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Retreatment with venetoclax and acalabrutinib for relapsed CLL

A Prospective, Multicenter, Phase-II Trial of Venetoclax Plus Acalabrutinib in Patients Who Have Relapsed After First Line Venetoclax + Anti-CD20 mAb Treatment for Chronic Lymphocytic Leukemia (CLL or SLL)

Phase 2 Interventional Stichting Hemato-Oncologie voor Volwassenen Nederland · NCT04523428

This study is testing if a new combination of venetoclax and acalabrutinib can help people with relapsed chronic lymphocytic leukemia (CLL) achieve better treatment results after their previous therapy.

Quick facts

PhasePhase 2
Study typeInterventional
Enrollment60 (estimated)
Ages18 Years and up
SexAll
SponsorStichting Hemato-Oncologie voor Volwassenen Nederland Academic / other
Drugs / interventionsrituximab, obinutuzumab, acalabrutinib, immunotherapy
Locations18 sites (Brussels and 17 other locations)
Trial IDNCT04523428 on ClinicalTrials.gov

What this trial studies

This study investigates the efficacy of a combination treatment using venetoclax and acalabrutinib for patients with chronic lymphocytic leukemia (CLL) who have previously received a fixed-duration regimen of venetoclax with a CD20 antibody and have relapsed. The goal is to determine if this novel combination can achieve undetectable minimal residual disease (uMRD) and allow for treatment discontinuation. Eligible participants must have documented CLL requiring treatment after an initial response to prior venetoclax-based therapy. The study aims to provide clinical data on the effectiveness of this retreatment strategy.

Who should consider this trial

Good fit: Ideal candidates are adults aged 18 and older with documented CLL or SLL who have relapsed after initial treatment with venetoclax and a CD20 antibody.

Not a fit: Patients who have not previously received venetoclax or those with CLL that does not require treatment may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment could offer a new option for patients with relapsed CLL, potentially leading to deeper remissions and reduced treatment duration.

How similar studies have performed: While the approach of retreating with venetoclax has not been formally proven, similar studies have shown promising results with venetoclax combinations in CLL treatment.

Eligibility criteria

Show full inclusion / exclusion criteria 
Inclusion Criteria:

* Documented CLL or SLL requiring treatment according to IWCLL criteria (appendix A) after at least (clinical) partial response as best response after the following initial study treatment: venetoclax-rituximab in HOVON 140/GAIA or venetoclax-obinutuzumab in HOVON 139/GIVE or HOVON 140/GAIA;
* WHO/ECOG performance status 0-3 (appendix C), stage 3 only if attributable to CLL
* Age at least 18 years;
* Adequate BM function defined as:

  * Hemoglobin \>5 mmol/l or Hb \> 8 g/dL
  * Absolute neutrophil count (ANC) \>0.75 x 109/L (750/μL), unless directly attributable to CLL infiltration of the BM, proven by BM biopsy
  * Platelet count \>30 x 109/L (30,000/μL) without transfusion and irrespective whether it is attributable to CLL infiltration in the BM;
* Estimated Glomerular Filtration Rate (eGFR) (MDRD) or estimated creatinine clearance (CrCl ≥ 30ml/min (Cockcroft-Gault appendix E); Please note: in case eGFR or CrCl is \<50ml/min the patient needs to be considered high risk for TLS
* 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 of nonhepatic origin);
* Prothrombin time (PT)/International normal ratio (INR) \<1.5 x ULN and activated partial thromboplastin time (aPTT) \<1.5 x ULN;
* 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). Subjects 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 HBV-DNA PCR 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.

Exclusion Criteria:

* Any prior therapy with BTK inhibitor;
* Prior treatment with venetoclax other than first line;
* Other therapy with exception of chemo-/immunotherapy which is allowed also after venetoclax first line relapse;
* Transformation of CLL (Richter's transformation);
* Patient with a history of confirmed progressive multifocal leukoencephalopathy (PML);
* Malignancies other than CLL 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 history of bleeding diathesis (e.g. hemophilia or von Willebrand disease);
* Active fungal, bacterial, and/or viral infection that requires systemic therapy; 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 (see appendix J) or anticoagulant therapy with warfarin or phenoprocoumon or other vitamin K antagonists; Please note: Patients being treated with DOACs apixaban, edoxaban or rivaroxaban can be included, but must be properly informed about the potential risk of bleeding under treatment with acalabrutinib. (see appendix J)
* History of stroke or intracranial hemorrhage within 6 months prior to registration;
* Severe cardiovascular disease (arrhythmias requiring chronic treatment, congestive heart failure or symptomatic ischemic heart disease, myocardial infarction within 6 months) (CTCAE grade III-IV, see appendix D);
* Severe pulmonary dysfunction (CTCAE grade III-IV, see appendix D);
* Severe neurological or psychiatric disease (CTCAE grade III-IV, see appendix D);
* 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;
* Steroid therapy within 10 days prior to registration, with the exception of inhaled steroids for asthma, topical steroids, steroids up to 20 mg or dose equivalents of prednisolone daily to control autoimmune phenomenon's, or replacement/stress corticosteroids;
* Pregnant women and nursing mothers;
* 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, sexual abstinence or combination of male condom with either cap, diaphragm, or sponge with spermicide (double barrier methods) during study treatment and for 30 days after end of treatment;
* Current participation in other clinical trial (other than follow up HOVON139/HOVON140);
* Any psychological, familial, sociological and geographical condition potentially hampering compliance with the study protocol and follow-up schedule.

Where this trial is running

Brussels and 17 other locations

Study contacts

How to participate

  1. Review the eligibility criteria above with your treating physician.
  2. Visit the official trial page on ClinicalTrials.gov for the most current contact information and recruitment status.
  3. Contact the listed study coordinator or principal investigator to request pre-screening. Pre-screening is free and never obligates you to enroll.
View on ClinicalTrials.gov → Find more trials like this →
Conditions CLL/SLL
Last reviewed 2026-06-13 by the Find a Trial editorial team. Information on this page is for educational purposes and is not medical advice. Always consult qualified healthcare professionals about clinical trial participation.