Eligibility

Eligible Ages

Over 18 Years

Eligible Sex

All

Accepts Healthy Volunteers

No

Criteria

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.

Exclusion Criteria

- Prior treatment with PRMT5 and MAT2A inhibitors.

- Exposure to an investigational agent within 30 days or 5 half-lives (whichever is
longer) prior to trial enrolment is not permitted.

- Participants with other primary cancers are excluded, except for adequately treated
nonmelanoma skin cancer, prostate cancer post-resection with undetectable PSA,
in-situ cervical cancer, ductal carcinoma in situ (DCIS) of the breast, Stage 1
Grade 1 endometrial carcinoma, or solid tumors (including lymphomas without bone
marrow involvement) curatively treated with no evidence of disease for ≥2 years
prior to study entry.

- Major surgery within 2 weeks of starting treatment is not permitted. Participants
must have recovered from the effects of any major surgery.

- Significant third-space fluid retention (e.g., ascites or peritoneal effusion) that
requires drainage within 1 month prior to randomization.

- Cardiac abnormalities including:

- Left ventricular ejection fraction < 50%

- History of prolonged QTc, or QT interval corrected for heart rate using
Fridericia's formula (QTcF) prolongation > 480 msec, except for right bundle
branch block

- Uncontrolled/symptomatic or significant cardiovascular conditions within 6
months prior to enrollment, including but not limited to any of the following:

- Cardiac angioplasty or stenting, myocardial infarction, stroke/transient ischemic
attack, coronary artery bypass graft surgery, symptomatic peripheral vascular
disease, New York Heart Association (NYHA) class III-IV congestive heart failure,
pericarditis, myocarditis, atrial fibrillation or other arrhythmias (e.g.,
ventricular tachycardia, ventricular fibrillation, or Torsade's de pointes)

- Ongoing need for a medication with a known risk of Torsade's de Pointes or known as
a strong inhibitor or strong inducer of CYP3A4 and/or P-glycoprotein or a
proton-pump inhibitor that cannot be switched to alternative treatment prior to
study entry. The following drug interaction databases and other literature can be
utilized to determine the CYP3A4/Pgp inhibitors and inducers:

- https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-anddrugin
teractions- table-substrates-inhibitors-and-inducers.

- https://druginteractions.medicine.iu.edu/MainTable.aspx. Note: Please consult
with the Sponsor Medical Monitor for any uncertainties regarding potential
CYP3A4 and P-gp modulators.

- Active viral hepatitis, including the following:

- Any positive test result for hepatitis B virus (HBV) indicating presence of
virus, e.g., HBV DNA positive would be excluded. Participants with anti-HBs
positive in line with prior vaccination or resolved infection are eligible to
enroll.

- Any positive test result for hepatitis C virus (HCV) indicating presence of
active viral replication (detectable HCV RNA).

- Participants with positive HCV antibody and an undetectable HCV RNA are
eligible to enroll.

- Known human immunodeficiency virus (HIV) positive with an AIDS-defining
opportunistic infection within the last year, or a current CD4 count < 350 cells/μL.
Participants with HIV are eligible if they have received established antiretroviral
therapy (ART) for at least 4 weeks prior to randomization and continue on ART as
clinically indicated while enrolled on study. Viral serology only to be conducted if
locally mandated and, if done, must be performed within 28 days of randomization.

- Evidence of active infection that requires systemic antibacterial, antiviral, or
antifungal therapy ≤ 7 days prior to the first dose of study intervention.

- Live/attenuated vaccine received within 30 days of first treatment. The use of
inactivated seasonal influenza vaccines (e.g., Fluzone®) will be permitted on study
without restriction.

- Any botanical preparation (e.g., herbal supplements or traditional Chinese
medicines) intended to treat the disease under study within 4 weeks prior to
treatment. The concurrent use of any botanical preparation is not permitted while on
study.

- Prior organ allograft.

- History of allergy to study intervention or any of its components.

- Known central nervous system (CNS) metastases or leptomeningeal disease is
exclusionary unless adequately treated and the participant is no longer on steroids
or anticonvulsants.

- Participants unable to swallow oral medication or with gastrointestinal disorders
that, per the treating physician's judgement, would likely to interfere with drug
absorption, are excluded.

- Pregnant or breastfeeding women are excluded.

- History of interstitial lung disease, history of slowly progressive dyspnea and
unproductive cough, sarcoidosis, silicosis, idiopathic pulmonary fibrosis, pulmonary
hypersensitivity pneumonitis, or multiple allergies.

Cohort 1 specific criteria:

- Radiographically detectable metastatic disease and/or locally advanced PDAC.

- Anticipated need for preoperative radiation therapy (as determined per the treating
medical team: medical oncologist and/or surgical oncologist at the time of study
enrollment)

Cohort 2 specific criteria:

- Radiographically detectable metastatic disease.

- Cytotoxic chemotherapy or targeted therapy within 28 days of Cycle 1 Day 1 is not
permitted. Palliative radiotherapy must have been completed 14 or more days prior to
Cycle 1 Day 1.

- Participants with more than one prior line of therapy are excluded.

- Clinically significant persistent toxicities (CTCAE v5.0 Grade ≥2) caused by
previous cancer therapy, excluding alopecia and Grade 2 neuropathy, are not allowed.

Cohort 3 specific criteria:

- Cytotoxic chemotherapy or targeted therapy within 28 days of Cycle 1 Day 1 is not
permitted. Palliative radiotherapy must have been completed 14 or more days prior to
Cycle 1 Day 1.

- Participants with more than one prior line of therapy are excluded.

- Clinically significant persistent toxicities (CTCAE v5.0 Grade ≥2) caused by
previous cancer therapy, excluding alopecia and Grade 2 neuropathy, are not allowed