A MULTICENTER, PHASE III, OPEN-LABEL, RANDOMIZED STUDY IN RELAPSED/REFRACTORY PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA TO EVALUATE THE BENEFIT OF GDC-0199 (ABT-199) PLUS RITUXIMAB COMPARED WITH BENDAMUSTINE PLUS RITUXIMAB
- Conditions
- CHRONIC LYMPHOCYTIC LEUKEMIA10024324
- Registration Number
- NL-OMON53139
- Lead Sponsor
- AbbVie Deutschland GmbH & Co. KG
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Completed
- Sex
- Not specified
- Target Recruitment
- 60
• 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 no
• 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 whic
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method <p>The primary efficacy outcome measure for this study is investigator-assessed<br /><br>PFS, defined as the time from randomization to the first occurrence of<br /><br>progression or relapse, determined using standard iwCLL guidelines (Hallek et<br /><br>al. 2008), or death from any cause, whichever comes first.</p><br>
- Secondary Outcome Measures
Name Time Method