CHRONIC LYMPHOCYTIC LEUKEMIA
Conditions
Interventions
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
Sponsors
AbbVie Deutschland GmbH & Co. KG
Eligibility
Age
18 Years to 99 Years
Inclusion criteria
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 no
Exclusion criteria
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 whic
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 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
| Measure | Time frame |
|---|---|
| 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. | — |
Countries
Netherlands
Outcome results
None listed