13011 Background: LEP-ETU is a liposomal formulation of paclitaxel designed to reduce toxicities while maintaining or enhancing the efficacy of the drug. A PKPD model was used to characterize the time course of neutrophils in relation to blood exposure of LEP-ETU in patients with solid tumors. Simulations were performed to provide justification for dosing schedule in Phase 3 trials. Methods: Data from 63 patients in two phase I studies with advanced malignancies were utilized. LEP-ETU was infused intravenously over 90 min. at 135, 175, 225, 275, 325, and 375 mg/m2 every 21 days (Q3W). A separate cohort received 175 mg/m2 of LEP-ETU infused over 3 hours following a Q3W regimen. Population PKPD modeling and simulations were performed to assess the influence of dose and schedule (275 - 325 mg/m2 Q3W vs. 90 - 110 mg/m2 QW) on neutropenia. Results: The temporal relationship between circulating neutrophils and paclitaxel concentrations was adequately characterized using a model representative of progenitor cells undergoing differentiation and maturation into neutrophils. Mean predicted (%SEM) baseline ANC was 4.3 (6) x 109/L, representative of a normal neutrophil count. Mean transit time (%SEM) was 80 (8) hr, representing a post-mitotic time delay to neutrophil maturation. The neutrophil T1/2 was 14 hr, comparable to published values. The drug effect (Slope·Cp) on the proliferation rate constant is decreased by 9- and 91-fold when 10 or 100 units of drug is present, indicative of paclitaxel’s inhibition of progenitor cell production in bone marrow. Simulations suggest a higher risk of neutropenia with the Q3W regimen and dose-dependent severity for both the Q3W and QW regimens. The predicted incidence of grade 4 toxicity increased from 33% - 42% across the dose range of 275 - 325 mg/m2 Q3W. For a dose of 110 mg/m2 given QW, the incidence of grade 4 neutropenia was 16% compared to 42% for the same total dose of 325 mg/m2 given Q3W. Conclusions: Modeling and simulation predict that a Q3W regimen of 325 mg/m2 LEP- ETU (MTD) provides acceptable neutropenia outcomes comparable to 175 mg/m2 paclitaxel Q3W, while minimizing the Cremophor- associated adverse events. Future consideration of QW regimens may be explored. No significant financial relationships to disclose.

PURPOSE: Raf proteins are key elements of growth-related cellular signaling pathways and are a component of cancer cell resistance to radiation therapy. Antisense oligonucleotides to c-raf-1 permit highly selective inhibition of the gene product and offer a strategy for sensitizing cancer cells to radiation therapy. In this dose escalation study, we evaluated the safety of combined liposomal formulation of raf antisense oligonucleotide (LErafAON) and radiation therapy in patients with advanced malignancies. EXPERIMENTAL DESIGN: Patients with advanced solid tumors were treated with LErafAON in a phase I dose escalation study while receiving palliative radiation therapy. Drug-related and radiation-related toxicities were monitored. Pharmacokinetics and expression of c-raf-1 mRNA and Raf-1 protein were determined in peripheral blood mononuclear cells. RESULTS: Seventeen patients with palliative indications for radiation therapy were entered into this study. Thirteen patients received daily infusions of LErafAON and four received twice-weekly infusions. Radiation therapy was delivered in daily 300-cGy fractions over 2 weeks. Patients tolerated radiation, and no unexpected radiation-related side effects were observed. Drug-related reactions (grade > or =2), such as back pain, chills, dyspnea, fatigue, fever, flushing, and hypertension, were observed in most patients and were managed by premedication with corticosteroids and antihistamines. Serious adverse events occurred in five patients, including acute infusion-related symptoms, abnormal liver function tests, hypoxia, dehydration, diarrhea, esophagitis, fever, hypokalemia, pharyngitis, and tachypnea. Twelve of 17 patients were evaluable for tumor response at completion of treatment; four showed partial response, four showed stable disease, and four experienced progressive disease. The intact rafAON was detected in plasma for 30 minutes to several hours. Six patients with partial response or stable disease were evaluable for c-raf-1 mRNA and/or Raf-1 protein expression. Inhibition of c-raf-1 mRNA was observed in three of five patients. Raf-1 protein was inhibited in four of five patients. CONCLUSION: This is the first report of the combined modality treatment using antisense oligonucleotides with radiation therapy in patients with advanced cancer. A dose of 2.0 mg/kg of LErafAON administered twice weekly is tolerated with premedication and does not enhance radiation toxicity in patients. The observation of dose-dependent, infusion-related reactions has led to further modification of the liposomal composition for use in future clinical trials.

