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

Plain English Summary

Study of Inlexisertib (DCC-3116) in Participants With RAS/MAPK Pathway Mutant Solid Tumors is a Phase 1 clinical trial sponsored by Deciphera Pharmaceuticals, LLC studying Non-Small Cell Lung Cancer, Advanced Solid Tumor, Metastatic Solid Tumor. This trial tests a new drug called inlexisertib (DCC-3116) alone or with other drugs (trametinib, binimetinib, or sotorasib). It is for adults with advanced or metastatic solid tumors that have specific genetic mutations (RAS/MAPK pathway mutations, including KRAS G12C). Participation involves taking study drugs, regular medical check-ups, and providing tumor biopsies. Alternative treatments depend on the specific cancer type and prior treatments received. The trial aims to enroll 91 participants.

Official Summary

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.

Who Can Participate

Here is what you need to know about eligibility for this trial. Adults aged 18 and older with specific genetic mutations in their tumors. Patients whose cancer has spread and has not responded to previous treatments. Patients must have a measurable tumor and be able to undergo biopsies. Individuals with certain heart conditions, recent major surgery, or active brain metastases may not be eligible. This trial is studying Non-Small Cell Lung Cancer, Advanced Solid Tumor, Metastatic Solid Tumor, so participants generally need a confirmed diagnosis.

What They're Measuring

The primary outcomes measure how safe the drug is, the highest dose that can be given without unacceptable side effects, and how often the drug shrinks tumors. The specific primary outcome measures are: Incidence of Adverse Events (Approximately 24 months); Maximum tolerated dose (MTD) (Escalation Phase) (Approximately 18 months); Objective response rate (ORR) (Expansion Phase) (Approximately 24 months). These endpoints are how researchers determine whether the treatment is effective and will form the basis of any future regulatory submissions.

About This Phase

This trial is in Phase 1, the first major stage of clinical testing. Phase 1 trials typically involve 20-100 participants and focus on safety, dosage levels, and side effects. The primary goal is not to test whether the treatment works but to establish that it is safe enough for further testing. About 70% of Phase 1 drugs advance to Phase 2. If successful, the treatment will proceed to Phase 2 efficacy testing.

Why This Trial Matters

This trial addresses a need for new treatments for advanced cancers with specific genetic mutations that are often difficult to treat. This research targets Non-Small Cell Lung Cancer, Advanced Solid Tumor, Metastatic Solid Tumor, where improved treatment options are needed.

Investor Insight

This trial explores a new drug targeting common cancer mutations, indicating potential for a new treatment option in a competitive market. Phase 1 trials have approximately a 10% chance of eventually gaining FDA approval.

Is This Trial Right for Me?

Ask your doctor about the potential benefits and risks of inlexisertib and the combination therapies. Understand the schedule of visits, tests, and drug administration. Be prepared for potential side effects and the need for tumor biopsies. The trial is being conducted at 10 sites. Always discuss clinical trial participation with your healthcare provider before making any decisions. This information is for educational purposes only and is not medical advice.

AI-generated analysis for educational purposes only. This is not medical advice. Discuss clinical trial participation with your doctor. Data sourced from ClinicalTrials.gov.

Study Design

• Study Type: INTERVENTIONAL
• Allocation: NON_RANDOMIZED
• Model: SEQUENTIAL
• Masking: NONE
• Enrollment: 91 participants

Interventions

• DRUG: Inlexisertib — Oral Tablet Formulation
• DRUG: Trametinib — Oral Tablet Formulation
• DRUG: Binimetinib — Oral Tablet Formulation
• DRUG: Sotorasib — Oral Tablet Formulation

Primary Outcomes

• Incidence of Adverse Events (Approximately 24 months)
• Maximum tolerated dose (MTD) (Escalation Phase) (Approximately 18 months)
• Objective response rate (ORR) (Expansion Phase) (Approximately 24 months)

Secondary Outcomes

• Duration of response (DoR) (Approximately 24 months)
• Disease Control Rate (DCR) (Approximately 24 months)
• Time to response (Approximately 24 months)
• Progression-free survival (PFS) (Approximately 24 months)
• Maximum observed concentration (Cmax) (Predose and up to 12 hours postdose)

Full Eligibility Criteria

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 tre

Trial Locations

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

Frequently Asked Questions

Related Conditions

• Non-Small Cell Lung Cancer
• Metastatic Solid Tumor
• RAS Pathway Mutations
• MAPK Pathway Mutations
• KRAS G12C Mutation
• Gastrointestinal Cancers
• Pancreatic Cancer
• Colorectal Cancer
• Melanoma
• Thyroid Cancer

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