A Phase 1/2 Study of DCC-3116 in Patients With RAS/MAPK Pathway Mutant Solid Tumors

Non-Small Cell Lung Cancer Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04892017
• Other study ID #: DCC-3116-01-001
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: June 15, 2021
• Est. completion date: August 2028

Study information

• Verified date: June 2024
• Source: Deciphera Pharmaceuticals LLC
• Contact: Clinical Team
• Phone: 833-432-2237
• Email: clinicaltrials[@]deciphera.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a Phase 1/2, multicenter, open label, first in human (FIH) study of DCC-3116 as monotherapy, and in combination with trametinib, binimetinib, or sotorasib in patients 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 173
• Est. completion date: August 2028
• Est. primary completion date: August 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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 DCC-3116 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: Patients with KRAS G12C mutant NSCLC

• Pathologically confirmed NSCLC with a documented mutation in KRAS G12C.
• Received at least 1 prior line but no more than 3 prior lines 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 that can be biopsied with acceptable risk as determined by the Investigator, and archival tumor tissue sample, if available. If a fresh tumor biopsy is not possible, then an archival tumor tissue sample must be provided.

5. Eastern Cooperative Oncology Group (ECOG) score of 0 to 2 (Dose Escalation) or 0 to 1 (Dose Expansion) at Screening

6. Adequate organ function and bone marrow function.

7. If a female of childbearing potential must have a negative pregnancy test prior to enrollment and agree to follow the contraception requirements.

8. Male participants must agree to follow contraception requirements.

9. 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-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. Have not recovered from all toxicities from prior therapy according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE).

3. Presence or history of central nervous system (CNS) metastases or leptomeningeal disease, with some exceptions

4. 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.

5. 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.

6. Left ventricular ejection fraction (LVEF) <50% at Screening

7. Systemic arterial thrombotic or embolic events within 6 months prior to the first dose of study drug

8. Systemic venous thrombotic events within 1 month prior to the first dose of study drug

9. Malabsorption syndrome

10. Bone disease that requires ongoing treatment or has required treatment.

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 DCC-3116 and trametinib combination or DCC-3116 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 DCC-3116 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 DCC-3116 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 DCC-3116 and binimetinib combination: Known Gilbert's syndrome

Related Conditions & MeSH terms

• Advanced Solid Tumor
• Metastatic Solid Tumor
• Neoplasms
• Non-Small Cell Lung Cancer

Intervention

Drug:
• DCC-3116
Oral Tablet Formulation
• Trametinib
Oral Tablet Formulation
• Binimetinib
Oral Tablet Formulation
• Sotorasib
Oral Tablet Formulation

Locations

Country	Name	City	State
United States	NEXT Oncology	Austin	Texas
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	The University of Texas MD Anderson Cancer Center	Houston	Texas
United States	University of Wisconsin Clinical Science Center	Madison	Wisconsin
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	Hospital of the University of Pennsylvania	Philadelphia	Pennsylvania
United States	Oregon Health and Science University	Portland	Oregon
United States	NEXT Oncology	San Antonio	Texas

Sponsors (1)

Lead Sponsor	Collaborator
Deciphera Pharmaceuticals LLC

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Incidence of Adverse Events	Identify the observed adverse events, serious adverse events associated with DCC-3116 as monotherapy and in combination with trametinib, binimetinib, or sotorasib.	Approximately 24 months
Primary	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 DCC-3116 as monotherapy and in combination with trametinib, binimetinib, or sotorasib.	Approximately 18 months
Primary	Objective response rate (ORR) (Expansion Phase)	Proportion of participants who achieve CR or PR per RECIST v1.1.	Approximately 24 months
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Maximum observed concentration (Cmax)	Measure the maximum observed concentration of DCC-3116 (single-agent and combinations).	Predose and up to 12 hours postdose
Secondary	Time to maximum observed concentration (Tmax)	Measure the time to maximum plasma concentration of DCC-3116 (single-agent and combinations).	Predose and up to 12 hours postdose
Secondary	Minimum observed concentration (Cmin)	Measure the minimum observed concentration of DCC-3116 (single-agent and combinations).	Predose and up to 12 hours postdose
Secondary	Area under the concentration-time curve (AUC)	Measure the AUC of DCC-3116 (single-agent and combinations).	Predose and up to 12 hours postdose