Study of Inlexisertib (DCC-3116) in Participants With RAS/MAPK Pathway Mutant Solid Tumors

A Phase 1/2, First-in-Human Study of DCC-3116 as Monotherapy and in Combination With RAS/MAPK Pathway Inhibitors in Patients With Advanced or Metastatic Solid Tumors With RAS/MAPK Pathway Mutations

This is a multicenter, open label, first in human (FIH) study of inlexisertib as monotherapy, and in combination with trametinib, binimetinib, or sotorasib in participants with advanced or metastatic solid tumors with RAS/MAPK pathway mutation. The study consists of 2 parts, a dose-escalation phase, and an expansion phase.

Study Overview

• Status: Terminated
• Conditions: Non-Small Cell Lung Cancer; Advanced Solid Tumor; Metastatic Solid Tumor
• Intervention / Treatment: Drug: Trametinib; Drug: Binimetinib; Drug: Sotorasib; Drug: Inlexisertib

• Study Type: Interventional
• Enrollment (Actual): 91
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
  • Missouri
    • St Louis, Missouri, United States, 63108
      • Washington University Siteman Cancer Center
  • New Jersey
    • New Brunswick, New Jersey, United States, 08901
      • Rutgers Cancer Institute
  • New York
    • New York, New York, United States, 10016
      • Laura & Isaac Perlmutter Cancer Center at NYU Langone Health
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health and Science University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Hospital of The University of Pennsylvania
  • Texas
    • Austin, Texas, United States, 78758
      • NEXT Oncology
    • Houston, Texas, United States, 77030
      • The University of Texas MD Anderson Cancer Center
    • San Antonio, Texas, United States, 78229
      • NEXT Oncology
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin Clinical Science Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Male or female participants ≥18 years of age

2. Dose Escalation Phase (Part 1):

   Escalation Cohort B combination with trametinib and Cohort C combination with binimetinib closed on January 8, 2024.

   1. Participants must have a pathologically confirmed diagnosis of an advanced or metastatic solid tumor with a documented RAS, NF1, or RAF mutations. A molecular pathology report documenting mutational status of RAS, NF1, or RAF must be available.

   2. Progressed despite standard therapies, and received at least 1 prior line of anticancer therapy.

      • Participants with a documented mutation in BRAF V600E or V600K must have received approved treatments known to provide clinical benefit prior to study entry.
   3. Participants enrolled in the inlexisertib and sotorasib cohort (Cohort D) must have a KRAS G12C mutation.

3. Dose Expansion Phase (Part 2):

   Expansion Cohorts 1, 2, 3 and 4 combinations will not open for enrollment.

   Cohort 5: Participants with KRAS G12C mutant NSCLC

   • Pathologically confirmed NSCLC with a documented mutation in KRAS G12C.
   • Received at least 1 prior line of systemic therapy in the advanced or metastatic setting.
   • Have not received prior sotorasib or other KRAS G12C inhibitor therapy.
4. Must provide a fresh tumor biopsy from a primary or metastatic cancer lesion if it can be biopsied with acceptable risk as determined by the Investigator.
5. Must have at least 1 measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST), v1.1
6. Eastern Cooperative Oncology Group (ECOG) score of 0 to 2 (Dose Escalation) or 0 to 1 (Dose Expansion) at Screening
7. Adequate organ function and bone marrow function.
8. If a female of childbearing potential must have a negative pregnancy test prior to enrollment and agree to follow the contraception requirements.
9. Male participants must agree to follow contraception requirements.
10. Must provide signed consent to participate in the study and is willing to comply with study-specific procedures.

