A Study to Characterize the Safety, Tolerability, and Preliminary Efficacy of CFT1946 as Monotherapy and Combination Therapy in Subjects With BRAF V600 Mutant Solid Tumors

Phase 1

Active, not recruiting

• Conditions: Solid Tumors; Melanoma; NSCLC; CRC; ATC
• Interventions: Drug: CFT1946; Drug: Trametinib; Drug: Cetuximab

• Registration Number: NCT05668585
• Lead Sponsor: C4 Therapeutics, Inc.

Brief Summary

The purpose of this study is to evaluate the safety and tolerability of CFT1946 as well as to determine the maximum tolerated dose (MTD) and/or the recommended Phase 2 dose (RP2D) of CFT1946 as monotherapy (Arm A) and in combination with trametinib (CFT1946 + trametinib; Arm B) or Cetuximab (CFT1946 + cetuximab; Arm C).

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2022-12-06
• Study Start: 2022-12-08
• Study First Submitted QC: 2022-12-19
• Study First Posted: 2022-12-30
• Status Verified: 2025-05
• Last Update Submitted: 2025-05-08
• Last Update Posted: 2025-05-13
• Primary Completion: 2027-03-11
• Study Completion: 2027-04-11

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 89

Inclusion Criteria

1. Subject (or legally authorized representative, where applicable) is willing and able to provide signed informed consent and can follow protocol requirements

2. Subject is ≥18 years of age at time of informed consent

3. Eastern Cooperative Oncology Group performance status of 0 or 1

4. Subject has documented evidence of a BRAF V600 mutation obtained from tumor tissue or liquid biopsy: (other protocol conditions may apply)

5. Subject must have received ≥1 prior line of SoC therapy for their unresectable locally advanced or metastatic disease with disease progression on or after last prior treatment. Prior regimens for these subjects vary by indication and investigational arm, but must have included the following:

   1. Melanoma or NSCLC (Phase 1 and Phase 2 Arms A1 and B1): Prior receipt of a BRAF inhibitor and an immune checkpoint inhibitor (any sequence or combination). Prior (neo)adjuvant immunotherapy may be acceptable.
   2. CRC: Subjects must have received no more than 4 lines of prior therapy which includes systemic chemotherapy-based regimen per SoC for unresectable locally advanced or metastatic disease, and previous treatment with BRAF inhibitor in combination with an EGFR monoclonal antibody. Subjects with documented MSI-H or dMMR CRC must have received prior immunotherapy. Subjects with MSS disease must have received at least 2 prior treatments. Subjects who received neo(adjuvant) chemotherapy regimens may be eligible.
   3. ATC: Subjects must have received SoC therapy options including BRAF inhibitor if available and of benefit to the subject
   4. Other BRAF V600 mutant solid tumors (non-CNS): Subjects must have received SoC therapy options per their Investigator's best judgment, including BRAF inhibitor if available and of benefit to the subject

6. Subject has measurable disease per RECIST v1.1

7. Adequate bone marrow, liver, renal, and cardiac function

8. A female subject may be eligible if not pregnant, planning a pregnancy, not breast feeding, a women of non-child bearing potential or a WOCBP willing to comply with protocol conditions relating to the use contraception, ova or blood donation and pregnancy testing prior to the first dose

9. A male subject must agree to comply with protocol conditions relating to the use of contraception, sperm and blood donation

