Ibrutinib lead-in Followed by Venetoclax Plus Ibrutinib in Patients With RR CLL

NCT03708003 | Terminated Phase 2 DMC

• 1 other identifier: SAKK 34/17
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 11

Brief Summary

Venetoclax and ibrutinib have complementary activity in clearing the disease across anatomical compartments. By combining ibrutinib with venetoclax, cells can be mobilized from tissues into the bloodstream by ibrutinib and killed in the blood by venetoclax. Consistently, the venetoclax-ibrutinib combination can achieve undetectable minimal residual disease (MRD-neg) in a sizable proportion of patients. Gentle debulking obtained with a lead-in phase of ibrutinib monotherapy may allow starting venetoclax when the disease has been reshaped in a size that fits for low-risk of tumor lysis syndrome (TLS), a rare adverse event (AE) of venetoclax. MRD-guided treatment duration may allow patients achieving a negative status to gain drug-free intervals and less medicalization, and may avoid all the potential, and not yet completely known implications of continuous therapy on long-term safety, drug interactions, quality of life, compliance to treatment, and economic sustainability.

Conditions

Relapsed/Refractory Chronic Lymphocytic Leukemia; Chronic Lymphocytic Leukemia; Leukemia

Keywords

lymphocytic leukemia; relapsed/refractory chronic lymphocytic leukemia; Ibrutinib; venetoclax

Outcome Measures

Primary Outcomes (1)

• MRD-neg CR/CRi at end of cycle 30

  The MRD-neg (Undetectable Minimal residual disease) Complete remission/Complete remission with incomplete marrow recovery CR/CRi rate is defined as the proportion of patients having achieved: * CR/CRi, according to the iwCLL (International workshop on chronic lymphocytic leukemia) guidelines (2018), and * MRD-neg in bone marrow BM, measured by flow cytometry with a quantitative lower limit of at least \< 10-4. MRD status will be considered as negative if the proportion of malignant cells is \< 10-4. Patients without any response or MRD BM assessment at end of cycle 30 (+/- 14 days) will be counted as non-responders (failures for the primary endpoint).

  after 840 days (1 cycle = 28 days)

Secondary Outcomes (5)

• ORR at end of cycle 30

  after 840 days (1 cycle = 28 days)

• CR/CRi rate at end of cycle 30

  after 840 days (1 cycle = 28 days)

• CR/CRi rate based on best response

  Day 1 of cycle 7, 13, 19, 25 and 31 (1 cycle = 28 days)

• MRD-neg rate

  Day 1 of cycle 7, 13, 19, 25 and 31 (1 cycle = 28 days)

• Progression-free survival (PFS)

  Day 169, 337, 505, 673, 841, yearly up to five years, end of trial treatment plus unscheduled (if progression is suspected)

Study Arms (1)

venetoclax + ibrutinib

EXPERIMENTAL

Ibrutinib lead-in followed by venetoclax plus ibrutinib administered until cycle 31. The combination treatment will be continued as maintenance treatment or stopped depending on MRD-neg CR/CRi status.

Drug: Ibrutinib; Drug: Venetoclax

Interventions

Ibrutinib DRUG

Patients receive 6 cycles (cycle = 28 days) of ibrutinib monotherapy at the daily dose of 420 mg (3x 140 mg). Venetoclax is added on ibrutinib treatment starting from cycle 7 as weekly dose ramp-up (20 mg, C7 day 1-7; 50 mg, C7 day 8-14; 100 mg, C7 day 15-21; 200 mg, C7 day 22-28; 400 mg, C8-31 day 1-28). Venetoclax (400 mg d1-28) and ibrutinib (420 mg d1-28) continue until cycle 31. Depending on MRD-neg CR/CRi patients will continue the combination treatment (maintenance) or stop treatment (observation) up to 5 years after cycle 31.

Also known as: Imbruvica

venetoclax + ibrutinib

Venetoclax DRUG

Venetoclax is added on ibrutinib treatment starting from cycle 7 as weekly dose ramp-up (20 mg, C7 day 1-7; 50 mg, C7 day 8-14; 100 mg, C7 day 15-21; 200 mg, C7 day 22-28; 400 mg, C8-31 day 1-28). Venetoclax (400 mg d1-28) and ibrutinib (420 mg d1-28) continue until cycle 31. Depending on MRD-neg CR/CRi patients will continue the combination treatment (maintenance) or stop treatment (observation) up to 5 years after cycle 31.

Also known as: Venclyxto

venetoclax + ibrutinib

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Written informed consent according to Swiss law and ICH/GCP regulations before registration and prior to any trial specific procedures
• Cytologically and immunophenotypically confirmed relapsed/refractory CLL (irrespective of the 17p deletion and/or TP53 mutation status and the duration of remission from last prior therapy)
• Patients in need of systemic treatment as defined by international workshop on chronic lymphocytic leukemia (iwCLL) criteria (at least one of the following indications must be fulfilled):
• Evidence of progressive marrow failure as manifested by the development of, or worsening of, anemia and/or thrombocytopenia. Cut-off levels of Hb \< 100 g/L or platelet counts of \< 100x109/L
• Massive (i.e., ≥ 6 cm below the left costal margin) or progressive or symptomatic splenomegaly
• Massive nodes (i.e., ≥ 10 cm in longest diameter) or progressive or symptomatic lymphadenopathy
• Progressive lymphocytosis with an increase of ≥ 50% over a 2-month period, or lymphocyte doubling time of less than 6 months
• Disease-related symptoms as defined by any of the following: (a) Unintentional weight loss ≥ 10% within the previous 6 months. (b) Significant fatigue (i.e., ECOG PS 2 or worse; cannot work or unable to perform usual activities). (c) Fevers ≥38.0° C for 2 or more weeks without evidence of infection. (d) Night sweats for ≥ 1 month without evidence of infection
• Age at least 18 years
• WHO performance status 0-2
• Hematological function:
• Absolute neutrophil count (ANC) ≥ 1 x 109/L or ANC \< 1 x 109/L, if attributable to the underlying CLL (growth factor support may be administered after screening)
• Platelet count ≥ 30 x 109/L
• Hepatic function:
• Bilirubin ≤ 1.5 x ULN (except for patients with Gilbert's disease ≤ 3.0 x ULN)