Exclusion Criteria:

1. Must not have received the following within the specified time periods prior to the first dose of study drug:

   1. Prior therapies (anticancer or therapies given for other reasons) that are known strong or moderate inhibitors or inducers of CYP3A4 or P-glycoprotein (P-gp) including certain herbal medications (e.g., St. John's Wort): 14 days or 5× the half-life of the medication (whichever is longer)
   2. All other prior anticancer therapies or any therapy that is investigational for the participant's condition with a known safety and PK profile: 14 days or 5× the half-life of the medication (whichever is shorter)
   3. Investigational therapies with unknown safety and PK profile: 28 days. If there is enough data on the investigational therapy to assess the risk for drug-drug interactions and late toxicities of prior therapy as low, the Sponsor's Medical Monitor may approve a shorter washout of 14 days
   4. Grapefruit or grapefruit juice: 14 days
2. Has a prior or concurrent malignancy that requires treatment or is expected to require treatment for active cancer during this study . Hormonal maintenance after treatment is allowed.
3. Have not recovered from all toxicities from prior therapy according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE).
4. Presence or history of central nervous system (CNS) metastases or leptomeningeal disease, with some exceptions
5. New York Heart Association Class III or IV heart disease, active ischemia, or any other uncontrolled cardiac condition such as angina pectoris, clinically significant cardiac arrhythmia requiring therapy, uncontrolled hypertension, congestive heart failure, or myocardial infarction within 6 months prior to the first dose of study drug.
6. Prolongation of the QT interval corrected by Fridericia's formula (QTcF) based on repeated demonstration of QTcF >450 ms in males or >470 ms in females at screening, or history of long QT syndrome.
7. Left ventricular ejection fraction (LVEF) <50% at Screening
8. Systemic arterial thrombotic or embolic events within 6 months prior to the first dose of study drug
9. Systemic venous thrombotic events within 1 month prior to the first dose of study drug
10. Malabsorption syndrome
11. Major surgery within 4 weeks of the first dose of study drug. All surgical wounds must be healed and free of infection or dehiscence before the first dose of the study drug.
12. Any other clinically significant comorbidities.
13. For participants receiving inlexisertib and trametinib combination or inlexisertib and binimetinib combination: previous treatment with trametinib or binimetinib that resulted in treatment discontinuation due to intolerability as a result of an adverse event (AE) that was considered related to trametinib or binimetinib.
14. For participants receiving inlexisertib and sotorasib combination in Dose Escalation Part 1: previous treatment with sotorasib that resulted in treatment discontinuation due to intolerability as a result of an adverse event (AE) that was considered related to sotorasib.
15. For participants receiving inlexisertib and sotorasib combination: Use of proton pump inhibitors (PPIs) and H2 receptor antagonists that cannot be discontinued 3 days prior to the start of study drug administration.
16. Known allergy or hypersensitivity to any component of the investigational drug products.

17. Known human immunodeficiency virus unless the following requirements are met:

    1. CD4 count >350/µL
    2. No AIDS-defining opportunistic infection in the last 12 months
    3. Stable anti-retroviral regimen with medications that are not prohibited by the protocol for at least 4 weeks with HIV viral load less than 400 copies/mL prior to enrollment.
18. Known active hepatitis B, active hepatitis C infection or if the participant is taking medications that are prohibited per protocol.
19. If female, the participant is pregnant or lactating.
20. Ongoing participation in an interventional study.
21. For participants receiving inlexisertib and binimetinib combination: Known Gilbert's syndrome

Study Plan

How is the study designed?

Design Details

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

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dose Escalation (Part 1, Cohort A Monotherapy); Inlexisertib tablets in escalating dose cohorts given orally twice daily (BID) in 28-day cycles as monotherapy (single agent). If no DLT in 3 participants or 1 DLT/6 participants is observed, dose escalation may continue to the next planned dose cohort.	Drug: Inlexisertib; Oral Tablet Formulation; Other Names: DCC-3116
Experimental: Dose Escalation (Part 1, Cohort B Combination); Upon determination of the RP2D/MTD single agent, inlexisertib will be dosed in combination with trametinib. Escalation Cohort B combination closed on January 8, 2024.	Drug: Trametinib; Oral Tablet Formulation; Drug: Inlexisertib; Oral Tablet Formulation; Other Names: DCC-3116
Experimental: Dose Escalation (Part 1, Cohort C Combination); Upon determination of the RP2D/MTD single agent, inlexisertib will be dosed in combination with binimetinib. Escalation Cohort C combination closed on January 8, 2024.	Drug: Binimetinib; Oral Tablet Formulation; Drug: Inlexisertib; Oral Tablet Formulation; Other Names: DCC-3116
Experimental: Dose Escalation (Part 1, Cohort D Combination); Upon determination of the RP2D/MTD single agent, inlexisertib will be dosed in combination with sotorasib.	Drug: Sotorasib; Oral Tablet Formulation; Drug: Inlexisertib; Oral Tablet Formulation; Other Names: DCC-3116
Experimental: Expansion Cohorts 1, 2, 3 and 4 (Part 2); Expansion Cohorts 1, 2, 3 and 4 inlexisertib combinations will not open for enrollment.	Drug: Inlexisertib; Oral Tablet Formulation; Other Names: DCC-3116
Experimental: Expansion Cohort 5 (Part 2); Inlexisertib tablets orally given in combination with sotorasib in 28-day cycles to evaluate safety and preliminary efficacy of participants with NSCLC (with a documented mutation in KRAS G12C). Trial terminated prior to start of Part 2.	Drug: Sotorasib; Oral Tablet Formulation; Drug: Inlexisertib; Oral Tablet Formulation; Other Names: DCC-3116