10. Subject can safely swallow a tablet or pill

Other protocol defined exclusion criteria may apply

Exclusion Criteria

1. Subject has had major surgery within 21 days prior to the planned first dose. Minor surgery is permitted within 21 days prior to enrollment
2. Subject with CNS involvement (primary tumor or metastatic disease), except if clinically stable, have no evidence of new or enlarging brain metastases and are on stable or tapering doses of steroids for at least 7 days prior to first dose. Subjects with untreated brain metastases may be eligible to enter without prior radiation therapy.
3. Subject with known malignancy other than trial indication that is progressing or has required treatment within the past 3 years, except for conditions that have undergone potentially curative therapy
4. Subject with history of thromboembolic or cerebrovascular events ≤6 months as defined in the protocol
5. Subject with impaired cardiac function or clinically significant cardiac disease, as defined in the protocol
6. Subject with history of uncontrolled diabetes mellitus (only for subjects who will receive CFT1946 + trametinib)
7. Subject with history or current evidence of retinal vein occlusion (RVO), chorioretinopathy, or current risk factors for RVO (only for subjects who will receive CFT1946 + trametinib)
8. Subject has received live, attenuated vaccine within 28 days prior to first dose administration
9. Subject has history of pneumonitis or interstitial lung disease
10. Subject has history of uveitis
11. Subject has clinically significant gastrointestinal abnormalities.
12. Subject has known human immunodeficiency virus (HIV) infection (with exceptions)
13. Subject has history of or known HBV or active HCV infection
14. Subject has concurrent administration of strong CYP3A4/5 inhibitors and inducers, including any herbal medications/supplements
15. Subject has presence of Grade ≥2 toxicity due to prior cancer therapy, excepting alopecia and hypothyroidism requiring thyroid replacement therapy
16. Subject has initiation or receipt of the following ≤7 days prior to first dose administration: Hematopoietic colony-stimulating growth factors, transfusion of packed red blood cells (pRBC), and transfusion of platelets
17. Subject is pregnant, breastfeeding, or expecting to conceive or father children any time during the study

Other protocol defined exclusion criteria may apply

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Phase 1: Arm B: CFT1946 + trametinib	CFT1946	Approximately 28 subjects with V600 Solid Tumors (non-CNS) (post BRAF inhibitor for NSCLC, CRC, melanoma)
Phase 1: Arm B: CFT1946 + trametinib	Trametinib	Approximately 28 subjects with V600 Solid Tumors (non-CNS) (post BRAF inhibitor for NSCLC, CRC, melanoma)
Phase 2: Arm A1: CFT1946	CFT1946	Approximately 30 subjects with V600 melanoma or NSCLC (post BRAF inhibitor)
Phase 2: Arm B1: CFT1946 + trametinib	CFT1946	Approximately 20 subjects with V600 melanoma or NSCLC (post BRAF Inhibitor)
Phase 2: Arm B1: CFT1946 + trametinib	Trametinib	Approximately 20 subjects with V600 melanoma or NSCLC (post BRAF Inhibitor)
Phase 1: Arm C: CFT1946 + cetuximab	CFT1946	Approximately 30 subjects with CRC (post BRAF inhibitor)
Phase 1: Arm C: CFT1946 + cetuximab	Cetuximab	Approximately 30 subjects with CRC (post BRAF inhibitor)
Phase 2: Arm C1: CFT1946 + cetuximab	CFT1946	Approximately 40 subjects with CRC (post BRAF inhibitor)
Phase 2: Arm C1: CFT1946 + cetuximab	Cetuximab	Approximately 40 subjects with CRC (post BRAF inhibitor)
Phase 1: Arm A: CFT1946	CFT1946	Approximately 40 subjects with V600 Solid Tumors (non-CNS) (post BRAF inhibitor for NSCLC, CRC, melanoma, ATC)

Primary Outcome Measures

Name	Time	Method
Frequency of dose interruptions and dose reductions	From enrollment until 30 days after completion of study treatment	Phase 1
Incidence of dose limiting toxicities (DLTs)	From enrollment until 28 days after first dose	Phase 1
Number of subjects with changes between baseline and post-baseline safety assessments based on safety laboratory results graded by CTCAE v5.0	From enrollment until 30 days after completion of study treatment	Phase 1
Frequency of AEs leading to discontinuation of study treatment(s)	From enrollment until 30 days after completion of study treatment	Phase 1
Overall response rate (ORR)	Up to approximately 43 months	Phase 2 only according to RECIST v1.1 criteria
Disease control rate (DCR) at 3, 6, and 12 months	Up to 12 months	Phase 2
Duration of Response (DOR)	Up to approximately 43 months	Phase 2
Frequency and severity of AEs and SAEs	From enrollment until 30 days after completion of study treatment	Phase 1

