The primary objective of the study is to evaluate the efficacy of obinutuzumab(GA101) plus venetoclax (GVe) versus standard chemoimmunotherapy (BR/FCR)[concerning MRD negativity measured by flow cytometry in peripheral blood (PB)at month 15] and…
ID
Source
Brief title
Condition
- Leukaemias
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Negativity rate of minimal residual disease (MRD) in peripheral blood
(PB) measured by flow cytometry at month (MO) 15 for the comparison
[GVe versus standard chemoimmunotherapy (SCIT)].
Progression free survival (PFS) for the comparison [GIVe versus SCIT]
Secondary outcome
Secondary endpoints:
1. MRD levels in PB at MO 15 (all other comparisons except for [GVe versus
SCIT])
2. MRD levels in PB at different time points (MO 2, 9 and 13; MRD at later
time points might be evaluated according to the discretion of the treating
physician at local laboratories)
3. MRD levels measured in bone marrow (BM) at final restaging (RE, 2
month after the end of last treatment cycle)
4. PFS (all other comparisons except for [GIVe versus SCIT])
5. Overall response rate (ORR) [MO 3, 9, 13, 15]
6. (Clinical) CR / CRi rate [Interim staging [IST], cycle 9 day 1 (or final
restaging
(RE) for patients in the SCIT arm), IR (or three month after RE for
patients in the SCIT arm respectively) and MO 15] (with regard to best
response achieved)
7. Event-free survival (EFS)
8. Overall survival (OS)
9. Duration of response in patients with:
-complete response (CR) or CR with incomplete recovery of the
bone marrow (CRi),
-partial response (PR)
10. Time to next CLL treatment
11. Safety parameters:
Type, frequency, and severity of
-adverse events (AEs) and
-adverse events of special interest (AESI)
and their relationship to study treatment
12. Health-related quality of life and compliance by MARS and EORTC QLQC30
and QLQ-CLL16 questionnaires
13. Exploratory evaluations of potential associations between biomarkers and
subject characteristics or outcome measures
Background summary
Chemoimmunotherapy is the standard of care in first-line treatment of CLL
patients
without del17p or TP 53 mutation; physically fit patients are treated with
fludarabine, cyclophosphamide and rituximab (FCR). Due to the high risk of
severe
neutropenias and infections with FCR, bendamustine and rituximab (BR)
must be considered in patients aged >65 years.
However, these conventional chemoimmunotherapies are associated with side
effects caused by the rather unspecific mode of action of the chemotherapy.
Therefore, there is an urgent need for alternatives, especially
chemotherapy-free
regimens.
In first line treatment of elderly patients with CLL and coexisting conditions,
the
anti-CD20-antibody obinutuzumab is the new standard therapy. In the CLL11 trial
the combination of obinutuzumab with chlorambucil proved to be safe and lead to
markedly improved response rates as well as PFS times in comparison to
chlorambucil
alone or combined with rituximab.
The BCL2 antagonist venetoclax (GDC-0199/ABT-199) showed striking activity
with tumor lysis syndrome as dose limiting toxicity, in patients with relapsed
and
refractory CLL. 400 mg venetoclax was determined to be a safe and efficacious
dose. Several patients treated with the combination of venetoclax and rituximab
in
relapsed refractory CLL even achieved MRD negativity. The FDA approved
Venetoclax
for the treatment of relapsed CLL with 17p/TP53 on 12th April 2016.
Therefore, venetoclax plus CD20-antibody based combinations have the potential
to induce higher rates of MRD negativity in frontline therapy of CLL and
concomitantly
induce lower rates of toxicities so that chemotherapy might be replaced.
Furthermore, venetoclax and obinutuzumab demonstrated synergistic activity in a
preclinical study of a murine Non-Hodgkin lymphoma xenograft model, and additive
activity in a CLL lymph node model. The combination appears tolerable in
the firstline treatment of CLL patients with coexisting conditions whilst the
toxicity
profile of both drugs compares favorably to those of the chemotherapies
currently
used in the treatment of CLL. Consequently, it should be tested if rituximab can
be replaced by obinutuzumab in combination with venetoclax in this trial.
Ibrutinib, a selective, irreversible small molecular inhibitor of Bruton*s
Tyrosine
Kinase (BTK), showed excellent responses and a safe toxicity profile, even in
combination with BR. Ibrutinib is approved for treatment of relapsed CLL as well
as frontline therapy of CLL by the FDA and EMA (April 29th 2016).
The combination of ibrutinib and venetoclax showed synergy in primary CLL
cells.
Study objective
The primary objective of the study is to evaluate the efficacy of obinutuzumab
(GA101) plus venetoclax (GVe) versus standard chemoimmunotherapy (BR/FCR)
[concerning MRD negativity measured by flow cytometry in peripheral blood (PB)
at month 15] and obinutuzumab plus ibrutinib plus venetoclax (GIVe) versus
standard chemoimmunotherapy (BR/FCR) [concerning progression free survival
(PFS)] in previously untreated, fit CLL patients without del(17p) or TP53
mutation.
Secondary objectives of the study are the evaluation of the efficacy of
rituximab
plus venetoclax (RVe) versus standard chemoimmunotherapy (BR/FCR), GVe
and GIVe [concerning MRD negativity measured by flow cytometry in PB at
month 15 and PFS].
Study design
Phase-III trial, prospective, multicenter, open-label, randomized
Intervention
Patients randomized for standard chemoimmunotherapy (SCIT) will receive 6
cycles of bendamustine or fludarabine/cyclophosphamide plus rituximab, each
with a duration of 28 days unless the administration is delayed.
