Clinical trial NCT03226301: A Prospective, Multicenter, Phase-II Trial of Ibrutinib Plus Venetoclax in Patients With Creatinine Clearance >= 30 ml/Min Who Have Relapsed or Refractory Chronic Lymphocytic Leukemia (RR-CLL) With or Without TP53 Aberrations
Official title: A Prospective, Multicenter, Phase-II Trial of Ibrutinib Plus Venetoclax in Patients With Creatinine Clearance >= 30 ml/Min Who Have Relapsed or Refractory Chronic Lymphocytic Leukemia (RR-CLL) With or Without TP53 Aberrations
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Chronic Lymphocytic Leukemia in Relapse
Chronic Lymphocytic Leukemia in Remission
Lead sponsor: Stichting Hemato-Oncologie voor Volwassenen Nederland
Sponsor class: OTHER
Collaborators: name: Nordic CLL Study Group
First posted: 2017-07-21
Enrollment: 230
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: All patients receive ibrutinib + venetoclax (with delayed start and ramp up of venetoclax from cycle 3) for the 15 cycles. Patients not achieving MRD negativity after cycle 12 (PB) AND/OR cycle 15 (PB+BM) continue on ibrutinib maintenance (non-randomized group). Patients achieving MRD negativity after cycle 12 (PB) AND cycle 15 (PB+BM) are randomized 1:2 between ibrutinib maintenance (arm A) and stopping treatment (observation, arm B).
Primary purpose: TREATMENT

Brief summary: The aim of the current trial is to evaluate if combination treatment with venetoclax + ibrutinib in patients with relapsed or refractory chronic lymphocytic leukemia (RR CLL) can lead to MRD negativity, which may induce long lasting remissions for MRD-negative patients randomized to stopping treatment after 15 induction cycles.


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 bone marrow function defined as:

    * Absolute neutrophil count (ANC) \>0.75 x 109/L
    * Platelet count \>30,000 /μL 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 (CrCL) ≥ 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 nonhepatic origin)
    * Prothrombin time (PT)/International normal ratio (INR) \<1.5 x ULN and PTT (activated partial thromboplastin time \[aPTT\]) \<1.5 x ULN (unless abnormalities are related 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 42 days prior to registration.
  * WHO/ECOG performance status 0-3 (appendix C), stage 3 only if attributable to CLL.
  * 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 (e.g. implants, injectables, combined oral contraceptives, some intrauterine devices \[IUDs\], complete abstinence , or sterilized partner) and a barrier method (e.g., 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 progressive multifocal leukoencephalopathy (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 (e.g., von Willebrand's disease or hemophilia).
* Uncontrolled or active infection.
* Patients requiring treatment with a strong cytochrome P450 (CYP) 3A inhibitor (see appendix K). 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 registration.
* Major surgery within 28 days prior to registration.
* 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
* 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.
* Pregnant women and nursing mothers.
* Any psychological, familial, sociological and geographical condition potentially hampering compliance with the study protocol and follow-up schedule.

