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)

Phase 2, Multicenter, Open Label, Platform Study Investigating ASP3082 in Patients With Metastaic/Locally 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).

Study Overview

• Status: Recruiting
• Conditions: Metastatic/Locally Advanced Non-Small-Cell Lung Cancer; Metastatic/Locally Pancreatic Ductal Adenocarcinoma
• Intervention / Treatment: Drug: ASP3082

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Yohann Loriot, MD, PhD; Phone Number: +33 (0)1 42 11 42 11; Email: Yohann.LORIOT@gustaveroussy.fr
• Study Contact Backup: Name: Chloé Serhal, PhD; Phone Number: +33 (0)1 42 11 42 11 ext 23 43; Email: chloe.serhal@gustaveroussy.fr

Study Locations

• France
  • Bordeaux, France
    • Not yet recruiting
    • Institut Bergonie
    • Contact: Véronique DEBIEN; Phone Number: +33 (0)5 56 33 33 33; Email: v.debien@bordeaux.unicancer.fr
  • Dijon, France
    • Not yet recruiting
    • Centre Georges Francois Leclerc
    • Contact: François GHIRINGHELLI; Phone Number: +33 (0)3 80 73 75 06; Email: dghiringhelli@cgfl.fr
  • Marseille, France
    • Not yet recruiting
    • Institut Paoli Calmettes
    • Contact: Brice CHANEZ; Phone Number: +33 (0)4 91 22 37 61; Email: chanezb@ipc.unicancer.fr
  • Saint-Herblain, France
    • Not yet recruiting
    • Institut De Cancerologie De L'Ouest
    • Contact: Sandrine HIRET; Phone Number: +33 (0)2 40 67 99 00; Email: sandrine.hiret@ico.unicancer.fr
  • Vandœuvre-lès-Nancy, France
    • Not yet recruiting
    • Institut de Cancérologie de Lorraine
    • Contact: Aurélien LAMBERT; Phone Number: +33 (0)3 83 59 85 64; Email: a.lambert@nancy.unicancer.fr
  • France
    • Villejuif, France, France, 94800
      • Recruiting
      • Gustave Roussy
      • Contact: Yohann Loriot, MD, PhD; Phone Number: +33 (0)1 42 11 42 11; Email: Yohann.LORIOT@gustaveroussy.fr
      • Contact: Fernanda Mosele, MD; Email: mariafernanda.mosele@gustaveroussy.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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 [unconjugated hyperbilirubinemia]) or <2 X ULN for patients with liver metastases
   • Serum albumin ≥ 3.0 g/dL
   • Prothrombin time (PT) or Prothrombin time- international normalized ratio (PT-INR) and activated partial thromboplastin time (aPTT)/partial thromboplastin time (PTT) ≤1.5 × (ULN), except for patients on coumarin-derivative anticoagulants or other similar anticoagulant therapy, who must have PT-INR within therapeutic range as deemed appropriate by the Investigator
10. Patients must have baseline oxygen saturation > 93% on room air
11. Females of reproductive/childbearing potential must have a negative serum or urine pregnancy test at screening and must agree to use a highly effective form of contraception or avoid intercourse during and upon completion of the study and for at least 6 months for females after the last dose of study drug.
12. Female patients must not donate, or retrieve for their own use, ova from the time of screening and throughout the study treatment period, and for at least 6 months after the final study drug administration
13. Male patients must be surgically sterile or must withhold heterosexual intercourse or must be willing to use a highly effective birth control upon enrollment, during the treatment period, and for at least 3 months following the last dose of study drug
14. Male patients must not freeze or donate sperm starting at screening and throughout the study period, and at least 3 months after the final study drug administration
15. Patients must understand, sign and date the written informed consent form prior to any protocol-specific procedures performed. Patients should be able and willing to comply with study visits and procedures as per protocol
16. Patients must be affiliated to a Social Security System or beneficiary of the same.

Exclusion criteria :

1. Patients unwilling to participate in the biological investigations and to perform blood and tissue sample collection as required in the protocol
2. Patients with NSCLC or PDAC amenable for treatment with curative intent
3. Patients with a history of severe hypersensitivity reactions to either the drug substances or any components of the formulation used

4. Inadequate washout period prior to cycle 1 day 1, defined as:

   1. Whole brain radiation therapy or stereotactic brain radiation therapy <14 days
   2. Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation <28 days or palliative radiation therapy <7 days. Participant must have recovered from all radiation-related toxicities and not have active radiation pneumonitis.
   3. Any investigational agents or other anticancer drug(s), including immunotherapy, from a previous cancer treatment regimen or clinical study <21 days or <5 half-lives, whichever is shorter, prior to first dose of ASP3082
   4. Major surgery (excluding placement of vascular access) < 28 days
   5. Live virus and live-attenuated vaccination <28 days
   6. Systemic steroid therapy or other immunosuppressive therapy < 7 days.
5. Prior treatment with a specific KRAS G12D inhibitor/degrader or pan-RAS inhibitor/degrader targeting KRAS G12D
6. Evidence of spinal cord compression or brain metastases, defined as being clinically active (symptomatic), or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms or untreated. Patients with treated brain metastases and clinically inactive (asymptomatic) (i.e., without neurologic signs or symptoms and do not require treatment with corticosteroids or anticonvulsants) may be included in the study. Patients must have a stable neurologic status for at least 28 days prior to cycle 1 day 1.
7. Patients with evidence of any leptomeningeal disease
8. Patients with unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to grade 1 or baseline according to the NCI-CTCAE v5.0
9. Any evidence of primary malignancy other than metastatic/locally advanced NSCLC or PDAC within 2 years prior to cycle 1 day 1, except adequately resected non-melanoma skin cancer, curatively treated in-situ disease, or other solid tumors curatively treated
10. Any evidence of severe or uncontrolled systemic diseases including active bleeding diatheses, active infection, psychiatric illness/social situations, geographical factors, substance abuse, or other factors which in the Investigator's opinion makes it undesirable for the patient to participate in the study or which would jeopardize compliance with the protocol. Screening for chronic conditions is not required
11. Patients have an active infection requiring intravenous antibiotic within 14 days prior cycle 1 day 1
12. Patients with clinically significant pleural effusion will be excluded and ascites requiring medical treatment within 30 days prior to ICF signature.

