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Relapsed/Refractory Chronic Lymphocytic LeukemiaPhase 2NCT03708003

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

A Phase 2 study testing Ibrutinib and Venetoclax in people with Relapsed/Refractory Chronic Lymphocytic Leukemia and Chronic Lymphocytic Leukemia, run by Swiss Cancer Institute at 11 sites in Switzerland.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Ibrutinib and Venetoclax
Could I receive a placebo?
No, everyone receives an active treatment
How many people
30 participants
Where
11 sitesSwitzerland
Study dates
11 Mar 2019to 30 Nov 2025
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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
Show all 22Show fewer
  • 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)
  • ALT and AST ≤ 3.0 x ULN
  • Renal function: Creatinine clearance > 30 mL/min (calculated according to institutional standards or using Cockcroft-Gault formula
  • Adequate coagulation parameters per local laboratory reference range as follows: activated partial thromboplastin time (aPTT) and international normalized ratio (INR) ≤ 1.5 × ULN
  • Women with child-bearing potential are using effective contraception, are not pregnant or lactating and agree not to become pregnant during trial treatment and during the 30 days thereafter. A negative pregnancy test before inclusion into the trial is required for all women with child-bearing potential
  • Men agree not to father a child during trial treatment and during 3 months thereafter
  • Patient is able and willing to swallow trial drugs as whole tablet/capsule
  • Patient is willing to participate in translational research

Who cannot join

  • 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)
Show all 17Show fewer
  • 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
  • Known allergy to both xanthine oxidase inhibitors and rasburicase
  • Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that in the opinion of the investigator may increase the risk associated with trial participation or investigational product administration or may interfere with the interpretation of trial results and/or would make the patient inappropriate for enrollment into this trial

Trial locations and contacts

11 sites in 1 country.

11 sites in 1 country

Switzerland11 sites

  • Kantonsspital Aarau

    Aarau, CH-5001

  • Universitätsspital Basel

    Basel, 4031

  • IOSI - Ospedale San Giovanni

    Bellinzona, 6501

  • Inselspital

    Bern, 3010

  • Kantonsspital Graubünden

    Chur, 7000

  • Kantonsspital Liestal

    Liestal, CH-4410

  • Luzerner Kantonsspital

    Lucerne, 6000

  • Kantonsspital Münsterlingen

    Münsterlingen, 8596

  • Spital STS AG Thun

    Thun, 3600

  • Kantonsspital Winterthur

    Winterthur, 8401

  • Universitätsspital Zürich

    Zurich, 8091

Other trials in Switzerland

About this study

Official title: Ibrutinib lead-in Followed by Venetoclax Plus Ibrutinib in Patients With Relapsed/Refractory Chronic Lymphocytic Leukemia. A Multicenter, Open-label, Phase II Trial

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.

Read the detailed description

Background:

The standard of care for treatment of patients with relapsed or refractory chronic lymphocytic leukemia (RR CLL) has substantially changed. Current standard for patients with a relapse later than 3 years from first-line therapy is a repetition with the first-line regimen used. This poses the risk of significant immunosuppression and infectious complications as well as a shorter event-free survival as expected for first-line treatment. Current standard for patients with refractory disease, early relapse or emerging TP53 defective clones, is a targeted treatment with ibrutinib, idelalisib + rituximab or venetoclax as continuous therapy until progression or toxicity.

Rationale:

Venetoclax and ibrutinib are both oral drugs whose tolerability when used in combination is not inferior to single agents. Venetoclax and ibrutinib have complementary activity in clearing the disease across anatomical compartments. Ibrutinib is more active in lymph nodes rather than blood where a small lymphocytosis might persist despite continuous treatment. Conversely, venetoclax appears to be more active in blood and bone marrow (BM) rather than lymph nodes. 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.

The primary objective of the trial is to assess efficacy after 30 cycles of trial treatment.

