Short-Term Fasting: Impact on Toxicity

OBJECTIVES:

I. To determine the safety and feasibility of short-term fasting prior to administration of
combination chemotherapy with platinum in patients with advanced solid tumor malignancies.

II. To evaluate the toxicity profile of platinum-based chemotherapy in subjects who eat
normally compared to those who undertake short-term starvation.

III. To investigate changes in plasma insulin, glucose, IGF1 and IGF binding protein (IGFBP)
levels, and oxidative stress markers in subjects who undertake short-term fasting compared to
controls.

IV. To investigate whether changes in grp78 expression occur after fasting and after
chemotherapy administration in human subjects.

OUTLINE:

STAGE I: Patients are assigned to 1 of 4 treatment groups. GROUP I: Patients fast for 24
hours on day-1.

GROUP II: Patients fast for 48 hours on days -2 and -1.

GROUP III: Patients fast for 72 hours on days -3, -2, and-1.

GROUP IV: Patients undergo a modified 48-hour fast with minimal caloric intake on days -2 and
-1.

STAGE II: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients fast for 72 hours on days -2, and on day 1.

ARM II: Patients proceed to chemotherapy without fasting.

All patients receive gemcitabine hydrochloride intravenously (IV) on days 1 and 8 and
cisplatin IV over 2 hours on day 1. Treatment repeats every 21 days for up to 4 courses in
the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up periodically.

Inclusion Criteria:

- Age > 18 years

- Histologically confirmed malignancy for which platinum-based chemotherapy on a 21 day
cycle or 14 day cycle is being recommended.

- Disease state:

- Stage I of the trial: newly diagnosed disease for which neoadjuvant or adjuvant
chemotherapy is planned in the curative setting, or metastatic disease.

- Stage II of the trial: Measurable disease by RECIST criteria must be present for
all subjects in the randomized component of the trial- if surgery or radiation is
planned, the target lesions may not be so treated until after the assessment of
the effect of chemotherapy.

- Prior chemotherapy

- Stage I: subjects may have already received no more than 2 cycle of
platinum-based chemotherapy, but should not have received other prior
chemotherapy regimens with the exception of patients with metastatic disease who
received neoadjuvant or adjuvant chemotherapy and that chemotherapy was completed
> 6 months prior to enrollment.

- Stage II: subjects must have received no prior chemotherapy regimens for
metastatic disease, and no more than 2 cycles of their current platinum
chemotherapy regimen for metastatic disease. They may have received prior
neoadjuvant or adjuvant chemotherapy, provided such therapy was completed >6
months prior to enrollment.

- Prior Radiotherapy is allowed, provided at least 2 weeks have elapsed from completion
of radiotherapy to initiation of protocol treatment.

- BMI > 18.5

- ECOG performance status 0-1

- Adequate renal function (Creatinine <1.25 ULIN or calculated creatinine clearance > 50
ml/min)

- Premenopausal women must have a negative pregnancy test and must agree to use barrier
contraception throughout the study period.

Exclusion Criteria:

- Diabetes Mellitus

- Recent significant or unexplained weight loss that the investigator feels may pose an
unacceptable risk for enrollment. Candidates who are overweight and have lost weight
intentionally via diet or exercise should not be excluded.

- Peripheral Neuropathy > grade 1

- History of significant cardiac disease, particularly uncompensated congestive heart
failure NYHA grade 2 or more or LVEF < 40% on any prior assessment. (Assessment of
LVEF prior to therapy is not required in the absence of other clinical indicators of
heart disease). Patients with a prior LVEF <40% will require re-evaluation prior to
study entry.

- Subjects on medications that may not be safely stopped during the fasting portion of
the study, or which may not be safely consumed without food.

- A history of syncope with calorie restriction in the past or other medical
comorbidity, which would make fasting potentially dangerous.