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1069 Background: PICN is a novel, solvent- and protein-free, 100-110 nm particle formulation of paclitaxel stabilized with polymer and lipids using Nanotecton Technology. We compared the safety and...

2566 Background: PICN is a novel Cremaphor-free composite of paclitaxel nano-particles stabilized with polymer and lipid using NanotectonTechnology. PICN started development with every-3-week sched...

e13567 Background: Paclitaxel and docetaxel share major parts of their structures and mechanism of action, but differ in several aspects. Both paclitaxel and docetaxel act at microtubule causing tubulin polymer generation but exhibit pharmacodynamic differences. These pharmacological differences may account for the differences observed between taxanes in their clinical activity and toxicity. Methods: Review of articles providing details of taxane pharmacology was conducted to evaluate pharmacological basis. Results: Greater uptake and slower efflux of docetaxel from tumor cells leads to longer retention time; whereas equal uptake and efflux of paclitaxel shorter retention time for paclitaxel. Hence, apoptotic and mitotic responses of paclitaxel is complete within 4 days implying that more frequent (weekly) administration of paclitaxel will be superior. High affinity to β-tubulin with docetaxel (1.9) than with paclitaxel (1.0) allows higher inhibition of tumor growth. Secondly, drug concentration causing maximum polymerization is 0.2 µM and 0.4 µM for docetaxel and paclitaxel, respectively; indicating that docetaxel is twice as potent as paclitaxel in causing microtubule polymerization. Docetaxel arrests cells in the radiosensitive G2/M phase of the cell cycle making it a potent radiosensetizer than paclitaxel. Mechanisms consistent with allosteric modulation of the reductases increase doxorubicinol formation at clinically relevant concentrations of paclitaxel when it is administered with doxorubicin. Enhanced formation of doxorubicinol aglycone, a metabolite potentially involved in the reversible phase of cardiotoxicity causes higher cardiotoxicty when doxorubicin is administered with paclitaxel than with docetaxel. Non linear pharmacokinetics and hypersensitivity with paclitaxel and fluid retention with docetaxel is attributed to excepient of the drug rather than drug itself. Conclusions: Influx and efflux mechanism support superior weekly administration of Paclitaxel. Pharmacological differences between taxanes justify the incomplete resistance seen between taxanes. The incomplete cross resistance is specifically related to docetaxelactivity in paclitaxel resistant cases.

e19119 Background: Systemic combination chemotherapy is accepted as a standard of care for patients with advanced non-small cell lung cancer (NSCLC). Substantial similarities in terms of treatment efficacy and survival have emerged over the years between the different systemic chemotherapy regimens used. Quality of life (QOL) analysis will help to customize chemotherapy to improve outcome in NSCLC patients. Methods: Using PUBMED database, a review of randomized controlled phase III trials of advanced NSCLC published in last 5 years reporting comparative safety and efficacy between chemotherapeutic regimens as end points was conducted. An evaluation of end points, difference in efficacy endpoints, QOL analysis, and final conclusion was conducted. Results: The search criteria identified 51 trials (33,481 patients). Out of these 51 clinical trials, 16 trials showed difference in efficacy (13 survival endpoint, 1 ORR (objective response rate), 2 survival without grade 3/4 toxicity) and 11 trials used validated QOL instruments and were included for review. Two trials; one comparing pemetrexed/cisplatin with gemcitabine/cisplatin, and other comparing cisplatin/weekly vinoralbine with cisplatin/vinoralbine on day 1 and 8; showed difference with QOL; though not statistically significant. The QOL reporting/analysis techniques were heterogeneous. Two trials used QOL as primary endpoint. Safety reporting included percentage adverse events with treatment arms. Conclusions: Based on our review, it seems critical to have QOL as an endpoint while evaluating newer combination chemotherapeutic regimens for NSCLC. Secondly, it is unlikely that a major difference exists in the global QOL associated with standard chemotherapy regimens for NSCLC. An effort to have uniform QOL assessment across trials evaluating newer combination regimens for NSCLC will help to customize treatment.