13. Uncontrolled or significant cardiovascular disease prior to cycle 1 day 1, including:

    1. Corrected QT interval >470 ms for females and >450 ms for males according to Fridericia's formula (QTcF) assessed by ECG
    2. LVEF <50% by either echocardiogram (ECHO) or multigated acquisition (MUGA) scan
    3. Myocardial infarction or unstable angina within 6 months
    4. NYHA > class II within 6 months
    5. Clinically significant pericardial effusion as determined by an ECHO or MUGA scan
    6. Symptomatic congestive heart failure, clinically significant cardiac disease
14. Participant with active hepatitis B (including acute HBV or chronic HBV) or HCV (RNA detected by qualitative assay). HCV RNA testing is not required in participants with negative HCV antibody testing.
15. Patient with diagnosis of human immunodeficiency virus (HIV). Patients with HIV infection on antiviral therapy and undetectable viral load are allowed with a requirement for regular monitoring for reactivation for the duration of treatment on study per local or institutional guidelines
16. Female patients who are pregnant or breastfeeding or intend to become pregnant during the study and for 6 months after study intervention administration
17. Patients with any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial
18. Patients under guardianship, curatorship, judicial protection, family habilitation or deprived of his/her liberty by a judicial or administrative decision or incapable of giving his/her consent
19. Patients require treatment with concomitant drugs that are strong inhibitors or inducers of CYP3A or CYP2D6
20. Participant requires treatment with concomitant drugs that are sensitive substrates of CYP2C8
21. Participation in another clinical trial (<30 days or <5 half-lives, whichever is longer) evaluating an experimental drug (except non-interventional research) and while on study treatment.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort NSCLC; Patients with metastatic/locally advanced NSCLC with the presence of KRAS G12D mutation	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.
Experimental: Cohort PDAC; Patients with metastatic/locally advanced PDAC with the presence of KRAS G12D mutation	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.

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration of response (DOR)	Defined as the time from the date of the first documentation of objective response (CR or PR) to the date of the first documentation of progression (PD) or death due to any cause.	From cycle 4 (Week 9; each cycle is 21 days) up to progression
Clinical benefit rate (CBR)	defined as the presence of at least a PR or CR, or a stable disease (SD) >6 months	During treatment period, response more than 6 months
Progression-free survival (PFS)	Defined as the time from date of first dose until the date of the first objective documentation of disease progression or death from any cause, whichever occurs first. For patients without documented radiological progression, follow-up will be censored at the date of last radiological assessment without progression, unless death occurs within 12 weeks following the date of last known progression-free, in which case the death will be counted as a PFS event	through treatment completion, median, 8 months
Overall survival (OS)		Up to 18 months after EOT
Frequency of all adverse events (AEs), treatment-emergent adverse events (TEAEs), and serious adverse events (SAEs)		Through treatment completion, median, 8 months
Severity of all adverse events (AEs), treatment-emergent adverse events (TEAEs), and serious adverse events (SAEs)	As defined by the NCI-CTCAE v5.0	Through treatment completion, median, 8 months
Evaluate treatment discontinuation, interruptions, and dose reductions due to any AEs		Treatment Period, median of 8 months
Frequency of laboratory abnormalities		Through treatment completion, median, 8 months
Severity of laboratory abnormalities	Defined by NCI-CTCAE v5.0	Through treatment completion, median, 8 months
To understand mecanism of action of ASP3082	This will be evaluated through the collection of tissue and blood samples throughout study	Through treatment completion, median, 8 months
To understand the mecanism of resistance	This will be evaluated through the collection of tissue and blood samples throughout study	Through treatment completion, median, 8 months

Collaborators and Investigators

• Sponsor: Gustave Roussy, Cancer Campus, Grand Paris
• Collaborators: Astellas Pharma Inc

Study record dates

Study Major Dates

• Study Start (Estimated): March 1, 2026
• Primary Completion (Estimated): September 1, 2027
• Study Completion (Estimated): October 1, 2027

Study Registration Dates

• First Submitted: March 3, 2026
• First Submitted That Met QC Criteria: March 16, 2026
• First Posted (Actual): March 19, 2026

Study Record Updates

• Last Update Posted (Actual): March 27, 2026
• Last Update Submitted That Met QC Criteria: March 23, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: KRASG12D
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Neoplastic Processes; Pathological Conditions, Signs and Symptoms; Neoplasm Metastasis
• Other Study ID Numbers: 2025-522533-54-00; 2025/4116 (Other Identifier: CSET number (Gustave Roussy ID))

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No