A Study of Pioglitazone and Carboplatin in Patients With Advanced Solid Tumors

- In Part I of the study, the maximum tolerated dose (MTD) will be determined. During
part I, Cycle 1, days 1-28, pioglitazone will be administered once daily. On cycle 1,
day 8, the first dose of carboplatin will be administered. On cycle 2, day 1, both
carboplatin and pioglitazone will be administered. Cycles 2 and onward are 21-day
cycles, with pioglitazone administered once daily and carboplatin administered once
every 3 weeks. Part I of the study will end when the MTD has been determined in a
minimum of 6 patients.

- In Part II of the trial, an MTD Expansion Cohort may be utilized to further
characterize the safety profile and pharmacodynamics of the drug. Patients in the MTD
Expansion Cohort will receive carboplatin alone on cycle 1, day 1. Over days 15-21 of
the cycle pioglitazone will be administered alone. On cycle 2, day 1, both carboplatin
and pioglitazone will be administered.

Cycle 2 and onward are 21-day cycles, with pioglitazone administered once daily and
carboplatin administered once every 3 weeks.

Inclusion Criteria:

- Histologically confirmed malignancy that is not curable with standard approaches and
where carboplatin is appropriate therapy.

- During Part I of the trial (MTD determining phase), measurable or evaluable disease
is acceptable. For Part II of the trial (expanded cohort) only, participants must
have measurable disease by RECIST criteria version 1.1.

- Participants enrolled in Part II of the trial (expanded cohort) must have disease
that is amenable to biopsy with reasonable safety and also be willing to undergo at
least two serial tumor biopsies for correlative biomarker investigation as defined in
Section 8.2.2.

- Any number of prior therapies are permitted. Prior carboplatin is allowed. Patients
who have documented allergy to carboplatin may receive carboplatin with
desensitization.

- Age ≥18 years old.

- ECOG performance status ≤ 1 (Appendix A).

- Participants must have normal organ and marrow function as defined below:

- Absolute neutrophil count ≥1,500/L

- Hematocrit ≥ 27

- Platelets ≥100,000/L

- Total bilirubin within normal institutional limits

- AST (SGOT)/ALT (SGPT)≤ 2.5 X institutional upper limit of normal

- Creatinine within normal institutional limits or creatinine clearance ≥ 60
mL/min/1.73 m2 for subjects with creatinine levels above institutional
normal.

- Able to swallow oral medication.

- Women of child-bearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry and
for the duration of study participation.

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

Exclusion Criteria:

Participants who exhibit any of the following conditions at screening will not be eligible
for admission into the study.

- Subjects who have been treated with standard chemotherapy or molecularly targeted
agents within the past 3 weeks prior to trial first drug administration.

- Subjects who were receiving experimental therapies must wait 3 weeks from their last
dose prior to enrolling. Subjects treated with nitrosoureas or mitomycin C cannot be
enrolled until 6 weeks has elapsed since their last treatment.

- Extensive prior radiotherapy on more than 25% of the bone marrow, or prior bone
marrow/stem cell transplantation. Prior radiation for local disease management is
allowed if last fraction was completed at least 4 weeks prior to trial entry.

- Subjects who have undergone a major surgical procedure within the 6 weeks prior to
trial entry.

- History of untreated central nervous system (CNS) metastases. Subjects with a history
of prior treated brain metastasis are eligible provided that 1 month following
treatment they are stable by CT scan without evidence of cerebral edema, and have no
requirements for corticosteroids.

- Diabetic patients who are currently requiring oral hypoglycemic agents or insulin
therapy.

- Patients who are currently receiving rosiglitazone or pioglitazone, or who have
received dosing with any other agent known to be a PPAR agonist within 3 months prior
to study entry.

- Left ventricular ejection fraction ≤ 50% on ECHO or MUGA

- Uncontrolled concomitant illness including, but not limited to ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris,
uncontrolled cardiac arrhythmia, or psychiatric illness/social situations that would
limit compliance with study requirements.

- Pregnant or nursing women.

- Known HIV positivity, active hepatitis C, or active hepatitis B.

- Patients with ≥ CTCAE Grade 2 peripheral neuropathy.

- Subjects with a known history of gastrointestinal disorder (such as partial
esophageal, gastric, small or large bowel obstruction), surgery or malabsorption that
could potentially impact the swallowing or the absorption of the study drug.

- Patients taking CYP2C8 inhibitors and inducers (rifampin, gemfibrozil, trimethoprim,
montelukast, and quercetin) are excluded from the trial.

- Other significant disease that in the Investigator's opinion would exclude the
subject from the trial.