Pancreatic Cancer Clinical Trials

• COHORT A (INCLUDING SAFETY RUN IN, STAGE I AND STAGE II) AND COHORT B:

• Patients must have pathologically or cytologically confirmed metastatic solid tumor of gastrointestinal origin with MTAP deletion including pancreatic cancer, biliary cancer, esophageal cancer and colon cancer (Cohort A) or other metastatic solid malignancy with MTAP deletion (Cohort B) confirmed by validated next generation sequencing tissue techniques only

‣ NOTE: Both internal and external validated next generation sequencing (NGS) panels are acceptable

• Progressive disease (PD) after one previous standard of care line of treatment

‣ NOTE: symptoms from clinical evaluation for PD will be sufficient

• Patients must have at least 1 measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1, measured preferably by computed tomography (CT) scan

‣ Note: Tumor lesions in a previously irradiated area are not considered measurable unless they show unequivocal progression

⁃ NOTE: There is no limit on previous treatment lines

• Patients who have received any neoadjuvant or systemic chemotherapy are eligible

‣ Note: treatment cannot have included prior pemetrexed unless in the case of non-small cell lung cancer (NSCLC) cancer type. Any prior intravesical therapy, or immunotherapy is allowed. At least 3 weeks (21 days) wash-out period from treatment since prior chemotherapy or radiation therapy or targeted agent is required

• Patients must be aged ≥ 18 years

• Patients must exhibit an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1

• Absolute neutrophil count (ANC) ≥ 1,500/mcL (growth factor allowed and can be added at the discretion of the treating oncologist

‣ Growth factors are excluded from being used during the DLT observation period (cycle 1) unless they are being used to treat a grade 4 adverse event which will be counted as a DLT. If growth factors are being used for grade ≤ 3 toxicity, then patients will not be evaluable for DLT assessment

• Hemoglobin (Hgb) ≥ 8.5 g/dL (without the need for transfusion within the previous one week)

• Platelets (PLT) ≥ 100,000/mL (without the need for platelet transfusion within the previous one week)

• Total bilirubin ≤ 1.5 x Institutional upper limit of normal (ULN), except subjects with Gilbert's syndrome or liver metastases, who must have a baseline total bilirubin ≤ 3.0 mg/dL

• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\]) ≤ 3 x institutional ULN or ≤ 5 x ULN if documented liver metastases are present

• Alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase \[SGPT\]) ≤ 3 x institutional ULN or ≤ 5 x ULN if documented liver metastases are present

• Creatinine clearance ≥ 60 mL/min/1.73 m\^2 using the standard Cockcroft and Gault formula

• Patients must have the ability to comply with folic acid, vitamin B12 and steroids as directed by study team and as per standard of care for pemetrexed use

• Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression

• Pemetrexed is known to be teratogenic. Reproductive toxicology studies with MRTX1719 have not been performed. The investigator or designee shall counsel patients of childbearing potential (POCBP) participants and male (as assigned at birth) participants who are sexually active with POCBP 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. If needed, participants should be advised to seek advice about egg or sperm donation and cryopreservation of germ cells before treatment

‣ Patients of childbearing potential POCBP

• A POCBP is any patient with an egg-producing reproductive tract who meets the following criteria:

‣ Has not undergone a hysterectomy or bilateral oophorectomy

⁃ Has had menses at any time in the preceding 12 consecutive months (and therefore has not been naturally postmenopausal for \> 12 months)

∙ POCBP 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. POCBP 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) 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 pemetrexed, whichever is longer

∙ POCBP participants must also agree not to donate eggs (ova, oocytes) for the purpose of reproduction for the same period

∙ Male (as assigned at birth) participants will be required to always use a latex or other synthetic condom during any sexual activity (eg, vaginal, anal, oral) with POCBP, 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 6 months after the last dose of study intervention, or according to approved local product label requirements for pemetrexed, whichever is longer

∙ POCBP partners of male (as assigned at birth) participants should be advised to use a highly effective method of contraception during the intervention period and for at least 6 months after the last dose of study intervention for the male participant, or according to approved local product label requirements for pemetrexed, whichever is longer

∙ Male (as assigned at birth) participants with a pregnant or breastfeeding partner must agree to remain abstinent from sexual activity or use a male condom during any sexual activity (eg, vaginal, anal, oral), even if the participant has undergone a successful vasectomy, 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 pemetrexed, whichever is longer

∙ Male (as assigned at birth) participants must refrain from donating sperm 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 pemetrexed, whichever is longer

∙ Breastfeeding partners of male (as assigned at birth) participants should be advised to consult their health care provider about using appropriate highly effective contraception during the time the male participant is required to use condoms

∙ POCBP must have a negative pregnancy test prior to registration on study

• The ability to interrupt nonsteroidal antiinflammatory drugs (NSAIDS) or aspirin at higher dose (\> 1.3 g daily) 2 days before (5 days for long-acting NSAIDs), the day of, and 2 days following administration of pemetrexed