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Trial registered on ANZCTR


Registration number
ACTRN12623000640606p
Ethics application status
Not yet submitted
Date submitted
22/03/2023
Date registered
14/06/2023
Date last updated
2/06/2024
Date data sharing statement initially provided
14/06/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
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.
Scientific title
CLL08 - A 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
Secondary ID [1] 309001 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Chronic Lymphocytic Leukaemia 329402 0
Condition category
Condition code
Cancer 326349 326349 0 0
Leukaemia - Chronic leukaemia

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Venetoclax is a novel, orally-available, small molecule BH3-mimetic that selectively targets BCL-2. Venetoclax for investigational use is supplied as tablets containing normally 10mg, 50mg or 100mg of venetoclax.

There will be two cohorts of patients recruited:
Cohort 1: disease progression between 12-24 months after completion of VenR
Cohort 2: disease progression greater than 24 months after completion of VenR

VENETOCLAX RAMP UP: 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 Tumour Lysis Syndrome (TLS) during the 24 hour period after the first dose:
• Electrolyte abnormalities will be treated according to the Electrolyte Management Guidelines provided by the manufacturer
• 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).


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 intravenously 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).

Overall treatment duration is 2 years post-enrollment. All treatment will be administered by the study team. Drug accountability will be performed by the administering institutions to assess compliance.
Intervention code [1] 325691 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 334211 0
Progression Free Survival (PFS) where progression will be assessed by blood tests and CT scans.
Timepoint [1] 334211 0
Defined as the time from enrolment to first occurrence of progression or relapse, or death from any cause at the end of study therapy (24 months).
Secondary outcome [1] 419845 0
Overall Survival (OS)
Timepoint [1] 419845 0
Defined as the time from enrolment to death from any cause.
Secondary outcome [2] 419846 0
Time to next treatment (TTNT) which will be assessed by review of medical records
Timepoint [2] 419846 0
Defined as the time from enrolment to start of new non-protocol anti-CLL therapy or death from any cause
Secondary outcome [3] 419847 0
Overall response (OR)
Timepoint [3] 419847 0
Defined as "Complete remission with incomplete count recovery" (CRi) and Partial Response (PR) at 4 weeks after day 1 of the last cycle of combined venetoclax/rituximab therapy (cycle 6). Assessed by blood tests and CT scans.
Secondary outcome [4] 419848 0
PFS at 12 months where progression will be assessed by blood tests and CT scans.
Timepoint [4] 419848 0
Time from enrolment to first occurrence of progression or relapse, or death from any cause at 12 months (day 1 of the last cycle (cycle 24) of study therapy.)
Secondary outcome [5] 419850 0
Evaluate total time of venetoclax benefit assessed by review of medical records, blood tests and CT scans.
Timepoint [5] 419850 0
Defined as the time from commencement of initial Ven-R therapy to first occurrence of progression or relapse, or death from any cause, following Ven-R re-treatment.
Secondary outcome [6] 419851 0
Evaluate PFS after next line of non-protocol anti-CLL treatment assessed by blood tests and CT scans.
Timepoint [6] 419851 0
Defined as the time from commencement of that treatment to first occurrence of progression or relapse, or death from any cause.
Secondary outcome [7] 419852 0
Evaluate safety of VenR re-treatment
Timepoint [7] 419852 0
Focusing on incidence of laboratory TLS and/or clinical TLS, serious adverse events, National Cancer Institute Common Terminology Criteria for Adverse Events, version 6.0 (NCI CTCAE, v6.0) grade greater than or equal to 3 adverse events, and grade greater than or equal to 3 laboratory toxicities.

Safety evaluation will be conducted when all patients have completed at least 2 years post-enrolment or withdrawn.

Eligibility
Key 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 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.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/09/2024
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
80
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
ACT,NSW,NT,QLD,SA,TAS,WA,VIC
Recruitment outside Australia
Country [1] 25342 0
New Zealand
State/province [1] 25342 0

Funding & Sponsors
Funding source category [1] 313214 0
Other Collaborative groups
Name [1] 313214 0
Australasian Leukaemia and Lymphoma Group (ALLG)
Country [1] 313214 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Australasian Leukaemia and Lymphoma Group (ALLG)
Address
Ground Floor, 35 Elizabeth St, Richmond VIC 3121
Country
Australia
Secondary sponsor category [1] 314935 0
None
Name [1] 314935 0
Address [1] 314935 0
Country [1] 314935 0

Ethics approval
Ethics application status
Not yet submitted
Ethics committee name [1] 312445 0
Peter MacCallum Cancer Centre Ethics Committee
Ethics committee address [1] 312445 0
Ethics committee country [1] 312445 0
Australia
Date submitted for ethics approval [1] 312445 0
11/09/2023
Approval date [1] 312445 0
Ethics approval number [1] 312445 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 124694 0
Dr Mary Ann Anderson
Address 124694 0
Peter MacCallum Cancer Centre 305 Grattan Street Melbourne VIC 3000
Country 124694 0
Australia
Phone 124694 0
+61 3 8559 5000
Fax 124694 0
Email 124694 0
[email protected]
Contact person for public queries
Name 124695 0
Delaine Smith
Address 124695 0
ALLG, 35 Elizabeth St, Richmond, VIC 3121
Country 124695 0
Australia
Phone 124695 0
+61 3 8373 9701
Fax 124695 0
Email 124695 0
[email protected]
Contact person for scientific queries
Name 124696 0
Delaine Smith
Address 124696 0
ALLG, 35 Elizabeth St, Richmond, VIC 3121
Country 124696 0
Australia
Phone 124696 0
+61 3 8373 9701
Fax 124696 0
Email 124696 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
De-identified IPD data for all data collected during the trial
When will data be available (start and end dates)?
Data available 3 months following publication, for an indefinite period
Available to whom?
Data are potentially available to:
• Researchers from not-for-profit organisations
• Commercial organisations
• Other
Based in:
• Any location
Further information:
All data requests will be considered by the primary sponsor on a case by case basis. Requests must include a methodologically sound proposal. Specific conditions of use may apply and will be specified in a data sharing agreement (or similar) that the requester must agree to before access is granted.
Available for what types of analyses?
Any type of analysis
Assessed on a case-by-case basis
How or where can data be obtained?
Access can be requested via the Health Data Australia catalogue (https://researchdata.edu.au/health/). Search for the ACTRN number in the catalogue to find datasets associated with this trial or email enquiries to [email protected]


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
23761Study protocol  [email protected] Access can be requested via the Health Data Austra... [More Details]



Results publications and other study-related documents

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