IIT CTI Bendamustine, Rituximab, Pixantrone in Relapsed/Refractory B Cell Non-Hodgkin's Lymphoma

Part 1: This is a phase I trial utilizing a traditional 3+3 design to evaluate maximum
tolerated dose (MTD) and optimal dose schedule of pixantrone in combination with bendamustine
(120mg/m2 on day 1 of each 21 day cycle) and rituximab (375mg/m2 on day 1 of each 21 day
cycle). No patients will be entered on an escalated dosage level until at least 3 patients
have been treated at the previous level and assessed for a dose limiting toxicity. Dose
levels will be escalated in cohorts of 3 patients as long as no drug-related DLT occurs in
the first 2 cycles. If one patient is observed to suffer a DLT, this cohort will be expanded
to include at least 6 patients total. If less than 2 patients in the expanded cohort of 6
patients experience a DLT, dose escalation will resume. If 2 of 6 patients enrolled at the
same dose level experience a DLT, the MTD has been exceeded, and the dose escalation will
cease. The next lower dose will be considered the MTD. If any patient withdraws from the
study prior to completing 2 cycles for reasons other than a DLT then that patient will be
replaced in order to determine the MTD.

If dose limiting toxicity is observed at the initial dose level in 2 patients, the MTD has
been exceeded and the starting dose level will be reduced to 25mg/m2. If 1 patient
experiences a DLT in the -1 dose range, the cohort will be expanded to at least 6 patients.
If a second patient experiences a DLT at the -1 dose level, the trial will be closed.

For part 1, those who have a confirmed diagnosis of relapsed/refractory B cell non-Hodgkin's
lymphoma of any subtype will be considered eligible for enrollment. Each cycle will be 21
days. Subjects will be assessed for DLTs during the first 2 cycles of study drug. They will
be assessed for response after cycle 2. Patients not experiencing a DLT during the first 2
cycles and who have stable disease or better may continue to receive up to 6 cycles of
treatment with the triplet combination. If any patient withdraws from the study prior to
completing 2 cycles for reasons other than a DLT then that patient will be replaced in order
to determine the MTD.

Part 2: It is a phase II, prospective, open label, single arm study of the combination of
bendamustine, pixantrone and rituximab. The dose of pixantrone will be the MTD determined
during Part 1 of the study. A confirmed diagnosis of aggressive, relapsed or refractory B
cell NHL, to include follicular lymphoma (FL) grade 3, Diffuse Large B Cell Lymphoma (DLBCL),
transformed NHL, mantle cell lymphoma (MCL), or any other B cell NHL aggressive histology
(per the updated 2008 WHO criteria) will be required to participate in the phase II portion
of the study.

Cycle length is 21 days. Restaging will be employed after cycle 2, and if the patient has
stable disease or better, then they may continue on study up to 6 cycles maximum with
restaging performed after hematologic recovery following the final cycle of therapy.

Bendamustine 120mg/m2 IV on day 1. Rituximab 375mg/m2 IV on day 1. Pixantrone will be the MTD
determined by Part 1 of the study.

Inclusion Criteria:

1. Part I: Subjects must have relapsed or refractory B cell NHL;

2. Part II: Subjects must have relapsed or refractory aggressive B cell NHL including
follicular lymphoma (FL) grade 3, Diffuse Large B Cell Lymphoma (DLBCL), transformed
NHL, mantle cell lymphoma (MCL), or other aggressive B cell NHL histology as per the
WHO 2008 criteria;

3. Refractory disease (defined as persistence of evaluable disease after therapy) or
relapsed disease following at least one prior treatment regimen that should include
autologous stem cell transplant unless a patient was not eligible or refused prior
transplant;

4. Age ≥ 18 years old;

5. Eastern Cooperative Oncology Group (ECOG) performance status of ≤2;

6. Subjects must have measurable or evaluable disease based on physical exam and/or
radiographs (CT, MRI, PET) or bone marrow involvement;

7. Female subject is either post-menopausal or surgically sterilized;

8. Laboratory Values:

- Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L; lower levels accepted if due to
marrow involvement by lymphoma

- Platelets ≥ 75,000/mcl; lower levels accepted if due to marrow involvement by
lymphoma

- Total bilirubin ≤ 1.5 X institutional upper limit of normal; ≤ 3.0 ULN accepted
in subjects with Gilbert's Syndrome

- AST/ALT ≤ 1.5 X institutional upper limit of normal. Subjects with known liver
involvement by lymphoma: AST/ALT ≤ 2 X institutional upper limit of normal

- Serum creatinine < 1.5 X institutional upper limit of normal

9. Ability to provide written informed consent obtained prior to participation in the
study and any related procedures being performed

Exclusion Criteria:

1. No chemotherapy, radiation, biologics or immunotherapy within 2 weeks prior to
registration (6 weeks if last received BCNU or mitomycin C).

2. No radioimmunotherapy within 2 months prior to registration.

3. Subjects receiving chronic, systemic treatment with corticosteroids equivalent to >
20mg of prednisone per day. Subjects receiving replacement for adrenal insufficiency
will be allowed on the study. Topical or inhaled corticosteroids are allowed.

4. Subjects with a history of another primary malignancy ≤ 3 years ago, with the
exception of inactive basal, squamous cell carcinoma of the skin or superficial
melanoma only requiring excision, prostate cancer with a PSA that has not increased
for at least 3 months, carcinoma in situ of the cervix.

5. Major surgery ≤ 4 weeks prior to registration. Minor surgery ≤ 2 weeks prior to
registration. Insertion of a vascular access device is not considered major or minor
surgery. Subjects must have recovered from all surgery related toxicities to ≤ grade 1
or to baseline if subject started with > grade 1 toxicity, not otherwise violating the
above inclusion criteria.

6. Subjects who have received investigational drugs ≤ 4 weeks prior to registration.

7. Impaired Cardiac Function:

- QTc > 480 on screening ECG.

- Previous history of angina pectoris or acute MI within 6 months

- Congestive heart failure (New York Heart Association functional classification
III-IV) or baseline MUGA/ECHO shows estimated LVEF < 45%

- Any history of torsade de pointes, ventricular fibrillation, uncontrolled
ventricular tachycardia, or uncontrolled atrial fibrillation.

8. Female patients who are pregnant or breastfeeding

9. Patients with history of untreated hepatitis B or who are known carriers of hepatitis
B will be excluded from this trial. All subjects will be screened prior to study
entry.

10. Concurrent use of other anti-cancer agents or anti-cancer treatments.