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

Study Overview
=================
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).

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

Conditions
-----------------
CRC, Solid Tumors, Melanoma, NSCLC, ATC

Intervention / Treatment
-----------------
* Drug: CFT1946
* Drug: Trametinib


Participation Criteria
=================
Eligibility Criteria
-----------------
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 Other protocol defined exclusion criteria may apply Exclusion Criteria: Subject has had major surgery within 21 days prior to the planned first dose. Minor surgery is permitted within 21 days prior to enrollment 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. 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 Subject with history of thromboembolic or cerebrovascular events ≤6 months as defined in the protocol Subject with impaired cardiac function or clinically significant cardiac disease, as defined in the protocol Subject with history of uncontrolled diabetes mellitus (only for subjects who will receive CFT1946 + trametinib) 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) Subject has received live, attenuated vaccine within 28 days prior to first dose administration Subject has history of pneumonitis or interstitial lung disease Subject has history of uveitis Subject has known human immunodeficiency virus (HIV) infection (with exceptions) Subject has history of or known HBV or active HCV infection Subject has concurrent administration of strong CYP3A4/5 inhibitors and inducers, including any herbal medications/supplements Subject has presence of Grade ≥2 toxicity due to prior cancer therapy, excepting alopecia and hypothyroidism requiring thyroid replacement therapy 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 Subject is pregnant, breastfeeding, or expecting to conceive or father children any time during the study Other protocol defined exclusion criteria may apply

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1: Arm A: CFT1946<br>Approximately 40 subjects with V600 Solid Tumors (non-CNS) (post BRAF inhibitor for NSCLC, CRC, melanoma, ATC) | Drug: CFT1946<br>* Specified oral dose on specified day<br>|
| Experimental: Phase 1: Arm B: CFT1946 + trametinib<br>Approximately 28 subjects with V600 Solid Tumors (non-CNS) (post BRAF inhibitor for NSCLC, CRC, melanoma) | Drug: CFT1946<br>* Specified oral dose on specified day<br>Drug: Trametinib<br>* Specified oral dose on specified day<br>|
| Experimental: Phase 2: Arm A1: CFT1946<br>Approximately 30 subjects with V600 melanoma or NSCLC (post BRAF inhibitor) | Drug: CFT1946<br>* Specified oral dose on specified day<br>|
| Experimental: Phase 2: Arm B1: CFT1946 + trametinib<br>Approximately 20 subjects with V600 melanoma or NSCLC (post BRAF Inhibitor) | Drug: CFT1946<br>* Specified oral dose on specified day<br>Drug: Trametinib<br>* Specified oral dose on specified day<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency and severity of AEs and SAEs | Phase 1 | From enrollment until 30 days after completion of study treatment | 
| Incidence of dose limiting toxicities (DLTs) | Phase 1 | From enrollment until 28 days after first dose | 
| 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 | 
| Frequency of dose interruptions and dose reductions | Phase 1 | From enrollment until 30 days after completion of study treatment | 
| Frequency of AEs leading to discontinuation of study treatment(s) | Phase 1 | From enrollment until 30 days after completion of study treatment | 
| Overall response rate (ORR) | Phase 2 only according to RECIST v1.1 criteria | Up to approximately 43 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency and severity of AEs and SAEs | Phase 2 | From enrollment until 30 days after completion of study treatment | 
| 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 | 
| Frequency of dose interruptions and dose reductions | Phase 2 | From enrollment until 30 days after completion of study treatment | 
| Frequency of AEs leading to discontinuation of study treatment(s) | Phase 2 | From enrollment until 30 days after completion of study treatment | 
| 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 | 
| PK-QTcF relationship | Phase 1 and Phase 2 | Up to approximately 8 weeks | 
| Overall response rate (ORR) | Phase 1 and Phase 2 | Up to approximately 43 months | 
| Disease control rate (DCR) at 3, 6, and 12 months | Phase 1 and Phase 2 | Up to 12 months | 
| Progression-free survival (PFS) | Phase 1 and Phase 2 | Up to approximately 43 months | 
| Duration of response (DOR) | Phase 1 and Phase 2 | Up to approximately 43 months | 
| 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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
NSCLC, ATC, Solid Tumors, Melanoma, BRAF mutant, CRC