Clinical trial NCT05668585: 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
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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
Conditions: Solid Tumors
Melanoma
NSCLC
CRC
ATC
Keywords: Solid Tumors
Melanoma
NSCLC
ATC
BRAF mutant
CRC
Lead sponsor: C4 Therapeutics, Inc.
Sponsor class: INDUSTRY
First posted: 2022-12-30
Enrollment: 89
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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).


Eligibility criteria: 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

Primary outcomes:
measure: Frequency and severity of AEs and SAEs
timeFrame: From enrollment until 30 days after completion of study treatment
measure: Incidence of dose limiting toxicities (DLTs)
timeFrame: From enrollment until 28 days after first dose
measure: Number of subjects with changes between baseline and post-baseline safety assessments based on safety laboratory results graded by CTCAE v5.0
timeFrame: From enrollment until 30 days after completion of study treatment
measure: Frequency of dose interruptions and dose reductions
timeFrame: From enrollment until 30 days after completion of study treatment
measure: Frequency of AEs leading to discontinuation of study treatment(s)
timeFrame: From enrollment until 30 days after completion of study treatment
measure: Overall response rate (ORR)
timeFrame: Up to approximately 43 months
measure: Disease control rate (DCR) at 3, 6, and 12 months
timeFrame: Up to 12 months
measure: Duration of Response (DOR)
timeFrame: Up to approximately 43 months
Secondary outcomes:
measure: Frequency and severity of AEs and SAEs
timeFrame: From enrollment until 30 days after completion of study treatment
measure: Number of subjects with changes between baseline and post-baseline safety assessments based on safety laboratory results graded by CTCAE v5.0
timeFrame: From enrollment until 30 days after completion of study treatment
measure: Frequency of dose interruptions and dose reductions
timeFrame: From enrollment until 30 days after completion of study treatment
measure: Frequency of AEs leading to discontinuation of study treatment(s)
timeFrame: From enrollment until 30 days after completion of study treatment
measure: Plasma concentration of CFT1946 to characterize the pharmacokinetics (PK) parameters of CFT1946 monotherapy and in combination with trametinib
timeFrame: Up to approximately 20 weeks
measure: PK-QTcF relationship
timeFrame: Up to approximately 8 weeks
measure: Overall response rate (ORR)
timeFrame: Up to approximately 43 months
measure: Disease control rate (DCR) at 3, 6, and 12 months
timeFrame: Up to 12 months
measure: Progression-free survival (PFS)
timeFrame: Up to approximately 43 months
measure: Duration of response (DOR)
timeFrame: Up to approximately 43 months
measure: Assess the pharmacodynamics by percent reduction from baseline of target protein
timeFrame: At multiple time points up to 4 weeks
Other outcomes:
Locations:
city: Tucson
country: United States
facility: University of Arizona - Cancer Center
state: Arizona
city: Sarasota
country: United States
facility: Florida Cancer Specialists
state: Florida
city: Indianapolis
country: United States
facility: Community Health Network
state: Indiana
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Minneapolis
country: United States
facility: Allina Health System DBA Virginia Piper Cancer Institute
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: New York
country: United States
facility: David H. Koch Center for Cancer Care at Memorial Sloan Kettering Cancer Center
state: New York
city: Nashville
country: United States
facility: Sarah Cannon and HCA Research Institute
state: Tennessee
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Fairfax
country: United States
facility: Virginia Cancer Specialists (NEXT Oncology Virginia)
state: Virginia
city: Madison
country: United States
facility: University of Wisconsin
state: Wisconsin
city: Bordeaux Cedex
country: France
facility: Institut Bergonie
city: Lille
country: France
facility: Chu de Lille
city: Lyon
country: France
facility: Centre Leon Berard
city: Toulouse
country: France
facility: IUCT Oncopole
city: Essen
country: Germany
facility: KEM | Evang. Kliniken Essen-Mitte gGmbH
city: Essen
country: Germany
facility: Universitaetsklinikum Essen
city: Barcelona
country: Spain
facility: NEXT Oncology Barcelona
city: Barcelona
country: Spain
facility: Hospital Universitario Vall d'Hebron
city: Jaén
country: Spain
facility: Complejo Hospitalario de Jaen
city: Madrid
country: Spain
facility: Hospital General Universitario Gregorio Maranon
city: Madrid
country: Spain
facility: South Texas Accelerated Research Therapeutics (START) Madrid - Hospital Fundacion Jiminez Diaz
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Valencia
country: Spain
facility: Hospital Clinico Universitario de Valencia
city: Glasgow
country: United Kingdom
facility: Beatson West of Scotland Cancer Centre
city: Manchester
country: United Kingdom
facility: The Christie NHS Foundation Trust
Study officials:
References: