A First-in-Human Trial of BLU-924 (SAR449336) in Advanced Solid Tumors Harboring KRAS Mutations

A Phase 1/2, Open-Label, Dose-Escalation, Dose-Enrichment, and Dose-Expansion Trial to Evaluate the Safety, Tolerability, Pharmacokinetics, and Antitumor Activity of BLU-924 (SAR449336) as Monotherapy and Combination Therapy in Participants With Advanced Pancreatic Cancer, Non-Small Cell Lung Cancer, or Colorectal Cancer Harboring KRAS Mutations

A first in human study to evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of BLU-924 / SAR449336, a pan-KRAS inhibitor, in participants with advanced Pancreatic Cancer, Non-Small Cell Lung Cancer, or Colorectal Cancer harboring KRAS mutations.

Study Overview

• Status: Recruiting
• Conditions: Colorectal Neoplasms; Non-Small Cell Lung Cancer; Advanced Solid Tumor; Pancreatic Ductal Adenocarcinoma
• Intervention / Treatment: Drug: BLU-924

Detailed Description

This is an open-label, multi-center, Phase 1/2 study designed to evaluate the safety, tolerability, pharmacokinetics (PK), and efficacy of BLU-924, a pan-KRAS inhibitor, in participants with metastatic KRAS mutant pancreatic ductal adenocarcinoma (PDAC), non-small cell lung cancer (NSCLC), or colorectal cancer (CRC). The monotherapy part of the study includes Dose Escalation, Dose Enrichment, and Dose Expansion. Participants enrolled during Dose Escalation and Dose Enrichment will be evaluated for dose limiting toxicities (DLTs) to determine the MTD. Participants enrolled into disease-specific Enrichment cohorts will enable a more robust characterization of safety, PK, pharmacodynamics, and preliminary clinical activity. Enrolment into Dose Expansion will follow the identification of at least 1 recommended dose for expansion (RDFE) based on data from the Dose Escalation and Dose Enrichment. No combination arm is active at this time.

• Study Type: Interventional
• Enrollment (Estimated): 265
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Blueprint Medicines; Phone Number: 1-888-258-7768; Email: medinfo@blueprintmedicines.com

Study Locations

• United States
  • Virginia
    • Fairfax, Virginia, United States, 22031
      • Recruiting
      • Next Oncology Virginia Cancer Specialist

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Pathologically confirmed diagnosis of metastatic Kirsten rat sarcoma viral oncogene homolog (KRAS)-mutant pancreatic ductal adenocarcinoma (PDAC), non-small cell lung cancer (NSCLC), or colorectal cancer (CRC) with evidence of a single KRAS G12C, G12D, G12V, G12A, G12S, or G13D mutation in tumor tissue or circulating tumor deoxyribonucleic acid (ctDNA).
2. Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
3. Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1.
4. Patients must have received all standard therapies for their cancer type in the metastatic setting, unless they are unable to receive such therapies due to clinical characteristics, comorbidities, or other medically justified reasons.

Exclusion Criteria:

1. History of additional malignancy within the last 2 years, with some exceptions as specified in the protocol.
2. Active brain metastases (participants with asymptomatic brain metastases may be eligible).
3. Have received prior targeted treatment(s) against KRAS, including pan-KRAS inhibitors, multi-RAS inhibitors, mutant-selective KRAS inhibitors, and RAS or KRAS degraders.
4. Active or uncontrolled systemic infection, such as tuberculosis, Hepatitis B virus (HBV), Hepatitis C virus (HCV), or Human immunodeficiency virus (HIV).

The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Monotherapy Part: BLU-924 Dose Escalation, Dose Enrichment, and Dose Expansion; Participants will receive BLU-924 oral tablet, once daily as monotherapy during Dose Escalation followed by Dose Enrichment. During Dose Enrichment, participants with PDAC, NSCLC or CRC will receive BLU-924 at selected dose levels below the current escalation dose or, if Dose Escalation is complete, below the MTD. During Dose Expansion, participants will receive RDFE of BLU-924 oral tablet, once daily as monotherapy determined during escalation monotherapy part. Dose Expansion may be initiated to further assess the safety, antitumor activity, PK, and pharmacodynamics of BLU-924 at RDFE in indication-specific cohorts (PDAC, NSCLC, or CRC) harboring a KRAS mutation.

