The primary objective for this study is as follows:* To evaluate clinical benefit in terms of PFS, as assessed by an IRF, for GA101 when used incombination with bendamustine compared with bendamustine alone in patients with indolentNHL refractory to…
ID
Source
Brief title
Condition
- Lymphomas non-Hodgkin's B-cell
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary Efficacy Outcome Measure
The primary efficacy endpoint, PFS, is defined as the time from randomization
to the first
occurrence of progression or relapse as assessed by an IRF according to the
modified response
criteria for NHL (Cheson et al. 2007) or death from any cause on study.
Secondary outcome
Secondary Efficacy Outcome Measures
* Overall survival
* CR, and overall response (CR or PR) at the end of 6 months of study
treatment, as assessed by the IRF according to the modified response criteria
for NHL (Cheson et al. 2007)
* Best response during treatment and up to 12 months after the start of
treatment, as assessed by the IRF
* PFS (progression-free survival) as assessed by Investigator
* Disease-free survival is defined for a best overall response of CR (i.e., as
the time from the first occurrence of a documented best response, as assessed
by the IRF, until relapse or death from any cause)
* Duration of response is defined as the time from the best overall response
(CR or PR) to the first occurrence of progression/relapse based on the IRF
assessments, or death from any cause on study.
* EFS is defined as the time between the date of randomization and the date to
disease progression/relapse based on IRF assessments, death from any cause, or
start of a new anti-lymphoma therapy.
* Medical resource utilization will include the number of hospitalizations
related to adverse events (as captured in the electronic Case Report Form
[eCRF] Serious Adverse Event Section), types of subsequent drug therapies, and
medical and surgical procedures (i.e., blood
transfusions, bone-marrow transplantation, or stem-cell transplantation).
* Change in health-related PROs from baseline to the end of study, as assessed
by the FACT-Lym instrument including:
Change from baseline in the total trial outcome (TOI): sum of physical well
being score (7 items), functional well being score (7 items), and Lym subscale
(15 items); score ranges from 0*116
Change from baseline in the FACT-Lym subscale score: 15 lymphoma-specific
items; total ranges from 0*60
Change from baseline in the FACT-Lym total score: sum of physical well being
score (7 items), social/family well being (7 items), emotional well being (6
items), functional well being (7 items), and Lym subscale (15 items); total
ranges from 0*168
* EQ-5D summary scores at baseline, during treatment, post-treatment and
progression-free, and at post-progression
Safety Outcome Measures
* Incidence, nature, and severity of adverse events with GA101 + bendamustine
versus bendamustine alone
* Changes in physical findings, and clinical laboratory results during and
following GA101 + bendamustine administration
* Incidence of HAHA
Pharmacokinetic/Pharmacodynamic Outcome Measures
* Pharmacokinetic profile (i.e., trough concentrations, clearance rate, AUC) of
GA101 in combination with bendamustine
* CD19 + B-cell counts over time in patients treated with GA101 + bendamustine
* Pharmacokinetic samples of bendamustine from the first 10 patients treated
with GA101 in combination with bendamustine and the first 10 patients treated
with bendamustine alone
Background summary
B-lymphoproliferative disorders describe a heterogeneous group of malignancies,
ranging from slow-growing, indolent non-Hodgkin*s lymphomas (NHLs), which
comprise about a third of all NHLs, to more aggressive forms of NHL. Examples
of indolent NHLs include follicular lymphoma, marginal zone lymphoma, and small
lymphocytic lymphoma. Follicular lymphoma accounts for approximately 20-25% of
new lymphomas and has a median survival of 8-10 years.
Follicular lymphoma is a neoplasm associated with follicle-center B cells and
typically contains the bcl-2 chromosomal translocation t(14:18), leading to the
overexpression of the intracellular anti-apoptotic protein, bcl-2. Patients
with low-grade or follicular NHL may achieve remission with conventional
chemotherapy,but these agents have had limited impact on survival, with 50% of
patients dying within 5 years of the first relapse.
Low-grade and follicular lymphomas are characterized by the expression of a
membrane antigen, CD20. Randomized trials have recently demonstrated that a
monoclonal antibody directed against CD20 (rituximab [Rituxan*,
MabThera*]),when added to chemotherapy, improved progression-free survival
(PFS) and overall survival (OS) in follicular lymphoma patients. However, a
growing population of patients with rituximab-refractory, indolent NHL is
emerging for which effective treatment choices are limited. Bendamustine has
recently been shown in two Phase II studies to be effective in the treatment of
rituximab-refractory indolent lymphoma, demonstrating an overall response rate
(ORR) of approximately 75%, complete response rate (CRR) of approximately 15%,
median duration of response of 6.7 - 9.2 months, and median PFS of 7.1 - 9.3
months in two separate Phase II studies (Friedberg et al. 2008; Kahl et al.
