Primary objective- To evaluate the efficacy of 6 cycles ibrutinib/obinutuzumab in converting patients who are not in CR or who have detectable MRD on combination ibrutinib and venetoclax in uMRD (BM) CR Secondary objectives- To explore the kinetics…
ID
Source
Brief title
Condition
- Leukaemias
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
- BM uMRD CR 3 months after end of intensification with ibrutinib/obinutuzumab
in patients who were not in CR or who had detectable MRD on combination
ibrutinib and venetoclax
Secondary outcome
- BM uMRD CR 9 months after registration 2 in all subjects
- Best BM MRD level on protocol
- MRD level in BM and PB at different time points on protocol and in follow up
- Best response by IWCLL on protocol
- Response by IWCLL at different time points
- Response by Deauville criteria on PET scan at different time points
- Progression free survival (PFS), defined as time from registration 1 and from
registration 2 to progression or death from any cause, whichever comes first
- Event free survival (EFS), defined as time from registration 1 and from
registration 2 to start new CLL treatment, progression or death, whichever
comes first
- Overall survival (OS), defined as time from registration 1 and from
registration 2 to death from any cause
- Treatment free interval (TFI), defined as date of last protocol treatment to
start date of first CLL treatment off protocol, or death from any cause
whichever comes first
- Predictive value of prognostic markers at diagnosis on uMRD and ORR by IWCLL
and Deauville criteria at end of ibrutinib/venetoclax and
ibrutinib/obinutuzumab
- CTCAE grade >=2 toxicities
- IWCLL hematological grade >=2toxicities
Exploratory endpoints
- MRD level in BM and PB at different time points on protocol and in follow up
by novel techniques
- Quantification of lesions on 18F-FDG PET-CT at different time points
- Amount of CLL cells in LN biopsy and FNA
- Immune cell subsets and function at different time points
- QoL at different time points on protocol and in follow up
Background summary
The BCL-2 antagonist venetoclax, specifically if combined with a CD20 antibody
proved highly active in clearance of chronic lymphocytic leukemia (CLL) cells
in peripheral blood (PB) and bone marrow (BM) but less so in lymph nodes (LN),
probably due to the abundant expression of additional anti-apoptotic proteins
within the LN compartment. We hypothesize that due to the forced egress from
the LN by ibrutinib, leukemic cells cannot escape from the apoptosis initiating
effects of venetoclax, making combination of these drugs highly effective.
Preliminary data from multiple ongoing trials on this combination are indeed
promising, with not only superior rates of undetectable minimal residual
disease (uMRD) than other ibrutinib combinations but perhaps more important,
achievement of complete LN responses in the majority of patients. Yet, also
with this combination, a significant subgroup of patients are expected to
remain with detectable MRD. A recent study showed that 6 cycles of obinutuzumab
when given after at least 1 year of ibrutinib did result in MRD conversion in a
significant proportion of patients (50%). The precise influence, timing and
interplay of venetoclax, ibrutinib and obinutuzumab on clearance of CLL cells
in different compartments (PB, BM, LN), and achievement of uMRD and complete
remission (CR) are not well known.
Therefore, we set out a study to evaluate whether patients who are not in CR or
who have detectable MRD after 12 months of combination treatment with ibrutinib
and venetoclax (15 months total treatment including three months ibrutinib
lead-in) could be converted into uMRD CR with an additional 6 cycles
obinutuzumab in combination with ibrutinib. In addition to efficacy, as
measured by undetectable MRD rate, emphasis of this trial will be on clearance
of different compartments (PB, BM, LN) at different time points on protocol and
in follow up. In addition, the toxicity profile is taken into consideration.
Study objective
Primary objective
- To evaluate the efficacy of 6 cycles ibrutinib/obinutuzumab in converting
patients who are not in CR or who have detectable MRD on combination ibrutinib
and venetoclax in uMRD (BM) CR
Secondary objectives
- To explore the kinetics of CLL clearance on protocol and in follow up within
the different compartments (PB, BM, LN) by regular test methods (MRD, PET-CT
and BM)
- To measure the conventional response and outcomes of the combination
ibrutinib/venetoclax and intensification with ibrutinib/obinutuzumab
- To evaluate prognostic parameters for response on ibrutinib/venetoclax and
intensification with ibrutinib/obinutuzumab
- To evaluate safety of ibrutinib/venetoclax and intensification with
ibrutinib/obinutuzumab
Exploratory objectives
- To explore kinetics of CLL clearance on protocol and in follow up within
different compartments (PB, BM, LN) by novel test methods (MRD, PET-CT, fine
needle aspiration (FNA) of LN)
- To evaluate the impact on immunity (e.g. expression of CD20 and CXCR4/CD5) of
ibrutinib/venetoclax and intensification with ibrutinib/obinutuzumab
To evaluate quality of life (QoL) during and after ibrutinib/venetoclax and
intensification with ibrutinib/obinutuzumab
Study design
The trial is designed as non-randomized non-comparative phase 2 study.
Intervention
Patients will receive 3 cycles lead-in with ibrutinib 420 mg/day. Here-after,
patients will continue with 13 induction cycles (including one bridging cycle)
combining ibrutinib 420 mg/day and venetoclax 400 mg/day (including a ramp up
of 5 weeks). Patients who are not in CR or who have detectable MRD after 15
cycles (3 cycles lead-in and 12 cycles induction) will continue with 6
intensification cycles ibrutinib in combination with obinutuzumab day 1, 2, 8,
15 for the first cycle and with obinutuzumab day 1 for the following 5 cycles.
Study burden and risks
The development of novel targeted therapies has led to new chemo-free treatment
options with better PFS than chemo-immunotherapy, reflected by a high
percentage of CR or uMRD. However, with the time-limited chemo-free combination
treatment ibrutinib/venetoclax a subset of patients still do not reach the goal
of CR with uMRD. Intensification with ibrutinib/obinutuzumab is likely to
increase the percentage of patients who reach CR with uMRD, which is expected
to translate to better PFS and OS. Important side effects of ibrutinib are
bleeding tendency and atrial fibrillation. The risk of tumor lysis syndrome
(TLS) in case of high tumorload with venetoclax is diminished by the lead-in
treatment with ibrutinib monotherapy. Obinutuzumab has a risk for infusion
related reactions (IRR) which tends to be less frequent when it is given in
combination with ibrutinib.
The risk from venipuncture, BM biopsy, LN biopsy/aspirate and PET-CT scan is
minimal. Discomfort from BM and LN biopsy/aspirate is substantial but
temporarily. From these procedures importa nt knowledge will be gained for
disease monitoring by assessing depth of response.
HOVON Centraal Bureau, VUMC, De boelelaan 1118
Amsterdam 1081 HZ
NL
HOVON Centraal Bureau, VUMC, De boelelaan 1118
Amsterdam 1081 HZ
NL
Listed location countries
Age
Inclusion criteria
• Documented CLL or SLL requiring treatment according to IWCLL criteria33,
including minimal required markers (CD5/CD19/CD23 triple positive with light
chain restriction);
• WHO performance status 0-3, stage 3 only if attributable to CLL/SLL;
• No prior treatment for CLL/SLL; prior treatment with rituximab for another
indication is allowed
• Age at least 18 years;
• Adequate BM function defined as:
- Hb > 5 mmol/l or Hb > 8 g/dL
- Absolute neutrophil count (ANC) >= 0.75 x 109/L or 750/µL
- Platelet count >= 50 x 109/L or 50,000 /µL
Unless directly attributable to CLL/SLL infiltration of the BM, proven by BM
biopsy;
• Estimated Glomerular Filtration Rate (eGFR) (MDRD) or estimated creatinine
clearance (CrCl) >= 30ml/min (Cockcroft-Gault );
Please note: in case eGFR or CrCl is <50ml/min the patient needs to be
considered high risk for TLS
• Adequate liver function as indicated:
- Serum aspartate transaminase (ASAT) and alanine transaminase (ALAT) <= 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
activated partial thromboplastin time (aPTT) <1.5 x ULN;
• Negative serological testing for hepatitis B virus (Hepatitis B surface
antigen (HBsAg) negative and hepatitis B core antibody (anti-HBc) negative) and
hepatitis C virus (hepatitis C antibody). Subjects who are positive for
hepatitis B core antibody, hepatitis B surface antigen, or hepatitis C antibody
must have a negative PCR result before enrollment. Those who are PCR positive
will be excluded;
• Ability and willingness to adhere to the study visit schedule and other
protocol requirements;
• Patient is capable of giving informed consent;
• Written informed consent.
Exclusion criteria
• Transformation of CLL (Richter*s transformation);
• Malignancies other than CLL/SLL currently requiring systemic therapy or not
being treated in curative intention or showing signs of progression after
curative treatment;
• Patient with CNS involvement
• Known allergy to xanthine oxidase inhibitors and/or rasburicase;
• Intolerance of exogenous protein administration;
• History of severe allergic or anaphylactic reactions to humanized or murine
monoclonal antibodies. Known sensitivity or allergy to murine products;
• Active fungal, bacterial, and/or viral infection that requires systemic
therapy;
• Concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled:
infection, auto-immune hemolysis, immune thrombocytopenia, diabetes,
hypertension, hyperthyroidism or hypothyroidism etc.);
• Patient known to be HIV-positive;
• Patient requiring treatment with a strong cytochrome P450 (CYP) 3A inhibitor
or anticoagulant therapy with warfarin or phenoprocoumon or other vitamin K
antagonists;
• History of stroke or intracranial hemorrhage within 6 months prior to
registration;
• Severe cardiovascular disease (arrhythmias requiring chronic treatment,
congestive
heart failure or symptomatic ischemic heart disease) (CTCAE grade III-IV);
• Severe pulmonary dysfunction (CTCAE grade III-IV);
• Patient with Child Pugh C
• Severe neurological or psychiatric disease (CTCAE grade III-IV);
• Vaccination with live vaccines within 28 days prior to registration;
• Use of any other experimental drug or therapy within 28 days prior to
registration
• Major surgery within 28 days prior to registration;
• Steroid therapy within 10 days prior to registration, with the exception of
inhaled steroids for
asthma, topical steroids, steroids up to 20 mg of dose equivalents of
prednisolone daily to control autoimmune phenomenon*s, or replacement/stress
corticosteroids;
• Pregnant women and nursing mothers.;
• Fertile men or women of childbearing potential unless: (1). surgically
sterile or >= 2 years after the onset of menopause, and/or (2) willing to use a
highly effective contraceptive method during study treatment and in female
patients for 3 months after end of induction treatment and 18 months after end
of treatment with obinutuzumab and male patients for 6 months after end of
treatment ; *• Current participation in other clinical trial;
• Any psychological, familial, sociological and geographical condition
potentially hampering
compliance with the study protocol and follow-up schedule.
Design
Recruitment
Medical products/devices used
Kamer G4-214
Postbus 22660
1100 DD Amsterdam
020 566 7389
mecamc@amsterdamumc.nl
Kamer G4-214
Postbus 22660
1100 DD Amsterdam
020 566 7389
mecamc@amsterdamumc.nl
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2019-002528-34-NL |
| CCMO | NL70874.018.19 |