BR in Patients With CLL With Comorbidities and/or Renal Dysfunction
|ClinicalTrials.gov Identifier: NCT01832922|
Recruitment Status : Active, not recruiting
First Posted : April 16, 2013
Last Update Posted : May 5, 2016
This is a non-randomized, open label, dose-ranging study of Bendamustine and Rituximab (BR) in patients with previously untreated or relapsed/refractory Chronic Lymphocytic Leukemia (CLL) who have multiple comorbidities with or without renal insufficiency. These agents are FDA approved for this indication. However, full dose bendamustine is associated with significant hematologic toxicity and a high rate of infectious complications in "unfit" patients and patients with significantly impaired renal function. This study will attempt to optimize and define adequate and safe treatment protocols for these patients with comorbidities and/or renal dysfunction.
The study will accrue two independent patient cohorts which will follow a standard Phase I design. Patients with CLL who have significant comorbidities with or without minor renal dysfunction (CrCL>40 mL/min) will be accrued onto Cohort 1 of the study. Patients with significant renal dysfunction (CrCL<40 mL/min) will be accrued onto Cohort 2. Once the maximum tolerated dose (MTD) is determined, two expansion cohorts will be enrolled.
There will be a treatment period of up to six 28-day cycles. On C1D1 all qualifying patients will provide samples for biomarker analysis. Six patients without renal dysfunction and 6 to 9 patients with renal dysfunction will also provide samples for bendamustine PK analysis.
Accrual of both patient cohorts will occur simultaneously and will take place at two centers: Norris Cotton Cancer Center (NCCC) and Dana-Farber Cancer Institute (DFCI). Coordination of accrual to the study cohorts will be centralized at NCCC by Dr. Alexey V. Danilov.
|Condition or disease||Intervention/treatment||Phase|
|Chronic Lymphocytic Leukemia Small Lymphocytic Lymphoma||Drug: Bendamustine Drug: Rituximab||Phase 1|
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.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||49 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Dose-Ranging Study of Bendamustine and Rituximab in Chronic Lymphocytic Leukemia (CLL) Patients With Comorbidities and/or Renal Dysfunction|
|Study Start Date :||April 2013|
|Estimated Primary Completion Date :||April 2017|
|Estimated Study Completion Date :||April 2018|
Experimental: Significant Comorbidiities
Significant comorbidities as defined by Cumulative Illness Rating Score (CIRS) of ≥7.
Other Name: TreandaDrug: Rituximab
Other Name: Rituxan
Active Comparator: Significant renal dysfunction
Significant renal dysfunction defined as CrCL 15-40 mL/min, but not receiving dialysis.
Other Name: TreandaDrug: Rituximab
Other Name: Rituxan
- Number of participants with adverse events [ Time Frame: within the first 30 days of treatment ]To evaluate the safety (MTD) of bendamustine in combination with rituximab in patients with CLL who have multiple comorbidities and/or significant renal dysfunction.
- tumor response to treatment [ Time Frame: 3 years ]To evaluate the efficacy of BR in patients with CLL who have multiple comorbidities and/or significant renal dysfunction.
- plasma bendamustine concentration versus time [ Time Frame: Days 1 and 2 ]To determine the pharmacokinetic (PK) disposition of reduced dose bendamustine in patients with renal dysfunction (CrCL≤40 mL/min).
- biomarker levels at baseline [ Time Frame: prior to Day 1 ]To assess whether established biomarkers (chromosomal abnormalities, immunoglobulin heavy chain [IGHV] mutational status, ZAP-70 and CD38 expression; p53 mutational status, microRNA expression profile) predict response to BR chemoimmunotherapy in patients with CLL who have significant comorbidities.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01832922
|United States, Massachusetts|
|Dana Farber Cancer Institute|
|Boston, Massachusetts, United States, 02215|
|United States, New Hampshire|
|Dartmouth-Hitchcock Medical Center, Norris Cotton Cancer Center|
|Lebanon, New Hampshire, United States, 03750|
|Principal Investigator:||Alexey V Danilov, MD||Dartmouth-Hitchcock Medical Center|