Efficacy ObjectivesThe primary efficacy objective:• To evaluate the efficacy of GDC-0199 and rituximab (GDC-0199+R) compared with bendamustine and rituximab (BR) in patients with relapsed or refractory chronic lymphocytic leukemia (CLL) as measured…
ID
Source
Brief title
Condition
- Leukaemias
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary efficacy outcome measure for this study is investigator-assessed
PFS, defined as the time from randomization to the first occurrence of
progression or relapse, determined using standard iwCLL guidelines (Hallek et
al. 2008), or death from any cause, whichever comes first.
Secondary outcome
The secondary efficacy outcome measures for this study are as follows:
• IRC-assessed PFS in the subset of CLL patients with 17p deletion identified
by FISH testing at a central laboratory.
• IRC-assessed PFS, defined as the time from randomization to the first
occurrence of progression or relapse, or death from any cause.
• Investigator-assessed PFS in the subset of CLL patients with 17p deletion
identified by FISH testing at a central laboratory.
• Overall response (OR; defined as complete response [CR], complete response
with incomplete marrow recovery [CRi], and partial response [PR]), PR, and
CR/CRi rates at 12 weeks after Day 1 of the last cycle of multi-agent therapy,
as assessed by the investigator. Disease response will be assessed according to
the iwCLL guidelines (Hallek et al. 2008).
• OR, PR, CR, and CRi rates 12 weeks after Day 1 of the last cycle of
multi-agent therapy, as assessed by the IRC.
• Investigator-assessed PFS and IRC-assessed PFS.
• Overall survival (OS), defined as the time from randomization to death from
any cause.
• Duration of response (DOR), defined for patients with a best OR of CR, CRi,
or PR as the time from first occurrence of a documented CR or PR to disease
progression/relapse, as assessed by the investigator, or death from any cause.
• Time to next anti-CLL treatment (TTNT), defined as the time from
randomization to start of new non-protocol anti-CLL therapy or death from any
cause.
• Proportion of patients with MRD-negativity at the disease response
assessment time points as measured at a central laboratory on peripheral blood
and/or BM samples.
Background summary
Chronic lymphocytic leukemia (CLL) is the most common of the chronic leukemias,
comprising 30% of all adult leukemias. More than 50% of CLL patients are
asymptomatic at diagnosis and require no treatment. Symptoms appear as the
disease progresses. Treatment is initiated when a patient*s disease becomes
symptomatic or progressive as defined by the international workshop on Chronic
Lymphocytic Leukemia (iwCLL)*s updated guidelines for diagnosis and treatment
of CLL (Hallek et al. 2008). Response rates to initial treatment are high, but
relapsed or refractory disease is often characterized by resistance to
chemotherapy (ie, fludarabine or alkylating agents). Rituximab is approved for
the treatment of both previously treated and previously untreated CLL in
combination with chemotherapy in Europe and with fludarabine and
cyclophosphamide (FC) in the U.S. Besides the regimen of FC and rituximab
(FCR), the combination regimen approved in the U.S., one of the more commonly
used and active regimens in relapsed CLL is the combination of bendamustine and
rituximab (BR). The BR regimen was demonstrated to have meaningful clinical
activity in relapsed/refractory CLL patients with an observed overall response
(OR) rate of 59% and a median progression-free survival (PFS) of 15.2 months
(Fischer et al. 2011).
GDC-0199 is an experimental drug that blocks the function of the protein Bcl-2.
Bcl-2 overexpression is a major contributor to the pathogenesis of several
lymphoid malignancies and is overexpressed in acute and chronic leukemias.
Bcl-2 is a *pro-survival* protein that helps cells survive and resist the
effects of anti-cancer treatments. It is thought that by blocking the function
of Bcl-2, GDC-0199 could kill CLL cells and/or make them more vulnerable to the
effects of other anti-CLL treatments. The purpose of this study is to test the
effects of the combination of GDC-0199 with rituximab versus a standard
treatment regimen, bendamustine plus rituximab.
Despite recent progress, CLL remains incurable; therefore, there is a need for
the development of new treatments, which could improve both response rate and
the survival of these patients.