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective response rate (ORR) (Expansion Phase)	Proportion of participants who achieve CR or PR per RECIST v1.1.	Approximately 24 months
Incidence of Adverse Events	Identify the observed adverse events, serious adverse events associated with inlexisertib as monotherapy and in combination with trametinib, binimetinib, or sotorasib.	Approximately 24 months
Maximum tolerated dose (MTD) (Escalation Phase)	Identify the dose-limiting toxicities for each dose level tested and determine the maximum tolerated dose/recommended Phase 2 doses of inlexisertib as monotherapy and in combination with trametinib, binimetinib, or sotorasib.	Approximately 18 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration of response (DoR)	DoR is defined as the time interval from the time that the measurement criteria are first met for CR or PR (whichever is first recorded) until the first date that the progressive disease is objectively documented or death, whichever occurs first.	Approximately 24 months
Disease Control Rate (DCR)	The DCR is defined as the proportion of participants who achieve CR, PR, or stable disease (SD) at the specified time point per RECIST v1.1.	Approximately 24 months
Time to response	Time to response is defined as the time from initiation of treatment until the first assessment demonstrating CR or PR per RECIST v1.1.	Approximately 24 months
Progression-free survival (PFS)	PFS is defined as the time from initiation of treatment until documented disease progression per RECIST v1.1 or death, whichever occurs first.	Approximately 24 months
Maximum observed concentration (Cmax)	Measure the maximum observed concentration of inlexisertib (single-agent and combinations).	Predose and up to 12 hours postdose
Time to maximum observed concentration (Tmax)	Measure the time to maximum plasma concentration of inlexisertib (single-agent and combinations).	Predose and up to 12 hours postdose
Minimum observed concentration (Cmin)	Measure the minimum observed concentration of inlexisertib (single-agent and combinations).	Predose and up to 12 hours postdose
Area under the concentration-time curve (AUC)	Measure the AUC of inlexisertib (single-agent and combinations).	Predose and up to 12 hours postdose

Collaborators and Investigators

• Sponsor: Deciphera Pharmaceuticals, LLC
• Investigators: Study Director: Clinical Team, Deciphera Pharmaceuticals, LLC

Study record dates

Study Major Dates

• Study Start (Actual): June 15, 2021
• Primary Completion (Actual): March 30, 2026
• Study Completion (Actual): March 30, 2026

Study Registration Dates

• First Submitted: May 6, 2021
• First Submitted That Met QC Criteria: May 13, 2021
• First Posted (Actual): May 19, 2021

Study Record Updates

• Last Update Posted (Actual): April 8, 2026
• Last Update Submitted That Met QC Criteria: April 3, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: KRAS G12C
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Site; Neoplasms; Respiratory Tract Diseases; Lung Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplastic Processes; Lung Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Pathological Conditions, Signs and Symptoms; Neoplasm Metastasis; Carcinoma, Non-Small-Cell Lung; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protein Kinase Inhibitors; trametinib; binimetinib; sotorasib
• Other Study ID Numbers: DCC-3116-01-001; 2022-501474-19-00 (Ctis)

Drug and device information, study documents

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