2017 Background: The prodrug irinotecan is converted into its active moiety, SN-38, with wide interpatient variability, due in part to differential expression of cellular carboxylesterases responsible for prodrug hydrolysis. The enzyme UDP-glucuronosyltransferase 1A1 (UGT1A1) detoxifies SN-38 by metabolizing it to SN-38 glucuronide. Polymorphisms in the UGT1A1 promoter lead to decreased expression of the enzyme and are associated with increased risk of irinotecan toxicity. Methods: This was a multi-center, dose-escalation study of Liposome Encapsulated SN-38 (LE-SN38) in patients with advanced cancer. To examine whether toxicities and appropriate dose levels might differ with UGT1A1*28 genotype, patients were stratified prospectively. LE-SN38 was infused intravenously over 90 minutes every 21 days until disease progression or unacceptable toxicity occurred. Tumor progression was monitored radiographically after every 2 cycles. Results: Enrollment is complete; 75 patients were treated with LE-SN38. Screened patients had genotype frequencies of 42.4% homozygous wild-type (WT/WT), 45.1% heterozygous (WT/*28), 10.9% homozygous variant (*28/*28), and 1.6% other. Across all genotypes the most frequent adverse events were fatigue, nausea, anorexia, diarrhea, and vomiting. Importantly, diarrhea was generally mild and self-limiting, and no late onset diarrhea was reported. DLTs of neutropenia/febrile neutropenia in WT/WT patients at 40 mg/m2 resulted in an MTD of 35 mg/m2. No DLTs occurred in *28/*28 patients; accrual was halted at 20 mg/m2 before the MTD was reached. PK results showed that *28/*28 patients had 2- to 3-fold greater drug exposure than WT/*28 or WT/WT patients at the same doses. Stable disease (≥4 cycles) was observed in 37% of patients. Conclusions: LE-SN38 was well tolerated in all patients, with no reported acute/delayed diarrhea. The MTD was not reached for *28/*28 patients. An MTD of 35 mg/m2 LE-SN38 was found for WT/WT patients. Since WT/WT and WT/*28 patients did not appear to exhibit clinically significant differences in safety or PK profiles, this dose will be evaluated in both groups in a Phase II study of patients with colon cancer. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration NeoPharm

2048 Background: LEP-ETU is an easy-to-use liposomal formulation of paclitaxel developed to reduce toxicities while maintaining or enhancing efficacy by eliminating the drug formulation component polyoxyethylated castor oil (CremophorEL). Methods: This Phase I, dose-escalation study was designed to determine the dose-limiting toxicity (DLT) and maximum-tolerated dose (MTD) of LEP-ETU in adult patients with advanced cancer. Paclitaxel pharmacokinetics (PK) and antitumor effects of LEP-ETU were also assessed. LEP-ETU was infused intravenously over 90 minutes once every 21 days. Results: A total of 25 patients received LEP-ETU at doses of 135 (n=3), 175 (n=4), 225 (n=3), 275 (n=3), 325 (n=6), and 375 (n=6) mg/m2. Primary tumor sites included breast, ovary, and colon. Initial patients (n=9, 135–225 mg/m2) were premedicated on the day of infusion to prevent infusion-related reactions (IRRs); later patients (n=16, 225–375 mg/m2) were not premedicated and 75% completed multiple infusions without IRRs. The remain...

