Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12625000732482
Ethics application status
Approved
Date submitted
3/06/2025
Date registered
9/07/2025
Date last updated
9/07/2025
Date data sharing statement initially provided
9/07/2025
Type of registration
Prospectively registered

Titles & IDs
Public title
CLL12 - An ALLG phase II trial of venetoclax treatment with epcoritamab in patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma
Scientific title
CLL12 - An ALLG phase II trial of venetoclax treatment (26 cycles) with 6 cycles or 12 cycles of epcoritamab in patients with relapsed or refractory chronic lymphocytic leukemia or small lymphocytic lymphoma
Secondary ID [1] 314558 0
Eu CT Number: 2022-500305-40
Universal Trial Number (UTN)
Trial acronym
AETHER trial (ABT199 + Epcoritamab THErapy for Relapsed/refractory CLL/SLL)
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Chronic Lymphocytic Leukemia 337659 0
small lymphocytic lymphoma 337660 0
Condition category
Condition code
Cancer 333992 333992 0 0
Leukaemia - Chronic leukaemia

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Epcoritamab is supplied as a concentrate for solution for intended subcutaneous injection.

Venetoclax will be administered orally once a day. The initial venetoclax dose is 20 mg. After one week, it increases to 50 mg, then to 100 mg, 200 mg, and finally 400 mg, each after one week.. After venetoclax ramp-up of up to 35 days, all patients will receive 26 cycles of venetoclax. Each cycle has a duration of 28 days. All patients will commence treatment with epcoritamab after completion of the venetoclax ramp-up phase.

Epcoritamab will be administered as a subcutaneous injection over a period of 6 (Arm 1) or 12 (Arm 2) cycles, with each cycle lasting 28 days at a consistent assigned dose level. All patients will be treated with epcoritamab weekly during cycle 1-3. Patients in Arm 1 will be dosed biweekly during cycle 4-6, while patients in Arm 2 will be dosed biweekly during cycle 4-9 and every 4 weeks during cycles 10-12.

All treatment will be administered by the study team. Drug accountability will be performed by the administering institutions to assess compliance.

The approximate duration of study participation for patients is a maximum of 5 years (1 year treatment, 4 years follow up)
Intervention code [1] 331183 0
Treatment: Drugs
Comparator / control treatment
Venetoclax treatment in combination with either 6 cycles of epcoritamab (Arm 1), which serves as the control arm, compared with 12 cycles of epcoritamab in combination with venetoclax (Arm 2).
Control group
Dose comparison

Outcomes
Primary outcome [1] 341655 0
Undetectable minimal residual disease less than 10^-4 (uMRD4) in the bone marrow (BM) in absence of progression according to the International Workshop on CLL (IWCLL) criteria
Timepoint [1] 341655 0
Day 28 of cycle 26.
Secondary outcome [1] 448216 0
To evaluate the efficacy of epcoritamab in combination with venetoclax in terms of MRD depth in peripheral blood (PB),
Timepoint [1] 448216 0
Cycle 4, 6, 9, 12, 15, 18, 21, 24 and 12 weeks after day 28 of cycle 26; following treatment: every 3 months for the first year, then every 6 months until relapse or until 6 years after randomization.
Secondary outcome [2] 448217 0
Progression Free Survival (PFS)
Timepoint [2] 448217 0
Time from randomization to the first occurrence of disease progression or death from any cause, whichever occurs first.
Secondary outcome [3] 448218 0
Overall survival (OS)
Timepoint [3] 448218 0
The time from randomization to death from any cause. Up to 6 years after randomization.
Secondary outcome [4] 448219 0
Event Free Survival (EFS)
Timepoint [4] 448219 0
Time from randomization to date of start of next treatment, progression or death, whichever comes first. Up to 6 years after randomization.
Secondary outcome [5] 448220 0
Overall response rate (ORR)
Timepoint [5] 448220 0
Proportion of patients with a complete response (CR), complete response with incomplete marrow recovery (CRi), or partial response (PR) according to IWCLL 2018 criteria. MRD measured in BM at cycle 9 and 12 weeks after day 29 of cycle 26. MRD measured in PB at cycle 4, 6, 9, 12, 15, 18, 21, 24 and 12 weeks after day 28 of cycle 26; following treatment: every 3 months for the first year, then every 6 months until relapse or until 6 years after randomization.
Secondary outcome [6] 448221 0
Time to next treatment (TTNT)
Timepoint [6] 448221 0
Time from randomization to next new line of treatment until 6 years after randomization.
Secondary outcome [7] 448222 0
Treatment Free Survival (TFS)
Timepoint [7] 448222 0
Time from date of last protocol treatment to date start of next (new) line of treatment, or death from any cause, whichever comes first. Up to 6 years after randomization.
Secondary outcome [8] 448223 0
To evaluate the safety and tolerability of epcoritamab in combination with venetoclax.
Timepoint [8] 448223 0
Baseline to 6 years after randomisation. Following treatment, patients will be assessed every 3 months for the first year, then every 6 months until relapse or until 6 years after randomization.
Secondary outcome [9] 448224 0
To evaluate quality of life (QoL) with epcoritamab in combination with venetoclax.
Timepoint [9] 448224 0
Within 42 days before registration, after registration. and annually until 6 years after registration or until progression, whichever comes first

