A Phase 1 Open-label Dose Escalation Study of CGX1321 in Subjects With Advanced Solid Tumors With Expansion in Advanced Gastrointestinal Tumors and Phase 1b Study of CGX1321 in Combination With Pembrolizumab in Subjects With Advanced Colorectal Cancer or in Combination With Encorafenib + Cetuximab in Subjects With BRAFV600E Mutated Advanced Colorectal Cancer

• Have measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 (Phase 1) or immune-related (ir)RECIST 1.1 (Phase 1b and Roll-over Cohort). Tumor lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions

• Minimum estimated life expectancy of 3 months

• Age 18 years or older

• Must have adequate organ function, including the following:

‣ Absolute neutrophil count (ANC) ≥ 1.5 x109/L; platelet count ≥ 100 x 109/L; hemoglobin ≥ 9 g/dL or ≥ 5.6 mmol/L

⁃ International normalized ratio (INR) or prothrombin time (PT) and activated partial thromboplastin Time (aPTT) ≤ 1.5 times the upper limit of normal (ULN) unless subject is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants

⁃ Hepatic: total bilirubin ≤ 1.5 times ULN, aspartate transaminase (AST) and/or alanine aminotransferase (ALT) ≤ 2.5 times ULN (≤ 5 times ULN if liver metastases)

⁃ Renal: serum creatinine ≤ 1.25 times the ULN or estimated creatinine clearance ≥ 60 mL/min (Cockcroft and Gault formula \[http://www.mdcalc.com/creatinine-clearance-cockcroft-gault-equation/\])

• Recovery (to baseline or to Grade 1 or less) from prior treatment-related toxicities

• Ability to swallow capsules

• Ability to comply with treatment, laboratory monitoring and required clinic visits

• Able to understand and willing to sign the informed consent form (ICF)

∙ In addition, the following criteria must be met based on the group to be enrolled into:

∙ For subjects in the Phase 1 Single Agent CGX1321 Dose Escalation phase:

• Pathologically-confirmed, locally advanced or metastatic solid tumors in subjects that have relapsed or are refractory to or are not considered medically suitable to receive standard of care treatment

• Eastern Cooperative Oncology Group (ECOG) score of 0 - 2

• Willingness for subjects of reproductive potential to use adequate methods of contraception during and for 3 months after study treatment

∙ For subjects in the Phase 1 Single Agent CGX1321 Dose Expansion phase:

• Histologically diagnosed advanced GI tumors, such as colorectal adenocarcinoma, gastric adenocarcinoma, pancreatic adenocarcinoma, bile duct carcinoma, hepatocellular carcinoma, esophageal carcinoma in subjects that have relapsed or are refractory to or are not considered medically suitable to receive standard of care treatment. Subjects must have confirmed genetic alterations (e.g., Rspo2 fusion, Rspo3 fusion or predicted loss-of-function mutations in RNF43) upstream in the WNT pathway and no predicted change-of-function alterations in genes (e.g., APC, CTNNB1 and Axin1) downstream in the WNT pathway

• ECOG score of 0 - 2

• Willingness for subjects of reproductive potential to use adequate methods of contraception during and for 3 months after study treatment

∙ For subjects in the Phase 1b or Roll-over Cohort CGX1321 in combination with pembrolizumab:

• Histologically or cytologically confirmed diagnosed advanced colorectal tumors that are mismatch repair-proficient or MSS in subjects that have relapsed or are refractory to or are not considered medically suitable to receive standard of care treatment (for dose escalation) and histologically or cytologically confirmed diagnosed advanced colorectal tumors with confirmed genetic alterations (e.g., Rspo2 fusion, Rspo3 fusion or predicted loss-of-function mutations in RNF43) upstream in the WNT pathway and no predicted change-of-function alterations in genes (e.g., APC, CTNNB1 and Axin1) downstream in the WNT pathway (for dose expansion) Note: Not applicable for subjects entering Roll-over Cohort

• Previous enrollment into either Phase 1 single agent dose escalation or Phase 1 single agent dose expansion with documented disease progression while on treatment with single agent CGX1321 Note: Not applicable for subjects entering Phase 1b

• ECOG score of 0 - 1

• Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile or abstain from heterosexual activity for the course of the study through 120 days after the last dose of pembrolizumab. Subjects of childbearing potential are those who have not been surgically sterilized or have been free from menses for \> 1 year.

∙ Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject Female subjects of childbearing potential must have a negative serum pregnancy test within 72 hours prior to receiving the first dose of study treatment Male subjects of childbearing potential must agree to use an adequate method of contraception starting with the first dose of pembrolizumab through 120 days after the last dose of pembrolizumab Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject

∙ For subjects in the Phase 1b Cohort CGX1321 in Combination with Encorafenib + Cetuximab:

• Histologically diagnosed advanced colorectal tumors (CRC) carrying a BRAF V600E mutation in tumor tissue, (as detected by an FDA-approved test) with confirmed genetic alterations (e.g., Rspo2 fusion, Rspo3 fusion or predicted loss-of-function mutations in RNF43) upstream in the WNT pathway and no predicted change-of-function alterations in genes (e.g., APC, CTNNB1 and Axin) downstream in the WNT pathway