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

Melanoma Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05668585
• Other study ID #: CFT1946-1101
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: December 8, 2022
• Est. completion date: April 11, 2027

Study information

• Verified date: May 2024
• Source: C4 Therapeutics, Inc.
• Contact: Study Medical Officer
• Phone: (617)231-0770
• Email: clinicaltrials[@]c4therapeutics.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 206
• Est. completion date: April 11, 2027
• Est. primary completion date: March 11, 2027
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• CRC
• Melanoma
• NSCLC
• Solid Tumors

Intervention

Drug:
• CFT1946
Specified oral dose on specified day
• Trametinib
Specified oral dose on specified day
• Cetuximab
Specified intravenous dose on specified day

Locations

Country	Name	City	State
France	Institut Bergonie	Bordeaux Cedex
France	Chu de Lille	Lille
France	Centre Leon Berard	Lyon
France	IUCT Oncopole	Toulouse
Spain	Hospital Universitario Vall d'Hebron	Barcelona
Spain	NEXT Oncology Barcelona	Barcelona
Spain	South Texas Accelerated Research Therapeutics (START) Madrid - Hospital Fundacion Jiminez Diaz	Madrid
Spain	Hospital Clinico Universitario de Valencia	Valencia
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	Virginia Cancer Specialists (NEXT Oncology Virginia)	Fairfax	Virginia
United States	MD Anderson Cancer Center	Houston	Texas
United States	University of Wisconsin	Madison	Wisconsin
United States	Sarah Cannon and HCA Research Institute	Nashville	Tennessee
United States	David H. Koch Center for Cancer Care at Memorial Sloan Kettering Cancer Center	New York	New York
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Florida Cancer Specialists	Sarasota	Florida

Sponsors (1)

Lead Sponsor	Collaborator
C4 Therapeutics, Inc.

Countries where clinical trial is conducted

United States,  France,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Frequency and severity of AEs and SAEs	Phase 1	From enrollment until 30 days after completion of study treatment
Primary	Incidence of dose limiting toxicities (DLTs)	Phase 1	From enrollment until 28 days after first dose
Primary	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
Primary	Frequency of dose interruptions and dose reductions	Phase 1	From enrollment until 30 days after completion of study treatment
Primary	Frequency of AEs leading to discontinuation of study treatment(s)	Phase 1	From enrollment until 30 days after completion of study treatment
Primary	Overall response rate (ORR)	Phase 2 only according to RECIST v1.1 criteria	Up to approximately 43 months
Primary	Disease control rate (DCR) at 3, 6, and 12 months	Phase 2	Up to 12 months
Primary	Duration of Response (DOR)	Phase 2	Up to approximately 43 months
Secondary	Frequency and severity of AEs and SAEs	Phase 2	From enrollment until 30 days after completion of study treatment
Secondary	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
Secondary	Frequency of dose interruptions and dose reductions	Phase 2	From enrollment until 30 days after completion of study treatment
Secondary	Frequency of AEs leading to discontinuation of study treatment(s)	Phase 2	From enrollment until 30 days after completion of study treatment
Secondary	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
Secondary	PK-QTcF relationship	Phase 1 and Phase 2	Up to approximately 8 weeks
Secondary	Overall response rate (ORR)	Phase 1	Up to approximately 43 months
Secondary	Disease control rate (DCR) at 3, 6, and 12 months	Phase 1	Up to 12 months
Secondary	Progression-free survival (PFS)	Phase 1 and Phase 2	Up to approximately 43 months
Secondary	Duration of response (DOR)	Phase 1	Up to approximately 43 months
Secondary	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