This is an open-label study. This means that people in this study and clinic staff will know that people will receive ASP3082. The study aims to check how safe and well-tolerated ASP3082 is for people with advanced solid tumors that have a specific mutation called KRAS G12D.

This study will be in 2 parts.

In Part 1, different small groups of people will receive lower to higher doses of ASP3082 by itself, or together with cetuximab. Any medical problems will be recorded at each dose. This is done to find suitable doses of ASP3082, by itself or together with cetuximab, to use in Part 2 of the study. The first group will receive the lowest dose of ASP3082. A medical expert panel will check the results from this group and decide if the next group can receive a higher dose of ASP3082. The panel will do this for each group until all groups have received ASP3082 (by itself or together with cetuximab) or until suitable doses have been selected for Part 2.

In Part 2, ASP3082 will be given in by itself, or in combination with the other study treatments.

Study treatments will be given through a vein. This is called an infusion. Each treatment cycle is 21 or 28 days long. They will continue treatment until: they have medical problems from the treatment they can't tolerate; their cancer gets worse; they start other cancer treatment; or they ask to stop treatment.

Inclusion Criteria:

• Participant has locally advanced (unresectable) or metastatic solid tumor malignancy with documented Kirsten rat sarcoma viral oncogene homolog [KRAS] G12D mutation and has received prior standard therapy and the investigator does not see any further clinical benefit from continuing such targeted therapy, or is ineligible to receive standard approved therapies (no limit to the number of prior treatment regimens).

• For the ASP3082 monotherapy escalation cohorts, participants with solid tumor malignancies are allowed to be enrolled. Participants with other known KRAS G12 mutations will not be eligible for the study

• For ASP3082 combination therapy with Nab-P+GEM or FOLFIRINOX or NALRIFOX: Participant must have mPDAC that has not been previously treated with chemotherapy. If a participant received (neo)adjuvant therapy, tumor recurrence or disease progression must have occurred at least 6 months after completing the last dose of the (neo)adjuvant therapy.

• Participant consents to provide tumor specimen in a tissue block or unstained serial slides or a tumor biopsy (core needle biopsy or excision) obtained after the last interventional treatment, but prior to start of study intervention. Participant also consents to provide a sample for tumor biopsy during the treatment period as indicated in the study protocol. If a participant cannot provide a fresh tissue biopsy sample, the site should consult with the sponsor/study medical monitor.

• Participant has at least 1 measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.

• Participant has an ECOG performance status of 0, 1 or 2 for dose escalation, and 0 or 1 for dose expansion.

• Participant's last dose of prior antineoplastic therapy, including any immunotherapy, was 21 days or 5 half-lives, whichever is shorter, prior to initiation of study intervention administration.

• Participant has completed any radiotherapy (including stereotactic radiosurgery) at least 14 days prior to the start of study intervention administration. Participants must have recovered from all radiation-related toxicities, not require corticosteroids (NOTE: Physiologic replacement dose of hydrocortisone or its equivalent [defined as up to 30 mg per day of hydrocortisone, 2 mg per day of dexamethasone, or up to 10 mg per day of prednisone] is permitted), and not have active radiation pneumonitis. A 1-week washout is permitted for palliative radiation (<= 2 weeks of radiotherapy) to non-central nervous system disease.

• Participant's adverse events [AEs] (excluding alopecia) from prior therapy have improved to grade 1 or baseline within 14 days prior to start of study intervention (or prior to staring SoC chemotherapy, for first line (1L) participants receiving Nab-P+GEM FOLFIRINOX or NALIRIFOX.

• Participant has adequate organ function as indicated by protocol laboratory value parameters (If a participant has received a recent blood transfusion, the laboratory tests must be obtained >= 14 days after any blood transfusion.).

• Female participant is not pregnant, confirmed by pregnancy test and medical evaluation by interview, and at least 1 of the following conditions apply:

  • Not a woman of childbearing potential (WOCBP).
  • WOCBP who agrees to follow the contraceptive guidance from the time of informed consent through at least 6 months after study intervention administration.
  • EU only: For combination therapy with carboplatin, follow contraception guidelines from the time of informed consent through at least 7 months after the final dose of carboplatin.
  • South Korea only: For combination therapy with oxaliplatin, follow contraception guidelines from the time of informed consent through at least 15 months after the final dose of oxaliplatin. For combination therapy with cisplatin, follow contraception guidelines from the time of informed consent through at least 14 months after the final dose of cisplatin.

• Female participant must agree not to breastfeed starting at screening and throughout the study period and for 6 months after study intervention administration.

• Female participant must not donate ova starting at first dose of study intervention and throughout the study period and for 6 months after study intervention administration.

• Male participant with female partner(s) of childbearing potential (including breastfeeding partner) must agree to use contraception throughout the treatment period and for 3 months after study intervention administration.

• Male participant must not donate sperm during the treatment period and for 3 months after study intervention administration.

