Phase 2 Safety, Tolerability and Efficacy Study of CPI-613 in Cancer Patients

Open-Label Single-Arm Design: This is an open-label study, and investigators and subjects
are not blinded to the treatment. Also, the assignment of patients will not be randomized,
since this is a single-arm study.

Treatment with CPI-613: A treatment cycle is 4 weeks, with CPI-613 given on Days 1 and 4 of
the first 3 weeks.

Dose and Sample Size: The dose of CPI-613 is 3,000 mg/m2. This is Maximum Tolerated Dose
(MTD) determined from the Phase I dose-escalated trial, Study# CL-CPI-613-009 (conducted in
patients with hematologic malignancies under IND 107,800). This dose has also been found to
be well tolerated in another Phase I dose-escalated trial, Study# CL-CPI-613-002 (conducted
in patients with solid tumor under IND 74,530). There will be 20 evaluable patients with
each tumor type. Once there are 20 evaluable patients with a particular tumor type has been
treated with at least 1 cycle, no patients of the same tumor type will be accrued. Dosing
Delay and Dose Modification of CPI-613 in the Event of Adverse Events: For adverse events
unrelated to serum creatinine elevation or reduction in renal function but are possibly
related to CPI-613, the occurrence of Grade 1 toxicity does not generally require dose
modification for subsequent doses for that patient. However, if Grade 2 toxicity (other than
alopecia and nausea) probably related to CPI-613 develops, treatment is to be withheld and
can resume only after the Grade 2 toxicity has been reduced to Grade 1 or below, and the
dose level for subsequent doses for that patient will be reduced by 25% of the dose at which
such Grade 2 toxicity occurs. Grade 2 alopecia and nausea do not require withholding
treatment or dose reduction. If Grade 3 or 4 toxicity probably related to CPI-613 develops,
dosing of CPI-613 of that patient will be withheld and the patient shall be monitored for
recovery from, and reversibility of, such Grade 3 or 4 toxicity. To resume treatment with
CPI-613 for a patient who has had CPI-613-related Grade 3 or 4 toxicity, the Grade 3 or 4
toxicity must be reduced to Grade 1 or below, and the dose level for subsequent doses for
that patient will be reduced to 50% of the dose at which such Grade 3 or 4 toxicity occurs.

For adverse events related to creatinine elevation or reduction in renal function that are
possibly related to CPI-613, dosing of the patient will be withheld even if the severity
level is Grade 1 or above. Treatment can resume only after the toxicity has been reduced to
Grade 0. The dose level for subsequent doses for that patient will be reduced by 15% if the
severity level is of Grade 1, by 25% for Grade 2 toxicity, and by 50% for Grade 3 or 4
toxicity.

Furthermore, if the toxicity possibly related to CPI-613 is acute renal failure and the
severity level is Grade 3 or 4, further patient enrollment will be temporarily suspended in
order to enable assessment of the following aspects of the trial and implementation of
corrective measures or protocol amendment, and if necessary:

- compliance of the study sites and investigators to the study protocol

- evaluation of the appropriateness of the procedures for monitoring renal function

Inclusion Criteria:

- Patients must have advanced and/or metastatic, histologically or cytologically
documented solid tumors, for whom there is no available therapy shown to provide
clinical benefit or for those who have refused further standard therapy

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

- Expected survival >3 months

- 18 years of age or older of both genders

- Women of child-bearing potential 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

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

- No radiotherapy, treatment with cytotoxic agents (except CPI-613), or treatment with
biologic agents within 3 weeks prior to treatment with CPI-613. At least 2 weeks must
have elapsed from any prior surgery or hormonal therapy. Patients must have fully
recovered from the acute toxicities of any prior treatment with any anti-cancer
drugs, radiotherapy or other anti-cancer modalities (returned to baseline status as
noted before most recent treatment). Patients with persisting, stable chronic
toxicities from prior treatment ≤Grade 1 are eligible, but must be documented as
such.

- Laboratory values ≤2 weeks must be:

- Adequate hematologic (white blood cell [WBC] ≥3500 cells/mm3 or ≥3.5 bil/L; platelet
count ≥150,000 cells/mm3 or ≥150 bil/L; absolute neutrophil count [ANC] ≥1500
cells/mm3 or ≥1.5 bil/L; and hemoglobin (Hgb) ≥9 g/dL or ≥90 g/L).

- Adequate hepatic function (aspartate aminotransferase [AST/SGOT] ≤3x upper normal
limit [UNL], alanine aminotransferase [ALT/SGPT] ≤3x UNL (≤5x UNL if liver metastases
present), bilirubin ≤1.5x UNL).

- Adequate renal function (serum creatinine ≤2.0 mg/dL or 177 μmol/L, and blood urea
nitrogen [BUN] ≤25 mg/dL).

- Adequate coagulation ("International Normalized Ratio or INR must be ≤1.5")

Exclusion Criteria:

- Serious medical illness

- Any active uncontrolled bleeding or patients with a bleeding diathesis

- Patients with active central nervous system (CNS) or epidural tumor

- 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

- Life expectancy less than 3 months

- Unwilling or unable to follow protocol requirements

- Dyspnea with minimal to moderate exertion, or patients with pleural, pericardial, or
peritoneal effusions

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

- A marked baseline prolongation of QT/QTc interval; a history of additional risk
factors for torsade de pointes.

- Requirement for immediate palliative treatment of any kind including surgery

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

- Albumin <2.5 g/dL or <25 g/L

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

- Patients with known HIV infection.

- Patients receiving any other standard or investigational treatment for their cancer,
or any other investigational agent for any indication within the past 3 weeks prior
to initiation of CPI-613 treatment.

- Patients who have received immunotherapy of any type within the past 4 weeks prior to
initiation of CPI-613 treatment

- Patients that have received a chemotherapy regimen with stem cell support in the
previous 6 months

- Troponin I above institution limit of normal