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A Prospective, Open-Label, Phase IIb/III Study to Evaluate the Risk of TLS and Optimization of the Initiation of Venetoclax in Combination with Obinutuzumab or Acalabrutinib With Different Ramp-Up Periods in Previously Untreated Subjects with CLL

Primary Objective (Part 1) To evaluate the incidence of treatment-emergent laboratory TLS per Howard criteria (2 or more lab abnormalities [hyperkalemia (potassium greater than 6.0 mmol/L), hyperphosphatemia (phosphorus greater than 4.5 mg/dL), hypocalcemia (corrected calcium lest than 7.0 mg/dL or ionized calcium lest than 4.5 mg/dL), hyperuricemia (uric acid greater than 8.0 mg/dL)] present during the same 24-hour period within 3 days before the start of therapy or up to 7 days after) or hyperkalemia (potassium greater than 6.0 mmol/L), requiring clinical intervention per Independent Review Committee (IRC) assessment in previously untreated subjects with CLL achieving a medium (any lymph node [LN] 5 cm to less than 10 cm OR absolute lymphocyte count [ALC] greater than or equal to 25 x109/L) tumor burden with CrCl of at least 80 ml/min or low (all LN less than 5 cm AND ALC less than 25 x109/L) tumor burden (regardless of CrCl level) after debulking therapy, during the venetoclax ramp-up period (5-, 6- or 7-week). Secondary Objectives (Part 1) To evaluate the incidence of treatment-emergent laboratory TLS per Howard criteria (as defined in the primary objective above) or hyperkalemia (potassium greater than 6.0 mmol/L), requiring clinical intervention per IRC assessment in previously untreated subjects with CLL achieving a medium tumor burden with CrCl of at least 80 ml/min or low tumor burden (regardless of CrCl level) after debulking therapy at each dose level and at each laboratory monitoring point during the ramp-up period To assess the incidence of the TLS-related events detailed below (overall, at each dose level and at each laboratory monitoring point during the ramp-up period) in previously untreated subjects with CLL achieving a medium tumor burden with CrCl of at least 80 ml/min or low tumor burden (regardless of CrCl level) after debulking therapy: Laboratory TLS per Howard criteria (as defined in the primary objective above) requiring clinical intervention per IRC assessment Hyperkalemia (potassium greater than 6.0 mmol/L) requiring clinical intervention per IRC assessment Laboratory TLS per Howard criteria (as defined in the primary objective above) irrespective of clinical intervention Hyperkalemia (potassium greater than 6.0 mmol/L) irrespective of clinical intervention Clinical TLS per Howard criteria irrespective of clinical intervention One of the following lab abnormalities requiring clinical intervention per Investigator: Hyperuricemia (uric acid greater than 8.0 mg/dL) Hyperphosphatemia (phosphorus greater than 4.5 mg/dL) Hyperkalemia (potassium greater than 6.0 mmol/L) Hypocalcemia (corrected calcium less than 7.0 mg/dL or ionized calcium less than 4.5 mg/dL) To assess adverse events (AEs) of TLS as reported by the Investigator during the venetoclax ramp-up period in previously untreated subjects with CLL achieving a medium tumor burden with CrCl of at least 80 ml/min or low tumor burden (regardless of CrCl level) after debulking therapy. To evaluate reduction of tumor burden from baseline to after debulking, in all enrolled subjects who have TLS assessments performed at both baseline and after debulking

Primary Objective (Part 1) To evaluate the incidence of treatment-emergent laboratory TLS per Howard criteria (2 or more lab abnormalities [hyperkalemia (potassium greater than 6.0 mmol/L), hyperphosphatemia (phosphorus greater than 4.5 mg/dL), hypocalcemia (corrected calcium lest than 7.0 mg/dL or ionized calcium lest than 4.5 mg/dL), hyperuricemia (uric acid greater than 8.0 mg/dL)] present during the same 24-hour period within 3 days before the start of therapy or up to 7 days after) or hyperkalemia (potassium greater than 6.0 mmol/L), requiring clinical intervention per Independent Review Committee (IRC) assessment in previously untreated subjects with CLL achieving a medium (any lymph node [LN] 5 cm to less than 10 cm OR absolute lymphocyte count [ALC] greater than or equal to 25 x109/L) tumor burden with CrCl of at least 80 ml/min or low (all LN less than 5 cm AND ALC less than 25 x109/L) tumor burden (regardless of CrCl level) after debulking therapy, during the venetoclax ramp-up period (5-, 6- or 7-week). Secondary Objectives (Part 1) To evaluate the incidence of treatment-emergent laboratory TLS per Howard criteria (as defined in the primary objective above) or hyperkalemia (potassium greater than 6.0 mmol/L), requiring clinical intervention per IRC assessment in previously untreated subjects with CLL achieving a medium tumor burden with CrCl of at least 80 ml/min or low tumor burden (regardless of CrCl level) after debulking therapy at each dose level and at each laboratory monitoring point during the ramp-up period To assess the incidence of the TLS-related events detailed below (overall, at each dose level and at each laboratory monitoring point during the ramp-up period) in previously untreated subjects with CLL achieving a medium tumor burden with CrCl of at least 80 ml/min or low tumor burden (regardless of CrCl level) after debulking therapy: Laboratory TLS per Howard criteria (as defined in the primary objective above) requiring clinical intervention per IRC assessment Hyperkalemia (potassium greater than 6.0 mmol/L) requiring clinical intervention per IRC assessment Laboratory TLS per Howard criteria (as defined in the primary objective above) irrespective of clinical intervention Hyperkalemia (potassium greater than 6.0 mmol/L) irrespective of clinical intervention Clinical TLS per Howard criteria irrespective of clinical intervention One of the following lab abnormalities requiring clinical intervention per Investigator: Hyperuricemia (uric acid greater than 8.0 mg/dL) Hyperphosphatemia (phosphorus greater than 4.5 mg/dL) Hyperkalemia (potassium greater than 6.0 mmol/L) Hypocalcemia (corrected calcium less than 7.0 mg/dL or ionized calcium less than 4.5 mg/dL) To assess adverse events (AEs) of TLS as reported by the Investigator during the venetoclax ramp-up period in previously untreated subjects with CLL achieving a medium tumor burden with CrCl of at least 80 ml/min or low tumor burden (regardless of CrCl level) after debulking therapy. To evaluate reduction of tumor burden from baseline to after debulking, in all enrolled subjects who have TLS assessments performed at both baseline and after debulking