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Clinical picture: CLL (Chronical Lymfatic Leukemia)

Trial: HOVON 141 CLL


News
1. Overview
2. Patient eligibility criteria
3. Registration (& randomization) of patients
4. Participating parties
5. Participating sites
6. Instruction videos
7. Download documentation / forms


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News


HO141 approval

20JUL2017: The study has been approved by EC, CA and the Biobank Committee in the Netherlands. All sites have been informed and may start with the local submission.

10JUL2017: The study has been approved in Denmark and the first site will open shortly.

The Netherlands is still awaiting approval from the Biobank Committee. As soon as we receive approval, the ITF will be sent to the sites.


1. Overview



Summary

A prospective, multicenter, phase-II trial of ibrutinib plus venetoclax in physically fit (CIRS ≤ 6) and unfit (CIRS > 6) patients with creatinine clearance ≥ 30 ml/min who have relapsed or refractory chronic lymphocytic leukemia (RR-CLL) with or without TP53 aberrations


Status

open


Members

HOVON, Nordic CLL Group


Type of study

Prospective randomized Phase II study


Echelon level

Level D


Type of monitoring for this study

Site evaluation visits


Target number of patients

208


Current number of patients

14


Date of activation

10-Jul-2017


Study objectives

The primary objective:
Evaluate efficacy of ibrutinib + venetoclax (VI) in terms of progression free survival (PFS, reinitiated treatment not considered progression) 12 months after stopping treatment for patients achieving MRD negativity at 12 and 15 months in previously treated patients with CLL.

Secondary objectives:
Evaluation of the efficacy in terms of MRD at 12 months after stopping treatment (month 27)
Evalution of efficacy in terms of PFS (IWCLL criteria)
number of patients reinitiating treatment, time to treatment failure after reinitiated treatment, time to next treatment, MRD month 12 (PB) and 15 (PB and BM) and at later time points in PB, QoL, OS, CR/PR/SD at month 3, 9, 12, 15, 27 and end of study
– all secondary endpoints for patients MRD negative randomized to stopping treatment at 15 months, patients randomized to ibrutinib maintenance and patients MRD positive at month 12/15 continuing on ibrutinib maintenance.
– To evaluatie 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.
– To evaluate patient related outcomes, measured in terms of health-related quality of life by EORTC QLQ-C30 and QLQ-CLL17 questionnaires.


2. Patient eligibility criteria



Inclusion criteria

Documented CLL or SLL requiring treatment according to IWCLL criteria after either being refractory to first line therapy or relapse after initial therapy.
Age at least 18 years.
Adequate hematologic function independent of transfusion and growth factor support for at least 7 days prior to screening defined as:
Absolute neutrophil count (ANC) >750/µL (750 cells/mm3 or 0.75 x 109/L)
Platelet count >30,000 /µL (30,000 cells/mm3 or 30 x 109/L).
Hemoglobin >8.0 g/dL (5 mmol/L)
Unless directly attributable to CLL infiltration of the bone marrow, proven by bone marrow biopsy
Creatinine clearance ≥ 30ml/min calculated according to the modified formula of Cockcroft and Gault or directly measured with 24hr urine collection.
Adequate liver function as indicated
Serum aspartate transaminase (AST) or alanine transaminase (ALT) ≤ 3.0 x upper limit of normal (ULN)
Bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin)
Prothrombin time (PT)/International normal ratio (INR) <1.5 x upper limit of normal (ULN) and PTT (activated partial thromboplastin time [aPTT]) <1.5 x ULN (unless abnormalities are unrelated to coagulopathy or bleeding disorder).
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 6 weeks prior to registration.
ECOG/ WHO performance status 0-3 (appendix C).
Negative pregnancy test at study entry (for women of childbearing potential).
Male and female subjects of reproductive potential must agree to use both a highly effective method of birth control (eg, implants, injectables, combined oral contraceptives, some intrauterine devices [IUDs], complete abstinence , or sterilized partner) and a barrier method (eg, condoms, cervical ring, sponge, etc) during the period of therapy and for 90 days after the last dose of study drug.
Ability and willingness to provide written informed consent and to adhere to the study visit schedule and other protocol requirements.
Written informed consent.