Study objective
Efficacy Objectives
The primary efficacy objective:
• To evaluate the efficacy of GDC-0199 and rituximab (GDC-0199+R) compared with
bendamustine and rituximab (BR) in patients with relapsed or refractory chronic
lymphocytic leukemia (CLL) as measured by investigator-assessed
progression-free survival (PFS).
While the primary efficacy endpoint is investigator-assessed PFS, PFS based on
IRC assessments will also be analyzed to support the primary analysis. In the
United States, IRC-assessed PFS will be the basis for regulatory decisions.
The secondary efficacy objectives:
• To analyze Independent Review Committee (IRC)-assessed PFS in the subset of
CLL patients with 17p deletion identified by fluorescence in situ hybridization
(FISH) testing performed at a central laboratory.
• To evaluate PFS as assessed by an IRC.
• To evaluate rate of best OR (defined as CR, CRi, nodular partial response
(nPR), and PR), as assessed by the invesgitator
• To evaluate OR rate, CR, CRi, nPR and PR at end of combination treatment
response visit, as assessed by the investigator
• To evaluate OR, CR, CRi, nPR and PR rates at end of combination treatment
response visit, as assessed by the IRC.
• To evaluate overall survival (OS).
• To evaluate event-free survival (EFS)
• To evaluate duration of response (DOR) for patients with a best overall
response of CR, CRi, nPR or PR.
• To evaluate time to next anti-CLL treatment (TTNT).
• To evaluate the proportion of patients with minimal residual disease
(MRD)-negativity at the disease response assessment time points.
Safety Objectives
• To evaluate the safety of GDC-0199 and rituximab compared with BR in patients
with relapsed or refractory CLL, focusing on serious adverse events, National
Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0
(NCI CTCAE, v4.0) Grade >= 3 adverse events, and Grade >= 3 laboratory
toxicities.
Pharmacodynamic Objectives
• To assess changes in lymphocyte subset counts during the study (eg, T and B
cells).
Pharmacokinetic Objectives
• To characterize the pharmacokinetics of GDC-0199 in patients with relapsed or
refractory CLL.
Patient-Reported Outcome Objectives
• To compare treatment-related symptoms following treatment with GDC-0199 and
rituximab compared with BR in patients with relapsed or refractory CLL, as
measured by M. D. Anderson Symptom Inventory (MDASI) and European Organisation
for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core
30 (QLQ-C30) and associated CLL module (QLQ-CLL16).
• To evaluate changes from baseline CLL symptoms scores using MDASI and EORTC
QLQC30 and QLQ-CLL16 questionnaires.
• To evaluate time to disease-related symptom progression using EORTC QLQ-CLL16
health-related quality of life (HRQoL) using global health status/quality of
life (QoL) and other functional subscales of QLQ-C30.
• To assess interference of treatment and disease-related symptoms on QoL using
the MDASI questionnaire.
Health Economic Objectives
• To compare the health economic effects of GDC-0199 in combination with
rituximab versus BR in patients with relapsed or refractory CLL as measured by
the EuroQol 5 Dimension (EQ-5D) questionnaire.
Exploratory Objectives
• To evaluate the relationship between efficacy outcome and potential
biomarkers, including Bcl-2 expression, for patients treated with GDC-0199 and
rituximab compared with BR.
• To evaluate potential biomarkers that are prognostic and/or predictive of
response and resistance to treatment with GDC-0199 and rituximab or with BR.
Study design
This is an open-label, international, multicenter, randomized, phase III study
to investigate the efficacy and safety of GDC-0199 in combination with
rituximab (GDC-0199+R) compared with bendamustine in combination with rituximab
(BR) in patients with relapsed or refractory CLL.
Approximately 370 patients will be enrolled and randomized 1:1 to receive
either GDC-0199+R (Arm A) or BR (Arm B). Randomization will be stratified
according to the following factors:
• 17p deletion: yes or no
• risk status: high risk or low risk
• geographic region: U.S./Canada, Australia/New Zealand, Western Europe,
Central and Eastern Europe, Asia, or Latin America.
Patients randomized to Arm A (GDC-199+R) will have a 4-5 week GDC-0199 dose
ramp-up period to reach the target dose of 400 mg daily. Following the GDC-0199
ramp-up period, patients will receive 6 cycles of rituximab consisting of a
single infusion on the first day of each 28-day cycle. Patients will continue
to take their daily dose of GDC-0199 during the rituximab cycles. Patients who
have not progressed following the completion of the 6 cycles will continue to
receive GDC-0199 until disease progression or for a maximum of 2 years from
Cycle 1 Day 1.