• South Korea only: For combination therapy with oxaliplatin, follow contraception guidelines from the time of informed consent through at least 12 months after the final dose of oxaliplatin. For combination therapy with cisplatin, follow contraception guidelines from the time of informed consent through at least 11 months after the final dose of cisplatin.

• Male participant with pregnant partner(s) must agree to remain abstinent or use a condom for the duration of the pregnancy throughout the study period and for 3 months after study intervention administration.

• Participant agrees not to participate in another interventional study while receiving study intervention (Participants who are currently in the follow-up period of an interventional clinical trial are allowed).

• For ASP3082 Combination Therapy with Pembrolizumab (Cohort G), or Platinum-based Chemotherapy + Pemetrexed +/- Pembrolizumab (Cohort H): Participant must have pathologically documented locally advanced or metastatic (unresectable Stage IIIB-IV) non-small cell lung cancer (NSCLC) (Note: for Cohort H only, the tumor must be non-squamous NSCLC) with KRAS G12D mutation and

  • have received prior platinum-containing chemotherapy (safety lead-in only) or
  • have never received systemic therapy (up to 1 cycle of SoC pembrolizumab [defined as one 21-day cycle of 200 mg] in Cohort G and up to 1 cycle of SoC platinum-based chemotherapy ± pembrolizumab [defined as one 21-day cycle of 200 mg] or pembrolizumab [defined as one 21-day cycle of 200 mg] in Cohort H is permitted prior to Screening, provided a 21-day washout occurs before C1D1) for locally advanced or metastatic NSCLC with no oncogenic driver mutations. Participants who received adjuvant or neoadjuvant platinum-based chemotherapy and developed recurrent or metastatic disease more than 12 months after completing therapy may be enrolled.

Exclusion Criteria:

• Participant has received investigational therapy within 21 days or 5 half-lives, whichever is shorter, prior to start of study intervention.
• Participant has symptomatic or untreated central nervous system (CNS) metastases. Participants with asymptomatic, treated CNS metastases are eligible.
• Participant has leptomeningeal disease as a manifestation of the current malignancy.
• Participant has a prior malignancy active (i.e., requiring treatment or intervention) within the previous 2 years, 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.
• Participant has a known or suspected hypersensitivity to ASP3082 or any components of the formulation used.
• Participant with active hepatitis B (including acute hepatitis B virus [HBV] or chronic HBV) or hepatitis C virus [HCV] (ribonucleic acid [RNA] detected by qualitative assay). HCV RNA testing is not required in participants with negative HCV antibody testing.
• Participant has a known history of human immunodeficiency virus [HIV] infection. No HIV testing is required unless mandated by a local health authority.
• Participant has had a myocardial infarction or unstable angina within 6 months prior to the start of study intervention, left ventricular ejection fraction (LVEF) < 50% as determined by multigated acquisition (MUGA) scan or echocardiogram (ECHO) or currently has an uncontrolled illness including, but not limited to symptomatic congestive heart failure, clinically significant cardiac disease, unstable angina pectoris, cardiac arrhythmia, obligate use of a cardiac pacemaker, or long QT syndrome.
• Participant has a corrected QT interval (single electrocardiogram [ECG]) using Fridericia's formula (QTcF) > 450 milliseconds (msec) (men) or >470 msec (women) during screening.
• Participant has received prior treatment with a specific KRAS G12D inhibitor/degrader or pan-RAS inhibitor/degrader targeting KRAS G12D. Participants who received prior treatment with a KRAS G12D inhibitor/degrader are eligible for the ASP3082 combination therapy cohort.
• Participant has an active infection requiring intravenous antibiotics within 14 days prior to study intervention.
• Participant is expected to require another form of antineoplastic therapy while on study treatment.
• Participant has any condition which makes the participant unsuitable for study participation (such as psychiatric illness/social situations that would limit compliance with study requirements).
• Participant has had major surgery within 4 weeks prior to first dose of study intervention.

For ASP3082 Combination Therapy:

• Prior discontinuation of cetuximab treatment due to toxicity or intolerance of cetuximab.
• History of interstitial lung disease requiring systemic steroid treatment. Note that a participant with resolved pulmonary infections or radiation pneumonitis is eligible.

Access to anonymized individual participant level data collected during the study, in addition to study-related supporting documentation, is planned for studies conducted with approved product indications and formulations, as well as products terminated during development. Studies conducted with product indications or formulations that remain active in development are assessed after study completion to determine if Individual Participant Data can be shared. Further details on Astellas' data sharing policy can be found at https://www.clinicaltrials.astellas.com/transparency/.

Access to participant level data is offered to researchers after publication of the primary manuscript (if applicable) and is available as long as Astellas has legal authority to provide the data.

Researchers must submit a proposal to conduct a scientifically relevant analysis of the study data. The research proposal is reviewed by an Independent Research Panel. If the proposal is approved, access to the study data is provided in a secure data sharing environment after receipt of a signed Data Sharing Agreement.