SAKK 34/17 - Ibrutinib as pre-treatment, followed by Ibrutinib plus Venetoclax as combination therapy for the treatment of patients with an untreated initial disease or with a relapse of chronic lymphocytic leukemia (CLL). A multicenter (conducted at multiple treatment centers), open phase II study

Switzerland (ICTRP)

ICTRP Trial ID
NCT03708003 (ICTRP)

Official title (approved by ethics committee)
Ibrutinib lead-in followed by venetoclax plus ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia. A multicenter, open-label, phase II trial (BASEC)

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

Public title
Ibrutinib lead-in Followed by Venetoclax Plus Ibrutinib in Patients With RR CLL (ICTRP)

Disease under investigation
Relapsed/Refractory Chronic Lymphocytic LeukemiaChronic Lymphocytic LeukemiaLeukemia (ICTRP)

Intervention under investigation
Drug: IbrutinibDrug: Venetoclax (ICTRP)

Type of trial
Interventional (ICTRP)

Trial design
Allocation: N/A. Intervention model: Single Group Assignment. Primary purpose: Treatment. Masking: None (Open Label). (ICTRP)

Inclusion/Exclusion criteria
Inclusion Criteria:

- 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)

- 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

Exclusion Criteria:

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

- 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 (ICTRP)

not available

Primary and secondary end points
MRD-neg CR/CRi at end of cycle 30 (ICTRP)

ORR at end of cycle 30;CR/CRi rate at end of cycle 30;CR/CRi rate based on best response;MRD-neg rate;Progression-free survival (PFS) (ICTRP)

Registration date
12.10.2018 (ICTRP)

Incorporation of the first participant
not available

Secondary sponsors
not available

Additional contacts
Davide Rossi, MD, Institute of Southern Switzerland IOSI, Bellinzona (ICTRP)

Secondary trial IDs
SAKK 34/17 (ICTRP)

Results-Individual Participant Data (IPD)
not available

Further information on the trial
https://clinicaltrials.gov/ct2/show/NCT03708003 (ICTRP)