Rituximab or obinutuzumab in combination with venetoclax will be administered
for 6 cycles, followed by 6 additional cycles venetoclax alone (each cycle
with a duration of 28 days).
Accordingly, obinutuzumab in combination with ibrutinib and venetoclax will be
administered for 6 cycles, followed by 6 additional cycles venetoclax plus
ibrutinib
(each cycle with a duration of 28 days).
The oral intake of ibrutinib will be continued for a maximum of 36 months or
until MRD negativity (in peripheral blood and confirmed by a bone marrow
aspirate 3 months later or by two consecutive peripheral blood samples 3
months apart), start of new anti-CLL therapy or inacceptable toxicity, whatever
occurs first.
Study burden and risks
Participation in this study will be associated with extra investigations
compared to standard patient care.
Extra investigations consist of MRD measurement in blood and bone marrow.
It is possible that the patient will experience different adverse events in
comparison to standard care.
Furthermore, patients will be requested to participate in Quality of Life
studies.
Kerpener Str. 62
Cologne 50924
DE
Kerpener Str. 62
Cologne 50924
DE
Listed location countries
Age
Inclusion criteria
-Documented CLL requiring treatment according to iwCLL criteria.
-Age at least 18 years.
-Life expectancy >= 6 months.
-Ability and willingness to provide written informed consent and to adhere to
the study visit
schedule and other protocol requirements.
-Adequate bone marrow function indicated by a platelet count >30 x10^9/l
(unless directly
attributable to CLL infiltration of the bone marrow proven by bone marrow
biopsy).
-GFR >=70ml/min directly measured with 24hr urine collection or calculated
according to the modified formula of Cockcroft and Gault (for men: GFR * ((140
- age) x
bodyweight) / (72 x creatinine), for women x 0, 85) or an equally accurate
method. For patients with creatinine values within the normal range the
calculation of the clearance is not necessary. Dehydrated patients with an
estimated creatinine clearance less than 70 ml/min may be eligible if a repeat
estimate after adequate hydration is > 70 ml/min.
-Adequate liver function as indicated by a total bilirubin<= 2 x, AST/ALT <= 2.5
x the institutional
ULN value, unless directly attributable to the patient*s CLL or to Gilbert*s
Syndrome.
-Negative serological testing for hepatitis B (HBsAg negative and anti-HBc
negative; patients
positive for anti-HBc may be included if PCR for HBV DNA is negative and HBVDNA
PCR is performed every month until 12 months after the last treatment cycle),
negative
testing for hepatitis C RNA within 6 weeks prior to registration.
-Eastern Cooperative Oncology Group Performance Status (ECOG) performance
status 0-
2.
Exclusion criteria
-Any prior CLL-specific therapies (except for corticoid treatment administered
due to necessary
immediate intervention; within the last 10 days before start of study treatment
only dose
equivalents up to 20 mg prednisolone are permitted).
-Transformation of CLL (Richter*s transformation).
-Decompensated hemolysis, defined as ongoing hemoglobin drop in spite of
prednisolone or intravenous immunoglobulins (IVIG). Prior treatment with
rituximab even for other indications than CLL is not permitted.
-Detected del(17p) or TP53 mutation.
-Patients with a history of confirmed PML.
-Any comorbidity or organ system impairment rated with a single CIRS
(cumulative illness rating
scale) score of 4, (excluding the eyes/ears/nose/throat/larynx organ system), a
total CIRS
score of more than 6 or any other life-threatening illness, medical condition
or organ system
dysfunction that - in the investigator*s opinion could compromise the patients
safety or interfere
with the absorption or metabolism of the study drugs (e.g, inability to swallow
tablets or impaired
resorption in the gastrointestinal tract).
-Urinary outflow obstruction.
-Malignancies other than CLL currently requiring systemic therapies, not being
treated in curative
intention before (unless the malignant disease is in a stable remission due to
the discretion
of the treating physician) or showing signs of progression after curative
treatment.
-Uncontrolled or active infection.
-Patients with known infection with human immunodeficiency virus (HIV).
-Requirement of therapy with strong CYP3A4 and CYP3A5 inhibitors/inducers.
-Anticoagulant therapy with warfarin or phenoprocoumon,(rotation to alternative
anticoagulation is allowed, but note that patients being treated with NOAKs can
be included, but must be properly informed about the potential risk of bleeding
under treatment with ibrutinib).
-History of stroke or intracranial hemorrhage within 6 months prior to
randomization.
-Use of investigational agents which might interfere with the study drug within
28 days prior to
registration.
-Vaccination with live vaccines 28 days prior to registration.
-Major surgery less than 30 days before start of treatment.
-History of severe allergic or anaphylactic reactions to humanized or murine
monoclonal antibodies,
known sensitivity or allergy to murine products.
-Known hypersensitivity to any active substance or to any of the excipients of
one of the drugs
used in the trial.
-Pregnant women and nursing mothers (a negative pregnancy test is required for
all women of
childbearing potential within 7 days before start of treatment; further
pregnancy testing will be
performed regularly).
-Fertile men or women of childbearing potential unless: surgically sterile or >=
2 years after the onset of menopause or willing to use two methods of reliable
contraception including one highly effective contraceptive method (Pearl Index
<1) and one additional effective (barrier) method during study
treatment and for 18 months after the end of study treatment.
-Legal incapacity.
-Prisoners or subjects who are institutionalized by regulatory or court order.
-Persons who are in dependence to the sponsor or an investigator.
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
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 | EUCTR2015-004936-36-NL |
| ClinicalTrials.gov | NCT02950051 |
| CCMO | NL58394.018.16 |