A Phase 1/2 Study of DCC-3116 as Monotherapy and Combination Therapy in Patients With MAPK Pathway Mutant Solid Tumors

Sponsor

Deciphera Pharmaceuticals LLC (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04892017

Collaborator

(none)

323

Enrollment

Locations

Arms

39.6

Anticipated Duration (Months)

64.6

Patients Per Site

1.6

Patients Per Site Per Month

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Pancreatic Ductal Adenocarcinoma Non-Small Cell Lung Cancer Colorectal Cancer Melanoma Advanced Solid Tumor Metastatic Solid Tumor	Drug: DCC-3116 Drug: Trametinib Drug: Binimetinib Drug: Sotorasib	Phase 1/Phase 2

Study Design

Study Type:

Interventional

Anticipated Enrollment :

323 participants

Allocation:

Non-Randomized

Intervention Model:

Sequential Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Jun 15, 2021

Anticipated Primary Completion Date :

Apr 1, 2024

Anticipated Study Completion Date :

Oct 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Dose Escalation (Part 1, Cohort A Monotherapy) DCC-3116 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: DCC-3116 Oral Tablet Formulation
Experimental: Dose Escalation (Part 1, Cohort B Combination) Upon determination of the RP2D/MTD single agent, DCC-3116 will be dosed in combination with trametinib.	Drug: DCC-3116 Oral Tablet Formulation Drug: Trametinib Oral Tablet Formulation
Experimental: Dose Escalation (Part 1, Cohort C Combination) Upon determination of the RP2D/MTD single agent, DCC-3116 will be dosed in combination with binimetinib.	Drug: DCC-3116 Oral Tablet Formulation Drug: Binimetinib Oral Tablet Formulation
Experimental: Dose Escalation (Part 1, Cohort D Combination) Upon determination of the RP2D/MTD single agent, DCC-3116 will be dosed in combination with sotorasib.	Drug: DCC-3116 Oral Tablet Formulation Drug: Sotorasib Oral Tablet Formulation
Experimental: Expansion Cohort 1 (Part 2) DCC-3116 tablets BID given in combination with trametinib in 28-day cycles to evaluate safety and preliminary efficacy of participants with advanced or metastatic pancreatic ductal adenocarcinoma (PDAC) (with a documented mutation in KRAS).	Drug: DCC-3116 Oral Tablet Formulation Drug: Trametinib Oral Tablet Formulation
Experimental: Expansion Cohort 2 (Part 2) DCC-3116 tablets orally BID given in combination with trametinib in 28-day cycles to evaluate safety and preliminary efficacy of participants with non-small cell lung cancer (NSCLC) (with a documented mutation in KRAS, NRAS, NF1,or BRAF).	Drug: DCC-3116 Oral Tablet Formulation Drug: Trametinib Oral Tablet Formulation
Experimental: Expansion Cohort 3 (Part 2) DCC-3116 tablets orally BID given in combination with trametinib in 28-day cycles to evaluate safety and preliminary efficacy of participants with colorectal cancer (CRC) (with a documented mutation in KRAS, NRAS, NF1, or BRAF).	Drug: DCC-3116 Oral Tablet Formulation Drug: Trametinib Oral Tablet Formulation
Experimental: Expansion Cohort 4 (Part 2) DCC-3116 tablets orally BID given in combination with binimetinib in 28-day cycles to evaluate safety and preliminary efficacy of participants with melanoma (with a documented mutation in NRAS).	Drug: DCC-3116 Oral Tablet Formulation Drug: Binimetinib Oral Tablet Formulation
Experimental: Expansion Cohort 5 (Part 2) DCC-3116 tablets orally BID 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).	Drug: DCC-3116 Oral Tablet Formulation Drug: Sotorasib Oral Tablet Formulation

Outcome Measures

Primary Outcome Measures

Incidence of Adverse Events [Approximately 24 months]
Identify the observed adverse events, serious adverse events associated with DCC-3116 as monotherapy and in combination with trametinib, binimetinib, or sotorasib.
Maximum tolerated dose (MTD) [Approximately 18 months]
Identify the dose-limiting toxicities for each dose level tested and determine the maximum tolerated dose of DCC-3116 as monotherapy and in combination with trametinib, binimetinib, or sotorasib. Recommended Phase 2 doses.
Objective response rate (ORR) (Expansion Phase) [Approximately 24 months]
Proportion of participants who achieve CR or PR per RECIST v1.1.

