• To determine the safety, toxicity, and the maximum (MTD) or optimal tolerated dose (OTD) of IT-101 administered intravenously to patients with relapsed or refractory cancer. [ Time Frame: Six months ] [ Designated as safety issue: No ]
• To determine the pharmacokinetics of IT-101 [ Time Frame: Six months ] [ Designated as safety issue: No ]

• To determine the safety, toxicity, and the maximum (MTD) or optimal tolerated dose (OTD) of IT-101 administered intravenously to patients with relapsed or refractory cancer. [ Time Frame: Six months ]
• To determine the pharmacokinetics of IT-101 [ Time Frame: Six months ]

RATIONALE: IT-101 is a conjugate of camptothecin (CPT) and a linear, cyclodextrin-based polymer. IT-101 is designed to increase the exposure of tumor cells to the chemotherapeutic drug while minimizing the toxic side effects.

PURPOSE: This phase I trial will:

• Determine the safety, toxicity, and the maximum tolerated dose (MTD) of IT-101 when administered intravenously to patients with relapsed or refractory cancer.
• Determine the pharmacokinetics of IT-101.
• Assess tumoral expression of topoisomerase I genes involved in response and resistance to IT-101.
• Assess anti-tumor activity of IT-101

Camptothecin (CPT), an alkaloid extract from plants such as Camptotheca acuminata, has a broad range of anticancer activity in animal models. Its activity is thought to be due to the inhibition of DNA topoisomerase I. CPT inhibits resealing of DNA that has been nicked in the course of DNA synthesis. This in turn halts nucleic acid synthesis and ultimately leads to cell death.

IT-101 is a conjugate of camptothecin (CPT) and a linear, cyclodextrin-based polymer (CDP). The components of CDP are beta-cyclodextrin and polyethylene-glycol (PEG), both of which are used in a variety of drug formulations. Camptothecin is covalently attached to CDP through a glycine linker which preserves CPT in its active form and increases its water solubility by greater than 1000 fold. Once injected into the blood circulation, camptothecin is slowly released from the polymer conjugate through hydrolysis of an ester linkage. In addition to improving solubility and stability, polymer-drug conjugation can enhance the accumulation of the drug in tumors by taking advantage of the enhanced permeability and retention (EPR) effect, a mechanism through which macromolecules extravasate out of the abnormally leaky vasculature of tumors.

This will be an open-label, dose-escalation, study of IT-101 administered in patients with solid tumor malignancies. Patients who satisfy the inclusion/exclusion criteria will receive injections of IT-101 every other week. Patients will be monitored for a response using RECIST criteria every 2 months.

• Cancer
• Ovarian Cancer
• Non Small Cell Lung Cancer
• Pancreatic Cancer
• Solid Tumor

• Schluep T, Hwang J, Cheng J, Heidel JD, Bartlett DW, Hollister B, Davis ME. Preclinical efficacy of the camptothecin-polymer conjugate IT-101 in multiple cancer models. Clin Cancer Res. 2006 Mar 1;12(5):1606-14.
• Schluep T, Cheng J, Khin KT, Davis ME. Pharmacokinetics and biodistribution of the camptothecin-polymer conjugate IT-101 in rats and tumor-bearing mice. Cancer Chemother Pharmacol. 2006 May;57(5):654-62. Epub 2005 Aug 26.
• Cheng J, Khin KT, Davis ME. Antitumor activity of beta-cyclodextrin polymer-camptothecin conjugates. Mol Pharm. 2004 May-Jun;1(3):183-93.

Inclusion Criteria:

• Male and female patients >18 years of age with advanced, histologically-confirmed solid tumors refractory to standard therapy or for which no standard therapy exists.
• Patients must have measurable or evaluable disease.
• Patients must not have received prior chemotherapy or radiation for >/= 4 weeks before study enrollment.
• Patients may be entered if they have received prior radiation therapy involving </= 30% of the bone marrow. Any prior radiation therapy must have been administered >/= 4 weeks before study enrollment and the patient must be recovered from the acute toxic effects of the treatment prior to study entry.
• Patients may be enrolled with a history of treated brain metastases that are clinically stable for >/= 4 weeks prior to enrollment.
• ECOG performance status of </= 2.
• Life expectancy of greater than 12 weeks.
• Patients must have acceptable organ and marrow function at screening and pre-dose visits.
• Electrocardiogram without evidence of clinically significant conduction abnormalities or active ischemia as determined by the investigator.
• The effects of IT-101 on the developing human fetus are unknown, therefore, women of childbearing potential must agree to use adequate contraception 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:

• Women who are pregnant or lactating.
• Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier.
• Patients with a pre-therapy ejection fraction by echocardiogram (ECHO) of < 45%
• Patients with serum amylase or lipase > upper limit of normal (ULN)
• Patients with known Gilbert's disease.
• Patients with previous high dose chemotherapy with autologous stem cell rescue bone marrow transplantation.
• Use of any investigational agents within 4 weeks of study enrollment.
• Metastatic disease to the CNS requiring treatment or radiation therapy.
• Patients with known untreated brain metastases or treated brain metastases that have not been stable >/= 4 weeks prior to study enrollment.
• Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements, as determined by the investigator.
• The presence of active coagulation disorder.
• Patients with marked baseline prolongation of QT/QTc interval (QTc interval > 470) using the Fridericia method as a main method of QTc analysis
• Refractory (no response to treatment) to a prior treatment with a topoisomerase I inhibitor (relapsed [return of symptoms and signs of disease after a period of improvement] to prior therapy is acceptable).