Treatment of chronic lymphocytic leukaemia with venetoclax and acalabrutinib in case of return of the disease after previous treatment with venetoclax in combination with immune therapy.

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Haemato Oncology Foundation For Adults Netherlands

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

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

Trial duration

23 Jul 2020 → ongoing

Decision date (initial)

2024-11-14

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

AbbVie B.V. · Acerta

External identifiers

EU CT number

2023-505449-18-00

EudraCT number

2019-004337-17

ClinicalTrials.gov

NCT04523428

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety, Therapy

To evaluate efficacy of acalabrutinib/venetoclax (AV) in terms of undetectable minimal residual disease (uMRD) response in bone marrow (BM) after 26 cycles of treatment in patients with CLL previously treated with venetoclax and anti-CD20 mAb.

Secondary objectives 7

1. To evaluate the efficacy of AV
2. To evaluate the safety and tolerability of AV
3. Exploratory: To evaluate value of different techniques for MRD testing
4. Exploratory: De impact op de immunologische functie van AV evalueren
5. Exploratory: To evaluate grading for hematological toxicity. according to International Workshop on Chronic Lymphocytic Leukemia (IWCLL) by assessing lab values
6. Exploratory: To evaluate quality of life (QoL) with AV
7. Exploratory: To asses impact on venetoclax pharmacokinetics (PK) in combination with acalabrutinib

Conditions and MedDRA coding

Patients with relapsed CLL

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. 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
2. WHO/ECOG performance status 0-3), stage 3 only if attributable to CLL
3. Age at least 18 years
4. 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
5. Estimated Glomerular Filtration Rate (eGFR) (MDRD) or estimated creatinine clearance (CrCl) ≥ 30ml/min (Cockcroft-Gault)
6. 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)
7. Prothrombin time (PT)/International normal ratio (INR) <1.5 x ULN and activated partial thromboplastin time (aPTT) <1.5 x ULN
8. 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
9. Patient is able and willing to adhere to the study visit schedule and other protocol requirements
10. Patient is capable of giving informed consent
11. Written informed consent

Exclusion criteria 26

1. Any prior therapy with BTK inhibitor
2. Prior treatment with venetoclax other than first line
3. Other therapy with exception of chemo-/immunotherapy which is allowed also after venetoclax first line relapse
4. Transformation of CLL (Richter’s transformation)
5. Patient with a history of confirmed progressive multifocal leukoencephalopathy (PML)
6. Malignancies other than CLL currently requiring systemic therapy or not treated in curative intention or showing signs of progression after curative treatment
7. Known allergy to xanthine oxidase inhibitors and/or rasburicase
8. History of drug-specific hypersensitivity or anaphylaxis to any study drug (including active product or excipient components)
9. Active bleeding or history of bleeding diathesis (e.g. hemophilia or von Willebrand disease)
10. Active fungal, bacterial, and/or viral infection that requires systemic therapy
11. Concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled: infection, auto-immune hemolysis, immune thrombocytopenia, diabetes, hypertension, hyperthyroidism or hypothyroidism etc.)
12. Patient known to be HIV-positive
13. 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
14. History of stroke or intracranial hemorrhage within 6 months prior to registration
15. Severe cardiovascular disease (arrhythmias requiring chronic treatment, congestive heart failure or symptomatic ischemic heart disease, myocardial infarction within 6 months) (CTCAE grade III-IV)
16. Severe pulmonary dysfunction (CTCAE grade III-IV)
17. Severe neurological or psychiatric disease (CTCAE grade III-IV)
18. Patient who has difficulty with or are unable to swallow oral medication, or have significant gastrointestinal disease that would limit absorption of oral medication
19. Vaccination with live vaccines within 28 days prior to registration
20. Use of any other experimental drug or therapy within 28 days of registration
21. Major surgery within 28 days prior to registration
22. 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
23. Pregnant women and nursing mothers
24. 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 during study treatment and for 30 days after end of treatment
25. Current participation in other clinical trial (other than follow up HOVON139/HOVON140)
26. Any psychological, familial, sociological and geographical condition potentially hampering compliance with the study protocol and follow-up schedule

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. uMRD in bone marrow (BM) by flow cytometry after 26 cycles

Secondary endpoints 12

1. Depth of MRD measured in BM after cycle 13 and 26
2. Depth of MRD measured in PB after cycle 8, 10, 13, 16, 19, 22, 26 and every 3-6 months thereafter
3. Best overall response rate (ORR) defined as the proportion of subjects with a complete response (CR), complete response with incomplete marrow recovery (CRi), or partial response (PR) according to IWCLL 2018 criteria
4. Progression free survival (PFS), defined as time from registration to the first occurrence of disease progression or death from any cause (whichever occurs first).
5. Event free survival (EFS), defined as time from registration to date start of first CLL treatment off protocol, progression or death, whichever comes first
6. Overall survival (OS), defined as the time from registration to death from any cause
7. Treatment free interval (TFI), defined as date of last protocol treatment to start date of first CLL treatment off protocol, or death from any cause whichever comes first
8. Incidence and severity of AEs, with severity determined according to NCI CTCAE v5.0
9. Exploratory: Depth of MRD by different techniques (flow cytometry, circulating tumor DNA (ctDNA), next-generation sequencing)
10. Exploratory: TruCulture and flow cytometry for immune subsets and function
11. Exploratory: Grading of hematological toxicity according to IWCLL20
12. Exloratory: Disease-related symptoms and health-related quality of life (HRQoL) measured by following questionnaires: EORTC QLQ-C30, EORTC QLQCLL17 and PRO-CTCAE

Investigational products

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

Test 4

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Haemato Oncology Foundation For Adults Netherlands

Sponsor organisation

Haemato Oncology Foundation For Adults Netherlands

Address

S Gravendijkwal 230

City

Rotterdam

Postcode

3015 CE

Country

Netherlands

Scientific contact point

Organisation

Haemato Oncology Foundation For Adults Netherlands

Contact name

A.P. Kater

Public contact point

Organisation

Haemato Oncology Foundation For Adults Netherlands

Contact name

HOVON

Third parties 2

Locations

3 EU/EEA countries · 20 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

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

Documents 39 files

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

Application history

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