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.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

C4 Therapeutics Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

27 Jun 2023 → 5 Nov 2025

Decision date (initial)

2023-05-16

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

C4 Therapeutics Inc.

External identifiers

EU CT number

2022-501618-70-00

WHO UTN

U1111-1281-8333

ClinicalTrials.gov

NCT05668585

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Dose response, Efficacy, Safety, Therapy, Pharmacokinetic, Pharmacodynamic

Phase 1: To characterize the safety and tolerability, maximum tolerated dose and/or initial recommended Phase 2 dose of CFT1946 as monotherapy and/or in combination with trametinib or cetuximab in subjects with BRAF-V600 mutant solid tumors who have received Standard of Care therapy.
Phase 2: To assess preliminary antitumor activity of CFT1946 as monotherapy and/or in combination with trametinib or cetuximab.

Secondary objectives 4

1. Phases 1 and 2: To characterize the Pharmacokinetics of CFT1946 as monotherapy and/or in combination with trametinib or cetuximab and assess drug-drug interaction potential.
2. Phases 1 and 2: To assess the relationship between Pharmacokinetics and Electrocardiogram parameters.
3. Phases 1 and 2: To evaluate anti-tumor activity of CFT1946 as monotherapy and/or in combination with trametinib or cetuximab.
4. Phase 2: To further characterize the safety and tolerability of CFT1946, as monotherapy and/or and in combination with trametinib or cetuximab.

Conditions and MedDRA coding

BRAF-V600 Mutant Solid Tumors including Melanoma, Non-small cell lung cancer, Colorectal cancer and Anaplastic thyroid carcinoma.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 17

1. 1. Subject (or legal guardian, where applicable) is willing and able to provide signed informed consent and can follow protocol requirements.
2. 5e. Other BRAF V600 mutant solid tumors (non-central nervous system): Subjects must have received Standard of Care therapy options per their Investigator's best judgment, including BRAF inhibitor if available and of benefit to the subject.
3. 6. Arm C and C1: Eligible to receive cetuximab per locally approved label.
4. 7. Subject has measurable disease per RECIST v1.1.
5. 8. Adequate bone marrow, liver, renal, and cardiac organ function.
6. 9. A female subject may be eligible if not pregnant, planning a pregnancy, not breast feeding, a women of non-child bearing potential or a woman of childbearing potential willing to comply with protocol conditions relating to the use contraception, ova or blood donation and pregnancy testing prior to the first dose.
7. 10. A male subject must agree to comply with protocol conditions relating to the use of contraception, sperm and blood donation.
8. 11. Subject can safely swallow a tablet or pill.
9. 2. Subject is ≥18 years of age at time of informed consent.
10. 3. Eastern Cooperative Oncology Group performance status of 0 or 1.
11. 4. Subject has documented evidence of a BRAF-V600 mutant solid tumor, including melanoma, non-small cell lung cancer, colorectal cancer, anaplastic thyroid cancer and non-central nervous system solid tumor.
12. 5. Subject must have received ≥1 prior line of Standard of Care therapy for their unresectable locally advanced or metastatic disease with disease progression on or after the last prior treatment. Prior regimens for these subjects vary by indication (ie, non-small cell lung cancer, colorectal cancer, anaplastic thyroid carcinoma or other BRAF-V600 mutation positive tumors) and investigational arm.
13. 5a. Melanoma or non-small cell lung cancer (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. If an immunotherapy regimen was not previously given due to intolerance or ineligibility to receive immunotherapy due to a pre-existing medical condition, subjects are eligible.
14. 5b. Non-small cell lung cancer (Phase 2 Arm B2): Prior receipt of a regimen including platinum-based therapy (if eligible), and an immune checkpoint inhibitor (any sequence or combination). Prior BRAF inhibitor in the metastatic or advanced setting, unless not available per local stadard of care. Prior (neo)adjuvant immunotherapy may be acceptable. If an immunotherapy regimen was not previously given due to intolerance or ineligibility to receive immunotherapy due to a pre-existing medical condition, subjects are eligible.
15. 5c. Colorectal cancer: Receipt of a Standard of Care systemic chemotherapy-based regimen and a prior BRAF inhibitor in combination with an epidermal growth factor receptor monoclonal antibody. Subjects with documented microsatellite instability-high or mismatch repair-deficient colorectal cancer must have received prior immunotherapy. Subjects with microsatellite stable disease must have received at least 2 prior treatments. Subjects who received neo(adjuvant) chemotherapy regimens may be eligible.
16. 5d. Anaplastic thyroid carcinoma: Subjects must have received SoC therapy options including BRAF inhibitor if available and of benefit to the subject.
17. Other protocol defined inclusion criteria may apply.