Eligibility
Key inclusion criteria
-Documented relapsed or refractory CLL or SLL (SLL in phase II part only) following at least one systemic 1st-line treatment
-Requiring treatment according to IWCLL criteria
-Age at least 18 years;
-ECOG/WHO performance status 0-2;
-In case of prior venetoclax treatment, enrollment can only occur at least 24 months after end of treatment and patients must not have progressed during venetoclax treatment;
- Adequate BM function defined as:
- Hemoglobin higher than 5.6 mmol/l or Hb higher than 9 g/dL, unless low Hb is directly attributable to CLL/SLL infiltration of the BM, proven by BM biopsy;
-Absolute neutrophil count (ANC) higher than 1.0 x 109/L (1,000/µL), unless low ANC is directly attributable to CLL/SLL infiltration of the BM, proven by BM biopsy;
- Platelet count higher than 30 x 109/L (30,000/µL), unless low platelets is directly attributable to CLL/SLL infiltration in the BM;
- Estimated Glomerular Filtration Rate (eGFR) (MDRD) or estimated creatinine clearance (CrCl) higher or equal to 50ml/min (Cockcroft-Gault);
- Adequate liver function as indicated:
- Serum aspartate transaminase (ASAT) and alanine transaminase (ALAT) lower or equal to 3.0 x upper limit of normal (ULN);
- Bilirubin lower or equal to 1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or controlled autoimmune hemolytic anemia);
- Prothrombin time (PT)/International normal ratio (INR) <1.5x ULN and activated partial thromboplastin time (aPTT) lower than 1.5 x ULN; unless receiving anticoagulation;
- Negative serological testing for hepatitis B virus (HBV) (Hepatitis B surface antigen (HBsAg) negative and hepatitis B core antibody (anti-HBc) negative) and hepatitis C virus (hepatitis C antibody). Patients who are positive for anti-HBc or hepatitis C antibody may be included if they have a negative PCR within 6 weeks before enrollment. Those who are PCR positive will be excluded;
Please note: For patients positive for anti-HBc or antibodies for hepatitis C, HBV-DNA or HCV-DNA PCR, respectively, has to be repeated every month until 12 months after last dose of study treatment;
- Patient is able and willing to adhere to the study visit schedule and other protocol requirements;
- Patient is capable of giving informed consent;
- Written informed consent.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
-Active CLL/SLL directed therapy within the last 14 days;
-Prior treatment with a CD3 × CD20 bispecific antibody or CAR T-cell therapy
- Transformation of CLL (Richter’s transformation);
- Prior allogeneic stem cell transplantation and/or solid organ transplantation;
- Patient with a history of confirmed progressive multifocal leukoencephalopathy (PML);
- Malignancies other than CLL/SLL currently requiring systemic therapy or not treated in curative intention or showing signs of progression after curative treatment;
- Known allergy to xanthine oxidase inhibitors and/or rasburicase;
- History of drug-specific hypersensitivity or anaphylaxis to any study drug (including active product or excipient components);
-Active bleeding or uncontrolled severe bleeding diathesis (e.g., hemophilia or severe von Willebrand disease);
-Active fungal, bacterial, and/or viral infection CTCAE grade higher than 1;
Please note: active controlled as well as chronic/recurrent infections are at risk of reactivation/infection during treatment;
- Concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled: infection, auto-immune hemolysis, immune thrombocytopenia, diabetes, hypertension, hyperthyroidism or hypothyroidism etc.);
- Patient known to be HIV-positive;
- Patient requiring treatment with a strong cytochrome P450 (CYP) 3A inhibitor/inducer;
-CTCAE grade III-IV cardiovascular disease including but not limited to:
- Unstable or uncontrolled disease/condition related to or affecting cardiac function, eg, unstable angina, congestive heart failure grade III or IV as classified by the New York Heart Association, uncontrolled clinically significant cardiac arrhythmia (CTCAE grade II or higher), or clinically significant electrocardiogram (ECG) abnormalities.
- Myocardial infarction within 6 months prior to registration.
- Subject age higher or equal to 75 and 2 or more active grade higher or equal to 2 cardiovascular conditions.
- Screening 12-lead ECG showing a baseline QT interval as corrected by Fridericia’s formula (QTcF) higher than 480 msec. NOTE: this criterion does not apply to subjects with a left bundle branch block.
- Stroke or intracranial hemorrhage within 6 months prior to registration.
-Severe pulmonary dysfunction (CTCAE grade III-IV);
-Severe neurological or psychiatric disease (CTCAE grade III-IV);
-Neuropathy greater than CTCAE grade II
-Patient who has difficulty with or are unable to swallow oral medication, or have significant gastrointestinal disease that would limit absorption of oral medication;
- Vaccination with live vaccines within 28 days prior to registration;
- Use of any other experimental drug or therapy within 28 days of registration;
- Major surgery within 28 days prior to registration;
-Pregnant women and nursing mothers;
-Fertile men or women of childbearing potential (WOCBP) unless: (1) surgically sterile or higher or equal to 2 years after the onset of menopause; (2) willing to use a highly effective contraceptive method such as oral contraceptives, intrauterine device or sexual abstinence during study treatment and for 12 months after last dose of epcoritamab and 30 days after last dose of venetoclax;
-Previous participation in the HO139 CLL or HO140 CLL trial and eligible for and willing to participate in the HO159 CLL trial;
-Current participation in other clinical trial with medicinal products;
-Any psychological, familial, sociological and geographical condition potentially hampering
compliance with the study protocol and follow-up schedule.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation concealment is achieved through a central online registration database. After registration by online, email, or by phone, each patient will immediately be given a unique patient study number.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomization will be performed by using random blocks. The block sizes will be chosen in such a way that the total number of 90 chronic lymphocytic leukemia (CLL) patients will be balanced across the two treatment groups at the end of the trial. In addition, separate blocks will be used for small lymphocytic lymphoma (SLL) patients so that the balance of CLL patients is guaranteed. A maximum of 10 SLL patients will be included. The target population is 100 participants: 90CLL + 10 SLL. Each patient will be given a unique patient study number (a sequence number by order of enrolment in the trial). Patient study number will be given immediately by the online registration database or phone and confirmed by email.
Masking / blinding
Who is / are masked / blinded?



