A prospective, multicenter, phase-II trial of ibrutinib plus venetoclax in physically fit patients with creatinine clearance ≥ 30 ml/min who have relapsed or refractory chronic lymphocytic leukemia (RR-CLL) with or without TP53 aberrations, HOVON 141 CLL / VIsion Trial of the HOVON and Nordic CLL study groups

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] - Neoplasms [C04], Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

10 Jul 2017 → 17 Dec 2025

Decision date (initial)

2024-07-11

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Janssen · AbbVie

External identifiers

EU CT number

2023-510557-42-00

EudraCT number

2016-002599-29

ClinicalTrials.gov

NCT03226301

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Therapy, Safety

Evaluate efficacy of ibrutinib + venetoclax (VI) in terms of proportion of patients fulfilling the criteria for progression free survival (PFS) at 12 months after stopping therapy (27 months after starting treatment) for patients randomized to stop treatment (arm B of the study), reinitiated treatment due to MRD positivity not considered progression

Secondary objectives 11

1. Evaluation of the efficacy in terms of minimal residual disease (MRD) at 12 months after stopping treatment (month 27)
2. Evaluation of efficacy in terms of PFS (IWCLL criteria)
3. Time to and number of patients reinitiating treatment
4. Time to treatment failure after reinitiated treatment
5. Time to next CLL treatment
6. MRD after cycle 12 (PB), at day 15 of cycle 15 (PB and BM) and at later time points in PB
7. Overall Survival (OS)
8. Complete response (CR)/ Partial Response (PR)/ Stable disease (SD) after cycle 3, 9, 12, 15, and at month 27 and month 51 (3 years after stopping treatment)
9. Duration of response
10. To evaluate safety with regards to type, frequency, and severity of adverse events (AEs) and adverse events of special interest (AESI) and their relationship to study treatment.
11. To evaluate patient related outcomes, measured in terms of health-related quality of life (QoL) by EORTC QLQ-C30 and QLQ-CLL16 questionnaires.

Conditions and MedDRA coding

chronic lymphocytic leukemia

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. Documented relapsed/refractory CLL or SLL requiring treatment according to IWCLL criteria (no limits on previous treatment lines; CD20 and steroids are not considered prior therapy lines)
2. Age at least 18 years
3. Adequate bone marrow function, unless directly attributable to CLL infiltration of the bone marrow, proven by bone marrow biopsy
4. Creatinine clearance (CrCL) ≥ 30ml/min calculated according to the modified formula of Cockcroft and Gault or directly measured with 24hr urine collection.
5. Adequate liver function as indicated
6. Negative serological testing for hepatitis B (HBsAg negative and anti-HBc negative; patients positive for anti-HBc may be included if PCR for HBV DNA is negative and HBV-DNA PCR is performed every month until 12 months after last dose), negative testing for hepatitis C RNA within 42 days prior to registration
7. Male and female subjects of reproductive potential must agree to use both a highly effective method of birth control and a barrier method during the period of therapy and for 90 days after the last dose of study drug.
8. Negative pregnancy test at study entry (for women of childbearing potential)
9. WHO/ECOG performance status 0-3 stage 3 only if attributable to CLL
10. Ability and willingness to provide written informed consent and to adhere to the study visit schedule and other protocol requirements
11. Written informed consent

Exclusion criteria 15

1. Any prior therapy with ibrutinib and/or venetoclax
2. Transformation of CLL (Richter’s transformation)
3. Patients with a history of confirmed progressive multifocal leukoencephalopathy (PML)
4. Malignancies other than CLL currently requiring systemic therapies or not being treated in curative intention before or showing signs of progression after curative treatment
5. Known allergy to xanthine oxidase inhibitors and/or rasburicase if no other appropriate prevention of tumorlysis is considered feasible by the treating physician
6. Known bleeding disorders (e.g., von Willebrand’s disease or hemophilia)
7. Uncontrolled or active infection
8. Patients requiring treatment with a strong cytochrome P450 (CYP) 3A inhibitor or anticoagulant therapy with warfarin or phenoprocoumon or other vitamin K antagonists. Please note: Patients being treated with NOACs can be included, but must be properly informed about the potential risk of bleeding under treatment with ibrutinib
9. History of stroke or intracranial hemorrhage within 6 months prior to registration
10. Major surgery within 28 days prior to registration
11. Use of investigational agents which might interfere with the study drug within 28 days prior to registration
12. Vaccination with live vaccines within 28 days prior to registration
13. Steroid therapy within 7 days prior to registration, with the exception of inhaled steroids for asthma, topical steroids, steroids up to 25 mg of prednisolone daily to control autoimmune phenomenon’s, or replacement/stress corticosteroids
14. Pregnant women and nursing mothers
15. 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. Proportion of patients fulfilling the criteria for progression free survival (PFS) at 12 months after stopping therapy for patients randomized to stop treatment. In this trial, reinitiated treatment due to MRD positivity will not be considered as progression, and symptomatic CLL according to IWCLL criteria within 12 months after randomization followed by reinitiation treatment resulting in a response before or at 12 months after randomization will neither be considered as progression

Secondary endpoints 16

1. Minimal residual disease (MRD) at 12 months after stopping treatment (month 27) for patients randomized to stop of treatment
2. PFS of all study groups
3. Time to and number of patients reinitiating treatment
4. Time to treatment failure after reinitiated treatment
5. Time to next CLL treatment
6. MRD after cycle 12 (PB), at day 15 of cycle 15 (PB and BM) and at later time points in PB
7. Overall survival (OS)
8. Complete response (CR)/ Partial Response (PR)/ Stable disease (SD) after cycle 3, 9, 12, 15 and month 27 and month 51 (3 years after stopping treatment)
9. Duration of response
10. Safety parameters: Type, frequency, and severity of adverse events (AEs) and adverse events of special interest (AESI) and their relationship to study treatment
11. Health-related quality of life (QoL) by EORTC QLQ-C30 and QLQ-CLL16 questionnaires
12. Exploratory endpoint: Evaluation of relationship between various baseline markers and clinical outcome parameters
13. Exploratory endpoint: Various markers at time of progression
14. Exploratory endpoint: Correlation between MRD in BM and PB
15. Exploratory endpoint: Correlation between MRD in BM and PFS/OS
16. Exploratory endpoint: Correlation between MRD in PB and PFS/OS

Investigational products

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

Test 4

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. A.P. Kater

Public contact point

Organisation

Hemato-Oncologie voor Volwassenen Nederland (Hovon) Stichting

Contact name

HOVON

Third parties 6

Locations

6 EU/EEA countries · 43 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

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