Astellas 3082-CL-0301: A Phase 3, Double-blind, Placebo-controlled, Randomized Study to Assess the Efficacy and Safety of ASP3082 in Combination with mFOLFIRINOX or NALIRIFOX as First-line Treatment in Participants with KRAS G12D-mutated Metastatic Pan

This study is a phase 3, double-blind, placebo-controlled, multicenter study of ASP3082 for the first-line treatment of participants with metastatic PDAC with KRAS G12D mutation in combination with mFOLFIRINOX or NALIRIFOX. The study will be conducted in approximately 250 study sites across Europe, Asia-Pacific and the Americas. 

Approximately 614 participants will be randomized in a 1:1 ratio to 1 of 2 study arms: 

1. ASP3082 Arm: ASP3082 (600 mg) on days 1, 8, 15 and 22 of every 28-day cycle, plus  mFOLFIRINOX (oxaliplatin, leucovorin [folinic acid or levofolinate], irinotecan and 5-FU) or NALIRIFOX (liposomal irinotecan, oxaliplatin, leucovorin [folinic acid or levofolinate] and 5-FU) on days 1 and 15 of every 28-day cycle. 
2. Placebo Arm: Placebo on days 1, 8, 15 and 22 of every 28-day cycle, plus the mFOLFIRINOX  or NALIRIFOX regimen, as detailed above, on days 1 and 15 of every 28-day cycle. 

KRAS is a membrane-bound protein, member of the RAS family of GTPases. Among KRAS mutations, KRAS G12D is one of the most frequent driver mutations and is found in approximately 35% to 45% of PDAC, 10% to 12% of CRC and 4% of lung adenocarcinoma, and in a subset of other solid tumors.

ASP3082 is a novel small molecule degrader that selectively degrades KRAS G12D-mutated protein and a targeted protein degrader that consists of a KRAS G12D-mutated protein binding moiety and VHL, an E3 ubiquitin ligase binding moiety connected by a linker. ASP3082 is currently being developed for the treatment of cancers harboring a KRAS G12D mutation, including PDAC, CRC and NSCLC. 

Nonclinical data and preliminary clinical results from the ongoing phase 1 study 3082-CL-0101 suggest that ASP3082 has an antitumor effect.  This pivotal phase 3 randomized, double-blind, placebo-controlled study will assess the efficacy, safety, tolerability, eCOAs, PK, pharmacodynamics and applicable biomarkers of ASP3082 administered 600 mg QW in combination with mFOLFIRINOX or NALIRIFOX, compared with 
placebo. 

For more information, visit: https://clinicaltrials.gov/study/NCT07488676

Inova Schar Cancer
8081 Innovation Park Drive
Fairfax, VA 22031

• Participant is ≥ 18 years of age at the time of signing informed consent. 
• 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). 
• Participant has no option for surgical resection or radiotherapy with curative intent. 
• Participant has KRAS G12D mutation from a tissue sample, based on local or central 
  testing.
• Participant consents to and provides a baseline tumor tissue specimen for the study 
  during screening. 
• Participant has a predicted life expectancy > 12 weeks, in the opinion of the investigator.
• Participant has an ECOG PS of 0 or 1 within 7 days prior to randomization. 

• Participant has symptomatic or untreated CNS metastases (participant with asymptomatic, treated CNS metastases is eligible). 
• Participant has leptomeningeal disease as a manifestation of the current malignancy. 
• Participant has neuroendocrine, acinar pancreatic carcinoma or pancreatic cancer with squamous/adenosquamous features. 
• 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. 
• 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. 
• 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 < 400 copies/mL prior to enrollment (HIV testing should be conducted per local requirements.
• 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).