Exclusion criteria 21

1. 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. 17. Subject is pregnant, breastfeeding, or expecting to conceive or father children any time during the study.
3. 18. Previously identified hypersensitivity to the administered study treatment(s) or excipients.
4. 19. History or current evidence of any condition, therapy, or laboratory abnormality that may confound trial results, interfere with subject's trial participation, or not in best interest of subject to participate in trial (in opinion of PI).
5. 20. Subject has acute ongoing or active infection requiring IV anti-infective treatment.
6. 21. Subject has received anti-neoplastic therapy within 21 days (or 5 half-lives, whichever is shorter) prior to first dose of CFT1946.
7. 22. Have a known contraindication to receive trametinib or cetuximab at planned doses.
8. 23. Unwilling/Unable to provide/understand written informed consent and comply with protocol.
9. 2. Subject with central nervous system 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.
10. 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.
11. 4. Subject with history of thromboembolic or cerebrovascular events ≤6 months as defined in the protocol.
12. 9. Subject has history of pneumonitis or interstitial lung disease.
13. 5. Subject with impaired cardiac function or clinically significant cardiac disease within 6 months prior to first dose of study treatment, as defined in the protocol.
14. 6. Subject with history of uncontrolled diabetes mellitus (only for subjects who will receive CFT1946 + trametinib).
15. 7. Subject with history or current evidence of retinal vein occlusion, chorioretinopathy, or current risk factors for retinal vein occlusion (only for subjects who will receive CFT1946 + trametinib).
16. 8. Subject has received live, attenuated vaccine within 28 days prior to first dose administration.
17. Other protocol defined exclusion criteria may apply.
18. 10. Subject has history of uveitis.
19. 11. Clinically significant gastrointestinal abnormalities that may alter absorption such as ulcerative disease, malabsorption syndrome or major resection of the stomach or bowels with decrease intestinal absorption and vomiting.
20. 12. Subject has known human immunodeficiency virus infection (with exceptions).
21. 13. Subject has history of or known Hepatitis B virus or active Hepatitis C virus infection.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 6

1. 1. Incidence of dose limiting toxicities.
2. 2. Frequency and severity of Adverse Events and Serious Adverse Events.
3. 3. Changes between baseline and post baseline safety assessments.
4. 4. Frequency of dose interruptions and dose reductions.
5. 5. Frequency of Adverse Events leading to discontinuation of study treatment(s).
6. 6. Overall response rate measured by RECIST v1.1 criteria per Independent Review Committee.

Secondary endpoints 10

1. 1. All primary endpoints except incidence of dose limiting toxicities.
2. 2. Single dose and multiple dose pharmacokinetics of CFT1946 (monotherapy and combination) and trametinib.
3. 3. Pharmacokinetics-QT interval corrected for heart rate using Fridericia’s formula relationship.
4. 4. Overall response rate measured by RECIST v1.1 per Investigator assessment.
5. 5. Disease control rate at 3, 6, and 12 months.
6. 6. Progression-free survival.
7. 7. Duration of response.
8. 8. Tumor BRAF degradation PD marker(s).
9. 9. MAPK pathway inhibition in BRAF tumor.
10. 10. Dose/pharmacokinetic correlation to pharmacodynamic endpoints.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 7

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

C4 Therapeutics Inc.

Sponsor organisation

C4 Therapeutics Inc.

Address

490 Arsenal Way Suite 120

City

Watertown

Postcode

02472-2988

Country

United States

Scientific contact point

Organisation

C4 Therapeutics Inc.

Contact name

Study Medical Officer

Public contact point

Organisation

C4 Therapeutics Inc.

Contact name

Study Medical Officer

Third parties 12

Locations

4 EU/EEA countries · 17 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Oversight and notifications

Regulatory notifications under CTR Articles 38, 52, 53, 54 and 77

Unexpected events 1 · Art. 53 CTR

Note: SUSARs are reported via EudraVigilance, not CTIS — events shown here are CTIS-public notifications only.

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 38 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

11 submissions — initial application plus substantial / non-substantial modifications