Secondary Outcome Measures

Name	Time	Method
Duration of response (DOR)	Up to approximately 43 months	Phase 1
Progression-free survival (PFS)	Up to approximately 43 months	Phase 1 and Phase 2
Plasma concentration of CFT1946 to characterize the pharmacokinetics (PK) parameters of CFT1946 monotherapy and in combination with trametinib	Up to approximately 20 weeks	Phase 1 and Phase 2
PK-QTcF relationship	Up to approximately 8 weeks	Phase 1 and Phase 2
Overall response rate (ORR)	Up to approximately 43 months	Phase 1
Disease control rate (DCR) at 3, 6, and 12 months	Up to 12 months	Phase 1
Assess the pharmacodynamics by percent reduction from baseline of target protein	At multiple time points up to 4 weeks	Tumor BRAF-V600 degradation at scheduled timepoints
Frequency and severity of AEs and SAEs	From enrollment until 30 days after completion of study treatment	Phase 2
Number of subjects with changes between baseline and post-baseline safety assessments based on safety laboratory results graded by CTCAE v5.0	From enrollment until 30 days after completion of study treatment	Phase 2
Frequency of dose interruptions and dose reductions	From enrollment until 30 days after completion of study treatment	Phase 2
Frequency of AEs leading to discontinuation of study treatment(s)	From enrollment until 30 days after completion of study treatment	Phase 2

Trial Locations

Locations (26)

Chu de Lille; 🇫🇷 Lille, France

Institut Bergonie; 🇫🇷 Bordeaux Cedex, France

University of Arizona - Cancer Center; 🇺🇸 Tucson, Arizona, United States

Florida Cancer Specialists; 🇺🇸 Sarasota, Florida, United States

Community Health Network; 🇺🇸 Indianapolis, Indiana, United States

Dana-Farber Cancer Institute; 🇺🇸 Boston, Massachusetts, United States

Allina Health System DBA Virginia Piper Cancer Institute; 🇺🇸 Minneapolis, Minnesota, United States

Washington University School of Medicine; 🇺🇸 Saint Louis, Missouri, United States

David H. Koch Center for Cancer Care at Memorial Sloan Kettering Cancer Center; 🇺🇸 New York, New York, United States

Sarah Cannon and HCA Research Institute; 🇺🇸 Nashville, Tennessee, United States

MD Anderson Cancer Center; 🇺🇸 Houston, Texas, United States

Virginia Cancer Specialists (NEXT Oncology Virginia); 🇺🇸 Fairfax, Virginia, United States

University of Wisconsin; 🇺🇸 Madison, Wisconsin, United States

Centre Leon Berard; 🇫🇷 Lyon, France

IUCT Oncopole; 🇫🇷 Toulouse, France

KEM | Evang. Kliniken Essen-Mitte gGmbH; 🇩🇪 Essen, Germany

Universitaetsklinikum Essen; 🇩🇪 Essen, Germany

NEXT Oncology Barcelona; 🇪🇸 Barcelona, Spain

Hospital Universitario Vall d'Hebron; 🇪🇸 Barcelona, Spain

Complejo Hospitalario de Jaen; 🇪🇸 Jaén, Spain

Hospital General Universitario Gregorio Maranon; 🇪🇸 Madrid, Spain

South Texas Accelerated Research Therapeutics (START) Madrid - Hospital Fundacion Jiminez Diaz; 🇪🇸 Madrid, Spain

Hospital Universitario 12 de Octubre; 🇪🇸 Madrid, Spain

Hospital Clinico Universitario de Valencia; 🇪🇸 Valencia, Spain

Beatson West of Scotland Cancer Centre; 🇬🇧 Glasgow, United Kingdom

The Christie NHS Foundation Trust; 🇬🇧 Manchester, United Kingdom