2501 Background: The prodrug irinotecan is converted into its active moiety, SN-38, with wide interpatient variability, due in part to differential expression of cellular carboxylesterases responsible for prodrug hydrolysis. The enzyme UDP-glucuronosyltransferase 1A1 (UGT1A1) detoxifies SN-38 by metabolizing it to SN-38 glucuronide. Polymorphisms in the UGT1A1 promoter lead to decreased expression of the enzyme and are associated with increased risk of irinotecan toxicity. This Phase I study in patients with advanced cancer is designed to assess the pharmacogenomics, pharmacokinetics, and safety of liposome encapsulated SN-38 (LE-SN38). Methods: Patients are stratified prospectively according to their UGT1A1 genotype, as defined by the number of TA repeats in the A(TA)nTAA promoter sequence. Strata consist of homozygous wild-type, homozygous variant, and heterozygous patients, who are expected to have normal, low, and intermediate levels of glucuronidation activity, respectively. LE-SN38 is infused intravenously over 90 minutes every 21 days until disease progression or unacceptable toxicity occurs. Dose escalation is planned with separate patient cohorts receiving 2.5 to 90 mg/m2 of LE-SN38. Tumor progression is monitored radiographically after every 2 cycles. Results: As of 16 December 2003, genotype frequencies of 90 screened patients were 43% homozygous wild-type, 43% heterozygous, and 13% homozygous variant. Dose escalation for the 3 strata has reached 40 mg/m2, 30 mg/m2, and 20 mg/m2, respectively. Diarrhea and neutropenia have not been dose limiting. Drug pharmacokinetic parameters appeared to be linear over the doses assessed. At the 10 mg/m2 LE-SN38 dose level, greatest SN-38 systemic exposure occurred in homozygous variant patients: AUCs were 2- to 3-fold higher than for heterozygous or homozygous wild-type patients, respectively. Conclusions: Dose escalation and patient accrual in all strata are continuing. These data show that drug exposure varies across genotypes. Thus, pharmacogenomic assessments should be used prospectively as a component of individualized patient dosing decisions. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration NeoPharm, Inc.

Astrocyte reactivity is implicated in the neuronal loss underlying Alzheimer's disease. Curcumin has been shown to reduce astrocyte reactivity, though the exact pathways underlying these effects are incompletely understood. Here we investigated the role of the small ubiquitin-like modifier (SUMO) conjugation in mediating this effect of curcumin. In beta-amyloid (Aβ)-treated astrocytes, morphological changes and increased glial fibrillary acidic protein (GFAP) confirmed reactivity, which was accompanied by c-jun N-terminal kinase activation. Moreover, the levels of SUMO-1 conjugated proteins, as well as the conjugating enzyme, Ubc9, were decreased, with concomitant treatment with curcumin preventing these effects. Increasing SUMOylation in astrocytes, by over-expression of constitutively active SUMO-1, but not its inactive mutant, abrogated Aβ-induced increase in GFAP, suggesting astrocytes require SUMO-1 conjugation to remain non-reactive.

2110 Background: The rationale for developing a liposomal formulation of paclitaxel is to improve the safety profile by eliminating toxicities associated with the drug formulation component, polyoxyethylated castor oil (Cremophor® EL), while maintaining or enhancing efficacy. This phase I study is designed to determine the MTD, DLT, and pharmacokinetics of LEP-ETU, an easy to use formulation of liposome entrapped paclitaxel, in patients with advanced cancers. Methods: Adult patients with incurable solid tumors receive intravenous LEP-ETU infusion over 90 minutes every 21 days until disease progression or unacceptable toxicity occurs. Dose escalation is planned with separate patient cohorts receiving 135 to 325 mg/m2 of LEP-ETU. Patients are monitored closely for any neurological changes and for tumor progression. Results: As of 16 December 2003, ten patients have received doses of 135 mg/m2 (n=3), 175 mg/m2 (n=4), or 225 mg/m2 (n=3). In the 6 men and 4 women enrolled, ages ranged from 23–80 years (median 65), and ECOG PS ranged from 0–2. Among the primary cancers were colon, breast, and pancreatic. Patients have completed up to 6 treatment cycles (median 2.5). To prevent infusion-related reactions (IRRs), patients have been premedicated on the day of infusion. In 25 of 26 such treatment cycles breakthrough IRRs have not occurred. Therefore, to assess whether premedication is clinically necessary, it is no longer required. No IRRs occurred in the single patient treated (225 mg/m2) without premedication to date. In the 225 mg/m2 cohort, 1 patient had Grade 2 neutropenia, and another had Grade 1 neuropathy, with both considered possibly related to study drug. No neutropenia or neuropathy considered related to study drug have occurred at the lower dose levels. No DLTs and no SAEs considered related to drug have been reported. Mean drug concentration versus time curves for the 135 and 175 mg/m2 cohorts parallel those reported for similar doses of paclitaxel/Cremophor EL. Conclusions: Patient accrual and dose escalation without premedication are continuing beyond the standard paclitaxel dose. At the doses administered thus far, LEP-ETU appears to be safe and well tolerated. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration NeoPharm, Inc.