2009). Given that disease remissions are still relatively short, there is still
a medical need to improve upon the degree of and duration of treatment response
for these patients.
Study objective
The primary objective for this study is as follows:
* To evaluate clinical benefit in terms of PFS, as assessed by an IRF, for
GA101 when used in
combination with bendamustine compared with bendamustine alone in patients with
indolent
NHL refractory to prior rituximab-containing therapy
The secondary objectives for this study are as follows:
* To compare PFS (progressive-free survival) as assessed by the investigator
* To compare OS between study arms
* To evaluate in each study arm and compare between study arms the following:
overall response rate and CRR at the Study Treatment Completion / Early Study
Termination Visit; best ORR achieved during treatment or within 12 months of
the start of treatment; disease-free survival in CR patients; and duration of
response in patients with CR and PR.
* To compare event-free survival (EFS) between the two study arms
* To evaluate and compare the safety profiles of patients treated with the
combination of
GA101 + bendamustine and bendamustine alone
* To characterize the pharmacokinetics of GA101 in combination with
bendamustine and evaluate
for drug-drug interactions by comparing the pharmacokinetics of the combination
with the
pharmacokinetics of bendamustine alone
* To analyze pharmacoeconomics (medical resource utilization) in both arms of
the study
* To assess patient-reported outcomes (PROs) in both treatment arms
Study design
This is an open-label, multicenter, randomized, Phase III study to investigate
the efficacy and safety of GA101 combined with bendamustine compared with
bendamustine alone in patients with rituximab-refractory, indolent NHL.
Patients will be randomly assigned in a 1:1 ratio to the two treatment arms.
The randomization scheme will ensure approximately equal sample sizes in the
two treatment arms for the following stratification factors:
1) indolent NHL subtype (follicular vs. other);
2) refractory type
(rituximab monotherapy vs. rituximab + chemotherapy);
3) prior therapies (£ 2 vs. > 2 or any prior
bendamustine); and
4) geographic region.
Randomization will be conducted with the aid of an interactive voice-response
system (IVRS).
In the control arm of the study (Arm A), bendamustine alone at 120 mg/m2/day
will be administered IV on Days 1 and 2 of each 28-day cycle for up to six
cycles.
In the experimental arm of the study (Arm B), GA101 will be administered by IV
infusion as an absolute (flat) dose of 1000 mg on Days 1, 8, and 15 of Cycle 1;
Day 1 of Cycles 2*6 (28-day cycles); and then every 2 months until disease
progression for up to 2 years. Bendamustine 90 mg/m2/day will be given IV on
Days 2 and 3 of Cycle 1 and on Days 1 and 2 of Cycles 2*6 of each 28-day cycle
for the first 10 patients and on Days 1 and 2 of Cycles 1*6 for the remaining
patients in the trial, in order to allow for pharmacokinetic testing in the
first 10 patients enrolled in experimental arm of the the study.
All patients will be assessed for disease response by the investigator using
regular clinical and laboratory examinations and computed tomography (CT)
scans, according to the modified response criteria for NHL (Cheson et al. 2007;
see Appendix E), approximately 4 weeks after Cycle 3 (prior to Cycle 4);
approximately 28-42 days after Cycle 6; and every 2 months (3 months for CT
scans) for 24 months after the first 6 months of treatment (up to 30 months in
total if the patients has not progressed). For those patients who have not
relapsed at Follow-up Visit 16 (approx. 31 months from study treatment
initiation), disease assessments will continue every 6 months for an additional
2 years or
until disease progression (whichever occurs first).
Patients who start a new anti-lymphoma therapy in the absence of disease
progression should be followed according to the protocol schedule unless they
withdraw consent.
Patients will be followed for OS until approximately 226 deaths have occurred
(approximately 96 months).
An independent review of the responses of all patients will also be conducted,
including a blinded review of CT scans at an IRF. Independent reviews will be
performed in batch prior to the interim and final efficacy analyses. Patients
who discontinue all components of study therapy prior to disease progression
(e.g., for toxicity) will continue on study and will be followed for
progressive disease and OS (regardless of whether or not they subsequently
receive new anti-lymphoma therapy).
Safety will be evaluated by monitoring all adverse and serious adverse events.