Intervention assignment
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
30/11/2025
Actual
Date of last participant enrolment
Anticipated
30/11/2028
Actual
Date of last data collection
Anticipated
30/11/2034
Actual
Sample size
Target
100
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment outside Australia
Country [1] 27103 0
Netherlands
State/province [1] 27103 0
Country [2] 27104 0
Germany
State/province [2] 27104 0
Country [3] 27105 0
Denmark
State/province [3] 27105 0

Funding & Sponsors
Funding source category [1] 319106 0
Other Collaborative groups
Name [1] 319106 0
Australasian Leukaemia and Lymphoma Group
Country [1] 319106 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Australasian Leukaemia and Lymphoma Group
Address
Country
Australia
Secondary sponsor category [1] 321569 0
None
Name [1] 321569 0
Address [1] 321569 0
Country [1] 321569 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 317703 0
St Vincent's Hospital Melbourne Human Research Ethics Committee
Ethics committee address [1] 317703 0
Ethics committee country [1] 317703 0
Australia
Date submitted for ethics approval [1] 317703 0
Approval date [1] 317703 0
12/05/2025
Ethics approval number [1] 317703 0

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

Contacts
Principal investigator
Name 141866 0
Prof Stephen Opat
Address 141866 0
Monash Health 246 Clayton Road Clayton VIC 3168 Australia
Country 141866 0
Australia
Phone 141866 0
+61 03 9594 4366
Fax 141866 0
Email 141866 0
[email protected]
Contact person for public queries
Name 141867 0
Delaine Smith
Address 141867 0
ALLG 35 Elizabeth St Richmond Vic 3121
Country 141867 0
Australia
Phone 141867 0
+61 03 83739701
Fax 141867 0
Email 141867 0
[email protected]
Contact person for scientific queries
Name 141868 0
Delaine Smith
Address 141868 0
ALLG 35 Elizabeth St Richmond Vic 3121
Country 141868 0
Australia
Phone 141868 0
+61 03 83739701
Fax 141868 0
Email 141868 0
[email protected]

Data sharing statement
Will the study consider sharing individual participant data?
Yes
Will there be any conditions when requesting access to individual participant data?
Persons/groups eligible to request access:
• Researchers

• -Researchers from not-for-profit organisations
-Commercial organisations

Conditions for requesting access:
• 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 that the requester must agree to before access is granted.

What individual participant data might be shared?
• All de-identified individual participant data
What types of analyses could be done with individual participant data?
• Any type of analysis. Assessed on a case-by-case basis

When can requests for individual participant data be made (start and end dates)?
From:
Data available 3 months following publication

To:
No end date
Where can requests to access individual participant data be made, or data be obtained directly?
• 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]

Are there extra considerations when requesting access to individual participant data?
No


What supporting documents are/will be available?

TypeCitationLinkEmailOther DetailsAttachment
Study 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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Documents added automatically
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