BR in Patients With CLL 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.

Inclusion Criteria:

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
treatment:

1. A minimum of any one of the following constitutional symptoms:

1. Unintentional weight loss >10% within the previous 6 months prior to
screening.

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
splenomegaly.

4. Massive nodes or clusters (ie, > 10 cm in longest diameter) or progressive
lymphadenopathy.

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
corticosteroids.

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 bleeding.

7. Ability to understand and the willingness to sign a written informed consent document.

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.

Exclusion Criteria:

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
hepatitis B.

10. Major surgery (requiring general anesthesia) within 30 days prior to initiation of
therapy.

11. Uncontrolled bacterial, viral, or fungal infection.

12. Inability to adhere to the study schedule or the required follow-up.