stabilization in all patients, demonstrating its efficacy.

Selumetinib, an oral selective inhibitor of the RAS-MAPK pathway, was well-tolerated with an acceptable toxicity profile, confirming its safety and effectiveness in a real-world setting, even for those previously treated with other medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Selumetinib for symptomatic, inoperable plexiform neurofibromas in children with neurofibromatosis type 1: A national real-world case series. Coltin, H., Perreault, S., Larouche, V., et al.[2022]

The neurofibromatoses (NF) are tumor-suppressor syndromes that lead to multiple tumor types and significant health challenges, necessitating tailored clinical trial designs for effective treatment evaluation.

The REiNS International Collaboration has established recommendations for standardizing clinical trial endpoints in NF, aiming to improve the assessment of treatment efficacy and facilitate drug approval processes for patients with these conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Achieving consensus for clinical trials: the REiNS International Collaboration. Plotkin, SR., Blakeley, JO., Dombi, E., et al.[2021]

In a study of various tumors associated with neurofibromatosis types 1 and 2, PD-L1 was found to be expressed in a significant number of tumor samples, indicating a potential target for immunotherapy.

The presence of tumor infiltrating lymphocytes (TILs) alongside PD-L1 expression suggests that NF1 and NF2-related tumors may respond to immune checkpoint inhibitors, warranting further clinical trials to explore this treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Programmed death ligand 1 expression and tumor infiltrating lymphocytes in neurofibromatosis type 1 and 2 associated tumors. Wang, S., Liechty, B., Patel, S., et al.[2022]

A 60-year-old male patient with malignant peripheral nerve sheath tumors (MPNSTs) showed a complete remission after receiving immune checkpoint therapy (ICT) with pembrolizumab, following a recurrence and progression on standard chemotherapy.

Molecular profiling revealed high PD-L1 expression (70%) in the tumor, suggesting that PD-L1 positivity may be a key factor for the effectiveness of ICT in treating MPNSTs, warranting further investigation into this treatment approach for similar cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab Achieves a Complete Response in an NF-1 Mutated, PD-L1 Positive Malignant Peripheral Nerve Sheath Tumor: A Case Report and Review of the Benchmarks. Larson, K., Russ, A., Arif-Tiwari, H., et al.[2023]

Selumetinib, a MEK inhibitor, has shown significant efficacy in treating plexiform neurofibromas in patients with neurofibromatosis type 1, with 68% of 50 symptomatic patients experiencing a partial response and a median tumor volume reduction of 27.9%.

The treatment demonstrated a favorable safety profile, with manageable adverse effects, and resulted in an 84% estimated progression-free survival at 3 years, marking it as the first FDA-approved therapy for inoperable plexiform neurofibromas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Review of Selumetinib in the Treatment of Neurofibromatosis Type 1-Related Plexiform Neurofibromas. Anderson, MK., Johnson, M., Thornburg, L., et al.[2022]

The study analyzed the immune profiles of 36 NF1-associated tumor samples, revealing that malignant peripheral nerve sheath tumors (MPNST) and certain neurofibromas exhibit similar immunogenic characteristics, which may make them potential candidates for immunotherapy.

Despite the potential for immunotherapy in treating MPNST and specific neurofibromas, the heterogeneity of tumors presents a significant challenge, indicating that responses to treatment may vary widely among patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immune profiling of NF1-associated tumors reveals histologic subtype distinctions and heterogeneity: implications for immunotherapy. Haworth, KB., Arnold, MA., Pierson, CR., et al.[2022]

Combining nivolumab and ipilimumab shows improved effectiveness in treating metastatic melanoma compared to using either drug alone, based on a retrospective analysis of approximately 7700 patients.

The combination therapy presents a safety profile that includes immune-related adverse events from both drugs, indicating that while the combination is effective, it also carries a heightened risk of toxicity that needs further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Retrospective Side Effect Profiling of the Metastatic Melanoma Combination Therapy Ipilimumab-Nivolumab Using Adverse Event Data. Soldatos, TG., Dimitrakopoulou-Strauss, A., Larribere, L., et al.[2022]

In a review of 10 patients with neurofibrosarcoma, radical surgery combined with radiation or chemotherapy showed a significantly lower local recurrence rate (1 out of 6) compared to local excision methods (8 out of 12), indicating that more aggressive surgical approaches may be more effective.

Despite achieving local disease control, 44% of patients still died from metastases, highlighting the aggressive nature of neurofibrosarcoma and the need for postoperative adjuvant chemotherapy trials to address distant disease recurrence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neurofibrosarcoma. Storm, FK., Eilber, FR., Mirra, J., et al.[2019]

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]

Immunotherapy targeting PD-1/PD-L1 and CTLA-4 has shown increased survival benefits in treating metastatic non-small cell lung cancer (NSCLC), but it is also associated with significant cardiotoxicity, particularly high-grade conduction disorders like 3rd degree heart block.

A case study highlighted a patient who developed 3rd degree heart block 16 days after starting combination therapy with ipilimumab and nivolumab, emphasizing that over 75% of immunotherapy-related cardiotoxicity cases occur within the first 6 weeks, which underscores the need for early identification and monitoring of high-risk patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Immunotherapy-associated complete heart block in a patient with NSCLC: A case report and literature review. Vartanov, A., Kalotra, A., Varughese, J., et al.[2021]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04465643

NCT04465643 | Neoadjuvant Nivolumab Plus Ipilimumab ... The purpose of the study is to evaluate safety and feasibility of neoadjuvant nivolumab plus ipilimumab prior to standard therapy (surgery, chemotherapy or ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10480481/

The quest for effective immunotherapies against malignant ... Surgical resection has been the mainstay of therapy in MPNSTs, but the recurrence rate is as high as 65%, and chemotherapy is generally ineffective. The immune ...

3. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCT04465643

Neoadjuvant Nivolumab plus Ipilimumab for the Treatment ... This phase I trial tests the safety, side effects and effectiveness of nivolumab plus ipilimumab in treating malignant and pre-malignant peripheral nerve ...

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11475700/

The Multimodality Management of Malignant Peripheral ... In general, just 20–30% of the patients will survive two years post-diagnosis. In terms of effectiveness, subsequent lines of chemotherapy are ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT04465643?term=malignant%20peripheral%20nerve%20sheath%20tumors&aggFilters=studyType:int,ages:adult%20older&viewType=Table&rank=2

Study Details | Neoadjuvant Nivolumab Plus Ipilimumab for ... The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure.

6. withpower.com withpower.com/trial/phase-1-neurofibrosarcoma-5-2021-ffa4b

Nivolumab + Ipilimumab for Neurofibrosarcoma The combination of Nivolumab and Ipilimumab has been used in treatments for conditions like melanoma and lung cancer, but it can cause serious side effects.

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11985850/

The outcomes and treatment strategies in metastatic soft ... Historical data showed that the rate of 5-year OS was about 22% in 1989, which increased to about 61% in 2018 in the metastatic setting (18).

8. mdpi.com mdpi.com/2072-6694/16/19/3266

The Multimodality Management of Malignant Peripheral ... The Alliance A091401, a phase II trial evaluating the use of nivolumab alone versus the combination of nivolumab and ipilimumab in patients with ...

9. academic.oup.com academic.oup.com/oncolo/article/28/5/e233/7076257

Emerging Trends in Immunotherapy for Adult Sarcomas The ipilimumab plus nivolumab combination therapy group demonstrated efficacy in multiple sarcoma subtypes, including UPS, LMS, angiosarcoma ...