Pancreatic Cancer Clinical Trials

∙ Eligibility Criteria

• Age ≥18 years.

• Homozygous MTAP deletion detected by NGS. Test can be performed on an archival tissue collected within 6 months from study enrollment and on blood samples.

• ECOG performance status 0-1.

• Histologically or cytologically confirmed pancreatic ductal adenocarcinoma (PDAC)

• Adequate organ and marrow function as defined below

‣ Hemoglobin ≥9.0 g/dL with no packed red blood cell transfusions in the past 7 days.

⁃ Absolute neutrophil count (ANC) ≥1.5 x 10⁹/L.

⁃ Platelet count ≥100 x 10⁹/L with no platelet transfusions in the past 7 days.

⁃ Total bilirubin ≤1.5 x institutional upper limit of normal (ULN).

⁃ AST (SGOT)/ALT (SGPT) ≤2.5 x institutional ULN value unless liver metastases are present, in which case ≤5 x ULN.

• Calculated creatinine clearance ≥50 mL/min (using Cockroft-Gault formula or 24-hour urine collection).

• Participants are allowed to have received 1 month of GA (cohort 1 and 2) and mFolfirinox (cohort 3) in consideration of the aggressive nature of PDAC and the time required for to test MTAP-deficiency

• Agree to follow the study protocol, including treatment, scheduled visits, and examinations, for the duration of the study.

• Ability to understand and the willingness to sign a written informed consent document.

• 1 Female (as assigned at birth) participants

• Women of child-bearing potential (WOCBP) include all female participants, between the onset of menses and 55 years unless the participant presents with an applicable exclusionary factor which may be one of the following (Refer to Pregnancy Assessment Policy MD Anderson Institutional Policy # CLN1114): :

‣ Postmenopausal (no menses in greater than or equal to 12 consecutive months).

⁃ History of hysterectomy or bilateral salpingo-oophorectomy.

⁃ Ovarian failure (Follicle Stimulating Hormone and Estradiol in menopausal range, who 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) during the intervention period and for at least 9 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 participants 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.

⁃ Approved methods of birth control are as follows: Hormonal contraception (i.e. birth control pills, injection, implant, transdermal patch, vaginal ring), Intrauterine device (IUD), Tubal Ligation or hysterectomy, Subject/Partner post vasectomy, and Implantable or injectable contraceptives. . Not engaging in sexual activity for the entire period of risk associated with the study intervention is an acceptable practice; however, periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of birth control. 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.

‣ 2 Male (as assigned at birth) participants

• 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 WOCBP, 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 individual chemotherapy agents, 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 individual chemotherapy agents, 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 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 (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, or according to approved local product label requirements for individual chemotherapy agents, whichever is longer, for the male participant.

∙ Cohort 1 specific criteria:

• Resectable or borderline resectable pancreatic adenocarcinoma per NCCN version 3.202432 that have not received any neoadjuvant treatment

• o Resectable PDAC will be defined as the tumor with:

• No arterial tumor contact (celiac axis \[CA\], superior mesenteric artery \[SMA\], or common hepatic artery \[CHA\])

• No tumor contact with the superior mesenteric vein (SMV) or portal vein (PV) or ≤180° contact without vein contour irregularity.

• Borderline PDAC will be defined as the tumor with:

• o For tumors of the pancreatic head/uncinate process:

• Solid tumor contact with CHA without extension to CA or hepatic artery bifurcation, allowing for safe and complete resection and reconstruction.

• Solid tumor contact with the SMA of ≤180°.

• Solid tumor contact with variant arterial anatomy (eg, accessory right hepatic artery, replaced right hepatic artery, replaced CHA, and the origin of replaced or accessory artery) and the presence and degree of tumor contact should be noted if present, as it may affect surgical planning.

• Solid tumor contact with the SMV or PV of \>180°, contact of ≤180° with contour irregularity of the vein or thrombosis of the vein but with suitable vessel proximal and distal to the site of involvement, allowing for safe and complete resection and vein reconstruction.

• Solid tumor contact with the inferior vena cava (IVC).

• o For tumors of the pancreatic body/tail:

• Solid tumor contact with the CA of ≤180°

∙ Cohort 2 specific criteria:

• Locally advanced, unresectable pancreatic cancer per NCCN version 3.202432

• o For tumors of the head/uncinate process:

• Solid tumor contact \>180° with the SMA or CA

• Unreconstructible SMV/PV due to tumor involvement or occlusion (can be due to tumor or bland thrombus).

• o For tumors of the pancreatic body/tail:

• Solid tumor contact of \>180° with the SMA or CA.

• Solid tumor contact with the CA and aortic involvement.

• No prior treatment with the exception of one month of chemotherapy with GA without progression of disease

∙ Cohort 3 specific criteria:

• Metastatic pancreatic adenocarcinoma.

• No prior treatment, except one month of chemotherapy with mFOLFIRINOX without progression of disease.