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

Description
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).

Objective
Primary:
-To characterize the safety and tolerability, as well as the MTD and/or RP2D of CFT1946 as monotherapy and in combination with trametinib in subjects with BRAF-V600 mutant solid tumors who have received SoC therapy1
-To assess preliminary antitumor activity of CFT1946 as monotherapy and in combination with trametinib

Secondary:
-To further characterize the safety and tolerability of CFT1946, both as monotherapy and in combination with trametinib
-To characterize the PK of CFT1946 as monotherapy and in combination with trametinib and assess drug-drug interaction potential between CFT1946 and trametinib
-To assess the relationship between PK and ECG parameters
-To evaluate anti-tumor activity of CFT1946 as monotherapy and in combination with trametinib
-To assess pharmacodynamics at one or multiple dose levels of CFT1946 including BRAF degradation and MAPK pathway inhibition in tumor samples) as well as the PD-dose/PK dependency relationship

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

Key Eligibility Inclusion Criteria:

Subject (or legally authorized representative, where applicable) is willing and able to provide signed informed consent and can follow protocol requirements

Subject is >/=18 years of age at time of informed consent

Eastern Cooperative Oncology Group performance status of 0 or 1

Subject has documented evidence of a BRAF V600 mutation obtained from tumor tissue or liquid biopsy: (other protocol conditions may apply)

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:



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.

CRC: Receipt of a 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.

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

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



Subject has measurable disease per RECIST v1.1

Adequate bone marrow, liver, renal, and cardiac function

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

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

Subject can safely swallow a tablet or pill

Applicable Disease Sites
Colon and Rectum; Lung; Melanoma/Skin cancer; Thyroid

Participating Institutions
UW Health Eastpark Medical Center; UW Health University Hospital