3039 Background: PICN is a novel solvent and protein-free 100-110 nm particle formulation of paclitaxel stabilized with polymer and lipid using Nanotecton Technology. Paclitaxel has shown superior safety and efficacy profile when administered on a weekly schedule. We studied safety, tolerability, and pharmacokinetics (PK) of PICN using a weekly schedule in patients with advanced solid malignancies. Methods: Patients aged18-65 years with advanced solid malignancies, ECOG performance status ≤ 2, estimated survival ≥ 12 weeks, and adequate organ function were enrolled. A standard phase I, 3+3 dose escalation design to determine the maximum tolerated dose (MTD) of PICN administered on a weekly schedule (three consecutive weeks, one week recovery) was employed. PICN dose was escalated at pre-determined fixed dose levels of 80, 100, 125, 150, 175, and 200 mg/m2. PICN was administered as a 30 min infusion without any premedication for hypersensitivity. Results: Twenty-one patients treated with PICN had a mean age of 52.1 yrs (range 35-67); 20 were female and entered with metastatic breast cancer (MBC; n=15), cervical cancer (n=3), skin cancer (n=2). One male had oral cancer. Doses studied were 80 (n=3), 100 (n=3), 125 (n=3), 150 (n=3), 175 (n=6), and 200 (n=3) mg/m2. Despite the lack of dexamethasone premedication, no patient receiving PICN reported hypersensitivity reaction. Two DLTs (neutropenia and febrile neutropenia; both grade 3) were reported at PICN 200 mg/m2. PICN PK (AUC0-24, AUC0-∞, and Cmax) increased in a dose proportionate manner from 80 to 200 mg/m2. Grade 3 or worse related AEs were: neutropenia, leucopenia, peripheral neuropathy, febrile neutropenia, anemia, thrombocytopenia, fatigue, syncope, hypotension and maculopapular rash. Partial responses were observed in MBC (100, 125, 150, 175, and 200 mg/m2) and cervical cancer (80 mg/m2). Conclusions: PICN on thrice monthly schedule was tolerable in the dose range evaluated. Two DTLs were reported: neutropenia and febrile neutropenia (both grade 3). Anti-tumor activity was observed in MBC and cervical cancer. Final trial data for PICN PK, safety, and efficacy will be presented at the conference. Clinical trial information: CTRI/2011/11/002124.

2557 Background: PICN is a novel Cremaphor-free composite of paclitaxel nano-particles stabilized with polymer and lipid using Nanotecton Technology. The MTD of PICN alone was previously determined to be 295 mg/m2 iv every 3 weeks in a South Asian population. This study aimed to determine the pharmacokinetic (PK) profile of PICN alone and with carboplatin (C), and the MTD of PICN plus C. Methods: Patients (pt) with advanced solid malignancies and ECOG PS 0-1 were eligible. Part A was a PK study designed to examine cohorts of 3 pts, receiving PICN over 30 min at dose levels of 175, 260, and 295 mg/m2 every 3 weeks; PK were performed at pre-determined time-points. Part B used a ‘3+3’ dose escalation scheme, designed to determine the MTD of PICN (220, 260, and 295 mg/m2) when combined with C at AUC 6. Only standard anti-emetic pre-medications were used. Adverse events (AEs) were graded using CTCAE 4.0 and tumor response by RECIST 1.1. Results: A total of 18 evaluable pts (9 in Part A, 9 in Part B) were enrolled from 2 US academic centers. No infusion reactions were observed with PICN. No dose limiting toxicity (DLT) was observed in Part A. In Part B, the DLTs were G3 febrile neutropenia and G4 thrombocytopenia requiring platelet transfusion at PICN 260/C AUC 6. A total of 6 pts were treated at PICN 220/C AUC 6 with no DLT. G3 or worse AEs for all cycles were as follow: Part A, bilateral lower extremity weakness, neuropathy, anorexia and neutropenia; Part B, anemia, thrombocytopenia, neutropenia and empyema. Partial responses were observed in biliary(Part A; PICN 260 mg/m2), breast (Part B 220/6) and anal cancers (Part B 260/6). PK analysis showed dose-proportional increase in total plasma paclitaxel level. Conclusions: PICN alone was tolerable in the dose range evaluated. When administered with C AUC 6, the MTD of PICN was 220 mg/m2 administered every 3 weeks. Anti-cancer activity was observed in biliary, breast, and anal cancers. Final PK, toxicity and efficacy data of PICN alone and with C will be presented at the conference. Clinical trial information: NCT01304303.

2592 Background: A polysorbate 80-free formulation of docetaxel may preclude the need for dexamethasone pre-medication and may also reduce toxic effects associated with polysorbate 80. DICN is a novel polysorbate 80-free formulation of docetaxel stabilized with lipid and polymer using NanotectonTM technology. We studied safety, tolerability, and the pharmacokinetics (PK) of DICN in patients with advanced solid malignancies. Methods: Entry criteria included: age 18-65 years, histologically/cytologically confirmed advanced malignancy, performance status ≤ ECOG 2, estimated survival ≥ 12 weeks, and adequate organ function. A standard phase I 3+3 dose escalation schema was employed with an increase of 12.5 to 50% over previous DICN dose level as per safety profile. The infusion was 60 min for 1 cycle and major objectives were to determine maximum tolerated dose (MTD), and PK and safety profiles. Premedication to prevent hypersensitivity was not administered to patients receiving DICN. Three patients were treated with docetaxel 75 mg/m2 to gather PK data. Plasma was analyzed for docetaxel level using a validated assay. Results: Twenty-seven patients treated with DICN had a mean age of 48.8 yrs (range 29-65); 21 were females; and entered with metastatic breast cancer (MBC; n=14), non-small cell lung carcinoma (NSCLC; n=6), ovarian (n=2), and other (n=5). Doses (mg/m2) studied were 60 (n=7), 75 (n=5), 100 (n=3), 125 (n=3), 150 (n=6), and 170 (n=3). Despite lack of dexamethasone premedication, no patient receiving DICN reported a hypersensitivity reaction. Two DLTs (febrile neutropenia) were reported at DICN 170 mg/m2. DICN PK (AUC0-24, AUC0-∞, and Cmax) increased in a dose proportionate manner from 60 to 170 mg/m2. Compared with docetaxel 75 mg/m2, Cmax and AUC0-24 of DICN 75 mg/m2 was 1.4 and 1.2 times higher, respectively, and 1.9 and 1.8 times higher, respectively for DICN 150 mg/m2. The median Tmax of DICN 75 mg/m2 and docetaxel 75 mg/m2 were 1.00 and 0.517 hours, respectively. Conclusions: In this study,DICN demonstrated acceptable tolerability and a favorable PK profile. A 150 mg/m2 is the recommended phase II dose for DICN.

e13127 Background: Phase I trials are performed with the aim of finding the maximum tolerated dose and often start with a very low dose that is subsequently escalated based on the toxicity seen. As a result patients treated on these trials often receive doses of chemotherapeutic agents that are frequently either below or above the biologically active level, thus reducing their chances for therapeutic benefit or increasing chances for toxicity. This evaluation was undertaken to determine how phase I trials are currently conducted and to correlate phase I doses tested with MTD and marketed doses. Methods: Published phase I trials of 16 chemotherapeutic agents tested on solid tumors and approved in last 10-years were identified by searching the Medline database and reviewed to determine methodology employed, cohorts taken to complete the trial, definition of dose limiting toxicity (DLT), number of cohorts treated below MTD, relation between MTD and marketed dose and DLT (dose limiting toxicity). Results: Twenty-three published trials involving 891 patients were identified. These trialsused the standard method of enrolling cohorts of patients at increasing dose levels and observing toxic effects to determine next dose.. Of these 15 used traditional dose escalation, 6 used accelerated titration, 2 used continual reassessment method. Six trials that used accelerated titration method of dose escalation, 2 were used to test cytotoxic agent (5 trials) while 1 tested targeted therapy. Sixty five cohorts were treated below MTD. Average number of cohorts required to complete trial were 6.2. Nineteen trials defined MTD as a dose below DLT dose while 4 trials defined MTD being DLT. Five of 23 trials were completed with-out reaching MTD. Marketed dose for these 16 chemotherapeutic agents was 0 to 50% lower than MTD. DLT reported was myelosupression, fatigue, rash, hypertension or diarrhea. Conclusions: These results show the need for methods to reduce cohorts to reduce number of patients recruited at doses significantly lower than MTD and complete the trials rapidly so that effective agents can be marketed sooner.