Clinical Trials List
Protocol NumberGO28667
NCT Number(ClinicalTrials.gov Identfier)NCT02005471
2013-11-01 - 2018-11-30
Phase III
Terminated7
ICD-9204.10
Chronic lymphoid leukemia, without mention of remission
A Multicenter, Phase III, Open-Label, Randomized Study in Relapsed/Refractory Patients With Chronic Lymphocytic Leukemia to Evaluate the Benefit of Venetoclax (GDC-0199/ABT-199) Plus Rituximab Compared With Bendamustine Plus Rituximab
-
Trial Applicant
AbbVie
-
Sponsor
F. Hoffmann-La Roche Ltd and AbbVie Inc
-
Trial scale
Multi-Regional Multi-Center
-
Update
2025/08/20
Investigators and Locations
Co-Principal Investigator
- Jih-Luh Tang Division of Hematology & Oncology
- Huai-Hsuan Huang Division of General Internal Medicine
- MING YAO Division of Hematology & Oncology
- Wen-Chien Chou Division of Hematology & Oncology
- - - Division of Hematology & Oncology
- - - Division of Hematology & Oncology
- Sheng-chieh Chou Division of Hematology & Oncology
The Actual Total Number of Participants Enrolled
0 Stop recruiting
Co-Principal Investigator
- Shang-Yin Wu Division of Hematology & Oncology
- Yu-Min Yeh Division of Hematology & Oncology
- Wei-Pang Chung Division of Hematology & Oncology
The Actual Total Number of Participants Enrolled
0 Stop recruiting
Co-Principal Investigator
- Li-Yuan Bai Division of Hematology & Oncology
- Ching-Chan Lin Division of Hematology & Oncology
- Chang-Fang Chiu Division of Hematology & Oncology
- Ming-Yu Lien Division of Hematology & Oncology
The Actual Total Number of Participants Enrolled
0 Stop recruiting
Co-Principal Investigator
- 楊陽生 Division of Hematology & Oncology
- Chieh-Lin Teng Division of Hematology & Oncology
The Actual Total Number of Participants Enrolled
0 Stop recruiting
Co-Principal Investigator
- Tung-Liang Lin Division of Hematology & Oncology
- Po-Nan Wang Division of Hematology & Oncology
The Actual Total Number of Participants Enrolled
0 Stop recruiting
The Actual Total Number of Participants Enrolled
0 Stop recruiting
Co-Principal Investigator
- 張肇松 Division of Hematology & Oncology
- 吳承翰 Division of Hematology & Oncology
- Hui-Hua Hsiao Division of Hematology & Oncology
- 蔡郁棻 Division of Hematology & Oncology
- Sheng-Fung Lin Division of Hematology & Oncology
- 許瑞峰 Division of Hematology & Oncology
- Shih-Feng Cho Division of Hematology & Oncology
- Yi-Chang Liu Division of Hematology & Oncology
The Actual Total Number of Participants Enrolled
0 Stop recruiting
Condition/Disease
CHRONIC LYMPHOCYTIC LEUKEMIA
Objectives
The primary efficacy objective for this study is as follows:
• 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).
The secondary efficacy objectives for this study are as follows:
• 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 analyze investigator-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 rates of overall response (OR; defined as complete response [CR], CRi
[complete response with incomplete marrow recovery], and PR [partial response]), PR, and
CR and CRi at 12 weeks after Day 1 of the last cycle of multi-agent therapy, as assessed
by the investigator.
• To evaluate OR, PR, CR, and CRi rates 12 weeks after Day 1 of the last cycle of multiagent therapy, as determined by the IRC.
• To evaluate PFS as assessed by the investigator and by the IRC.
• To evaluate overall survival (OS).
• To evaluate duration of response (DOR) for patients with a best overall response of CR,
CRi, 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.
Test Drug
GDC-0199(ABT-199)
Active Ingredient
GDC-0199(ABT-199)
Dosage Form
Tablet
Dosage
10 / 50 / 100
Endpoints
The primary efficacy endpoint 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. For
patients who have not progressed, relapsed, or died at the time of analysis, PFS will be
censored on the date of the last disease assessment. If no disease assessments were
performed after the baseline visit, PFS will be censored at the time of randomization.
Treatment comparison will be made using a two-sided stratified log-rank test (0.05 significance
level, appropriately adjusted for an interim analysis) stratified by 17p deletion status (yes/no),
early or late relapse or progression after prior chemotherapy-containing therapy (within
12 months after monotherapy or within 24 months after chemoimmunotherapy versus more than
12 months or 24 months after either), and geographic region (U.S./Canada, Australia/New
Zealand, Western Europe, Central and Eastern Europe, Asia, or Latin America). If the null
hypothesis is rejected and the observed hazard ratio is favorable for the GDC-0199+R
combination, then it is shown that GDC-0199+R has significantly longer PFS than BR.
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. For
patients who have not progressed, relapsed, or died at the time of analysis, PFS will be
censored on the date of the last disease assessment. If no disease assessments were
performed after the baseline visit, PFS will be censored at the time of randomization.
Treatment comparison will be made using a two-sided stratified log-rank test (0.05 significance
level, appropriately adjusted for an interim analysis) stratified by 17p deletion status (yes/no),
early or late relapse or progression after prior chemotherapy-containing therapy (within
12 months after monotherapy or within 24 months after chemoimmunotherapy versus more than
12 months or 24 months after either), and geographic region (U.S./Canada, Australia/New
Zealand, Western Europe, Central and Eastern Europe, Asia, or Latin America). If the null
hypothesis is rejected and the observed hazard ratio is favorable for the GDC-0199+R
combination, then it is shown that GDC-0199+R has significantly longer PFS than BR.