Exclusion criteria

Any prior therapy with ibrutinib and/or venetoclax.
Transformation of CLL (Richter’s transformation).
Patients with a history of confirmed PML.
Malignancies other than CLL currently requiring systemic therapies or not being treated in curative intention before or showing signs of progression after curative treatment.
Known allergy to xanthine oxidase inhibitors and/or rasburicase.
Known bleeding disorders (eg, von Willebrand’s disease or hemophilia).
Uncontrolled or active infection.
Requires treatment with a strong cytochrome P450 (CYP) 3A inhibitor (see Appendix X).
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.
History of stroke or intracranial hemorrhage within 6 months prior to randomization.
Major surgery within 4 weeks of first dose of study drug.
Use of investigational agents which might interfere with the study drug within 28 days prior to registration.
Vaccination with live vaccines within 28 days prior to registration
Pregnant women and nursing mothers.
Any psychological, familial, sociological and geographical condition potentially hampering compliance with the study protocol and follow-up schedule.


3. Registration (& randomization) of patients



Registration

Eligible patients should be registered before start of treatment. Patients need to be registered at the HOVON Data Center by one of the following options:
Trial Online Process (TOP, https://www.hdc.hovon.nl/top). A logon to TOP can be requested at the HOVON Data Center for participants.
By faxing the completed registration/randomization CRF +31.10.7041028 Monday through Friday, from 09:00 to 17:00 CET
By phone +31.10.7041560 Monday through Friday, from 09:00 to 17:00 CET


Registration criteria

The following information will be requested:



♦ Protocol number
♦ Institution name
♦ Name of caller/responsible investigator
♦ Local patient code (optional)
♦ Sex
♦ Year of birth
♦ Date written informed consent
♦ Specific items patient gives consent for (see ICF)
♦ Eligibility criteria


4. Participating parties



Principal Investigator(s)

Dhr. Dr. A.P. Kater (AMC)


Co-Investigator(s)

Mw. Dr. S. Kersting (Hagaziekenhuis, locatie Leyweg)
Dhr. Dr. M.D. Levin (A. Schweitzer ZH, Dordwijk)


Coordinating Investigator(s)

Dr. M. Mattsson (Uppsala Akademiska Sjukhuset)
Dr. C. Niemann (Rigshospitalet Copenhagen)
Dr. T. Salmi (Turku University Central Hospital)
Dr. H.T.T. Tran (Akershus University Hospital)


Statistician(s)

Dhr. K. Nasserinejad (Erasmus MC - Centrum)


Monitor - Site Evaluation Visits

MonitorTeamCTC (Erasmus MC - Daniel)


Other functions

Central Coordinator - MRD - CLLlabAmsterdam (AMC)
Central Coordinator - MRD - CLLlabCopenhagen (Rigshospitalet Copenhagen)
Central Coordinator - MRD - Dhr. J. Dobber (AMC)
Central Coordinator - MRD - J. Dubois (AMC)
Central Coordinator - MRD - Ms. B. Gall (Rigshospitalet Copenhagen)
Central Coordinator - MRD - Ms. T. Hahn Enevoldsen (Rigshospitalet Copenhagen)
Central Coordinator - MRD - Trialbureau Hematologie AMC (AMC)


Principal investigator

Dr. A.P. Kater (a.p.kater@amc.uva.nl)
Dr. C. Utoft-Niemann (carsten.utoft.niemann@regionh.dk)


Coordinating investigator(s)

Dr. M.D. Levin (m-d.levin@asz.nl)
Dr. M. Mattsson (mattias.mattsson@akademiska.se)


Statistician(s)

K. Nasserinejad (k.nasserinejad@erasmusmc.nl)


Trial manager

Rebecca Roach (r.roach@erasmusmc.nl)


Central data management

Rene Hollestein (r.hollestein@erasmusmc.nl)


5. Participating sites



Site
Included patients *
BE-Leuven-UZ Gasthuisberg
2
DK-Copenhagen-Rigshospitalet Copenhagen
5
NL-Amsterdam-AMC
7
NL-Utrecht-UMCU
0

* Please note that if TOP is not used to register patients for a study, the number of patients shown is zero.

6. Instruction videos



7. Download documentation / forms


 Protocol

 Patient Information & IC form (NL)



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