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.

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.

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.