Patients randomized to Arm B (BR) will receive 6 cycles of BR consisting of a
single infusion of rituximab on Day 1 and bendamustine infusions on Days 1 and
2 of each 28-day cycle. After completion of the 6 cycles, patients will
continue to be followed up until progression or study end.
All patients will be assessed for response to treatment by the investigator
using standard clinical and laboratory examinations and CT scans according to
iwCLL guidelines (Hallek et al. 2008) at screening and at the following time
points (selected to mirror those used in current phase III CLL protocols
[CLL10, CLL11]):
• interim assessment (within 14 days of Cycle 4, Day 1)
• at completion of multi-agent therapy (4 weeks +/- 7 days after Day 1 of the
last cycle of rituximab (Arm A) or BR (Arm B), clinical assessment only)
• 8-12 weeks after multi-agent therapy (defined as 8-12 weeks after Day 1 of
Cycle 6 or 8-12 weeks after Day 1 of the last cycle for early termination).
Following 6 cycles of multi-agent therapy, patients in both arms who have not
progressed will be followed clinically every 3 months through Year 3 from
initiation of multi-agent therapy (Cycle 1, Day 1). Patients will then be
followed every 6 months until disease progression, study withdrawal, or end of
study, whichever comes first. At each follow-up visit, patients will be
assessed for response/progression by physical examination and laboratory tests.
In addition, at any time during follow-up when clinical or laboratory findings
suggest that the response may have improved from stable disease (SD) to PR, or
from PR to CR, imaging should be performed to confirm the response. Imaging is
not routinely required to determine PD, as objective evidence of PD is most
often documented by measurement of elevated peripheral CLL cells. However, when
PD cannot be documented by increasing peripheral blood counts, imaging is
required to document PD detected by physical examination or suspected based on
symptoms.
After 5 years in the study or after disease progression (whichever comes
first), patients will be followed annually for OS, PD, and new anti-CLL therapy
until up to 3 years after the last patient is enrolled, withdrawal of consent,
or the end of study, whichever comes first. Annual follow-up may be conducted
by telephone contact.
Patients who discontinue all components of study therapy either prior to
completion of planned therapy or prior to disease progression (eg, for
toxicity) will continue to be followed for MRD levels, PD, and OS (regardless
of whether they subsequently receive new anti-CLL therapy).
An independent review of the responses of all patients will also be conducted
to confirm the primary PFS endpoint, including blinded review of clinical and
laboratory findings as well as blinded radiology review of imaging assessments.
Intervention
Test Product
Arm A: GDC-0199 and Rituximab (GDC-0199+R)
• GDC-0199 tablets will be administered daily orally, starting with a test
dose of 20 mg on Day 1 of the GDC-0199 dose ramp-up period, followed (if
tolerated) by 50 mg daily from Day 2 to Day 7 followed by 100 mg daily from Day
8 to Day 14, followed by 200 mg daily from Day 15 to Day 21, followed by 400 mg
daily from Day 22 to Day 28. There is a possibility that this dose ramp-up
period may be one extra week longer to account for a possible continuation of
the 20 mg test dose for 1 week prior to increasing the dose to 50 mg. GDC-0199
will then be self-administered at 400 mg per day for a maximum of 2 years from
Cycle 1, Day 1 or until disease progression (whichever is earlier). Multi-agent
therapy consisting of 6 cycles of rituximab and daily GDC-0199 dosing will
start after completion of the GDC-0199 ramp-up period.
• Rituximab will be administered intravenously at a dose of 375 mg/m2 on Day 1
of Cycle 1 followed by 500 mg/m2 IV on Day 1 of Cycles 2 through 6.
Comparator
Arm B: Bendamustine and Rituximab (BR):
• Bendamustine will be administered at 70 mg/m2 IV on Days 1 and 2 of Cycles 1
through 6.
• Rituximab will be administered at 375 mg/m2 IV on Day 1 of Cycle 1 and 500
mg/m2 IV on Day 1 of Cycles 2 through 6.
Study burden and risks
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Age
Inclusion criteria
• Signed informed consent.
