BR in Patients With CLL With Comorbidities and/or Renal Dysfunction
Phase: Phase 1
NCT ID: NCT01832922
(View complete trial on ClinicalTrials.gov)
DFCI Protocol ID: 13-310
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.
Dana-Farber Cancer Institute, Brigham and Women's Hospital
Jennifer Brown, MD, PhD,
Dana-Farber Cancer Institute
Dana-Farber Cancer Institute:
1. Patients must have histologically or flow cytometry confirmed diagnosis of B-cell
chronic lymphocytic leukemia/small lymphocytic lymphoma (B-CLL/SLL) according to
NCI-WG 1996 guidelines (41). The malignant B cells must co-express CD5 with CD19 or
CD20. Patients who lack CD23 expression on their leukemia cells should be examined
for (and found NOT to have) either t(11;14) or cyclin D1 overexpression, to rule out
mantle cell lymphoma.
2. Active disease meeting at least 1 of the following IWCLL 2008 criteria for requiring
1. A minimum of any one of the following constitutional symptoms:
1. Unintentional weight loss >10% within the previous 6 months prior to
2. Extreme fatigue (unable to work or perform usual activities).
3. Fevers of greater than 100.5 F for ≥2 weeks without evidence of infection.
4. Night sweats without evidence of infection.
2. Evidence of progressive marrow failure as manifested by the development of, or
worsening of anemia or thrombocytopenia.
3. Massive (ie, >6 cm below the left costal margin), progressive or symptomatic
4. Massive nodes or clusters (ie, > 10 cm in longest diameter) or progressive
5. Progressive lymphocytosis with an increase of >50% over a 2-month period, or an
anticipated doubling time of less than 6 months.
6. Autoimmune anemia or thrombocytopenia that is poorly responsive to
3. Prior treatment: Patients have not had prior treatment of CLL OR Previously treated
relapsed CLL patients must have received not more than 3 prior therapies for CLL.
Prior bendamustine and rituximab are allowed.
4. Patients must have ECOG performance status 0-3.
5. Patients must have a Cumulative Illness Risk Score [CIRS]≥7 with at least one grade
3-4 category [CLL will not be considered a comorbidity]; or estimated creatinine
clearance (CrCL) using the Cockcroft-Gault equation ≥15 mL/min but ≤40 ml/min
(Appendix 1: CCI Criteria).
6. Patients must have organ function as defined below:
- direct bilirubin ≤2 X institutional ULN (unless due to known Gilbert's syndrome
or compensated hemolysis directly attributable to CLL)
- AST or ALT < 2.5 X institutional ULN
- estimated CrCL using the Cockcroft-Gault equation ≥15 mL/min.
- Absolute neutrophil count (ANC) ≥500/mm3 independent of growth factor support;
- platelets ≥30,000/mm3 independent of transfusion support with no active
7. Ability to understand and the willingness to sign a written informed consent
8. Women of childbearing potential must have a negative serum human chorionic
gonadotropin or urine pregnancy test at screening.
9. All patients of reproductive potential (heterosexually active men and women) must
agree to a use of a barrier method of contraception and a second method of
contraception and men must agree not to donate sperm during the study and for 3
months after receiving the last dose of study treatment.
1. Recent therapeutic intervention including a) prior nitrosoureas or mitomycin C within
6 weeks; b) therapeutic anticancer antibodies (including rituximab) within 4 weeks;
c) radio- or toxin-immunoconjugates within 10 weeks; d) all other chemotherapy,
radiation therapy within 3 weeks prior to initiation of therapy.
2. Inadequate recovery from adverse events related to prior therapy to grade ≤1
(excluding Grade 2 alopecia and neuropathy).
3. Bendamustine-refractory (no response to a regimen containing bendamustine) or relapse
following treatment with a bendamustine-containing regimen within 6 months of
treatment with that regimen.
4. Chronic use of corticosteroids in excess of prednisone 20 mg/day or its equivalent or
chronic use of other immunosuppressive agents (azathioprine, methotrexate,
tacrolimus, cyclosporine). Stem cell transplant recipients must have no evidence of
active graft-versus-host disease.
5. History of prior malignancy except: a) Malignancy treated with curative intent and no
known active disease present for ≥ 2 years prior to initiation of therapy on current
study; b) adequately treated non-melanoma skin cancer or lentigo maligna without
evidence of disease; c) adequately treated in situ carcinomas (eg, cervical,
esophageal, etc.) without evidence of disease; d) asymptomatic prostate cancer
managed with "watch and wait" strategy.
6. Uncontrolled immune hemolysis or thrombocytopenia (positive direct antiglobulin test
in absence of hemolysis is not an exclusion).
7. Known Richter's transformation.
8. Advanced renal failure (estimated CrCL < 15 mL/min) or on dialysis.
9. Human Immunodeficiency Virus (HIV) or Hepatitis C antibody positivity, or active
10. Major surgery (requiring general anesthesia) within 30 days prior to initiation of
11. Uncontrolled bacterial, viral, or fungal infection.
12. Inability to adhere to the study schedule or the required follow-up.