Inclusion Criteria
Age
1.    Participant is ≥ 18 years of age at the time of signing informed consent.
Type of Participant and Disease Characteristics
2.    Participant has histologically confirmed metastatic PDAC with documented KRAS G12D mutation based on local or central testing (a participant’s positive KRAS G12D mutation status result must be available prior to randomization).
3.    Participant has no option for surgical resection or radiotherapy with curative intent.
Sex and Contraceptive Requirements
4.    Female participant:
●    is not pregnant (see [Section ‎10.2]) and ≥ 1 of the following conditions apply:
a.    Not a WOCBP (see [Section ‎10.2])
b.    WOCBP who has a negative serum pregnancy test at screening (refer to [Section ‎10.9.3.4.1] for Japan-specific requirements) and agrees to follow the contraceptive guidance (see [Section ‎10.2]) from the time of informed consent through ≥ 9 months after the final administration of oxaliplatin and ≥ 6 months after the final administration of all other study intervention drugs (e.g., ASP3082/placebo, leucovorin [folinic acid or levofolinate], [liposomal] irinotecan and/or 5 FU).
●    Must not be breastfeeding or lactating starting at screening and throughout the treatment period and for ≥ 6 months after the final administration of any study intervention (e.g., ASP3082/placebo, mFOLFIRINOX or NALIRIFOX).
●    Must not donate ova starting at first administration of study intervention and throughout the treatment period and for ≥ 6 months after the final administration of any study intervention (e.g., ASP3082/placebo, mFOLFIRINOX or NALIRIFOX).
5.    Male participant:
●    Must agree to use contraception (see [Section ‎10.2]) with female partner(s) of childbearing potential (including breastfeeding partner) throughout the treatment period and for ≥ 6 months after the final administration of any study intervention (e.g., ASP3082/placebo, mFOLFIRINOX or NALIRIFOX).
●    Must agree to remain abstinent or use a condom with pregnant partner(s) for the duration of the pregnancy throughout the treatment period and for ≥ 6 months after the final administration of any study intervention (e.g., ASP3082/placebo, mFOLFIRINOX or NALIRIFOX).
●    Must not donate sperm during the treatment period and for ≥ 6 months after the final administration of any study intervention (e.g., ASP3082/placebo, mFOLFIRINOX or NALIRIFOX).
Informed Consent
6.    The participant has provided informed consent, as described in [Section ‎10.1.3], which includes compliance with the requirements and restrictions listed in the ICF and protocol. 
Diagnostic Assessments
7.    Participant has KRAS G12D mutation from a tissue sample, based on local or central testing (refer to [Section ‎7.7.2.1] for additional requirements).
8.    Participant consents to and provides a baseline tumor tissue specimen for the study during screening. The sample must meet the requirements described in the laboratory manual and the tumor sample guidance.
9.    Participant has a predicted life expectancy > 12 weeks, in the opinion of the investigator.
10.    Participant has an ECOG PS of 0 or 1 within 7 days prior to randomization.
11.    Participant AEs (excluding alopecia) from prior therapy must have improved to grade 1 or baseline at least 7 days prior to randomization. If the participant has ongoing grade 2 toxicities associated with mFOLFIRINOX/NALIRIFOX (as assessed by the investigator) administered during screening, the medical monitor should be contacted for guidance.
12.    Participant must have recovered from all radiation-related toxicities and must not require corticosteroids (Note: Physiologic replacement dose of hydrocortisone or its equivalent [defined as ≤ 30 mg per day of hydrocortisone, 2 mg per day of dexamethasone, or ≤ 10 mg per day of prednisone] is permitted) and must not have active radiation pneumonitis. A 1-week washout for palliative radiation (≤ 2 weeks of radiotherapy) for non-CNS disease is permitted, based on the date of randomization.
13.    Participant has adequate organ function as indicated by the following laboratory values within 7 days prior to randomization (if a participant has received a recent blood transfusion, the latest laboratory tests must be obtained ≥ 14 days after any blood transfusion). The laboratory values prior to the initiation of the first dose of ASP3082/placebo (or mFOLFIRINOX/NALIRIFOX, if chemotherapy is administered during the screening period) should be used to determine eligibility. Participants who receive mFOLFIRINOX/NALIRIFOX during the screening period must meet these criteria within 7 days prior to the start of on-treatment chemotherapy (i.e., C1D1).
Parameter    Laboratory Value
Hematological
ANC    ≥ 1500/µL
Platelets    ≥ 100 000/µL
Hemoglobin    ≥ 9 g/dL
Renal
eGFR    ≥ 60 mL/min/1.73 m2, adjusted based on the participant’s BSA1
Hepatic
TBL    Either:
a)    ≤ 1.5 x ULN (or b)    Direct bilirubin ≤ ULN and TBL AST (SGOT) and ALT (SGPT)    ≤ 2.5 x ULN (or Albumin    > 3.0 g/dL (30 g/L)
ALT: alanine aminotransferase; ANC: absolute neutrophil count, AST: aspartate aminotransferase; BSA: body surface area; eGFR: estimated glomerular filtration rate; SGOT: serum glutamic oxaloacetic transaminase; SGPT: serum glutamic pyruvic transaminase; TBL: total bilirubin; ULN: upper limit of normal. 