• Age greater than or equal to 18 years.
• Diagnosis of CLL that meets published diagnostic criteria (Hallek et al.
2008). Patients must have peripheral blood B-lymphocyte counts which clonally
express CD5, CD19/20, and CD23 and are either kappa or lambda
light-chain-restricted. Pro-lymphocytes may comprise no more than 55% of total
circulating lymphocytes. At initial diagnosis of CLL (ie, prior to front-line
treatment), the peripheral lymphocyte count must have been greater than
5000/mm3. Patients must meet the following criteria for relapsed or refractory
CLL (per the iwCLL guidelines [Hallek et al. 2008]):
• Relapsed disease: a patient who previously achieved a CR or PR, but after a
period of 6 months or more demonstrates evidence of progression;
• Refractory disease: treatment failure or disease progression within 6 months
of the last anti-leukemia therapy.
• Previously treated with at least one but not more than three lines of therapy
(a line of therapy is defined as completing at least two cycles of treatment
for a given line of therapy), including at least one prior standard
chemotherapy-containing regimen according to current guidelines.
• For patients with 17p deletion, previously treated with at least one but not
more than three lines of therapy, including at least one prior standard
chemotherapy-containing regimen according to current guidelines OR at least one
prior alemtuzumab-containing therapy.
• Patients previously treated with bendamustine only if their duration of
response was greater than or equal to 24 months.
• Patient requires treatment in the opinion of the investigator.
• Eastern Cooperative Oncology Group (ECOG) performance score of less than or
equal to 1.
• Adequate BM function independent of growth factor or transfusion support, per
local laboratory reference range at screening as follows:
• platelet count greater than or equal to 75 000/mm3;
• absolute neutrophil count (ANC) greater than or equal to 1000/mm3 unless
cytopenia is clearly due to marrow involvement of CLL;
• total hemoglobin greater than or equal to 9 g/dL (without transfusion
support within 2 weeks of screening);
• if any of the above-mentioned cytopenias are present, there should be no
evidence of myelodysplastic syndrome (MDS) or hypoplastic BM.
• Adequate renal and hepatic function, per laboratory reference range at
screening as follows:
• Calculated creatinine clearance greater than or equal to 50 mL/min using
24-hour creatinine clearance or modified Cockcroft - Gault equation (using
ideal body mass [IBM] instead of mass):
eCCr = (140 - Age) • IBM (kg) • [0.85 if female] /
72 • serum creatinine (mg/dL)
Or, if serum creatinine is in micromol/L:
eCCr = (140 - Age) • IBM (kg) • [1.23 if male, 1.04 if female]
serum creatinine (micromol/L)
IBM should be used:
IBM (kg) = [(height in cm - 154) x 0.9] + (50 if male, 45.5 if female)
• aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less than
or equal to 3.0 x the upper limit of normal (ULN) of the institution's normal
range;
• bilirubin greater than or equal to 1.5 x ULN. Patients with Gilbert's
syndrome may have a bilirubin level greater than 1.5 x ULN, per discussion
between the investigator and the Medical Monitor;
• prothrombin time (or international normalized ratio) and partial
thromboplastin time not to exceed 1.2 x the institution*s normal range
(patients with an elevated prothrombin time and known lupus anticoagulant may
be eligible for participation after consulting the Medical Monitor).
• Female patients must be surgically sterile, postmenopausal (for at least 1
year), or have negative results for a pregnancy test performed as follows:
• at screening, on a serum sample obtained within 14 days prior to initiation
of study treatment, and
• prior to dosing, on a urine sample obtained on Week 1 Day 1 if it has been
more than 7 days since obtaining the serum pregnancy test result.
• Female patients who are not surgically sterile or postmenopausal (for at
least 1 year) must practice at least one of the following methods of birth
control throughout the duration of study participation and for at least 30 days
after study treatment or 12 months after completing therapy with rituximab,
whichever is later:
• total abstinence from sexual intercourse;
• a vasectomized partner;
• hormonal contraceptives (oral, parenteral, vaginal ring, or transdermal) that
started at least 3 months prior to study drug administration;
• double-barrier method (condom + diaphragm or cervical cup with spermicidal
contraceptive sponge, jellies, or cream).
