HO182 CLL: Treatment of patients with chronic lymphocytic leukemia (CLL) with 6 cycles of rituximab in combination with 6 or 26 cycles of venetoclax upon recurrence of the disease after previous treatment

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Hemato-Oncologie voor Volwassenen Nederland (Hovon) Stichting

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15]

Decision date (initial)

2026-06-08

Transition trial

No

Low-intervention

Yes

Rare-disease indication

No

Vulnerable population

No

Funding sources

Treatmeds · ZonMw

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Safety, Efficacy, Pharmacoeconomic

To compare progression free survival (PFS) from the time of randomization between continuation of treatment with venetoclax for 20 cycles (Arm A) versus discontinuation of treatment (Arm B), in patients treated with 6 cycles Ven-R.

Secondary objectives 10

1. To evaluate overall response rate (ORR).
2. To evaluate overall survival (OS).
3. To evaluate event free survival (EFS).
4. To evaluate time to next treatment (TTNT).
5. To evaluate overall response rate to next line treatment (ORR2).
6. To evaluate second progression free survival after next line treatment (PFS2).
7. To evaluate depth and kinetics of response by measuring minimal residual disease (MRD).
8. To compare safety and tolerability between continuation of treatment with venetoclax for 20 cycles (arm A) versus discontinuation of treatment (arm B), in patients treated with 6 cycles Ven-R.
9. To evaluate quality of life (QoL).
10. To calculate the budget impact of cessation of venetoclax after 6 months versus continuation until 24 months.

Conditions and MedDRA coding

Relapsed or refractory chronic lymphocytic leukemia

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

1. Documented relapsed or refractory CLL or SLL following at least one systemic 1st-line treatment.
2. Requiring treatment according to IWCLL 2018 criteria.
3. Age at least 18 years.
4. WHO performance status 0-3; stage 3 only if attributable to CLL/SLL.
5. Adequate BM function defined as:  Hemoglobin (Hb) > 5.0 mmol/l, unless low Hb is directly attributable to CLL/SLL infiltration of the BM;  Absolute neutrophil count (ANC) > 0.75 x 109/L (1,000/μL), unless low ANC is directly attributable to CLL/SLL infiltration of the BM;  Platelet count > 30 x 109/L (30,000/μL), unless low platelets is directly attributable to CLL/SLL infiltration in the BM.
6. Estimated Glomerular Filtration Rate (eGFR) (MDRD) or estimated creatinine clearance (CrCl) ≥ 30ml/min (Cockcroft-Gault).
7. Adequate liver function as indicated:  serum aspartate transaminase (ASAT) and alanine transaminase (ALAT) ≤ 3.0 x upper limit of normal (ULN); bilirubin ≤ 1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or controlled autoimmune hemolytic anemia).
8. Negative serological testing for hepatitis B virus (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, HBsAg, or hepatitis C antibody must have a negative PCR result before enrollment. Those who are PCR positive will be excluded.
9. IGHV mutation status assessed at least once.
10. TP53 mutation status tested after last treatment.
11. Del17p mutation status tested after last treatment.
12. Patient is able and willing to adhere to the study visit schedule and other protocol requirements.
13. Written informed consent.
14. Patient is capable of giving informed consent.

Exclusion criteria 20

1. Transformation of CLL (Richter’s transformation).
2. Severe neurological or psychiatric disease (CTCAE grade III-IV).
3. Patient with Child Pugh C.
4. Concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled diabetes, infection, hypertension, etc.).
5. Patient known to be HIV-positive.
6. Patient who has difficulty with or are unable to swallow oral medication, or have significant gastrointestinal disease that would limit absorption of oral medication.
7. Pregnant women and nursing mothers.
8. Fertile men or women of childbearing potential unless: (1) surgically sterile or ≥ 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 30 days after last dose of venetoclax and/or 12 months after the last dose of rituximab.
9. Previous participation in the HO139 CLL or HO140 CLL trial, and eligible for and willingness to participate in the HO159 CLL trial.
10. Active treatment with anti-neoplastic drugs in another clinical trial.
11. Any psychological, familial, sociological and geographical condition potentially hampering compliance with the study protocol and follow-up schedule.
12. Patient received prior venetoclax treatment within 24 months of registration OR patient had progressed during previous venetoclax treatment.
13. Patient with central nervous system involvement.
14. Malignancies other than CLL/SLL currently requiring systemic therapy, not treated with curative intent, or showing signs of progression after curative treatment.
15. Patient with a history of confirmed progressive multifocal leukoencephalopathy (PML).
16. Known allergy to xanthine oxidase inhibitors and/or rasburicase.
17. History of drug-specific hypersensitivity or anaphylaxis to any study drug.
18. Severe cardiovascular disease (arrhythmias requiring chronic treatment, congestive heart failure or symptomatic ischemic heart disease) (CTCAE grade III-IV).
19. Severe pulmonary dysfunction (CTCAE grade III-IV).
20. Active fungal, bacterial, and/or viral infection that requires systemic therapy.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. PFS, defined as the time from randomization to the first occurrence of disease progression or death due to any cause, whichever occurs first.

Secondary endpoints 9

1. ORR, defined as the proportion of patients with a complete response (CR), complete response with incomplete marrow recovery (CRi), or partial response (PR) according to IWCLL 2018 criteria.
2. OS, defined as the time from randomization to death due to any cause. Patients still alive at date of last contact will be censored.
3. EFS, defined as time from randomization to progression, death or premature cessation of venetoclax due to toxicity, whichever comes first.
4. TTNT, defined as time from randomization to start of next new line of CLL treatment.
5. ORR2, defined as the proportion of patients with a complete response (CR), complete response with incomplete marrow recovery (CRi), or partial response (PR) according to IWCLL 2018 criteria after next line of treatment.
6. PFS2, time from randomization to the earliest occurrence of either second disease progression or death from any cause, following the initiation of the next line of treatment.
7. Depth (level) of MRD based on flow cytometry measured in peripheral blood at baseline, randomization and week 84 after randomization.
8. Type, frequency, and severity of AEs and their relationship to study treatment (determined according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v6.0).
9. Health-related quality of life (QoL) as assessed by EORTC QLQ-C30, QLQ-CLL17 and PRO-CTCAE questionnaires.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Hemato-Oncologie voor Volwassenen Nederland (Hovon) Stichting

Sponsor organisation

Hemato-Oncologie voor Volwassenen Nederland (Hovon) Stichting

Address

Dr. Molewaterplein 40

City

Rotterdam

Postcode

3015 GD

Country

Netherlands

Scientific contact point

Organisation

Hemato-Oncologie voor Volwassenen Nederland (Hovon) Stichting

Contact name

Dr. R. Mous

Public contact point

Organisation

Hemato-Oncologie voor Volwassenen Nederland (Hovon) Stichting

Contact name

Dr. M.C. Breems-de Ridder

Third parties 1

Locations

1 EU/EEA country · 35 investigational sites

By country

Investigational sites

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 11 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications