This study has been transitioned to CTIS with ID 2023-503469-49-00 check the CTIS register for the current data. Primary ObjectiveThe primary objective of the study is to assess progression-free survival (PFS) from treatment with ibrutinib plus…
ID
Source
Brief title
Condition
- Leukaemias
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Efficacy evaluations will include imaging, physical examinations, evaluation of
blood and bone marrow, disease-related symptoms, and assessment of
patient-reported outcomes (PRO). Safety evaluations will include adverse event
(AE) monitoring, physical examinations, laboratory tests, and review of
concomitant medications.
Secondary outcome
To better understand the molecular and protein markers associated with response
to and relapse following study treatment, bone marrow and peripheral blood
samples will be collected. For subjects assigned to the I+VEN treatment arm,
sparse samples will be collected for pharmacokinetic (PK) analysis.
Background summary
Refer to question answer C4.
Hypothesis:
Treatment with the combination of I+VEN will result in longer PFS compared with
G-Clb in subjects with previously untreated chronic lymphocytic leukemia (CLL)/
small lymphocytic lymphoma (SLL).
Study objective
This study has been transitioned to CTIS with ID 2023-503469-49-00 check the CTIS register for the current data.
Primary Objective
The primary objective of the study is to assess progression-free survival (PFS)
from treatment with ibrutinib plus venetoclax (I+VEN) compared with
obinutuzumab plus chlorambucil (G-Clb) as assessed by an Independent Review
Committee (IRC).
Secondary Objectives
Key secondary objectives are to evaluate the following: rate of minimal
residual disease (MRD)-negative remissions; overall response rate (ORR),
including complete response (CR) rate, and response duration as assessed by an
IRC; overall survival (OS); time-to-next treatment; trough levels of ibrutinib
when given in combination with venetoclax; and safety.
Study design
This is a randomized (1:1), open-label, multicenter, Phase 3 study to determine
the efficacy and safety of the combination of I+VEN, compared with G-Clb, in
approximately 200 subjects with previously untreated CLL/SLL who meet the
International Workshop on CLL (iwCLL) treatment criteria.
Randomization will be stratified by immunoglobulin heavy-chain variable region
(IGHV) gene mutational status (mutated vs. unmutated vs. not available) and
presence of deletion of the long arm of chromosome 11 ([del11q] yes vs. no).
Subject participation will include a Screening Phase, a Treatment Phase, and a
Follow-up Phase. After treatment completion, subjects will enter a Follow-up
Phase, and those without progression will continue disease evaluations until
disease progression or death. Study end is defined as approximately 5 years
after the last subject is randomized into the study or after 50% of subjects
have died, whichever occurs first.
If the disease worsens after receiving Treatment Group A or Treatment Group B
and further treatment is required, the subject might be eligible to receive
further treatment with only ibrutinib. The purpose of this part of the study
is to look at the effectiveness in patients who were initially treated with
Treatment Group A (combination of ibrutinib and venetoclax). If the subject
was receiving Treatment Group B (obinutuzumab in combination with chlorambucil)
the subject may also be eligible to receive this further treatment with only
ibrutinib. Ibrutinib alone is an approved second line therapy for subjects
whose CLL/SLL worsens after prior treatments or therapy.
Intervention
Subjects randomly assigned to Arm A (I+VEN) will receive ibrutinib (420 mg/day
orally) given as leadin treatment for 3 cycles. Starting at Cycle 4, venetoclax
dose ramp up (from 20 mg to 400 mg over 5 weeks) will begin, and venetoclax
will be administered with ibrutinib for 12 cycles. Subjects randomly assigned
to Arm B (G-Clb) will receive G-Clb for 6 cycles. Obinutuzumab will be
administered intravenously at a dose of 1000 mg on Days 1, 8 and 15 in Cycle 1.
In Cycles 2 to 6, 1000 mg obinutuzumab will be given on Day 1. Chlorambucil
will be administered orally at a dose of 0.5 mg/kg body weight, on Days 1 and
15 of Cycles 1 to 6. A cycle will be defined as 28 days.
If the subject was receiving Treatment Group B (obinutuzumab in combination
with chlorambucil) the subject may also be eligible to receive this further
treatment with only ibrutinib. Ibrutinib alone is an approved second line
therapy for subjects whose CLL/SLL worsens after prior treatments or therapy.
Study burden and risks
Burden (both arm A and B): hospital visits on a more frequent schedule than
standard, including additional assessments like questionnaires and CT-scans.
Risks: Adverse events from Ibrutinib, Venetoclax, Chlorambucil and
Obinutuzumab: see informed consent, SmPC and IB. Side effects from bloodtests
and bone marrow biopsy and bone marrow aspirate.
Graaf Engelbertlaan 75
Breda 4837DS
NL
Graaf Engelbertlaan 75
Breda 4837DS
NL
Listed location countries
Age
Inclusion criteria
1. Adult subjects who are: , a. >=65 years old or, , b. 18 to 64 years old and
have at least 1 of the following:, - Cumulative Illness Rating Scale (CIRS)
score >6, - Creatinine clearance (CrCl) estimated <70 mL/min using the
Cockcroft-Gault equation., 2. Diagnosis of CLL or SLL that meets iwCLL
criteria. , 3. Active CLL/SLL requiring treatment per the iwCLL criteria: , a.
Evidence of progressive marrow failure as manifested by the development of, or
worsening of, anemia or thrombocytopenia or both;, b. Massive (ie, at least 6
cm below the left costal margin) or progressive or symptomatic splenomegaly;,
c. Massive nodes (ie, at least 10 cm in longest diameter) or progressive or
symptomatic lymphadenopathy;, d. Progressive lymphocytosis with an increase of
more than 50% over a 2-month period or lymphocyte doubling time of less than
six months;, e. Constitutional symptoms, defined as 1 or more of the
following:, - Unintentional weight loss >=10% within the previous 6 months prior
to the start of screening;, - Significant fatigue (inability to work or perform
usual activities);, - Fevers higher than 100.5°F or 38.0°C for 2 or more weeks
without evidence of infection; , - Night sweats for more than 1 month without
evidence of infection., 4. Measurable nodal disease (by computed tomography
[CT]) is defined as at least one lymph node >;1.5 cm in longest diameter. ,
5. ECOG Performance Status Grade <=2., 6. Adequate organ function defined as
follows:, a. Absolute neutrophil count (ANC) >=750 cells/µL independent of
growth factor support;, b. Platelets >=50,000 cells/µL independent of
transfusion support for at least 7 days prior to randomization;, c. Hemoglobin
>8.0 g/dL independent of transfusion support for at least 7 days prior to
randomization;, d. Alanine aminotransferase (ALT) and aspartate
aminotransferase (AST) <=3.0 x upper limit of normal (ULN);, e. Total bilirubin
<=1.5 x ULN (unless due to Gilbert*s syndrome);, f. Estimated CrCl >=30 mL/min
(Cockcroft-Gault equation).
Exclusion criteria
1. Prior anti-leukemic therapy for CLL or SLL., 2. Presence of del17p or known
TP53 mutation., 3. Major surgery within 4 weeks of first dose of study
treatment. , 4. Known bleeding disorders (eg, von Willebrand*s disease or
hemophilia)., 5. Central nervous system (CNS) involvement or suspected
Richter*s syndrome., 6. An individual organ/system impairment score of 4 as
assessed by CIRS, except for the eyes, ears, nose, throat, and larynx system,
limiting the ability to receive treatment in this study., 7. Uncontrolled
autoimmune hemolytic anemia or autoimmune thrombocytopenia (Coombs positivity
in the absence of hemolysis is not an exclusion)., 8. Chronic use of
corticosteroids more than 20 mg/day of prednisone or its equivalent within 7
days of initiation of study treatment., 9. History of prior malignancy,
except:, a. Malignancy treated with curative intent and with no known active
disease present for >=24 months before randomization;, b. Adequately treated
non-melanoma skin cancer or lentigo maligna without evidence of disease;, c.
Adequately treated cervical carcinoma in situ without evidence of disease;, d.
Malignancy, which is considered cured with minimal risk of recurrence., 10.
Received live, attenuated vaccine within 4 weeks of randomization., 11. History
of renal, neurologic, psychiatric, endocrinologic, metabolic, immunologic, or
hepatic condition that in the opinion of the investigator would adversely
affect a subject*s participation in the study., 12. Currently active,
clinically significant Child-Pugh Class B or C hepatic impairment according to
the Child Pugh classification (see Attachment 4 Child-Pugh classification), 13.
Uncontrolled active systemic infection or any life-threatening illness, medical
condition, or organ system dysfunction which, in the investigator*s opinion,
could compromise the subject*s safety or put the study outcomes at undue risk.,
14. Inability or difficulty swallowing capsules/tablets, malabsorption
syndrome, or any disease or medical condition significantly affecting
gastrointestinal function.
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
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 |
|---|---|
| EU-CTR | CTIS2023-503469-49-00 |
| EudraCT | EUCTR2017-004699-77-NL |
| CCMO | NL64467.018.18 |