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

Inclusion Criteria:

1. Subject (or legally authorized representative, where applicable) is willing and ableto 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 tissueor liquid biopsy: (other protocol conditions may apply)

5. Subject must have received ≥1 prior line of SoC therapy for their unresectablelocally advanced or metastatic disease with disease progression on or after lastprior treatment. Prior regimens for these subjects vary by indication andinvestigational arm, but must have included the following:

6. Melanoma or NSCLC (Phase 1 and Phase 2 Arms A1 and B1): Prior receipt of a BRAFinhibitor and an immune checkpoint inhibitor (any sequence or combination).Prior (neo)adjuvant immunotherapy may be acceptable.

7. CRC: Subjects must have received no more than 4 lines of prior therapy whichincludes systemic chemotherapy-based regimen per SoC for unresectable locallyadvanced or metastatic disease, and previous treatment with BRAF inhibitor incombination with an EGFR monoclonal antibody. Subjects with documented MSI-H ordMMR CRC must have received prior immunotherapy. Subjects with MSS disease musthave received at least 2 prior treatments. Subjects who received neo(adjuvant)chemotherapy regimens may be eligible.

8. ATC: Subjects must have received SoC therapy options including BRAF inhibitorif available and of benefit to the subject

9. Other BRAF V600 mutant solid tumors (non-CNS): Subjects must have received SoCtherapy options per their Investigator's best judgment, including BRAFinhibitor if available and of benefit to the subject

10. Subject has measurable disease per RECIST v1.1

11. Adequate bone marrow, liver, renal, and cardiac function

12. A female subject may be eligible if not pregnant, planning a pregnancy, not breastfeeding, a women of non-child bearing potential or a WOCBP willing to comply withprotocol conditions relating to the use contraception, ova or blood donation andpregnancy testing prior to the first dose

13. A male subject must agree to comply with protocol conditions relating to the use ofcontraception, sperm and blood donation

14. 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. Minorsurgery is permitted within 21 days prior to enrollment

2. Subject with CNS involvement (primary tumor or metastatic disease), except ifclinically stable, have no evidence of new or enlarging brain metastases and are onstable 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 priorradiation therapy.

3. Subject with known malignancy other than trial indication that is progressing or hasrequired treatment within the past 3 years, except for conditions that haveundergone potentially curative therapy

4. Subject with history of thromboembolic or cerebrovascular events ≤6 months asdefined in the protocol

5. Subject with impaired cardiac function or clinically significant cardiac disease, asdefined in the protocol

6. Subject with history of uncontrolled diabetes mellitus (only for subjects who willreceive 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 willreceive CFT1946 + trametinib)

8. Subject has received live, attenuated vaccine within 28 days prior to first doseadministration

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, exceptingalopecia and hypothyroidism requiring thyroid replacement therapy

16. Subject has initiation or receipt of the following ≤7 days prior to first doseadministration: Hematopoietic colony-stimulating growth factors, transfusion ofpacked red blood cells (pRBC), and transfusion of platelets

17. Subject is pregnant, breastfeeding, or expecting to conceive or father children anytime during the study

Other protocol defined exclusion criteria may apply