Primary outcomes:
measure: Number of patients with progression free survival 27 months after starting treatment
timeFrame: 27 months after last patient in trial
Secondary outcomes:
measure: Number of patients with MRD negativity 27 months after starting treatment
timeFrame: 27 months after last patient in trial
measure: Number of patients with progression free survival
timeFrame: 7 years after last patient in
measure: Number of patients reinitiating treatment
timeFrame: 7 years after last patient in
measure: Number of patients with treatment failure after reinitiating treatment
timeFrame: 7 years after last patient in
measure: Number of patients initiating new CLL treatment
timeFrame: 7 years after last patient in
measure: Number of patients with MRD negativity 12 (peripheral blood) and 15 months (peripheral blood and bone marrow) after starting treatment
timeFrame: 15 months after last patient in trial
measure: Number of patients alive
timeFrame: 7 years after last patient in
measure: Number of patients with complete remission, partial remission and stable disease and the duration of remission for each group
timeFrame: 7 years after last patient in
measure: Number and grading of adverse events, serious adverse events and adverse events of special interest (bleeding, atrial fibrillation and tumorlysis)
timeFrame: 7 years after last patient in
measure: Number of patients with improved quality of life (by EORTC QLQ-C30 and QLQ-CLL16 questionnaires)
timeFrame: 51 months after last patient in trial
Other outcomes:
Locations:
city: Antwerpen
country: Belgium
facility: BE-Antwerpen-ZNASTUIVENBERG
city: Brugge
country: Belgium
facility: BE-Brugge-AZBRUGGE
city: Brussels
country: Belgium
facility: BE-Bruxelles-STLUC
city: Haine-Saint-Paul
country: Belgium
facility: BE-Haine-Saint-Paul-JOLIMONT
city: Leuven
country: Belgium
facility: BE-Leuven-UZLEUVEN
city: Aalborg
country: Denmark
facility: DK-Aalborg-AALBORGUH
city: Copenhagen
country: Denmark
facility: DK-Copenhagen-RIGSHOSPITALET
city: Herlev
country: Denmark
facility: DK-Herlev-HERLEV
city: Holstebro
country: Denmark
facility: DK-Holstebro-HOLSTEBRO
city: Odense
country: Denmark
facility: DK-Odense-OUH
city: Roskilde
country: Denmark
facility: DK-Roskilde-ROSKILDE
city: Helsinki
country: Finland
facility: FI-Helsinki-HUS
city: Jyväskylä
country: Finland
facility: FI-Jyvaskyla-KSSHP
city: Kuopio
country: Finland
facility: FI-Kuopio-KYS
city: Tampere
country: Finland
facility: FI-Tampere-TAYS
city: Turku
country: Finland
facility: FI-Turku-TYKS
city: Alkmaar
country: Netherlands
facility: NL-Alkmaar-NWZ
city: Amersfoort
country: Netherlands
facility: NL-Amersfoort-MEANDERMC
city: Amsterdam
country: Netherlands
facility: NL-Amsterdam-AMC
city: Amsterdam
country: Netherlands
facility: NL-Amsterdam-AVL
city: Amsterdam
country: Netherlands
facility: NL-Amsterdam-VUMC
city: Arnhem
country: Netherlands
facility: NL-Arnhem-RIJNSTATE
city: Breda
country: Netherlands
facility: NL-Breda-AMPHIA
city: Delft
country: Netherlands
facility: NL-Delft-RDGG
city: Den Haag
country: Netherlands
facility: NL-Den Haag-HAGA
city: Dordrecht
country: Netherlands
facility: NL-Dordrecht-ASZ
city: Enschede
country: Netherlands
facility: NL-Enschede-MST
city: Gouda
country: Netherlands
facility: NL-Gouda-GROENEHART
city: Groningen
country: Netherlands
facility: NL-Groningen-UMCG
city: Heerlen
country: Netherlands
facility: NL-Heerlen-ATRIUMMC
city: Helmond
country: Netherlands
facility: NL-Helmond-ELKERLIEK
city: Nieuwegein
country: Netherlands
facility: NL-Nieuwegein-ANTONIUS
city: Nijmegen
country: Netherlands
facility: NL-Nijmegen-CWZ
city: Rotterdam
country: Netherlands
facility: NL-Rotterdam-ERASMUSMC
city: Rotterdam
country: Netherlands
facility: NL-Rotterdam-MAASSTADZIEKENHUIS
city: Sittard
country: Netherlands
facility: NL-Sittard-Geleen-ZUYDERLAND
city: Sneek
country: Netherlands
facility: NL-Sneek-ANTONIUSSNEEK
city: Tilburg
country: Netherlands
facility: NL-Tilburg-ETZ
city: Uden
country: Netherlands
facility: NL-Uden-BERNHOVEN
city: Utrecht
country: Netherlands
facility: NL-Utrecht-UMCUTRECHT
city: Zaandam
country: Netherlands
facility: NL-Zaandam-ZAANSMC
city: Zwolle
country: Netherlands
facility: NL-Zwolle-ISALA
city: Lørenskog
country: Norway
facility: NO-Lørenskog-AKERSHUS
city: Trondheim
country: Norway
facility: NO-Trondheim-STOLAV
city: Borås
country: Sweden
facility: SE-Boras-SASBORAS
city: Linköping
country: Sweden
facility: SE-Linköping-REGIONOSTERGOTLAND
city: Luleå
country: Sweden
facility: SE-Luleå-SUNDERBY
city: Lund
country: Sweden
facility: SE-Lund-SUH
city: Uppsala
country: Sweden
facility: SE-Uppsala-UPPSALAUH
Study officials:
References:
citation: Kater AP, Levin MD, Dubois J, Kersting S, Enggaard L, Veldhuis GJ, Mous R, Mellink CHM, van der Kevie-Kersemaekers AF, Dobber JA, Poulsen CB, Frederiksen H, Janssens A, Schjodt I, Dompeling EC, Ranti J, Brieghel C, Mattsson M, Bellido M, Tran HTT, Nasserinejad K, Niemann CU. Minimal residual disease-guided stop and start of venetoclax plus ibrutinib for patients with relapsed or refractory chronic lymphocytic leukaemia (HOVON141/VISION): primary analysis of an open-label, randomised, phase 2 trial. Lancet Oncol. 2022 Jun;23(6):818-828. doi: 10.1016/S1470-2045(22)00220-0.
citation: Levin MD, Kater AP, Mattsson M, Kersting S, Ranti J, Thi Tuyet Tran H, Nasserinejad K, Niemann CU. Protocol description of the HOVON 141/VISION trial: a prospective, multicentre, randomised phase II trial of ibrutinib plus venetoclax in patients with creatinine clearance >/=30 mL/min who have relapsed or refractory chronic lymphocytic leukaemia (RR-CLL) with or without TP53 aberrations. BMJ Open. 2020 Oct 15;10(10):e039168. doi: 10.1136/bmjopen-2020-039168.