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