Phase 3 Study of Daraxonrasib (RMC-6236) in Patients With Previously Treated Metastatic Pancreatic Ductal Adenocarcinoma (PDAC)

This is a global, randomized, open-label, Phase 3 study designed to evaluate whether treatment with RMC-6236 will improve progression free survival (PFS) or overall survival (OS) compared to Investigator's choice of standard of care chemotherapy in patients with metastatic PDAC who were previously treated with one prior line of therapy with 5-fluorouracil (5-FU) based or gemcitabine-based regimen.

Patients will be randomized in a 1:1 ratio to receive RMC-6236 (Arm A) or Investigator's choice of standard of care chemotherapy (Arm B).

Primary Outcome Measures

1. Progression free survival (PFS) in the RAS G12-mutant population
   PFS is defined as the time from randomization until disease progression or death from any cause, whichever occurs first. Progression is per response evaluation criteria in solid tumors (RECIST) v1.1 and as assessed by blinded independent central review (BICR)
2. Overall survival (OS) in the RAS G12-mutant population
   OS is defined as the time from randomization until death from any cause.

Secondary Outcome Measures

1. PFS in the all-patient population
   PFS is defined as the time from randomization until disease progression or death from any cause, whichever occurs first. Progression is per RECIST v1.1 and as assessed by BICR.
2. OS in the all-patient population
   OS is defined as the time from randomization until death from any cause.
3. Objective response in the RAS G12 and all-patient populations
   Objective response is defined as partial response (PR) or completed response (CR) per RECIST v1.1, assessed by BICR.
4. Time to deterioration (TTD) in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Pancreatic Cancer Module (EORTC QLQ-PAN26) in the RAS G12 and all-patient populations
   TTD is defined as the time from randomization to the first occurrence of deterioration as defined by a change of at least 10 points, or death, whichever occurs first, in each subscale in EORTC QLQ-PAN26.
5. Time to deterioration (TTD) in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) in the RAS G12 and all-patient populations
   TTD is defined as the time from randomization to the first occurrence of deterioration as defined by a change of at least 10 points, or death, whichever occurs first, in each subscale and global QoL score in EORTC QLQ-C30.
6. Objective response per investigator in RAS G12 and all- patient populations
   Objective response is defined as PR or CR per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, as assessed by the investigator.
7. Duration of response (DOR) in RAS G12 and all-patient populations
   DOR is defined as time from first evidence of objective response (PR or CR) to disease progression or death due to any cause, whichever occurs first, as assessed by BICR and by the investigator.
8. Time to response (TTR) in RAS G12 and all-patient populations
   TTR is defined as time from randomization to first evidence of objective response (PR or CR), as assessed by BICR and by the investigator.
9. Percentage of patients with adverse events (AEs)
10. Pharmacokinetics of RMC-6236 in RAS G12 and all-patient populations
    Pharmacokinetics are defined by blood concentrations of RMC-6236 over time.