Inclution Criteria
Patients must meet the following criteria for study entry:
• Signed informed consent.
• Age ≥ 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 > 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 (Appendix 8).
• 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 alemtuzumabcontaining therapy.
• Patients previously treated with bendamustine only if their duration of response
was ≥ 24 months.
• Patient requires treatment in the opinion of the investigator.
• Eastern Cooperative Oncology Group (ECOG) performance score of ≤ 1 (see
Appendix 7).
• Adequate BM function independent of growth factor or transfusion support, per local
laboratory reference range at screening as follows:
– platelet count ≥ 75 000/mm3
;
– absolute neutrophil count (ANC) ≥ 1000/mm3
unless cytopenia is clearly due to
marrow involvement of CLL;
– total hemoglobin ≥ 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 ≥ 50 mL/min using 24-hour creatinine clearance
or modified Cockcroft −Gault equation (using ideal body mass [IBM] instead of
mass):
(140−Age) • IBM (kg) • [0.85 if female] eCCr = 72 • serum creatinine (mg/dL)
Or, if serum creatinine is in μmol/L:
(140−Age) • IBM (kg) • [1.23 if male, 1.04 if female] eCCr = serum creatinine (μmol/L)
IBM should be used:
IBM (kg) = [(height in cm− 154) × 0.9] + (50 if male, 45.5 if female)
– aspartate aminotransferase (AST) and alanine aminotransferase
(ALT) ≤ 3.0 ×the upper limit of normal (ULN) of the institution's normal range;
– bilirubin ≤ 1.5 ×ULN. Patients with Gilbert's syndrome may have a bilirubin
level > 1.5 ×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 × 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 > 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 12 months after completing therapy
with rituximab:
– 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
12 months after completing therapy with rituximab:
– 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).
• Signed informed consent.
• Age ≥ 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 > 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 (Appendix 8).
• 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 alemtuzumabcontaining therapy.
• Patients previously treated with bendamustine only if their duration of response
was ≥ 24 months.
• Patient requires treatment in the opinion of the investigator.
• Eastern Cooperative Oncology Group (ECOG) performance score of ≤ 1 (see
Appendix 7).
• Adequate BM function independent of growth factor or transfusion support, per local
laboratory reference range at screening as follows:
– platelet count ≥ 75 000/mm3
;
– absolute neutrophil count (ANC) ≥ 1000/mm3
unless cytopenia is clearly due to
marrow involvement of CLL;
– total hemoglobin ≥ 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 ≥ 50 mL/min using 24-hour creatinine clearance
or modified Cockcroft −Gault equation (using ideal body mass [IBM] instead of
mass):
(140−Age) • IBM (kg) • [0.85 if female] eCCr = 72 • serum creatinine (mg/dL)
Or, if serum creatinine is in μmol/L:
(140−Age) • IBM (kg) • [1.23 if male, 1.04 if female] eCCr = serum creatinine (μmol/L)
IBM should be used:
IBM (kg) = [(height in cm− 154) × 0.9] + (50 if male, 45.5 if female)
– aspartate aminotransferase (AST) and alanine aminotransferase
(ALT) ≤ 3.0 ×the upper limit of normal (ULN) of the institution's normal range;
– bilirubin ≤ 1.5 ×ULN. Patients with Gilbert's syndrome may have a bilirubin
level > 1.5 ×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 × 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 > 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 12 months after completing therapy
with rituximab:
– 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
12 months after completing therapy with rituximab:
– 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
Patients who meet any of the following criteria will be excluded from study entry:
• 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 hepatitis serology (serology testing required at screening), as follows:
– Hepatitis B virus (HBV): Patients with positive serology for hepatitis B defined
as positivity for hepatitis B surface antigen (HBsAg) or hepatitis B core antibody
(anti-HBc).
– Hepatitis C virus (HCV): Patients with positive hepatitis C serology unless HCV
(RNA) is confirmed negative. Note that patients with HCV- or hepatitis C virus
core antibody (HCVcAB)-positivity who have received recent IV IgG should be
evaluated further for risk of viral reactivation and may be eligible for the study
after discussion with the Medical Monitor.
• 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 (see Appendix 9).
• Received potent CYP3A4 inducers (such as rifampin, carbamazepine, phenytoin,
St. John’s Wort) within 7 days prior to the first dose of GDC-0199 (see Appendix 9).
• 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 ≥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 ≥ 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.
• 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 hepatitis serology (serology testing required at screening), as follows:
– Hepatitis B virus (HBV): Patients with positive serology for hepatitis B defined
as positivity for hepatitis B surface antigen (HBsAg) or hepatitis B core antibody
(anti-HBc).
– Hepatitis C virus (HCV): Patients with positive hepatitis C serology unless HCV
(RNA) is confirmed negative. Note that patients with HCV- or hepatitis C virus
core antibody (HCVcAB)-positivity who have received recent IV IgG should be
evaluated further for risk of viral reactivation and may be eligible for the study
after discussion with the Medical Monitor.
• 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 (see Appendix 9).
• Received potent CYP3A4 inducers (such as rifampin, carbamazepine, phenytoin,
St. John’s Wort) within 7 days prior to the first dose of GDC-0199 (see Appendix 9).
• 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 ≥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 ≥ 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.
The Estimated Number of Participants
-
Taiwan
22 participants
-
Global
370 participants
