BMS-98650 for the Treatment of Unresectable, Locally Advanced or Metastatic Peripheral Nerve Sheath Tumor with Homozygous MTAP Deletion

Inclusion Criteria

• Male or female patients ≥ 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 malignant peripheral nerve sheath tumor (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therapy at the time of enrollment to baseline or ≤ grade 1 (excluding alopecia, peripheral neuropathy, and parameters superseded by other eligibility criteria [eg, hematology parameters]).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 version [v] 5.0) of all prior chemotherapy prior to the entering study (exceptions: alopecia, anorexia, mass pain)
• Peripheral absolute neutrophil count (ANC) ≥ 1500/mcL
• 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 (platelet transfusion is not allowed up to 14 days prior to starting BMS-986504 treatment to meet eligibility)
• 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)
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 3 x ULN for age, or < 5 x ULN if associated with liver metastatic disease
• Serum albumin ≥ 2.0 g/dL
• Prothrombin time (PT) and/or international normalization ratio (INR) ≤ 1.5 x ULN, or within therapeutic range if receiving anticoagulant therapy
• Creatinine < 1.5 times institutional ULN for age
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1 for patients ≥ 18 years old (at time of screening)
• Lansky performance status (ages 12-15) or Karnofsky performance status (ages 16-17) ≥ 50 (at time of screening)
• The investigator or designee has counseled individuals of childbearing potential (IOCBP) participants and male (as assigned at birth) participants who are sexually active with IOCBP on the importance of pregnancy prevention, the implications of an unexpected pregnancy, and the potential of fetal toxicity occurring due to transmission of study intervention present in seminal fluid to a developing fetus, even if the participant has undergone a successful vasectomy or if the partner is pregnant. The investigator or designee has evaluated the patient’s understanding of the effectiveness of the contraceptive method prior to the first dose of study intervention. Female (as assigned at birth) participants who are not of childbearing potential have documented proof (documentation can be obtained from the site personnel’s review of the participant’s medical records, medical examination, or medical history interview) or follicle-stimulating hormone (FSH) measured at screening. Individuals who are not of childbearing potential are exempt from contraceptive requirements
• IOCBP must have a negative highly sensitive urine or serum (as required by local regulations) pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin) within 24 hours prior to start of study intervention. If a urine test cannot be confirmed as negative (e.g., ambiguous result), a serum pregnancy test is required. In such cases, the participant must be excluded from participation if the serum pregnancy result is positive. The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to potentially decrease the risk for inclusion of an individual with an undetected pregnancy
• IOCBP and male (as assigned at birth) participants who are sexually active with IOCBP must agree to follow instructions for method(s) of contraception included in the informed consent form (ICF). IOCBP are not permitted to use hormonal contraceptive methods alone as a highly effective method of contraception, and must use an additional non-hormonal highly effective method of contraception
• A female (as assigned at birth) is eligible to participate if she is not pregnant or breastfeeding and is not an IOCBP or is an IOCBP using a combination of a hormonal and a non-hormonal contraceptive method or a non-hormonal contraception method alone that is highly effective during the intervention period and for at least 1 month after the last dose of study intervention and agrees not to donate eggs (ova, oocytes) for the purpose of reproduction for the same period
• Male (as assigned at birth) participants must agree to always use a latex or other synthetic condom during any sexual activity (e.g., vaginal, anal, oral) with IOCBP, even if the participant has undergone a successful vasectomy or if the partner is pregnant or breastfeeding. Male (as assigned at birth) participants should continue to use a condom during the intervention period and for at least 1 month after the last dose of study intervention. They must refrain from donating sperm during the intervention period and for at least 1 month after the last dose of study intervention
• Azoospermic males are not exempt from contraceptive requirements and must agree to always use a latex or other synthetic condom during any sexual activity (e.g., vaginal, anal, oral) with IOCBP, even if the participant has undergone a successful vasectomy or if the partner is pregnant
• IOCBP partners of male (as assigned at birth) participants must agree to use a highly effective method of contraception during the intervention period and for at least 1 month after the last dose of study intervention for the male participant
• Breastfeeding partners of male (as assigned at birth) participants must consult their health care provider about using appropriate highly effective contraception during the time the male participant is required to use condoms

Exclusion Criteria

• Patients who have been treated previously with a PRMT5 inhibitor
• Patients 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
• Patients 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 induce of CYP3A4 and/or P-gp or a PPI that cannot be switched to an alternative treatment prior to randomization