1.    BSA should be calculated using the locally applicable formula (e.g., Mosteller, DuBois, etc.)
Other Inclusion Criteria
14.    Participant agrees not to participate in another interventional study while receiving study intervention in the present study (participant who is currently in the follow-up period of an interventional clinical trial is allowed). 
 

Exclusion Criteria
Participant will be excluded from participation in the study if any of the following apply:
Medical Conditions
1.    Participant has symptomatic or untreated CNS metastases (participant with asymptomatic, treated CNS metastases is eligible).
2.    Participant has leptomeningeal disease as a manifestation of the current malignancy.
3.    Participant has neuroendocrine, acinar pancreatic carcinoma or pancreatic cancer with squamous/adenosquamous features.
4.    Participant has another prior malignancy active (i.e., requiring treatment, including hormonal therapies, or intervention) within the previous 2 years different from the primary malignancy for this study, except for local malignancies that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer or carcinoma in situ of the cervix or breast, which are allowed.
5.    Participant has active hepatitis B (including acute HBV or chronic HBV) or HCV (RNA detected by qualitative assay). HCV RNA testing is not required in participant with negative HCV antibody testing.
6.    Participant with HIV infection may be eligible if the participant has not had an opportunistic infection within the past 12 months. Participant must be on established antiretroviral therapy for ≥ 4 weeks and must have an HIV viral load 7.    Participant has an active infection requiring IV antibiotics or drainage within 14 days prior to the first dose of ASP3082/placebo (or mFOLFIRINOX/NALIRIFOX, if chemotherapy is administered during the screening period).
8.    Participant has known low or absent DPD activity (where required by local regulations, testing for DPD deficiency must be performed using a validated method that is recommended by local health authorities).
9.    Participant has chronic inflammatory bowel disease, bowel obstruction and/or severe uncontrolled diarrhea.
10.    Participant has peripheral sensory neuropathy with functional impairment.
11.    Participant has ascites and/or pleural effusion that require invasive interventions within 30 days prior to randomization or have an indwelling drainage catheter.
12.    Participant has symptomatic pulmonary embolism or pulmonary embolism not being treated with anticoagulation.
13.    Participant has a history of interstitial lung disease or pulmonary fibrosis.
14.    Participant has uncontrolled seizure disorder or refractory to antiepileptics.
15.    Participant has homozygous UGT1A1 polymorphism.
16.    Participant has had a myocardial infarction, unstable angina or coronary artery bypass surgery within 6 months prior to randomization or currently has an uncontrolled illness including but not limited to symptomatic congestive heart failure, clinically significant cardiac disease (e.g., cardiomyopathy, infiltrative cardiac disease, etc.), unstable angina pectoris, cardiac arrhythmia, obligate use of a cardiac pacemaker or long QT syndrome. 
Prior/Concomitant Therapy
17.    Participant is expected to require radiotherapy with curative intent during the study (palliative radiotherapy may be used, as applicable; refer to [Section ‎6.8.2]).
18.    Participant has received any radiotherapy (including stereotactic radiosurgery) within 14 days prior to the start of study intervention (e.g., ASP3082/placebo or mFOLFIRINOX/NALIRIFOX) administration.
19.    Participant has received any prior systemic therapy for their metastatic PDAC (except with up to 2 doses [i.e., 28 days; 1 cycle] of mFOLFIRINOX or NALIRIFOX during the screening period. If a participant received [neo]adjuvant chemotherapy, tumor recurrence or disease progression must have occurred ≥ 6 months after completing the last dose of the [neo]adjuvant therapy).
20.    Participant has had prior treatment with a KRAS G12D targeted agent.
21.    Participant requires treatment with concomitant drugs that are strong inhibitors or inducers of CYP3A or CYP2D6. Refer to [Section ‎10.5.3] for additional details.
22.    Participant has had major surgery within 4 weeks prior to randomization.
23.    Participant may not use other antineoplastic therapy for their PDAC during the study, including cytotoxics, targeted agents, endocrine therapy or antibodies.
24.    Participant may not use antiretroviral therapies with overlapping toxicities with the NALIRIFOX (including the agent zidovudine) or mFOLFIRINOX regimens during the study. 
Prior/Concurrent Clinical Study Experience
25.    Participant has received treatment for their PDAC through other treatments or herbal medications that have known antitumor activity within 28 days prior to randomization.
26.    Participant has present or previous history of participation in a study of ASP3082.
Diagnostic Assessments
27.    Participant has a corrected QTcF (single ECG) > 470 msec during the screening period.
Other Exclusion Criteria
28.    Participant has any condition that, in the investigator’s opinion, makes the participant unsuitable for study participation.
29.    Participant has a known or suspected hypersensitivity to ASP3082/placebo, mFOLFIRINOX, NALIRIFOX or any components of the formulations used.