Pharmacokinetic, Safety and Efficacy Study of Nanoparticle Paclitaxel in Patients With Peritoneal Cancers

A Phase 1 Study of Intraperitoneal Nanoparticle Paclitaxel in Patients With Peritoneal Malignancies

The purpose of this study is to evaluate the safety, pharmacokinetics and preliminary efficacy of an intraperitoneally administered suspension of nanoparticulate paclitaxel in patients with refractory malignancies principally confined to the peritoneal cavity.

This is an open-label, Phase 1, dose-escalation study evaluating the safety, pharmacokinetics and preliminary efficacy of an intraperitoneally administered suspension of nanoparticle paclitaxel (Nanotax) in patients with refractory malignancies principally confined to the peritoneal cavity.

Nanotax will be administered via intraperitoneal infusion once every 28 days (equals one treatment cycle), continuing on this treatment schedule until disease progression or unacceptable toxicity is experienced.

This study will treat one patient per predefined dose level until one patient experiences a dose limiting toxicity (DLT) or until one patient has a Grade 2 or higher non-hematological toxicity or a Grade 3 or higher hematological toxicity during the first cycle of treatment. At this time, two additional patients will be treated at this dose level. If these 2 additional patients do not experience a DLT, then the next cohort of three patients will be treated at the next highest dose level. If 2/3 or 3/3 patients experience a DLT then the next cohort of three patients is enrolled at the next lower dose level. If 1/3 of the patients experience a DLT, then the next cohort of three patients is enrolled at the same dose level. If 0/3 patients experience a DLT, then the next cohort of three patients is enrolled at the next highest dose level. If 2 (or more)/6 patients at a given level experience a DLT, then the maximum tolerated dose has been exceeded and another cohort of three patients is treated at the next lower dose level.

The protocol will not treat above the highest dose level of 275 mg/m2.

Adverse event data will be collected throughout the study. Peritoneal fluid and blood samples will be collected prior to Nanotax administration and up to 14 days following infusion for Cycle 1 and Cycle 2 only. Evaluation of tumor response using RECIST criteria will be conducted following each treatment cycle.

Inclusion Criteria:

• Patients must be at least 18 years of age.
• Patients must have histologic or cytologic diagnosis of carcinoma predominantly confined to the peritoneal cavity.
• Patients must have failed all potentially curative therapy and have no other systemic treatment options available for extra-peritoneal disease. Patients with ovarian cancer that are platinum sensitive must have failed primary and at least one salvage regimen. Patients may undergo surgical debulking prior to entry into the trial.
• At least 28 days must have elapsed since completion of any other previous chemotherapy treatment received prior to registration in this study.
• Patients may have received prior abdominal surgery greater than 2 weeks prior to registration. Patients must have recovered from all effects of the surgical procedure.
• Patients must have a Zubrod Performance Status of 0 - 2.
• Patients must have a pretreatment granulocyte count greater than or equal to 1,500/microliter and platelet count greater than or equal to 100,000/microliter obtained within 14 days prior to registration.
• Patients must have adequate renal function as documented by a serum creatinine less than or equal to 1.5 times the institutional upper limit of normal obtained within 14 days prior to registration.
• Patients must have adequate hepatic function as documented by a bilirubin of less than or equal to 2 times the institutional upper limit of normal and an SGOT less than 5 times the institutional upper limit of normal obtained within 14 days prior to registration. Patients with hepatobiliary stents are eligible for this trial if the bilirubin meets the above parameter.
• There should be no plans for the patient to receive concomitant radiation therapy, hormonal therapy, or other chemotherapy for their tumor while on this protocol.

Exclusion Criteria:

• Patients with active inflammatory bowel disease or chronic diarrhea
• Patients with uncontrolled hypertension, unstable angina, symptomatic congestive heart failure, myocardial infarction within previous 6 months or serious uncontrolled cardiac arrhythmia
• Patients with active infection requiring systemic therapy
• Pregnant or nursing women
• Patients with Grade 2 or greater sensory neuropathy (by NCI Common Toxicity Criteria) at the time of study registration
• Patients taking concomitant medications demonstrated to inhibit or induce CYP3A4 or CYP2C8
• Patients with pre-existing conditions that prohibit the use of intravenous dexamethasone at the recommended dose