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.

Phase 2

• Conditions: Chronic Lymphocytic Leukaemia; Cancer - Leukaemia - Chronic leukaemia

• Registration Number: ACTRN12623000640606
• Lead Sponsor: Australasian Leukaemia and Lymphoma Group (ALLG)

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2023-06-14
• Last Update Posted: 10 June 2024

Recruitment & Eligibility

• Status: ot yet recruiting
• Sex: All
• Target Recruitment: 80

Inclusion Criteria

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

Exclusion Criteria

1. Patient is known to be positive for HIV.
2. Evidence of other clinically significant uncontrolled condition(s) including, but not limited to:
(a) Uncontrolled and/or active systemic infection (viral, bacterial or fungal)
(b) Chronic active hepatitis B virus (HBV) or hepatitis C (HCV) requiring treatment.
i. Note: patients with serologic evidence of prior vaccination to HBV (i.e. hepatitis B surface (HBs) antigen negative-, anti-HBs antibody positive and anti-hepatitis B core (HBc) antibody negative) or positive anti-HBc antibody from intravenous immunoglobulins (IVIG) may participate.
ii. Patients who have cleared active hepatitis B infection as defined by the following are also eligible to enrol, provided they have monitoring of the hepatitis B viral load at three monthly intervals and are managed with entecavir: HBsAg negative, HBsAb positive, HBcAb positive and HBV PCR negative
(c) Uncontrolled autoimmune haemolytic anaemia or immune thrombocytopenia
3. Patients requiring the use of warfarin (due to potential drug-drug interactions that may increase the exposure of warfarin).
4. Patients who have received BCL2 inhibitor therapy prior to VenR.
5. Presence of BCL2 mutations known to confer venetoclax resistance, including but not limited to BCL2 G101V.
6. Received CYP3A4 inhibitors (such as fluconazole, ketoconazole, and clarithromycin) within 7 days prior to the first dose of venetoclax.
7. Received potent CYP3A4 inducers (such as rifampicin, carbamazepine, phenytoin, St. John’s Wort) within 7 days prior to the first dose of venetoclax.
8. Consumed grapefruit or grapefruit products, Seville oranges (including marmalade containing Seville oranges), or star fruit within 3 days prior to the first dose of venetoclax.
9. A cardiovascular disability status of New York Heart Association Class greater than or equal to 3.
a. Class 3 is defined as cardiac disease in which patients are comfortable at rest but marked limitation of physical activity due to fatigue, palpitations, dyspnoea, or anginal pain.
10. Women who are pregnant or lactating.
11. History of prior other malignancy that could affect compliance with the protocol or interpretation of results
12. Malabsorption syndrome or other condition that precludes enteral route of administration.
13. Patients who have been unable to tolerate venetoclax 400mg daily whilst on VenR treatment.

Study & Design

• Study Type: Interventional
• Study Design: Not specified