• Non-vasectomized male patients must practice at least one of the following
methods
of birth control throughout the duration of study participation and for at
least 30 days after study treatment or 12 months after completing therapy with
rituximab,
whichever is later:
• a partner who is surgically sterile or postmenopausal (for at least 1 year)
or who is taking hormonal contraceptives (oral, parenteral, vaginal ring, or
transdermal) for at least 3 months prior to study drug administration;
• total abstinence from sexual intercourse;
• double-barrier method (condom + diaphragm or cervical cup with spermicidal,
contraceptive sponge, jellies, or cream).
Exclusion criteria
• Transformation of CLL to aggressive NHL (eg, Richter*s transformation,
prolymphocytic leukemia, or DLBCL) or CNS involvement by CLL.
• Undergone an allogeneic stem cell transplant.
• Uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia.
• History of intolerance to prior bendamustine treatment (defined as toxicity
requiring permanent discontinuation of bendamustine) or other contraindication
to bendamustine treatment.
• History of severe (ie, requiring permanent discontinuation of prior rituximab
therapy) prior allergic or anaphylactic reactions to rituximab.
• Known HIV-positivity.
• Positive test results for chronic hepatitis B infection (defined as positive
HBsAg serology) Patients with occult or prior hepatitis B infection (defined as
positive total HBcAb and negative HBsAg) may be included if HBV DNA is
undetectable. These patients must be willing to undergo monthly PCR HBV DNA
testing.
• Positive test results for hepatitis C (HCV antibody serology testing)
Patients positive for HCV antibody are eligible only if PCR is negative for HCV
RNA.
• Requires the use of warfarin (due to potential drug - drug interactions that
may potentially increase the exposure of warfarin). Patients may be eligible
if able to be taken off warfarin and started on an alternative anticoagulant.
• Received an anti-CLL monoclonal antibody within 8 weeks prior to the first
dose of study drug.
• Received any of the following agents within 14 days prior to the first dose
of study drug, or has not recovered to less than Grade 2 clinically significant
adverse effect(s)/toxicity(s) of the previous therapy:
• any anti-cancer therapy including chemotherapy or radiotherapy and steroid
therapy for anti-neoplastic intent;
• investigational therapy, including targeted small-molecule agents.
• Received potent CYP3A4 inhibitors (such as fluconazole, ketoconazole, and
clarithromycin) within 7 days prior to the first dose of GDC-0199.
• Received potent CYP3A4 inducers (such as rifampin, carbamazepine, phenytoin,
St. John*s Wort) within 7 days prior to the first dose of GDC-0199.
• History of prior GDC-0199 treatment.
• Consumed grapefruit or grapefruit products, Seville oranges (including
marmalade containing Seville oranges), or star fruit within 3 days prior to the
first dose of GDC-0199.
• A cardiovascular disability status of New York Heart Association Class
greater than or equal to 3. Class 3 is defined as cardiac disease in which
patients are comfortable at rest but marked limitation of physical activity due
to fatigue, palpitations, dyspnea, or anginal pain.
• A significant history of renal, neurologic, psychiatric, endocrine,
metabolic, immunologic, cardiovascular, or hepatic disease that, in the opinion
of the investigator, would adversely affect the patient*s participation in this
study or interpretation of study outcomes.
•Major surgery within 30 days prior to the first dose of GDC-0199.
•A female patient who is pregnant or breast-feeding.
• History of prior other malignancy that could affect compliance with the
protocol or interpretation of results with the exception of the following:
• curatively treated basal cell carcinoma or squamous cell carcinoma of the
skin or carcinoma in situ of the cervix at any time prior to study;
• other cancers not specified above which have been curatively treated by
surgery and/or radiation therapy from which patient is disease-free for more
than or equal to 5 years without further treatment.
• Malabsorption syndrome or other condition that precludes enteral route of
administration.
• Known allergy to both xanthine oxidase inhibitors and rasburicase.
• Evidence of other clinically significant uncontrolled condition(s) including,
but not limited to, uncontrolled systemic infection (viral, bacterial, or
fungal).
• Vaccination with a live vaccine within 28 days prior to randomization.
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 | EUCTR2013-002110-12-NL |
| Other | EUDRACT NUMBER: 2013-002110-12, IND NUMBER: 110159 |
| CCMO | NL46429.018.13 |