CLL08: This study is recruiting people with chronic lymphocytic leukaemia (CLL) that has progressed after two years of prior Venetoclax and Rituximab (VenR) treatmentA phase 2 study of venetoclax/rituximab (VenR) re-treatment in relapsed/refractory CLL patients with disease progression following VenR as their last line of therapy

Inclusion

1. Signed informed consent.
2. Age 18 years or above.
3. Diagnosis of CLL that meets published diagnostic criteria
(a) Patients must have peripheral blood B-lymphocyte counts which clonally express CD5, CD19, CD20, and CD23 and are either kappa or lambda light-chain-restricted.
(b) Prolymphocytes may comprise no more than 55per cent of total circulating lymphocytes. At initial diagnosis of CLL (i.e. prior to front-line treatment), the peripheral lymphocyte count must have been > 5000 per mm3
(c) Patients must meet the following criteria for relapsed or refractory CLL (per the iwCLL guidelines:
(a) Relapsed disease: a patient who previously achieved a CR or PR, but after a period of 6 months or more demonstrates evidence of progression.
(b) Refractory disease: treatment failure or disease progression within 6 months of the last anti-leukaemia therapy.
4. Completed a full, 24-month course of VenR for relapsed/refractory CLL with a clinical response, defined as partial response or complete response with or without incomplete count recovery.
5. Subsequent disease progression meeting iwCLL criteria for treatment, at least 12 months after completion of VenR therapy:
(a) Cohort 1: disease progression between 12-24 months after completion of VenR
(b) Cohort 2: disease progression greater than 24 months after completion of VenR
6. ECOG performance score of less than or equal to 1
7. Adequate bone marrow function without growth factor or transfusion support, defined as:
(a) Haemoglobin greater than 8 g per dL without transfusion support within 2 weeks of screening
(b) ,Absolute neutrophil count (ANC) greater than 500/mm3 – the use of G-CSF to achieve this is permitted
(c) Platelets greater than 50,000/mm3.
(d) If any of the above cytopenias are present, there should be no evidence of myelodysplastic syndrome (MDS) or hypoplastic bone marrow
8. Adequate renal and hepatic function defined as:
(a) CrCl greater than 30mL per minute using 24-hour creatinine clearance or modified Cockcroft-Gault equation using ideal body mass (IBM) instead of mass
(b) AST and ALT less than 5 x upper limit of normal (ULN) of institution's normal range
(c) Bilirubin less than 1.5 x ULN (except patients with Gilbert's syndrome)
(d) PT/INR and APTT less than 1.2 x ULN of institution’s normal range. Patients with an elevated prothrombin time and known lupus anticoagulant may be eligible for participation after consulting the Medical Monitor.
9. Female patients must be surgically sterile, postmenopausal (for at least 1 year) or have negative results for a pregnancy test,
(a) At screening, on a serum sample obtained within 14 days prior to initiation of study treatment, and
(b) Prior to dosing, on a urine sample obtained on Week 1, Day 1 if it has been more than 7 days since obtaining the serum pregnancy test result.
10. Females of childbearing potential must practice at least one of the following methods of birth control throughout the duration of study participation and for at least 12 months after completing therapy with rituximab:
(a) Total abstinence from sexual intercourse
(b) A vasectomised partner
(c) Hormonal contraceptives (oral, parenteral, vaginal ring or transdermal) that started at least 3 months prior to study drug administration
(d) Double-barrier method (condom + diaphragm or cervical cup with spermicidal contraceptive sponge, jellies or cream)
11. Non-vasectomised must practice at least one of the following methods of birth control throughout the duration of study participation and for at least 12 months after completing therapy with rituximab:
(a) Total abstinence from sexual intercourse
(b) A partner who is surgically sterile or postmenopausal (for least 1 year) or who is taking hormonal contraceptives (oral, parenteral, vaginal ring or transdermal) for at least 3 months prior to study drug administration
(c) Double-barrier method (condom + diaphragm or cervical cup with spermicidal contraceptive sponge, jellies or cream)
12. Patients must agree not to donate blood, semen or sperm while on study treatment and for at least 12 months after treatment discontinuation.
13. Patients may be eligible if they are able to be taken off warfarin and started on an alternative anticoagulant.
14. Prior BTKi therapy is permitted.
15. Those with history of the below prior other malignancy may be eligible:
a. Curatively treated basal cell carcinoma or squamous cell carcinoma of the skin or carcinoma in situ of the cervix at any time prior to study.
b. Other cancers not specified above which have been curatively treated by surgery and/or radiation therapy, from which patient is disease-free for greater than or equal to 5 years without further treatment.