A Study of Valemetostat Tosylate (DS-3201b) With Atezolizumab and Bevacizumab in HCC

This is a phase Ib/II, dose escalation and dose expansion study of valemetostat (DS-3201) with atezolizumab and bevacizumab in patients advanced Hepatocellular carcinoma (HCC) who did not receive prior systemic therapy for advanced HCC.

Inclusion Criteria: Subjects must meet all the following criteria to be eligible for enrollment into the study: 1. Sign and date the informed consent form (ICF), prior to the start of any study-specific qualification procedures. 2. Subjects ≥18 years of age or the minimum legal adult age (whichever is greater) at the time the ICF is signed 3. HCC diagnosis confirmed by histology/cytology or clinically by American Association for Study of Liver Diseases (AASLD) 36 criteria in cirrhotic patients. 4. At least one measurable untreated lesion per RECIST v1.1 (see Section 12). Patients who received prior liver directed therapy (ie., Trans arterial chemoembolization \[TACE\], Y-90, liver directed radiation etc.) are eligible provided the target lesion(s) have not been previously treated with liver directed therapy or the target lesion(s) within the field of local therapy have subsequently progressed in accordance with RECIST v1.1 (See Section 12) 5. Locally advanced, metastatic, or unresectable disease. 6. No prior systemic therapy for advanced HCC. 7. Child Pugh Class A. 8. Barcelona Clinic Liver Cancer (BCLC) Stage B (not amenable to liver directed therapy) or Stage C. 9. ECOG Performance Status (PS) 0 or 1. 10. The following laboratory values obtained ≤ 28 days prior to registration. Local laboratory data must meet the following criteria at both Screening and prior to dosing on the planned Cycle 1 Day 1 visit to confirm relatively preserved organ function: * Absolute neutrophil count (ANC) ≥1500/mm3 * Platelet count 100,000/mm3 (platelet transfusion is not allowed within 14 days prior to screening assessment). * Hemoglobin (Hgb) 9.0 g/dL (red blood cell transfusion is not allowed within 14 days prior to screening assessment). * Total bilirubin (TBIL) ≤1.5 x ULN. * ALT and AST ≤3 x ULN * For patients not receiving therapeutic anticoagulation INR or aPTT ≤2 x ULN * Creatinine clearance ≥40 mL/min (measured by the Cockcroft-Gault equation) 11. If the subject is a female of childbearing potential, she must have a negative serum pregnancy test at Screening and must be willing to use highly effective birth control, as detailed in Section 4.4, upon enrollment, during the Treatment Period, and for 6 months, following the last dose of study drug. A female is considered of childbearing potential following menarche and until becoming postmenopausal (no menstrual period for a minimum of 12 months) unless permanently sterile (undergone a hysterectomy, bilateral salpingectomy or bilateral oophorectomy) with surgery at least 1 month before the first dose of study drug or confirmed by follicle stimulating hormone (FSH) test \>40 mIU/mL and estradiol \ 325 mg/day) or treatment with dipyramidole, ticlopidine, clopidogrel, and cilostazol. 17. Current or recent (within 10 days prior to study treatment start) use of full-dose oral or parenteral anticoagulants or thrombolytic agents for therapeutic (as opposed to prophylactic) purpose. Prophylactic anticoagulation for the patency of venous access devices is allowed provided the activity of the agent results in an INR \< 1.5 x ULN and aPTT is within normal limits within 14 days prior to initiation of study treatment. Prophylactic use of low molecular-weight heparin (i.e., enoxaparin 40 mg/day) is allowed. 18. Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 3 days prior to the first dose of bevacizumab. 19. History of abdominal or tracheoesophageal fistula, gastrointestinal (GI) perforation, or intra-abdominal abscess within 6 months prior to initiation of study treatment 20. History of intestinal obstruction and/or clinical signs or symptoms of GI obstruction including sub-occlusive disease related to the underlying disease or requirement for routine parenteral hydration, parenteral nutrition, or tube feeding within 6 months prior to initiation of study treatment. Patients with signs/symptoms of sub-/occlusive syndrome/intestinal obstruction at time of initial diagnosis may be enrolled if they had received definitive (surgical) treatment for symptom resolution. 21. Evidence of abdominal free air that is not explained by paracentesis or recent surgical procedure. 22. Serious, non-healing or dehiscing wound, active ulcer, or untreated bone fracture 23. Metastatic disease that involves major airways or blood vessels, or centrally located mediastinal tumor masses (\< 30 mm from the carina) of large volume Patients with vascular invasion of the portal or hepatic veins may be enrolled. 24. History of intra-abdominal inflammatory process within 6 months prior to initiation of study treatment, including but not limited to peptic ulcer disease, diverticulitis, or colitis 25. Radiotherapy within 28 days and abdominal/ pelvic radiotherapy within 60 days prior to initiation of study treatment, except palliative radiotherapy to bone lesions within 7 days prior to initiation of study treatment 26. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to initiation of study treatment, or abdominal surgery, abdominal interventions or significant abdominal traumatic injury within 60 days prior to initiation of study treatment or anticipation of need for major surgical procedure during the course of the study or non-recovery from side effects of any such procedure 27. Chronic daily treatment with a non-steroidal anti-inflammatory drug (NSAID). Occasional use of NSAIDs for the symptomatic relief of medical conditions such as headache or fever is allowed. 28. Known fibrolamellar carcinoma (FLC), sarcomatoid HCC, or combined hepatocellular-cholangiocarcinoma (cHCC-CC) 29. Patients with untreated or incompletely treated varices with bleeding or high-risk for bleeding. Patients must undergo an esophagogastroduodenoscopy (EGD), and all size of varices (small to large) must be assessed and treated per local standard of care prior to enrollment. Patients who have undergone an EGD within 6 months of prior to initiation of study treatment do not need to repeat the procedure. 30. History of allogenic organ transplantation. 31. Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease \[e.g., colitis or Crohn's disease\], diverticulitis \[with the exception of diverticulosis\], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome \[granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc\]). The following are exceptions to this criterion: * Patients with vitiligo or alopecia * Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement * Any chronic skin condition that does not require systemic therapy * Patients without active disease in the last 5 years may be included but only after consultation with the study physician * Patients with celiac disease controlled by diet alone 32. History of leptomeningeal carcinomatosis or intracranial metastases 33. Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients. 34. Current or prior use of immunosuppressive medication ≤ 14 days prior to registration. The following are exceptions to this criterion: * Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection) * Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent * Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication) 35. Receipt of live attenuated vaccine ≤30 days prior to registration. Note: Patients, if enrolled, should not receive live vaccine whilst on study treatment and up to 30 days after the last dose of study treatment.