You may not qualify if:

• Any potential patient who meets any of the following criteria has to be excluded from entering the trial.
• Transformation of CLL (i.e. Richter's transformation, prolymphocyctic leukemia)
• Patients with a prior malignancy and treated with curative intention are eligible if all treatment of that malignancy was completed at least 2 years before registration and the patient has no evidence of disease at registration. Less than 2 years is acceptable for malignancies with low-risk of recurrence and/or no late recurrence
• Prior treatment with venetoclax and/or ibrutinib
• Major surgery and any systemic anti-cancer treatment within 3 weeks prior to registration
• Steroid therapy for anti-neoplastic intent; strong and moderate CYP3A inhibitors; strong and moderate CYP3A inducers must be stopped at least 7 days prior to the first dose of trial drug (see http://medicine.iupui.edu/ and useful tools for examples)
• Severe or uncontrolled cardiovascular disease (congestive heart failure NYHA III or IV), unstable angina pectoris, history of myocardial infarction within the last six months, serious arrhythmias requiring medication (with exception of atrial fibrillation or paroxysmal supraventricular tachycardia on direct oral anticoagulants (DOAC), Aspirin or low molecular weight heparins (LMWH) but not on Vitamin K antagonist), significant QT-prolongation, uncontrolled hypertension
• History of cerebrovascular accident or intracranial hemorrhage within 6 months prior to registration and known bleeding disorders (e.g., von Willebrand's disease or hemophilia)
• Patients with a history of confirmed progressive multifocal leukoencephalopathy (PML)
• Concomitant diseases that require anticoagulant therapy with warfarin or phenoprocoumon or other vitamin K antagonists. Patients being treated with factor Xa inhibitors (e.g. rivaroxaban, apixaban, edoxaban), direct thrombin inhibitors (e.g. dabigatran) LMWH, or anti-platelets agents (e.g. aspirin, clopidogrel) can be included, but must be properly informed about the potential risk of bleeding under treatment with ibrutinib
• Malabsorption syndrome or other condition that precludes enteral route of administration
• Any uncontrolled active systemic infection requiring intravenous antimicrobial treatment
• Known history of human immunodeficiency virus (HIV) infection. Active hepatitis B infection (defined as the presence of detectable HBV DNA, HBe antigen or HBs antigen). Patients with serologic evidence of prior vaccination (HBsAg negative, anti-HBs antibody positive, anti-HBc antibody negative) are eligible. Patients who are HBsAg negative/HBsAb positive but HBcAb positive are eligible, provided HBV DNA is negative. Active hepatitis C, defined by the detectable hepatitis C ribonucleic acid (RNA) in plasma by polymerase chain reaction (PCR)
• Active, uncontrolled autoimmune phenomenon (autoimmune hemolytic anemia or immune thrombocytopenia) requiring steroid therapy with \> 20mg daily of prednisone dose or equivalent
• Known hypersensitivity to trial drugs or to any component of the trial drugs

Sponsors & Collaborators

• Swiss Cancer Institute: lead

Study Sites (11)

Kantonsspital Aarau

Aarau, CH-5001, Switzerland

Location

Universitätsspital Basel

Basel, 4031, Switzerland

Location

IOSI - Ospedale San Giovanni

Bellinzona, 6501, Switzerland

Location

Inselspital

Bern, 3010, Switzerland

Location

Kantonsspital Graubünden

Chur, 7000, Switzerland

Location

Kantonsspital Liestal

Liestal, CH-4410, Switzerland

Location

Luzerner Kantonsspital

Lucerne, 6000, Switzerland

Location

Kantonsspital Münsterlingen

Münsterlingen, 8596, Switzerland

Location

Spital STS AG Thun

Thun, 3600, Switzerland

Location

Kantonsspital Winterthur

Winterthur, 8401, Switzerland

Location

Universitätsspital Zürich

Zurich, 8091, Switzerland

Location

Related Publications (1)

• Condoluci A, Romano I, Dietrich D, Pini K, Stussi G, Muller G, Cantoni N, Cathomas R, Mey U, Widmer A, Zenz T, Gregor M, Heim D, Andres M, Benz R, Rossi D. Ibrutinib lead-in followed by venetoclax plus ibrutinib for relapsed/refractory chronic lymphocytic leukemia: the SAKK 34/17 trial. Blood. 2025 May 29;145(22):2587-2598. doi: 10.1182/blood.2024026879.

  PMID: 40009495 DERIVED

MeSH Terms

Conditions

Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia; Leukemia, Lymphoid

Interventions

ibrutinib; venetoclax

Condition Hierarchy (Ancestors)

Leukemia, B-Cell; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• Davide Rossi, MD

  Institute of Southern Switzerland IOSI, Bellinzona

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: A multicenter, single-arm, open-label, phase-II trial.

Study Record Dates

• First Submitted: October 12, 2018
• First Posted: October 16, 2018
• Study Start: March 11, 2019
• Primary Completion: November 30, 2025
• Study Completion: November 30, 2025
• Last Updated: December 30, 2025

Record last verified: 2025-12

Locations

CH (11)