Chronic Lymphocytic Leukemia
Conditions
Keywords
B-cell chronic lymphocytic leukemia, stage III chronic lymphocytic leukemia, stage IV chronic lymphocytic leukemia, stage I chronic lymphocytic leukemia, stage II chronic lymphocytic leukemia
Brief summary
RATIONALE: Monoclonal antibodies, such as alemtuzumab, can block cancer growth in different ways. Some block the ability of cancer cells to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. PURPOSE: This phase I/II trial is studying the side effects and best dose of alemtuzumab in treating patients with B-cell chronic lymphocytic leukemia.
Detailed description
OBJECTIVES: * To determine the safest dose of alemtuzumab as consolidation therapy in patients in second remission after fludarabine phosphate alone; fludarabine phosphate and cyclophosphamide; fludarabine phosphate, cyclophosphamide, and rituximab; bendamustine hydrochloride alone; or bendamustine hydrochloride and rituximab. * To determine the frequency of cytomegalovirus reactivations or infections during or after alemtuzumab treatment. * To determine which dose of alemtuzumab is efficient to eliminate minimal residual disease in peripheral blood and bone marrow (i.e., to turn a clinical partial remission into a clinical complete remission \[CR\], to turn a flow cytometry-positive CR into a flow cytometry-negative CR, or to turn a PCR-positive CR into a PCR-negative CR). * To determine the pharmacokinetic profile of alemtuzumab. * To compare the pharmacokinetic profile between intravenous versus subcutaneous administration of alemtuzumab. OUTLINE: This is a multicenter, dose-escalation study of alemtuzumab. * Group 1: Patients receive escalating doses of alemtuzumab IV over 2 hours once weekly for 8 weeks until the maximum tolerated dose (MTD) is determined. * Group 2: Patients receive escalating doses of alemtuzumab subcutaneously once weekly for 8 weeks, beginning with the MTD determined in group 1 until a second MTD is determined. Patients undergo bone marrow and blood sample collection periodically for laboratory and pharmacokinetic studies. Samples are analyzed for minimal residual disease and T-cell subsets (i.e., CD4 and CD8) via quantitative-PCR analysis and flow cytometry and cytomegalovirus antigens via PCR. After completion of study treatment, patients are followed at 3, 6, 9, 12, 18, and 24 months.
Interventions
BIOLOGICALAlemtuzumab i.v.
Alemtuzumab will be administered once per week as a 2 h infusion * Dose level I: 10mg once weekly (start with dose escalation : 3 mg on day 1, 10mg on day 2) Duration * Dose level II: 20mg once weekly (start with dose escalation: 3mg on day 1, 10mg on day 2, 20mg on day 3) * Dose level III: 30mg once weekly (start with dose escalation: 3mg on day 1, 10mg on day 2, 30mg on day 3)
BIOLOGICALAlemtuzumab s.c.
Alemtuzumab will be administered once per week subcutaneously * Dose level I: 10mg once weekly (start with dose escalation : 3 mg on day 1, 10mg on day 2) Duration * Dose level II: 20mg once weekly (start with dose escalation: 3mg on day 1, 10mg on day 2, 20mg on day 3) * Dose level III: 30mg once weekly (start with dose escalation: 3mg on day 1, 10mg on day 2, 30mg on day 3)
Sponsors
German CLL Study Group
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
DISEASE CHARACTERISTICS: Inclusion criteria: * Diagnosis of B-cell chronic lymphocytic leukemia (B-CLL) * Disease in complete or partial remission after completion of 4-6 courses of second-line cytoreductive therapy no less than 90 days and no more than 150 days ago * Second-line cytoreductive therapy must comprise 1 of the following regimens: * Fludarabine phosphate alone (F) * Fludarabine phosphate and cyclophosphamide (FC) * Fludarabine phosphate, cyclophosphamide, and rituximab (FCR) * Bendamustine hydrochloride alone (B) * Bendamustine hydrochloride and rituximab chemotherapy (BR) * Complete minimal residual disease response defined by the following: * At least negativity of 4-color-cytometry and/or even PCR-amplifiable clonal CDR III rearrangement of the IgV\_H * For PCR analysis, blood sample need to be taken at beginning or during second-line cytoreductive therapy before achievement of a clinical complete remission * Disease not refractory to first-line F/FC/FCR/B/BR if received such therapy
Exclusion criteria
* Presence of bulky lymph nodes (\> 5 cm) after second-line F/FC/FCR/B/BR * Clinically apparent autoimmune cytopenia (i.e., autoimmune hemolytic anemia, autoimmune thrombocytopenia, or pure red cell aplasia) * CNS involvement with B-CLL PATIENT CHARACTERISTICS: Inclusion criteria: * ECOG performance status 0-1 * ANC ≥ 1,500/µL * Platelets ≥ 50,000/µL * Creatinine ≤ 1.5 times the upper normal limit (ULN) * Conjugated bilirubin ≤ 2 times ULN * Thyroid function normal * Not pregnant or nursing * Fertile patients must use effective contraception
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose-limiting toxicity | 28 days after the last dose of study medication | • Dose-limiting toxicity (DLT) and maximal tolerable dose (MTD) DLT is defined as a) all grade III/IV non-hematologic toxicity and b) all grade IV hematologic toxicity lasting for more than 2 weeks (excluding lymphopenia) occuring during or within 4 weeks after end of consolidation therapy. |
| Maximum tolerated dose | 28 days after the last dose of study medication | • Dose-limiting toxicity (DLT) and maximal tolerable dose (MTD) DLT is defined as a) all grade III/IV non-hematologic toxicity and b) all grade IV hematologic toxicity lasting for more than 2 weeks (excluding lymphopenia) occuring during or within 4 weeks after end of consolidation therapy. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Rate of infections (especially CMV infections and reactivations) | upt to 24 months after last dose of study medication (end of study) | — |
| Rate of severe hematologic and non-hematologic side effects | 28 days after the last dose of study medication | — |
| Pharmacokinetics of alemtuzumab (after IV and subcutaneous administration) | up to 8 weeks during the alemtuzumab treatment | Pharmacokinetic samples will be taken at week 4 and 8 during alemtuzumab treatment at the following time points: 0, 4, 8, 24, 48, 96, 168 h |
| Rate of complete minimal residual disease response | will be tested repeatedly, first time 3 months after the last dose of study medication, last time point 24 months after last dose of study medication | • Rate of molecular responses (defined by negativity of 4- colour- cytometry in BOTH peripheral blood AND bone marrow in patients in clinical CR) The approved laboratory diagnostics for detection of MRD response is 4-colour flow cytometry. Collaterally, it is possible to take samples for potential PCR- analysis for confirmation if available. |
| Overall survival | upt to 24 months after last dose of study medication (end of study) | — |
| Complete remission rate | 28 days after the last dose of study medication | — |
| Progression-free survival | upt to 24 months after last dose of study medication (end of study) | — |
| Rate of immunophenotypic remission using 4-color flow cytometry | will be tested repeatedly, first time 3 months after the last dose of study medication, | — |
Countries
Germany
Outcome results
None listed