CGX1321 in Subjects With Advanced Solid Tumors and CGX1321 With Pembrolizumab or Encorafenib + Cetuximab in Subjects With Advanced GI Tumors (Keynote 596)

All subjects must be excluded from participating in the study if subjects meet any of the following criteria:

1. Prior exposure to a WNT inhibitor. Note: Not applicable for subjects entering Roll-over Cohort

2. Received any of the following within the specified time frame prior to administration of study drug:

• Previous therapy for malignancy within 21 days, including any investigational agents, chemotherapy, immunotherapy, biological or hormonal therapy Note: Only applicable for subjects in single-agent dose escalation cohorts

3. Major surgery within 4 weeks of first dose of study treatment

4. Radiotherapy within 2 weeks of first dose of study treatment. Note for Phase 1b or Roll-over Cohorts: Subjects must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease.

5. Significant GI or variceal bleeding or subdural hematoma within 3 months of first dose of study treatment

6. Known active central nervous system metastases and/or carcinomatous meningitis Note: Subjects with previously treated brain metastases may participate provided they are radiographically stable (without evidence of progression by imaging (using the identical imaging modality for each assessment, either magnetic resonance imaging \[MRI\] or computed tomography \[CT\] scan) for at least four weeks prior to the first dose of study treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 14 days prior to the first dose of study treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability

7. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone or equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug

8. Currently receiving medications known to be inhibitors of CYP3A4/5. Subjects currently receiving medications of known inducers of CYP3A4/5 or substrates of CYP2C8/9 and CYP1A2 may be excluded unless determined by the Investigator to be in the best interest of the subject and are approved by the Sponsor

9. Osteoporosis based on a T-score of \< -2.5 at the left or right total hip, left or right femoral neck or lumbar spine (L1 - L4) as determined by dual-energy x-ray absorptiometry (DXA) scan

10. Subjects with bone metastases that:

* Have a prior history of a pathologic fracture

* Have a lytic lesion requiring an orthopedic intervention or

* Are not receiving a bisphosphonate (zoledronic acid or denosumab) as per institutional guidelines

11. Current bisphosphonate therapy for symptomatic hypercalcemia

12. History within last 6 months of New York Heart Association Class III or IV heart failure, acute myocardial infarction, angina pectoris, uncontrolled arrhythmia, acute coronary syndromes, stent placement, uncontrolled hypertension

13. Subjects with QTc interval of \> 470 msec

14. Known human immunodeficiency virus positive (such patients are at increased risk of lethal infections when treated with potentially marrow-suppressive therapy)

15. Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer

16. Active systemic infection requiring IV antibiotics within 2 weeks of the first dose of study treatment

17. History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject's participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating Investigator

18. Known psychiatric or substance abuse disorders that would interfere with the subject's ability to cooperate with the requirements of the study.

19. Pregnancy or lactation

20. Has had an allogeneic tissue/solid organ transplant

In addition, subjects must be excluded from participating if they meet any of the following criteria based on the group to be enrolled into:

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

1\. Known active hepatitis A, B or C Note: Subjects who are HBsAg+ and have DNA load \< 2000 IU/mL (104 copies/mL) are eligible to participate in the Phase 1 study

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

1. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen \[HBsAg\] reactive) or known active Hepatitis C virus (defined as HCV RNA \[qualitative\] is detected) infection.

Note: No testing for Hepatitis B and Hepatitis C is required unless mandated by local health authority

2. Received transfusion of blood products (including platelets or red blood cells) or administration of colony stimulating factors (including G-CSF, GM-CSF or recombinant erythropoietin) within 4 weeks prior to first dose of study treatment

3. Active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment

4. History of (non-infectious) pneumonitis that required steroids or current pneumonitis

5. History of interstitial lung disease

6. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study, starting with the screening visit through 120 days after the last dose of study treatment

7. Received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX 40, CG137) and was discontinued from that treatment due to a Grade 3 or higher irAE or if the patient has previously participated in Merck MK-3475 clinical studies

8. Has severe (≥ Grade 3) hypersensitivity to any of the excipients of pembrolizumab

9. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from AEs due to agents administered more than 4 weeks earlier

10. Received a live-virus vaccination within 30 days of planned treatment start. Seasonal flu vaccines that do not contain live virus are permitted

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

1. Symptomatic brain metastases or leptomeningeal disease

2. History or current evidence of retinal vein occlusion or current risk factors for retinal vein occlusion (e.g., uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes)

3. Known history of acute or chronic pancreatitis

4. History of chronic inflammatory bowel disease or Crohn's disease requiring medical intervention (immunomodulatory or immunosuppressive medications or surgery) ≤12 months prior to enrollment

5. Uncontrolled blood pressure despite medical treatment

6. Impaired GI function or disease that may significantly alter the absorption of encorafenib (e.g., ulcerative diseases, uncontrolled vomiting, malabsorption syndrome, small bowel resection with decreased intestinal absorption)

7. History of thromboembolic or cerebrovascular events ≤ 6 months prior to starting study treatment including transient ischemic attacks, cerebrovascular accidents, deep vein thrombosis or pulmonary emboli

8. Concurrent neuromuscular disorder that is associated with the potential of elevated creatinine (phosphor)kinase (CK) (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy)

9. Active hepatitis B or hepatitis C infection

10. Known history of Gilbert's syndrome

11. Known contraindication to receive Encorafenib or Cetuximab at the planned doses

What this study is about