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

• Sponsor: C4 Therapeutics, Inc. (Industry)
• Overall Status: Recruiting
• CT.gov ID: NCT05668585
• Collaborator: (none)
• Enrollment: 122
• Locations: 10
• Arms: 5
• Anticipated Duration (Months): 52.1
• Patients Per Site: 12.2
• Patients Per Site Per Month: 0.2

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	Phase
Solid Tumors; Melanoma; NSCLC; CRC; ATC	Drug: CFT1946; Drug: Trametinib	Phase 1/Phase 2

Study Design

• Study Type: Interventional
• Anticipated Enrollment: 122 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 1/2 Open-Label Multicenter Trial to Characterize the Safety, Tolerability, and Preliminary Efficacy of CFT1946 as Monotherapy and in Combination With Trametinib in Subjects With BRAF V600 Mutant Solid Tumors
• Actual Study Start Date: Dec 8, 2022
• Anticipated Primary Completion Date: Mar 11, 2027
• Anticipated Study Completion Date: Apr 11, 2027

Arms and Interventions

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 2: Arm B2: CFT1946 + trametinib Approximately 20 subjects with V600 NSCLC (BRAF inhibitor naive)	Drug: CFT1946; Specified oral dose on specified day; Drug: Trametinib; Specified oral dose on specified day

Outcome Measures

Primary Outcome Measures

1. Frequency and severity of AEs and SAEs [From enrollment until 30 days after completion of study treatment]

   Phase 1

2. Incidence of dose limiting toxicities (DLTs) [From enrollment until 28 days after first dose]

   Phase 1

3. 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

4. Frequency of dose interruptions and dose reductions [From enrollment until 30 days after completion of study treatment]

   Phase 1

5. Frequency of AEs leading to discontinuation of study treatment(s) [From enrollment until 30 days after completion of study treatment]

   Phase 1

6. Overall response rate (ORR) [Up to approximately 43 months]

   Phase 2 only according to RECIST v1.1 criteria

Secondary Outcome Measures

1. Frequency and severity of AEs and SAEs [From enrollment until 30 days after completion of study treatment]

   Phase 2

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

3. Frequency of dose interruptions and dose reductions [From enrollment until 30 days after completion of study treatment]

   Phase 2

4. Frequency of AEs leading to discontinuation of study treatment(s) [From enrollment until 30 days after completion of study treatment]

   Phase 2

5. 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

6. PK-QTcF relationship [Up to approximately 8 weeks]

   Phase 1 and Phase 2

7. Overall response rate (ORR) [Up to approximately 43 months]

   Phase 1 and Phase 2

8. Disease control rate (DCR) at 3, 6, and 12 months [Up to 12 months]

   Phase 1 and Phase 2

9. Progression-free survival (PFS) [Up to approximately 43 months]

   Phase 1 and Phase 2

10. Duration of response (DOR) [Up to approximately 43 months]

    Phase 1 and Phase 2

11. 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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Subject (or legal guardian, 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 locally advanced or metastatic disease, NSCLC, CRC, ATC or other BRAF-V600 mutation positive tumors:

6. 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.

7. NSCLC (Phase 2 Arm B2): Prior receipt of a regimen including an immune checkpoint inhibitor (any sequence or combination). BRAF inhibitor naïve. Prior (neo)adjuvant immunotherapy may be acceptable.

8. CRC: Receipt of a SoC chemotherapy regimen and a prior 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.

9. ATC: Subjects must have received SoC therapy options including BRAF inhibitor if available and of benefit to the subject

10. Other BRAF V600 mutant solid tumors (non-CNS): Subjects must have received SoC therapy options per their Investigator's best judgment and be BRAF inhibitor naïve

11. Subject has measurable disease per RECIST v1.1

12. Adequate bone marrow, liver, renal, and cardiac organ function

13. 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

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

15. 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 known human immunodeficiency virus (HIV) infection (with exceptions)

12. Subject has history of or known HBV or active HCV infection

13. Subject has concurrent administration of strong CYP3A4/5 inhibitors and inducers, including any herbal medications/supplements

14. Subject has presence of Grade ≥2 toxicity due to prior cancer therapy, excepting alopecia and hypothyroidism requiring thyroid replacement therapy

15. 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

16. Subject is pregnant, breastfeeding, or expecting to conceive or father children any time during the study

Other protocol defined exclusion criteria may apply

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02215
2	David H. Koch Center for Cancer Care at Memorial Sloan Kettering Cancer Center	New York	New York	United States	10021
3	Sarah Cannon and HCA Research Institute	Nashville	Tennessee	United States	37203
4	MD Anderson Cancer Center	Houston	Texas	United States	77030
5	Virginia Cancer Specialists (NEXT Oncology Virginia)	Fairfax	Virginia	United States	22031
6	Institut Bergonie	Bordeaux Cedex		France	33076
7	NEXT Oncology Barcelona	Barcelona		Spain	08023
8	Hospital Universitario Vall d'Hebron	Barcelona		Spain	08035
9	South Texas Accelerated Research Therapeutics (START) Madrid - Hospital Fundacion Jiminez Diaz	Madrid		Spain	28040
10	Hospital Clinico Universitario de Valencia	Valencia		Spain	46010

Sponsors and Collaborators

• C4 Therapeutics, Inc.

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: C4 Therapeutics, Inc.
• ClinicalTrials.gov Identifier: NCT05668585
• Other Study ID Numbers: CFT1946-1101
• First Posted: Dec 30, 2022
• Last Update Posted: Dec 30, 2022
• Last Verified: Dec 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Neoplasms; Melanoma; Trametinib

Study Results

No Results Posted as of Dec 30, 2022