PRMT5 Inhibition with BMS-986504 and PARP Inhibition with Olaparib for the Treatment of Advanced and Metastatic Solid Tumors with MTAP Loss

Inclusion Criteria

• Age ≥ 18 years
• All patients must have a histologically confirmed advanced or metastatic solid tumor that has been refractory to standard therapy or are not eligible for standard therapy and have no alternative curative-intent treatment options at the time of patient enrollment. For the dose escalation, any solid tumor is eligible, but enrollment will be enriched for cholangiocarcinoma (CCA) and pancreatic cancer. For the pharmacodynamic expansion, patients must have histologically confirmed advanced or metastatic CCA or pancreatic cancer
• Homozygous deletion of MTAP as detected by Clinical Laboratory Improvement Amendments-certified next-generation sequencing test or absence of MTAP protein as detected by CLIA-certified immunohistochemistry test
• Patients in Part A must have archived tumor tissue available for retrospective analysis or agree to pre-treatment biopsy
• Ability to understand and the willingness to sign a written informed consent document
• Ability to comply with the study protocol, in the investigator’s judgment
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Life expectancy ≥ 3 months
• Patients in the pharmacodynamic expansion must have measurable and biopsiable disease per the Respone Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1. Patients in the dose escalation can have evaluable or measurable disease
• Patients must have adequate washout from prior therapy at the time of study treatment initiation: 3 weeks from any treatment specifically for systemic tumor control: 5 half-lives from small molecule targeted agents and ≥ 2 weeks from radiotherapy (except for patients with brain metastasis treatment with Gamma Knife; in these cases, > 1 week is required). Palliative radiotherapy is permitted for a preexisting lesion, provided it does not interfere with the assessment of tumor target lesions (e.g., the lesion to be irradiated must not be a site of measurable disease)
• Patients must have recovered from toxicities of prior anticancer therapy (grade ≤ 1 toxicity) except for alopecia and peripheral neuropathy
• Hemoglobin ≤ 9.0 g/dL (within 28 days prior to study treatment initiation)
• Absolute neutrophil count (ANC) ≥ 1500/mm^3 (within 28 days prior to study treatment initiation)
• Platelets ≥ 100,000/mm^3 (within 28 days prior to study treatment initiation)
• Estimated glomerular filtration rate ≥ 50 mL/min/1.73 m^2 by the Chronic Disease Epidemiology Collaboration equation (within 28 days prior to study treatment initiation)
• Serum creatinine ≤ 1.5 x upper limit of normal (ULN) or estimated creatinine clearance ≥ 50 mL/min (calculated using institutional standard method) (within 28 days prior to study treatment initiation)
• Total bilirubin ≤ 1.5 x ULN (within 28 days prior to study treatment initiation) * Patients with Gilbert's syndrome with total bilirubin ≤ 2.0 x ULN and direct bilirubin within normal limits are permitted
• Aspartate aminotransferase/alanine aminotransferase (ALT) ≤ 3 x institutional ULN or ≤ 5 x ULN for patients with liver metastases (within 28 days prior to study treatment initiation)
• For patients not receiving therapeutic anticoagulation: international normalized ratio or activated partial thromboplastin time ≤ 1.5 x ULN (within 28 days prior to study treatment initiation)
• For patients receiving therapeutic anticoagulation: stable anticoagulant regimen (within 28 days prior to study treatment initiation)
• Patients must be able to take PO medications
• Women of childbearing potential (WOCBP) must have a negative serum pregnancy test result within 72 hours prior to study treatment initiation * WOCBP must agree to use adequate contraception as described below from the screening visit through at least 6 months after the last dose of study treatment. This includes all female patients, between the onset of menses (as early as 8 years of age) and 55 years unless the patient presents with an applicable exclusionary factor which may be one of the following: ** Postmenopausal (no menses in ≥ 12 consecutive months) ** History of hysterectomy or bilateral salpingo-oophorectomy ** Ovarian failure (follicle-stimulating hormone and estradiol in menopausal range and have received whole pelvic radiation therapy) ** History of bilateral tubal ligation or another surgical sterilization procedure * WOCBP must agree to use a combination of a hormonal and a non-hormonal contraceptive method or a non-hormonal method alone that is highly effective (with a failure rate of < 1% per year: copper intrauterine device) during the intervention period and for at least 6 months after the last dose of study intervention, or according to approved local product label requirements for individual chemotherapy agents, whichever is longer * WOCBP 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 * WOCBP must also agree not to donate eggs (ova, oocytes) for the purpose of reproduction for the same period. Participants should be advised to seek advice about egg donation and cryopreservation of germ cells before treatment * Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately * Male participants with a pregnant or breastfeeding partner must agree to remain abstinent from sexual activity or to use adequate contraception in any sexual activity, even if the participant has undergone a successful vasectomy, during the intervention period and for at least 3 months after the last dose of study intervention or according to approved local product label requirements for individual chemotherapy agents, whichever is longer * Male participants must refrain from donating sperm during the intervention period and for at least 3 months after the last dose of study intervention, or according to approved local product label requirements for individual chemotherapy agents, whichever is longer. Participants should be advised to seek advice about sperm donation and cryopreservation of germ cells before treatment. WOCBP partners of male participants should be advised to use a highly effective method of contraception during the intervention period and for at least 3 months after the last dose of study intervention, or according to approved local product label requirements for individual chemotherapy agents, whichever is longer, for the male participant
• For patients with evidence of chronic hepatitis B virus (HBV) infection the HBV viral load must be undetectable within 6 months of enrollment
• Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load within 6 months of enrollment
• Human immunodeficiency virus-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial

Exclusion Criteria

• Part B only: Prior treatment with a PRMT5 or methionine adenosyltransferase 2A inhibitor
• Patients who have a known additional malignancy that is progressing or requires active treatment at time of study treatment initiation. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy, and in situ cervical cancer
• Patients with meningeal carcinomatosis, leptomeningeal carcinomatosis, spinal cord compression, or symptomatic or unstable brain metastases. Note: Patients with stable brain metastases (defined as asymptomatic or no requirement for high-dose or increasing dose of systemic corticosteroids and without imminent need of radiation therapy) are eligible (including those with untreated brain metastases). If applicable, patients must have completed brain radiation therapy and recovered adequately from any associated toxicity and/or complications prior to eligibility assessment
• Concomitant use of strong cytochrome P450 (CYP)3A inhibitors or inducers are prohibited within 14 days or 5 half-lives, whichever is longer, prior to study treatment initiation and during the study treatment period
• Any clinically significant comorbidities such as uncontrolled pulmonary disease, known impaired cardiac function or clinically significant cardiac disease (including but not limited to known left ventricular ejection fraction < 50%, congenital long QT syndrome, corrected QT interval using Fridericia's formula ≥ 480 msec on screening electrocardiogram [ECG], unstable angina pectoris ≤ 3 months prior to study treatment initiation, and acute myocardial infarction ≤ 3 months prior to study treatment initiation), or any other condition that could compromise the patient's participation in the study
• Treatment with a live, attenuated vaccine within 4 weeks prior to study treatment initiation. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, Bacille Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed. Non-live COVID vaccines will be allowed on study, but it is recommended to avoid their use during the first treatment cycle (from 3 days prior to cycle 1 day 1 through cycle 2 day 3)
• Concomitant use of medications known to be sensitive substrates of breast cancer resistance protein (including, but not limited to, rosuvastatin and sulfasalazine) or P-glycoprotein (P-gp; including, but not limited to, dabigatran etexilate, digoxin, fexofenadine)
• Patients who are pregnant or breastfeeding or expecting to conceive within the projected duration of the study, starting with the screening visit through 7 months after the last dose of study treatment
• Any known psychiatric, substance abuse, or other disorder that would interfere with cooperation with the requirements of the study, in the opinion of the investigator
• Patients who are receiving any other investigational agents
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to the study drugs
• Patients who have an active infection requiring intravenous (IV) antibiotics
• Patients with any gastrointestinal disorder that would significantly alter the absorption of the study drugs (e.g., active ulcerative diseases, uncontrolled nausea, uncontrolled vomiting, uncontrolled diarrhea, malabsorption syndrome)