A Dose-Ranging Study of Bendamustine and Rituximab in Chronic Lymphocytic Leukemia (CLL) Patients With Comorbidities and/or Renal Dysfunction
This is a non-randomized open label dose-ranging study of Bendamustine and Rituximab (BR) in
patients with previously untreated or relapsed/refractory CLL who have multiple
comorbidities (Cumulative Illness Rating Scale [CIRS]≥7) with or without renal insufficiency
(estimated creatinine clearance [CrCL] 15-40 mL/min, but not receiving dialysis).
The study will accrue two independent patient cohorts. Both cohorts will follow a standard
3+3 Phase I design. Once the maximum tolerated dose (MTD) is determined, two expansion
cohorts will be enrolled. Dose limiting toxicities (DLT) will be assessed during the 1st
cycle of treatment.
Patients with CLL who have significant comorbidities (CIRS≥7; at least one category grade
3-4), with or without minor renal dysfunction (CrCL>40 mL/min) will be accrued onto Cohort 1
of the study. At dose level 1, patients will receive bendamustine 45 mg/m2 in combination
with rituximab (375 mg/m2 with cycle 1 and 500 mg/m2 with subsequent cycles). If safe, the
dose of bendamustine will be escalated to 70 mg/m2 (dose level 2). By contrast, dose
de-escalation to 25 mg/m2 (dose level -1) will occur in this cohort if DLT's are encountered
at dose level 1. Once an MTD is determined an expansion cohort will be accrued at that dose
level to allow assessment of DLT's during subsequent cycles.
Because bendamustine has not been formally studied in patients with renal failure and due to
the potential for increased frequency of toxic events in such patients, patients with
significant renal dysfunction (CrCL 15-40 mL/min, but not receiving dialysis) will be
accrued on Cohort 2. DLT's in 0/3 (or ≤1/6) subjects with renal dysfunction at dose level 1
(as above) will permit continued accrual of such subjects onto the expansion cohort (N=10).
If unacceptable toxicity is encountered, bendamustine dose will be reduced to 25 mg/m2 (dose
level -1), followed by an expansion cohort if safe (10 patients). Dose escalation will not
be allowed in this cohort.
Accrual of both patient cohorts will occur simultaneously (see Schema) and will take place
at two centers: the ambulatory Hematology Clinics at the Norris Cotton Cancer Center (NCCC)
at Dartmouth-Hitchcock Medical Center (DHMC), Lebanon, NH (Lead [Dartmouth] Principal
Investigator [Lead PI] - Alexey Danilov M.D., Ph.D.), and the CLL Center at Dana-Farber
Cancer Institute (DFCI), Boston, MA (DFCI Principal Investigator [DFCI PI] - Jennifer Brown
M.D., Ph.D.). Coordination of accrual to the study cohorts will be centralized at the Norris
Cotton Cancer Center/DHMC by Dr. Alexey V. Danilov.
Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Number of participants with adverse events
To evaluate the safety (MTD) of bendamustine in combination with rituximab in patients with CLL who have multiple comorbidities and/or significant renal dysfunction.
within the first 30 days of treatment
Alexey V Danilov, MD
Dartmouth-Hitchcock Medical Center
United States: Institutional Review Board
|Dana Farber Cancer Institute||Boston, Massachusetts 02115|
|Dartmouth-Hitchcock Medical Center, Norris Cotton Cancer Center||Lebanon, New Hampshire 03756|