Being tested
Ibrutinib, Venetoclax
Keywords
lymphocytic leukemia, relapsed/refractory chronic lymphocytic leukemia, Ibrutinib, venetoclax
Medical subject headings
Leukemia, Lymphocytic, Chronic, B-Cell, Leukemia, Leukemia, Lymphoid

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • IbrutinibDrug

    Also called Imbruvica

    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.

  • VenetoclaxDrug

    Also called Venclyxto

    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.

Study groups in NCT03708003
Study groupRoleWhat they receive
venetoclax + ibrutinibExperimentalIbrutinib 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.
Receives: Drug: Ibrutinib; Drug: Venetoclax

What is being measured

The primary outcome is the main question the study is designed to answer.

  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).

    Measured: after 840 days (1 cycle = 28 days)

Secondary outcomes (5)

  1. ORR at end of cycle 30

    The ORR (Overall response rate) is defined as the proportion of patients having achieved a CR/CRi or PR according to the iwCLL guidelines (2018) and will be evaluated at end of cycle 30 (+/- 14 days). Patients without any response assessment at end of cycle 30 (+/- 14 days) will be counted as non-responders.

    Measured: after 840 days (1 cycle = 28 days)

  2. CR/CRi rate at end of cycle 30

    The CR/CRi rate (Complete remission/Complete remission with incomplete marrow recovery) is defined as the proportion of patients having achieved a CR/CRi according to the iwCLL guidelines (2018) and will be evaluated at end of cycle 30 (+/- 14 days). Patients without any response assessment at end of cycle 30 (+/- 14 days) will be counted as non-responders.

    Measured: after 840 days (1 cycle = 28 days)

  3. CR/CRi rate based on best response

    The CR/CRi rate based on best response is defined as the proportion of patients having achieved a CR/CRi according to the iwCLL guidelines (2018) as best response during trial therapy including maintenance. Patients without any post-baseline response assessment will be counted as non-responders.

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

  4. MRD-neg rate

    The MRD-neg rate is defined as the proportion of patients having achieved MRD-neg at any time during trial therapy including maintenance. Patients without any post-baseline MRD assessment will be counted as MRD positive patients. As MRD status will be assessed from PB or BM, both PB MRD-neg rate and BM MRD-neg rate will be calculated.

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

  5. Progression-free survival (PFS)

    PFS is defined as the time from registration until progression according the iwCLL criteria or death from any cause, whichever occurs first. Patients not having an event at the time of analysis as well as patients starting a new antileukemic therapy in the absence of an event will be censored at the date of their last tumor assessment showing nonprogression before starting a new anti-leukemic treatment, if any.

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

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted16 Oct 2018
  2. Study start11 Mar 2019
  3. Primary completion30 Nov 2025
  4. Study completion30 Nov 2025

Why it stopped: The board decision has been made to conclude the trial ahead of schedule. The primary endpoint has been successfully achieved and published, and funding was secured to support these three years of followup.

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Model description
A multicenter, single-arm, open-label, phase-II trial.
Masking
None (open label)
Enrolment
30 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03708003
Sponsor's protocol ID
SAKK 34/17
Status last verified
Dec 2025
First submitted
12 Oct 2018
Last updated
30 Dec 2025
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No

Publications

  • 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.

    PubMed 40009495

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Ibrutinib and Venetoclax in people with Relapsed/Refractory Chronic Lymphocytic Leukemia and Chronic Lymphocytic Leukemia, run by Swiss Cancer Institute at 11 sites in Switzerland.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 22 inclusion and 17 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 30 Dec 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 11 sites in Switzerland. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study was stopped early (reason given: The board decision has been made to conclude the trial ahead of schedule. The primary endpoint has been successfully achieved and published, and funding was secured to support these three years of followup.). Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

MRD-neg CR/CRi at end of cycle 30 (time frame: after 840 days (1 cycle = 28 days)). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03708003, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 30 Dec 2025; AzTrials last refreshed its copy on 8 Nov 2026.

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