CLL08 - A study to evaluate the efficacy of venetoclax/rituximab (VenR) re-treatment in relapsed/refractory Chronic Lymphocytic Leukaemia (CLL) patients with disease progression following VenR as their last line of therapy.

The purpose of this study is to evaluate the efficacy of retreatment with Venetoclax and Rituximab in relapse and refractory CLL patients. Who is it for? You may be eligible for this study if you are aged 18 and above and have relapsed/refractory chronic lymphocytic leukaemia (CLL) with disease progression following two years of VenR therapy. Study details This study design involves two phases of study treatment: 1) VENETOCLAX RAMP UP: this phase will have two parallel cohorts that will receive the same treatment. -Cohort A: for patients with 12-24 months since last dose of Ven -Cohort B: for patients with greater than or equal to 24 months since last dose of Ven An initial dose of 20mg venetoclax is administered orally for all patients on day 1 - If a patient demonstrates one or more electrolyte abnormalities suggestive of laboratory TLS during the 24 hour period after the first dose: • Electrolyte abnormalities will be treated according to the Electrolyte Management Guidelines • Following resolution of electrolyte abnormalities, patients may be instructed to resume self-administration of venetoclax at 20mg daily for an additional 6 days. • Patients will then increase the venetoclax dose to 50mg daily and be monitored as described above. If the 50mg dose is tolerated without any abnormalities, daily dosing of venetoclax will continue at 50mg daily for a total of 7 days. • The venetoclax dose is then increased to 100mg daily for 1 week (week 3), followed by 200mg daily for 1 week (week 4) and then increased to 400mg daily (week 5). For patients who do not show any evidence of electrolyte abnormalities suggestive of laboratory TLS during the 24 hours after the initial 20mg dose: • Venetoclax will be escalated to 50mg on day 2 and patients will be monitored for TLS over 24 hours. • If the 50mg dose is tolerated, daily dosing of 50mg venetoclax will continue for a total of 6 days. • The venetoclax dose is then increased to 100mg daily for 1 week (week 2), followed by 200mg daily for 1 week (week 3) and then increased to 400mg daily (week 4). 2) VENETOCLAX IN COMBINATION WITH RITUXIMAB - After the patient has completed the venetoclax ramp-up period and received the target dose of 400 mg of venetoclax for 1 week with no evidence of laboratory or clinical TLS, the patient will begin combination therapy consisting of 6 cycles of rituximab (infusions occurring on Day 1 of each 28-day cycle) in combination with the 400mg daily dose of venetoclax. -Rituximab will be administered to patients in both treatment arms at 375 mg/m2 IV on Day 1 of Cycle 1 followed by 500 mg/m2 on Day 1 of Cycles 2 through 6 (total of six infusions of rituximab). It is hoped this research will determine if patients with relapsed/refractory CLL can further clinically benefit from VenR re-treatment.