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

Chronic Lymphocytic Leukemia in Relapse Clinical Trial

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03226301
• Other study ID #: HO141 CLL / VIsion trial
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: June 23, 2017
• Est. completion date: June 21, 2026

Study information

• Verified date: August 2022
• Source: Stichting Hemato-Oncologie voor Volwassenen Nederland
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 230
• Est. completion date: June 21, 2026
• Est. primary completion date: June 30, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Chronic Lymphocytic Leukemia in Relapse
• Chronic Lymphocytic Leukemia in Remission
• Leukemia
• Leukemia, Lymphocytic, Chronic, B-Cell
• Leukemia, Lymphoid

Intervention

Drug:
• Ibrutinib + Venetoclax 15 cycles
Cycle 1 + 2: 420 mg ibrutinib, day 1-28 | Cycle 3: 420 mg ibrutinib, day 1-28 | 20 mg venetoclax, day 1-7 | 50 mg venetoclax, day 8-14 | 100 mg venetoclax, day 15-21 | 200 mg venetoclax, day 22-28 | Cycle 4-15: 420 mg ibrutinib, day 1-28 + 400mg venetoclax, day 1-28
• Ibrutinib until progression/relapse
420mg ibrutinib daily until progression/relapse
• Possible reinitiation treatment: Ibrutinib + Venetoclax 12 cycles
Cycle 1: 420 mg ibrutinib | 20 mg venetoclax, day 1-7 | 50 mg venetoclax, day 8-14 | 100 mg venetoclax, day 15-21 | 200 mg venetoclax, day 22-28 | cycles 2-12: 420 mg ibrutinib, day 1-28 + 400 mg venetoclax, day 1-28

Locations

Country	Name	City	State
Belgium	BE-Antwerpen-ZNASTUIVENBERG	Antwerpen
Belgium	BE-Brugge-AZBRUGGE	Brugge
Belgium	BE-Bruxelles-STLUC	Brussels
Belgium	BE-Haine-Saint-Paul-JOLIMONT	Haine-Saint-Paul
Belgium	BE-Leuven-UZLEUVEN	Leuven
Denmark	DK-Aalborg-AALBORGUH	Aalborg
Denmark	DK-Copenhagen-RIGSHOSPITALET	Copenhagen
Denmark	DK-Herlev-HERLEV	Herlev
Denmark	DK-Holstebro-HOLSTEBRO	Holstebro
Denmark	DK-Odense-OUH	Odense
Denmark	DK-Roskilde-ROSKILDE	Roskilde
Finland	FI-Helsinki-HUS	Helsinki
Finland	FI-Jyvaskyla-KSSHP	Jyväskylä
Finland	FI-Kuopio-KYS	Kuopio
Finland	FI-Tampere-TAYS	Tampere
Finland	FI-Turku-TYKS	Turku
Netherlands	NL-Alkmaar-NWZ	Alkmaar
Netherlands	NL-Amersfoort-MEANDERMC	Amersfoort
Netherlands	NL-Amsterdam-AMC	Amsterdam
Netherlands	NL-Amsterdam-AVL	Amsterdam
Netherlands	NL-Amsterdam-VUMC	Amsterdam
Netherlands	NL-Arnhem-RIJNSTATE	Arnhem
Netherlands	NL-Breda-AMPHIA	Breda
Netherlands	NL-Delft-RDGG	Delft
Netherlands	NL-Den Haag-HAGA	Den Haag
Netherlands	NL-Dordrecht-ASZ	Dordrecht
Netherlands	NL-Enschede-MST	Enschede
Netherlands	NL-Gouda-GROENEHART	Gouda
Netherlands	NL-Groningen-UMCG	Groningen
Netherlands	NL-Heerlen-ATRIUMMC	Heerlen
Netherlands	NL-Helmond-ELKERLIEK	Helmond
Netherlands	NL-Nieuwegein-ANTONIUS	Nieuwegein
Netherlands	NL-Nijmegen-CWZ	Nijmegen
Netherlands	NL-Rotterdam-ERASMUSMC	Rotterdam
Netherlands	NL-Rotterdam-MAASSTADZIEKENHUIS	Rotterdam
Netherlands	NL-Sittard-Geleen-ZUYDERLAND	Sittard
Netherlands	NL-Sneek-ANTONIUSSNEEK	Sneek
Netherlands	NL-Tilburg-ETZ	Tilburg
Netherlands	NL-Uden-BERNHOVEN	Uden
Netherlands	NL-Utrecht-UMCUTRECHT	Utrecht
Netherlands	NL-Zaandam-ZAANSMC	Zaandam
Netherlands	NL-Zwolle-ISALA	Zwolle
Norway	NO-Lørenskog-AKERSHUS	Lørenskog
Norway	NO-Trondheim-STOLAV	Trondheim
Sweden	SE-Boras-SASBORAS	Borås
Sweden	SE-Linköping-REGIONOSTERGOTLAND	Linköping
Sweden	SE-Luleå-SUNDERBY	Luleå
Sweden	SE-Lund-SUH	Lund
Sweden	SE-Uppsala-UPPSALAUH	Uppsala

Sponsors (2)

Lead Sponsor	Collaborator
Stichting Hemato-Oncologie voor Volwassenen Nederland	Nordic CLL Study Group

Countries where clinical trial is conducted

Belgium,  Denmark,  Finland,  Netherlands,  Norway,  Sweden, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of patients with progression free survival 27 months after starting treatment	arm B of the study	27 months after last patient in trial
Secondary	Number of patients with MRD negativity 27 months after starting treatment	all arms of the study	27 months after last patient in trial
Secondary	Number of patients with progression free survival	all arms of the study	7 years after last patient in
Secondary	Number of patients reinitiating treatment	arm B of the study	7 years after last patient in
Secondary	Number of patients with treatment failure after reinitiating treatment	arm B of the study	7 years after last patient in
Secondary	Number of patients initiating new CLL treatment	all arms of the study	7 years after last patient in
Secondary	Number of patients with MRD negativity 12 (peripheral blood) and 15 months (peripheral blood and bone marrow) after starting treatment	all arms of the study	15 months after last patient in trial
Secondary	Number of patients alive	all arms of the study	7 years after last patient in
Secondary	Number of patients with complete remission, partial remission and stable disease and the duration of remission for each group	all arms of the study	7 years after last patient in
Secondary	Number and grading of adverse events, serious adverse events and adverse events of special interest (bleeding, atrial fibrillation and tumorlysis)	all arms of the study	7 years after last patient in
Secondary	Number of patients with improved quality of life (by EORTC QLQ-C30 and QLQ-CLL16 questionnaires)	all arms of the study	51 months after last patient in trial

External Links

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