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

A Phase 1/2 Open-Label Multicenter Trial to Characterize the Safety, Tolerability, and Preliminary Efficacy of CFT1946 as Monotherapy and Combination Therapy in Subjects With BRAF V600 Mutant Solid Tumors

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).

Study Overview

• Status: Completed
• Conditions: Melanoma; NSCLC; Solid Tumors; CRC; ATC
• Intervention / Treatment: Drug: CFT1946; Drug: Trametinib; Drug: Cetuximab

• Study Type: Interventional
• Enrollment (Actual): 89
• Phase: Phase 1

Contacts and Locations

Study Locations

• France
  • Bordeaux, France, 33076
    • Institut Bergonie
  • Lille, France, 59037
    • CHU de Lille
  • Lyon, France, 69008
    • Centre Léon Bérard
  • Toulouse, France, 31059
    • IUCT Oncopole
• Germany
  • Essen, Germany, 45147
    • Universitaetsklinikum Essen
  • Essen, Germany, 45136
    • KEM | Evang. Kliniken Essen-Mitte gGmbH
• Spain
  • Barcelona, Spain, 08035
    • Hospital Universitario Vall d'Hebron
  • Barcelona, Spain, 08023
    • Next Oncology Barcelona
  • Jaén, Spain, 23007
    • Complejo Hospitalario de Jaén
  • Madrid, Spain, 28041
    • Hospital Universitario 12 de Octubre
  • Madrid, Spain, 28007
    • Hospital General Universitario Gregorio Marañon
  • Madrid, Spain, 28040
    • South Texas Accelerated Research Therapeutics (START) Madrid - Hospital Fundacion Jiminez Diaz
  • Valencia, Spain, 46010
    • Hospital Clínico Universitario de Valencia
• United Kingdom
  • Glasgow, United Kingdom, G12 0YN
    • Beatson West Of Scotland Cancer Centre
  • Manchester, United Kingdom, M20 4BX
    • The Christie Nhs Foundation Trust
• United States
  • Arizona
    • Tucson, Arizona, United States, 85719
      • University of Arizona - Cancer Center
  • Florida
    • Sarasota, Florida, United States, 34232
      • Florida Cancer Specialists
  • Indiana
    • Indianapolis, Indiana, United States, 46250
      • Community Health Network
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana-Farber Cancer Institute
  • Minnesota
    • Minneapolis, Minnesota, United States, 55407
      • Allina Health System DBA Virginia Piper Cancer Institute
  • Missouri
    • St Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • New York
    • New York, New York, United States, 10021
      • David H. Koch Center for Cancer Care at Memorial Sloan Kettering Cancer Center
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Sarah Cannon and HCA Research Institute
  • Texas
    • Houston, Texas, United States, 77030
      • MD Anderson Cancer Center
  • Virginia
    • Fairfax, Virginia, United States, 22031
      • Virginia Cancer Specialists (NEXT Oncology Virginia)
  • Wisconsin
    • Madison, Wisconsin, United States, 53792
      • University of Wisconsin

Participation Criteria

Eligibility Criteria

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

Description

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 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: Phase 1: Arm A: CFT1946; Approximately 40 subjects with V600 Solid Tumors (non-CNS) (post BRAF inhibitor for NSCLC, CRC, melanoma, ATC)	Drug: CFT1946; Specified oral dose on specified day
Experimental: Phase 1: Arm B: CFT1946 + trametinib; Approximately 28 subjects with V600 Solid Tumors (non-CNS) (post BRAF inhibitor for NSCLC, CRC, melanoma)	Drug: CFT1946; Specified oral dose on specified day; Drug: Trametinib; Specified oral dose on specified day
Experimental: Phase 2: Arm A1: CFT1946; Approximately 30 subjects with V600 melanoma or NSCLC (post BRAF inhibitor)	Drug: CFT1946; Specified oral dose on specified day
Experimental: Phase 2: Arm B1: CFT1946 + trametinib; Approximately 20 subjects with V600 melanoma or NSCLC (post BRAF Inhibitor)	Drug: CFT1946; Specified oral dose on specified day; Drug: Trametinib; Specified oral dose on specified day
Experimental: Phase 1: Arm C: CFT1946 + cetuximab; Approximately 30 subjects with CRC (post BRAF inhibitor)	Drug: CFT1946; Specified oral dose on specified day; Drug: Cetuximab; Specified intravenous dose on specified day
Experimental: Phase 2: Arm C1: CFT1946 + cetuximab; Approximately 40 subjects with CRC (post BRAF inhibitor)	Drug: CFT1946; Specified oral dose on specified day; Drug: Cetuximab; Specified intravenous dose on specified day

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: C4 Therapeutics, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): December 8, 2022
• Primary Completion (Actual): November 5, 2025
• Study Completion (Actual): November 5, 2025

Study Registration Dates

• First Submitted: December 6, 2022
• First Submitted That Met QC Criteria: December 19, 2022
• First Posted (Actual): December 30, 2022

Study Record Updates

• Last Update Posted (Actual): November 21, 2025
• Last Update Submitted That Met QC Criteria: November 19, 2025
• Last Verified: November 1, 2025

More Information

Terms related to this study

• Keywords: NSCLC; Melanoma; Solid Tumors; CRC; BRAF mutant; ATC
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Skin Diseases; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neuroendocrine Tumors; Nevi and Melanomas; Skin Neoplasms; Skin and Connective Tissue Diseases; Melanoma; Amino Acids, Peptides, and Proteins; Proteins; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Cetuximab; trametinib
• Other Study ID Numbers: CFT1946-1101

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No