Secondary Outcome Measures

Duration of response (DoR) (Escalation Phase) [Approximately 24 months]
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.
Disease Control Rate (DCR) (Escalation Phase) [Approximately 24 months]
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.
Time to response (Escalation Phase) [Approximately 24 months]
Time to response is defined as the time from initiation of treatment until the first assessment demonstrating CR or PR per RECIST v1.1.
Progression-free survival (PFS) (Escalation Phase) [Approximately 24 months]
PFS is defined as the time from initiation of treatment until documented disease progression per RECIST v1.1 or death, whichever occurs first.
Maximum observed concentration (Cmax) [Predose and up to 12 hours postdose.]
Measure the maximum observed concentration of DCC-3116 (single-agent and combinations)
Time to maximum observed concentration (Tmax) [Predose and up to 12 hours postdose.]
Measure the time to maximum plasma concentration of DCC-3116 (single-agent and combinations)
Minimum observed concentration (Cmin) [Predose and up to 12 hours postdose.]
Measure the minimum observed concentration of DCC-3116 (single-agent and combinations)
Area under the concentration-time curve( AUC) [Predose and up to 12 hours postdose.]
Measure the AUC of DCC-3116 (single-agent and combinations)

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Male or female participants ≥18 years of age
Dose Escalation Phase (Part 1):
Participants must have a histologically confirmed diagnosis of an advanced or metastatic solid tumor with a documented RAS, NF1, or RAF mutations.
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.

Participants enrolled in the DCC-3116 and sotorasib cohort (Cohort D) must have a KRAS G12C mutation.
Dose Expansion Phase (Part 2):
Cohort 1: Patients with Pancreatic Ductal Adenocarcinoma (PDAC).

Histologically confirmed PDAC with a documented mutation in KRAS.
Received only 1 prior line of systemic therapy in the advanced or metastatic setting.

Cohort 2: Patients with Non-Small Cell Lung Cancer (NSCLC)

Histologically confirmed NSCLC with a documented mutation in KRAS, NRAS, NF1, or BRAF.
Received at least 2 prior lines but no more than 4 prior lines of systemic therapy in the advanced or metastatic setting.

Cohort 3: Patients with Colorectal Cancer (CRC)

Histologically confirmed CRC with a documented mutation in KRAS, NRAS, NF1, or BRAF.
Received 2-3 prior lines of systemic therapy in the advanced or metastatic setting.

Cohort 4: Patients with Melanoma

Histologically confirmed melanoma with a documented mutation in NRAS.
Received 1-2 prior lines of systemic therapy in the advanced or metastatic setting that included T-cell checkpoint inhibitor-based therapy.
Have not received prior MEK inhibitor therapy.

Cohort 5: Patients with KRAS G12C mutant NSCLC

Histologically 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.

Must be able to provide tumor tissue sample
Eastern Cooperative Oncology Group (ECOG) score of 0 to 2 (Dose Escalation) or 0 to 1 (Dose Expansion) at Screening
Adequate organ function and bone marrow function.
If a female of childbearing potential must have a negative pregnancy test prior to enrollment and agree to follow the contraception requirements.
Male participants must agree to follow contraception requirements.
Must provide signed consent to participate in the study and is willing to comply with study-specific procedures.

Exclusion Criteria:

Must not have received the following within the specified time periods prior to the first dose of study drug:
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 (eg, St. John's Wort): 14 days or 5× the half-life of the medication (whichever is longer)
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)
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
Grapefruit or grapefruit juice: 14 days
Have not recovered from all toxicities from prior therapy according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE).
Symptomatic central nervous system (CNS) metastases or presence of leptomeningeal disease Note: A participant with previously treated brain metastases may participate provided that they are stable.
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.
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.
Left ventricular ejection fraction (LVEF) <50% at Screening
Systemic arterial thrombotic or embolic events
Systemic venous thrombotic events
Malabsorption syndrome
Bone disease that requires treatment.
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.
Any other clinically significant comorbidities.
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.
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.
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.
Known allergy or hypersensitivity to any component of the investigational drug products.
Known human immunodeficiency virus or hepatitis C infection only if the participant is taking medications that are excluded per protocol, active hepatitis B, or active hepatitis C infection.
If female, the participant is pregnant or lactating.
Ongoing participation in an interventional study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
2	Hospital of the University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104
3	NEXT Oncology	Austin	Texas	United States	78758
4	The University of Texas MD Anderson Cancer Center	Houston	Texas	United States	77030
5	NEXT Oncology	San Antonio	Texas	United States	78229