Drug: BLU-924; Tablet; Other Names: SAR449336

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dose Escalation and Enrichment: Percentage of Participants with Dose-limiting Toxicity (DLTs)	Any of the prespecified AEs that are attributable to the study treatment, occurring in the DLT observation period are considered DLTs, excluding toxicities clearly due to underlying disease or extraneous causes.	Up to 5 years
Dose Escalation, Enrichment and Expansion: Incidence and Severity of Treatment-emergent Adverse Events (TEAEs) and Serious AEs	An adverse event (AE) is any untoward medical occurrence in a participant who received study medication without regard to possibility of causal relationship to it.	Up to 5 years
Dose Escalation and Enrichment: Maximum Tolerated Dose (MTD) of BLU-924		Up to 5 years
Dose Escalation and Enrichment: Recommended Dose for Expansion (RDFE) of BLU-924		Up to 5 years
Dose Expansion: Overall Response Rate (ORR)		Up to 5 years

Secondary Outcome Measures

Outcome Measure	Time Frame
Dose Escalation and Enrichment: Overall Response Rate (ORR)	Up to 5 years
Dose Escalation, Enrichment, and Expansion: Duration of Response (DOR)	Up to 5 years
Dose Escalation, Enrichment, and Expansion: Disease Control Rate (DCR)	Up to 5 years
Dose Escalation, Enrichment and Expansion: Progression-free Survival (PFS)	Up to 5 years
Dose Expansion: Overall Survival (OS)	Up to 5 years
Dose Escalation, Enrichment and Expansion: AUC - Area Under the Plasma Concentration Time Curve for BLU-924	Up to 2 years
Dose Escalation, Enrichment and Expansion: Cmax - Maximum Plasma Concentration for BLU-924	Up to 2 years
Dose Escalation, Enrichment and Expansion: Cmin - Minimum Plasma Concentration of BLU-924	Up to 2 years
Dose Escalation, Enrichment and Expansion: Tmax - Time to Maximum Plasma Drug Concentration for BLU-924	Up to 2 years
Dose Escalation, Enrichment and Expansion: t1/2 - Terminal Half-life of BLU-924	Up to 2 years
Dose Escalation, Enrichment and Expansion: CL/F - Apparent Oral Clearance of BLU-924	Up to 2 years
Dose Escalation, Enrichment and Expansion: Vc/F- Apparent Volume of Central Compartment of BLU-924	Up to 2 years
Dose Escalation, Enrichment and Expansion: Vd- Volume of Distribution of BLU-924	Up to 2 years

Collaborators and Investigators

• Sponsor: Blueprint Medicines Corporation
• Collaborators: Sanofi

Study record dates

Study Major Dates

• Study Start (Estimated): June 30, 2026
• Primary Completion (Estimated): September 1, 2029
• Study Completion (Estimated): July 1, 2031

Study Registration Dates

• First Submitted: June 1, 2026
• First Submitted That Met QC Criteria: June 1, 2026
• First Posted (Actual): June 5, 2026

Study Record Updates

• Last Update Posted (Actual): June 5, 2026
• Last Update Submitted That Met QC Criteria: June 1, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: NSCLC; Colorectal cancer; Rectal cancer; Advanced cancer; Lung cancer; Targeted therapy; Solid tumor; KRAS G12C; Pancreatic cancer; Metastatic solid tumor; Pancreatic ductal adenocarcinoma; Precision oncology; Metastatic colorectal cancer; Metastatic pancreatic cancer; Colon cancer; First-in-human; PDAC; Metastatic Pancreatic Ductal Adenocarcinoma; KRAS G12V; KRAS G12D; KRAS-mutant; Solid Tumor, Adult; KRAS G12A; KRAS G13D; KRAS inhibitor; Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) Mutation; Metastatic Non-Small Lung Cell Cancer; Metastatic Colorectal Cancer (CRC); KRAS G12S; KRAS-positive; Pan-KRAS inhibitor; Adult solid tumor
• Additional Relevant MeSH Terms: Endocrine System Diseases; Pathologic Processes; Neoplasms by Site; Neoplasms; Intestinal Diseases; Respiratory Tract Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Lung Diseases; Endocrine Gland Neoplasms; Pancreatic Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Colonic Diseases; Neoplastic Processes; Carcinoma, Bronchogenic; Bronchial Neoplasms; Pathological Conditions, Signs and Symptoms; Rectal Neoplasms; Lung Neoplasms; Colorectal Neoplasms; Colonic Neoplasms; Neoplasm Metastasis; Pancreatic Neoplasms; Carcinoma, Non-Small-Cell Lung
• Other Study ID Numbers: BLU-924-1101

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://vivli.org.

Drug and device information, study documents

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