Safety and Efficacy of BMS-986504 in Unresectable Malignant Peripheral Nerve Sheath Tumor

A Phase II Trial to Assess the Safety and Efficacy of BMS-986504 in Unresectable Malignant Peripheral Nerve Sheath Tumor Patients With Homozygous MTAP Deletion

People who have a cancer called MPNST, or Malignant Peripheral Nerve Sheath Tumor, may be eligible for this study. The purpose of this study is to see if a new medicine called BMS-986504 may work better than other available medicines for people with MPNST. Methylthioadenosine Phosphorylase (MTAP) loss is a gene mutation that some people have. MTAP loss seems to increase the chance that BMS-986504 can kill MPNST cancer cells. People who are missing MTAP from their tumor may be able to enroll in this study. Treating MPNST based on MTAP loss is considered experimental and is not approved by the US Food and Drug Administration (FDA) for determining whether BMS-98650 will be active against cancer. The purpose of this study is to evaluate the safety and effectiveness of BMS-986504 in participants with MPNST.

Study Overview

• Status: Not yet recruiting
• Conditions: Malignant Peripheral Nerve Sheath Tumors; MPNST
• Intervention / Treatment: Drug: BMS-986504

Detailed Description

Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are fast-growing, aggressive cancers that develop in soft tissues. They are the main cause of serious illness and death in people with neurofibromatosis type 1 (NF1), a condition that increases the risk of cancer. MPNSTs are rare, affecting about 1 in 100,000 people. In the United States, about 800 to 1,000 new cases are diagnosed each year. The 5-year survival rate is about 50%. However, this drops to about 20% when the cancer has spread or cannot be removed with surgery. Chemotherapy is often less effective, especially when the tumor cannot be removed by surgery, with response rates under 20%. There is a strong need to develop new and more targeted therapies for this type of cancer.

When some benign (non-cancerous) nerve tumors, called neurofibromas, turn into MPNST, it is often caused by the loss of a group of genes called CDKN2A on chromosome 9. These genes normally help prevent tumors from forming. When a part of chromosome 9 called 9p21 is deleted, it can also cause the loss of a nearby gene called MTAP. MTAP is missing in about 25-50% of people with MPNST. MTAP plays an important role in the methionine salvage pathway and serves a critical role in methylation reactions. When MTAP is lost, cells have problems with purine metabolism and become more dependent on another pathway, the arginine methylation pathways. This pathway is important for processes like DNA repair and control of the cell cycle. An enzyme called protein arginine methyltransferase 5 (PRMT5) helps carry out arginine methylation by adding small chemical groups (methyl groups) to proteins. When both copies of the MTAP gene are lost (called homozygous deletion), cells rely even more on PRMT5 to survive. At the same time, a substance called methylthioadenosine builds up and partly blocks PRMT5 activity. Because of this, completely blocking PRMT5 can cause MTAP-deficient cancer cells to die, a concept known as "synthetic lethality." For people with MPNST who have homozygous MTAP deletion confirmed by next-generation sequencing (NGS), drugs that block PRMT5 may help shrink tumors. A drug called BMS-986504 is a first-in-class PRMT5 inhibitor designed to specifically target MTAP-deficient tumor cells by binding to the PRMT5-MTA complex.

BMS-986504 was recently studied in a Phase 1 trial and showed evidence of anti-tumor activity. People with tumors that could not be removed with surgery with a homozygous MTAP deletion and whose disease had gotten worse since their last treatment were given varying doses of BMS-986504. Three of the 6 people enrolled had disease progression. The remaining 3 participants had partial responses, meaning that there was a >30% improvement from their baseline per RECIST v1.1 criteria. Each of these 3 participants had different doses of the study drug, which suggests a dose-independent response.

Since the current treatments for MPNST that cannot be removed through surgery are poor, it is important to identify new treatment strategies that may improve how long someone lives with this type of cancer and their health outcomes. This study aims to assess the safety and efficacy of BMS-986504 in people with MPNST that cannot be removed with surgery and with homozygous MTAP deletion.