These will be graded using the National Cancer Institute Common Terminology
Criteria for Adverse Events (NCI CTCAE), Version 4.0.
Laboratory safety assessments will include regular routine monitoring of
urinalysis, hematology and blood chemistry, and tests of immunological
parameters. In addition, tests for the presence of human anti*human antibodies
(HAHA), human anti-chimeric antibodies (HACA), and rituximab levels will be
performed (tests for HACA and rituximab levels will only be performed at
baseline).
Intervention
STUDY TREATMENT:
GA101
In Arm B, GA101 will be administered by IV infusion as an absolute (flat) dose
of 1000 mg for six cycles on Days 1, 8, and 15 of Cycle 1; Day 1 of Cycles 2*6;
and every 2 months thereafter until progression for up to 2 years.
Bendamustine
This study will use a bendamustine dose of 120 mg/m2 administered IV over 60
minutes on 2 consecutive days of each 28-day cycle for six cycles, given as
monotherapy in Arm A. In Arm B, this study will use a bendamustine dose of 90
mg/m2 administered IV over 60 minutes on 2 consecutive days of each 28-day
cycle for six cycles, given in combination with GA101.
Study burden and risks
SAFETY PLAN
This trial is designed to allow for premature termination or a modification of
the protocol (in particular, the dosing regimens) on the advice of an external
DSMB for safety concerns. After the first 20 patients (i.e., approximately 10
per arm) have received one cycle of therapy, an early safety interim analysis
will be conducted to evaluate for overt excess toxicity the combination of
GA101 + bendamustine.
Prior to this first safety interim analysis, the DSMB will conduct monthly
reviews of serious adverse events. After the first safety interim analysis, the
DSMB will continue to conduct periodic interim reviews of safety summaries
approximately twice annually. At the early and periodic interim safety
analyses, the DSMB will review summary tables of adverse events, serious
adverse events, deaths, drug exposure, early treatment discontinuations, and
early study withdrawals. The DSMB will also perform a formal interim analysis
for efficacy and futility later during the study.
Emil-Barell Strasse 1
Grenzach-Wyhlen 3446 GR
DE
Emil-Barell Strasse 1
Grenzach-Wyhlen 3446 GR
DE
Listed location countries
Age
Inclusion criteria
*History of histologically documented, CD20+, indolent NHL
*Refractory to any previous regimen containing rituximab, defined as no response to, or progression within 6 months of completion of, the last dose of rituximab therapy (either as monotherapy or in combination with chemotherapy)
*Previously treated with a maximum of four unique chemotherapy containing treatment regimens
*All patients must have at least one bi-dimensionally measurable lesion
Exclusion criteria
*Prior use of any monoclonal antibody (other than anti-CD20) within 3 months of the start of Cycle 1
*Chemotherapy or other investigational therapy within 28 days prior to the start of Cycle 1
*Prior treatment with bendamustine within 2 years of the start of cycle 1
*Prior allogeneic stem cell transplant
*History of severe allergic or anaphylactic reactions to monoclonal antibody therapy (e.g., patients in whom re-dosing with rituximab would be contraindicated for safety reasons)
*History of sensitivity to mannitol
*Central nervous system lymphoma, prior DLBLC, or histological evidence of transformation to high grade or diffuse large B-cell lymphoma
*History of other malignancy that could affect compliance with the protocol or interpretation of results
*Patients with a history of confirmed progressive multifocal encephalopathy (PML)
*Evidence of significant, uncontrolled concomitant diseases that could affect compliance with the protocol or interpretation of results
*Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) or any major episode of infection requiring treatment with intraveneous antibiotics or hospitalization (relating to the completion of the course of antibiotics) within 4 weeks of the start of cycle 1
*Vaccination with a live vaccine a minimum of 28 days prior to randomization
*Recent major surgery (within 4 weeks of the start of cycle 1), other than for diagnosis
*Presence of positive test results for Hepatitis B or Hepatitis C
*Known history of HIV seropositive status
*Positive test results for human T-lymphotropic virus type I (HTLV 1) in endemic countries
*Women who are pregnant or lactating
*Agreement to use an effective form of contraception for the duration of the study.
*Ongoing corticosteroid use > 30 mg/day prednisone or equivalent
*Radiation therapy within 42 days prior to the start of cycle 1
Design
Recruitment
Medical products/devices used
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 | EUCTR2009-015504-25-NL |
| ClinicalTrials.gov | NCT01059630 |
| CCMO | NL32564.029.10 |