CPI-613, Bendamustine Hydrochloride, and Rituximab in Treating Patients With Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) of CPI-613, when used in combination with
bendamustine (bendamustine hydrochloride) and rituximab in patients with relapsed or
refractory B-cell non-Hodgkin lymphoma (NHL), who have or have not received hematopoietic
cell transplant.

SECONDARY OBJECTIVES:

I. To evaluate response rate (RR) and disease control rate (DCR), derived from the modified
International Work Group (IWG) criteria.

II. To evaluate overall survival (OS) and progression-free-survival (PFS), and possible
correlation between RR and DCR derived from the modified IWG criteria vs. OS and PFS.

III. To evaluate assessment of bone marrow biopsy, and possible correlation between complete
response (CR) vs. bone marrow biopsy assessment (e.g., clear of infiltration of leukemic
cells accordingly to morphology, and/or negative on leukemic cells according to
immunohistochemistry).

IV. To evaluate safety of the CPI-613 + bendamustine + rituximab combination.

OUTLINE: This is a dose-escalation study of 6,8-bis(benzylthio)octanoic acid.

Patients receive 6,8-bis(benzylthio)octanoic acid intravenously (IV) over 2 hours on days 1-4
(week 1) and days 1 and 4 (weeks 2 and 3). Patients also receive bendamustine hydrochloride
IV over 30 minutes on days 4 and 5 and rituximab on day 5 of week 1. Treatment repeats every
4 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 2 months.

Inclusion Criteria:

- Histologically and cytologically confirmed B-cell NHL that has relapsed from, or is
refractory to, all standard therapies (including autologous transplantation) known to
provide clinical benefit, but have not been treated with bendamustine for their
lymphoma

- Must have measurable disease (e.g., a tumor mass > 1 cm)

- Eastern Cooperative Oncology Group (ECOG) performance status 0-2

- Expected survival > 3 months

- Women of child-bearing potential (i.e., women who are pre-menopausal or not surgically
sterile) must use accepted contraceptive methods (abstinence, intrauterine device
[IUD], oral contraceptive or double barrier device) during the study, and must have a
negative serum or urine pregnancy test within 1 week prior to treatment initiation

- Fertile men must practice effective contraceptive methods during the study, unless
documentation of infertility exists

- At least 2 weeks must have elapsed from any prior surgery

- Aspartate aminotransferase (AST/serum glutamic oxaloacetic transaminase [SGOT]) and
alanine aminotransferase (ALT/serum glutamate pyruvate transaminase [SGPT]) =< 3 x
upper normal limit (UNL) (=< 5 x UNL if liver metastases present)

- Bilirubin =< 1.5 x UNL

- Serum creatinine =< 1.5 mg/dL or 133 umol/L

- "International normalized ratio" or INR must be =< 1.5

- No evidence of active infection and no serious infection within the past month

- Mentally competent, ability to understand and willingness to sign the informed consent
form

Exclusion Criteria:

- Known cerebral metastases, central nervous system (CNS) or epidural tumor

- Having "currently active" second malignancy unrelated to Hodgkin lymphoma (HL) or NHL,
unless they have completed anti-cancer therapy, are in complete response and are
considered by their physicians to be at less than 30% risk of relapse

- Patients receiving any other standard or investigational treatment for their cancer,
or any other investigational agent for any indication, within the past 2 weeks prior
to initiation of treatment with study drugs

- Serious medical illness that would potentially increase patients' risk for toxicity

- Any active uncontrolled bleeding, and any patients with a bleeding diathesis (e.g.,
active peptic ulcer disease)

- History of abdominal fistula or gastrointestinal perforation =< 6 months prior to
treatment with study drugs

- Pregnant women, or women of child-bearing potential not using reliable means of
contraception

- Lactating females

- Fertile men unwilling to practice contraceptive methods during the study period

- Any condition or abnormality which may, in the opinion of the investigator, compromise
the safety of patients

- Unwilling or unable to follow protocol requirements

- Active heart disease including but not limited to symptomatic congestive heart
failure, symptomatic coronary artery disease, symptomatic angina pectoris, symptomatic
myocardial infarction or symptomatic congestive heart failure

- Patients with a history of myocardial infarction that is < 3 months prior to
registration

- Evidence of active infection, or serious infection within the past month

- Patients with known human immunodeficiency virus (HIV) infection, hepatitis B, or
hepatitis C

- Patients who have received cancer immunotherapy of any type within the past 2 weeks
prior to initiation of CPI-613 treatment

- Requirement for immediate palliative treatment of any kind including surgery