• Study Type: Interventional
• Enrollment (Estimated): 17
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Ankit Mangla, MD; Phone Number: 216-844-6031; Email: ankit.mangla@uhhospitals.org

Study Locations

• United States
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center
      • Principal Investigator: Ankit Mangla, MD
      • Contact: Ankit Mangla, MD; Phone Number: 216-844-6031; Email: ankit.mangla@uhhospitals.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Male or female participants ≥ 12 years of age at the time of screening.
• Ability to understand and willingness to sign documentation of informed consent if ≥ 18 years of age or documentation of assent if 12-17 years of age.

• Pathohistological verification of MPNST.

  • Measurable disease (size of primary tumor and metastatic lesions can be trended by CT or MRI scans).
  • Unresectable (locally advanced or metastatic) disease.
• Confirmation of homozygous MTAP deletion by next generation sequencing
• Recovery from the adverse effects of prior therapy at the time of enrollment to baseline or ≤ Grade 1 (excluding alopecia, peripheral neuropathy, and parameters superseded by other eligibility criteria [eg, hematology parameters]). Note: Participants with prior endocrine adverse effects are permitted to enroll if they are stably maintained on appropriate replacement therapy and are asymptomatic.
• Recovery from the acute toxic effects (≤ grade 1 as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events v5.0) of all prior chemotherapy prior to the entering study (exceptions: alopecia, anorexia, mass pain).

• Normal marrow function and recovery of blood cell counts from any myelosuppressive chemotherapy prior to entering study:

  • Peripheral absolute neutrophil count (ANC) ≥ 1500/mcL (microliter).
  • Hemoglobin ≥ 9 g/dL (packed red blood cell transfusion is not allowed up to 14 days prior to starting BMS-986504 treatment to meet eligibility).
  • Platelet count ≥ 100,000/mcL (microliter) (platelet transfusion is not allowed up to 14 days prior to starting BMS-986504 treatment to meet eligibility).

  • Adequate organ function, including:

    • Liver function:

      • Total bilirubin ≤ 1.5 times the upper limit of normal (ULN) for age, or ≤ 3 x ULN if associated with liver metastatic disease or Gilbert's disease).
      • ALT (alanine transaminase) and AST (aspartate aminotransferase) < 3 x ULN for age, or < 5 x ULN if associated with liver metastatic disease.
      • Serum albumin ≥ 2.0 g/dL.
      • PT (prothrombin time) and/or INR (International Normalized Ratio) ≤ 1.5 x ULN, or within therapeutic range if receiving anticoagulant therapy.

    • Renal function:

      • Creatinine < 1.5 times institutional ULN for age.

• Performance status at time of screening:

  • ECOG (Eastern Cooperative Oncology Group) performance status 0-1 for participants ≥ 18 years old.
  • Lansky performance status (ages 12-15) or Karnofsky performance status (ages 16-17) ≥ 50.
• Individuals of childbearing potential (IOCBP) must practice effective contraception during the trial.

Exclusion Criteria:

• Participants who have been treated previously with a PRMT5 inhibitor.
• Participants who are unable to swallow tablets.
• History of gastrointestinal disease, inflammatory bowel disease, major gastric surgery or other gastrointestinal conditions (eg, uncontrolled nausea, vomiting, malabsorption syndrome) likely to alter absorption of study treatment or result in inability to swallow oral medications.
• Participants with active drug use.
• Any botanical preparation (e.g., herbal supplements or traditional Chinese medicines) intended to treat the disease under study received within 4 weeks prior to randomization. The concurrent use of any botanical preparation is not permitted while on study.
• Ongoing need for a medication known as a strong inhibitor or strong inducer of CYP3A4 and/or P-gp or a PPI (proton pump inhibitor) that cannot be switched to an alternative treatment prior to randomization.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: BMS-986504; Participants will receive BMS-986504 on Days 1-28 of each cycle. Treatment will continue until disease progression, unacceptable toxicity, or withdrawal of consent.

