Study Investigating ASP3082 in Patients With Metastatic/Locally Advanced Non-small-cell Lung Cancer (NSCLC) and Pancreatic Ductal Adenocarcinoma (PDAC), With Biomarker Analysis to Characterize Response/Resistance

UNLOCK ASP3082 is an open label, single arm, multicenter, phase 2 platform study that aims to evaluate the mechanisms of action and resistance to ASP3082 in metastatic/locally advanced Non-Samll-Cell Lung Cancer (NSCLC) and Pancreatic Ductal Adenocarcinoma (PDAC) with the presence of KRAS G12D mutation. The two cohorts of patients are the following : i. cohort NSCLC : patients with NSCLC with KRAS G12D mutation. ii. cohort PDAC : patients with PDAC with KRAS G12D mutation. Patients enrolled in the both cohorts will receive treatment with ASP3082 at the dose of 600 mg QW thereafter in a 21-day cycle. ASP3082 will be administred in intravenous route until disease progression, unacceptable toxicity, or consent withdrawal. Tumor and blood samples will be collected at baseline, on-treatment and at the end of treatment visit only from patients who develop acquired resistance (acquired resistance is defined as a best response of CR, PR, or SD lasting more than 6 months, followed by PD).

Drug: ASP3082. Patients enrolled in both cohorts will receive treatment with ASP3082 at the dose of 600 mg QW thereafter in a 21-day cycle. ASP3082 will be administred in intravenous route until disease progression, unacceptable toxicity, or consent withdrawal.

Cohort NSCLC (experimental): Patients with metastatic/locally advanced NSCLC with the presence of KRAS G12D mutation

Cohort PDAC (experimental): Patients with metastatic/locally advanced PDAC with the presence of KRAS G12D mutation

Evaluate the best overall response (BOR) based on investigator assessment per RECIST v1.1. Time frame: Through treatment completion, median, 8 months.

Duration of response (DOR). Time frame: From cycle 4 (Week 9; each cycle is 21 days) up to progression.

Clinical benefit rate (CBR). Time frame: During treatment period, response more than 6 months.

Progression-free survival (PFS). Time frame: through treatment completion, median, 8 months.

Overall survival (OS). Time frame: Up to 18 months after EOT.

Frequency of all adverse events (AEs), treatment-emergent adverse events (TEAEs), and serious adverse events (SAEs). Time frame: Through treatment completion, median, 8 months.

Severity of all adverse events (AEs), treatment-emergent adverse events (TEAEs), and serious adverse events (SAEs). Time frame: Through treatment completion, median, 8 months.

Inclusion Criteria: 1. Age ≥18 years 2. Patients with histologically confirmed diagnosis of locally advanced (unresectable) or metastatic NSCLC (cohort 1) or PDAC (cohort 2) and documented KRAS G12D mutation on the most recent tumor biopsy or circulating tumor DNA (ctDNA) analysis 3. For patients with NSCLC : 1. Patients with no known targetable genomic alterations, or an alteration for which no targeted therapy is approved (or accessible), must have been treated with at least 1 line of prior therapy, including a platinum-based regimen and a PD-(L) 1 blocker, combined or sequenced, and they must have experienced progression 2. Patients who have known actionable genomic alterations (EGFR, BRAF, and MET mutations or ALK, ROS1, RET, NTRK fusions) must have exhausted the available targeted therapy and have experienced disease progression after a platinum-based regimen 4. Patients with PDAC must have received only one prior line of chemotherapy for a minimum duration of 5 months and have experienced disease progression 5. Patients must have an ECOG performance status ≤1 at the time of screening 6. Patients must have a minimum life expectancy of 3 months 7. Patients must have at least one radiologically measurable lesion according to response evaluation criteria in solid tumors (RECIST) v1.1 criteria 8. Patients must have a tumor site easily accessible to biopsy, avoiding bone biopsy when possible. Patient must have accepted to perform pre-treatment, on-treatment, and end-of-treatment tumor and blood biopsies 9. Patients must have adequate bone marrow reserve and organ function, based on local laboratory data within 21 days prior to cycle 1, day 1 defined as : * Platelet count ≥100 000/mm3 or ≥100 × 109/L (platelet transfusions are not allowed up to 14 days prior to cycle 1 Day 1 to meet eligibility) * Hemoglobin (Hgb) ≥9.0 g/dL (transfusion and/or growth factor support is allowed) * Absolute neutrophil count (ANC) ≥1500/mm3 or ≥1.5 × 109/L (use of growth factors is not allowed in the 14 days prior cycle 1) * Creatinine clearance (CrCl) : Creatinine clearance (CrCl) ≥60 mL/min as calculated using the Cockcroft-Gault equation or measured CrCl; confirmation of CrCl is only required when SCr is \>1.5 × ULN * Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) and alkaline phosphatase (ALP) \<3 x ULN (or \<5 x ULN for patients with liver metastases) * Total bilirubin (TBL) \<1.5 x ULN (\<3 x ULN in the presence of documented Gilbert's Syndrome …

Enrollment: 60 participants (estimated).