Drug: BMS-986504; Participants will receive 600 milligrams (mg) of BMS-986504 taken orally (by mouth) on Days 1-28 of each 28-day cycle. Treatment will continue until disease progression, unacceptable toxicity, or withdrawal of consent (up to 2 years). Participants who experience dose-limiting toxicity can be transitioned to 400 mg daily, then 200 mg daily of BMS-986504, or taken off the clinical trial. Nine participants will be enrolled in stage 1. If ≥ 1 participant demonstrates a complete or partial response in stage 1, the trial will proceed to stage 2, where an additional eight participants will be enrolled. If there are no responses or significant safety concerns arise, the trial will be halted.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective response rate (ORR)	ORR is defined as the proportion of participants with a confirmed complete response (CR) or partial response (PR) per Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1). CR is defined as disappearance of all target lesions. PR is defined as at least a 30% decrease in the sum of diameters of target lesions.	Up to 2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression free survival (PFS)	Progression-Free Survival (PFS) is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first.	Up to 2 years
Overall survival (OS)	OS is defined as the time from treatment initiation to death from any cause.	Up to 2 years
Incidence of adverse events (AEs)	AEs will be defined and graded per the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0).	30 days post-treatment discontinuation (up to 2 years)
Rate of treatment discontinuation	Proportion of participants discontinuing treatment due to toxicity will be calculated.	Up to 2 years

Collaborators and Investigators

• Sponsor: Ankit Mangla, MD
• Investigators: Principal Investigator: Ankit Mangla, MD, Case Comprehensive Cancer Center, University Hospitals

Publications and helpful links

General Publications

• Miller, D.T., et al. (2019). Health supervision for children with neurofibromatosis type 1. Pediatrics, 143(5): e20190660. doi:10.1542/peds.2019-0660.
• Kolb, S., et al. (2021). The Role of Radiation Therapy in the Treatment of Malignant Peripheral Nerve Sheath Tumors. Journal of Clinical Oncology. 39(25): 2762-2773. doi:10.1200/JCO.21.01232.
• Montoya, P., et al. (2023). Methylthioadenosine Phosphorylase Deficiency in MPNST: Implications for Targeted Therapies. Neuro-Oncology. 25(S5): v238. doi:10.1093/neuonc/noad243.
• Zhang, Y., et al. (2021). Loss of MTAP in cancer cells drives metabolic dependency on the arginine methylation pathway. Cancer Research. 81(13): 3538-3549. doi: 10.1158/0008-5472.CAN-21-0766.
• Turner, J., et al. (2022). Targeting methylthioadenosine phosphorylase and arginine methylation for synthetic lethality in MTAP-deficient cancers. Nature Communications. 13(1): 1167. doi: 10.1038/s41467-022-29032-2.
• Chang, L., et al. (2021). Protein arginine methyltransferase 5 inhibitors as therapeutic agents for cancer. Journal of Medicinal Chemistry.
• Liu, W., et al. (2023). PRMT5 inhibition as a therapeutic strategy for MTAP-deficient cancers. Clinical Cancer Research. 29(3): 721-731. doi:10.1158/1078-0432.CCR-22-2479.
• Walker, L., et al. (2023). Targeting PRMT5 in MTAP-deleted cancers: A synthetic lethal approach. Journal of Clinical Oncology. 41(4): 157-167. doi:10.1200/JCO.22.00399.

Study record dates

Study Major Dates

• Study Start (Estimated): April 1, 2026
• Primary Completion (Estimated): April 1, 2028
• Study Completion (Estimated): July 1, 2028

Study Registration Dates

• First Submitted: April 18, 2026
• First Submitted That Met QC Criteria: April 18, 2026
• First Posted (Actual): April 23, 2026

Study Record Updates

• Last Update Posted (Actual): April 23, 2026
• Last Update Submitted That Met QC Criteria: April 18, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: BMS-986504
• Additional Relevant MeSH Terms: Nervous System Diseases; Neoplasms; Neuromuscular Diseases; Peripheral Nervous System Diseases; Neoplasms by Histologic Type; Neoplasms, Nerve Tissue; Nervous System Neoplasms; Nerve Sheath Neoplasms; Peripheral Nervous System Neoplasms; Sarcoma; Neoplasms, Connective and Soft Tissue; Neoplasms, Connective Tissue; Neurofibroma; Fibrosarcoma; Neoplasms, Fibrous Tissue; Neurofibrosarcoma
• Other Study ID Numbers: CASE3725

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No