Computational Experiments on Workflow Balancing of Parallel Machine Scheduling with Precedence Constraints and Sequence Independent Setup Time

The workflow balancing of parallel machines scheduling (PMS) with precedence constraints and sequence independent setup time is considered for study. The setup time consideration produces alternate schedule along with lesser relative percentage of imbalance (RPI) value for PMS problem is demonstrated with an example. The lesser RPI indicates better workflow balancing among machines. The computational experiments are conducted on large instances of randomly generated PMS problems with precedent constraints and setup time. The various combinations of heuristics are used to solve the problems. The results show that genetic algorithm (GA) performs well against the other heuristics with lesser RPI values

Phase Ia/b study of combination carboplatin, paclitaxel, and ridaforolimus in patients with solid, endometrial, and ovarian cancers.

TPS3114 Background: mTOR is a member of the PI3K family. Ridaforolimus (RIDA) is a mTOR inhibitor that has demonstrated tolerability as intravenous (IV) and oral formulations. PI3K/AKT/mTOR signalling is associated with resistance to taxanes. In cancer (ca) cells, inhibition of mTOR signalling counteracts AKT-mediated resistance to drugs inhibiting tubulin. Paclitaxel and carboplatin (PC) have broad activity including endometrial, ovarian, and many cancers. mTOR inhibition with PC has synergistic and additive effects in solid tumors. A common defect in endometrioid ca is mutation of PTEN, causing activation of the PI3K/AKT/mTOR pathway. RIDA improved PFS over hormonal therapy of metastatic endometrial cancer in a randomized phase II study (Oza AM, et al. J Clin Oncol. 2011;29 [suppl; abstr 5009]). In 35 patients in a phase II study of RIDA, there were 7.7% partial response (PR) and 58% with stable disease with median duration 6.6 months (Mackay H et al. J Clin Oncol. 2011;29 [suppl; abstr 5013]). Ovarian ca ultimately develops a phenotype resistant to taxanes that may be overcome with mTOR inhibition. RIDA may therefore potentiate the response of endometrial, ovarian, and other solid cancers to PC. Methods: Patients (pts) with advanced solid ca and measureable disease and up to 3 prior therapies received P (175mg/m2 IV) and C (AUC 5 to 6 mg/ml/min IV) on day (D)1 of each 3-week cycle. RIDA in escalating cohorts of 10-40 mg is administered orally daily for 5 days per week (D1-5, D 8-12, D 15-19) in phase IA cohorts. Samples for pharmacokinetics of RIDA and P and pharmacodynamics (PD) are collected. More than 1 anticipated DLT of thrombocytopenia or neutropenia in the latter part of the cycle shifts the escalation of RIDA to an alternate schedule (D1-5, D 8-12). Escalation continues in a 3X3 design until 40 mg/day of RIDA or MTD. Seven pts have been enrolled; 5 ovarian, 1 endometrial, 1 urethral ca. The second cohort of an alternate schedule has been filled and evaluation continues. Further characterization of tolerability, efficacy, and PD are planned at the MTD in the phase IB expansion cohorts of 15 ovarian/15 endometrial cancers.

Randomized Crossover Study Evaluating the Effect of Gemcitabine Infusion Dose Rate: Evidence of Auto-Induction of Gemcitabine Accumulation

PurposeControversy exists over the optimal dose rate for administration of gemcitabine. There is a strong pharmacologic rationale for increased intracellular accumulation with prolonged infusions, but this failed to translate into a significant benefit in a large randomized study. The purpose of this study was to compare the intracellular pharmacokinetics of gemcitabine given for 30 minutes or for 100 minutes in a crossover design.Patients and MethodsWe randomly assigned 33 patients to a standard dose of 1,000 mg/m2over either 30 minutes or 100 minutes. At the second week, they were transferred to the alternate schedule. Blood samples were collected at various times after the gemcitabine infusion. Gemcitabine and difluorodeoxyuridine were measured in plasma by high-performance liquid chromatography (HPLC), and gemcitabine-triphosphate was measured by HPLC in leukocytes.ResultsIntracellular accumulation was greater during the 100-minute infusion, which was consistent with previous data. This effect was confounded by an increase in gemcitabine-triphosphate accumulation between weeks 1 and 2, which was consistent with self-induction of gemcitabine accumulation. There was significant heterogeneity: 27% of patients had greater WBC accumulation during the 30-minute infusion (regardless of treatment order). Patients with relatively greater levels of gemcitabine-triphosphate in WBCs tended to have less under-dosing and a greater reduction in midcycle neutrophils. However, this observation did not correlate with plasma gemcitabine levels.ConclusionThis work identifies significant variations in intracellular gemcitabine-triphosphate accumulation between and within individuals, and it provides evidence that this variation has potential clinical significance. The observed self-induction of gemcitabine metabolism has broad implications for the dosing of nucleoside analogs.

Phase I and Pharmacologic Study of Sequences of Gemcitabine and the Multitargeted Antifolate Agent in Patients With Advanced Solid Tumors

PURPOSE: Multitargeted antifolate (MTA) is an investigational agent that, like gemcitabine, exhibits broad activity in solid tumors. A phase I trial of MTA and gemcitabine was undertaken, based on the demonstration of preclinical cytotoxic synergy. PATIENTS AND METHODS: Thirty-five patients (group I) received 164 courses (median, four; range, one to 14 courses) of treatment of gemcitabine at doses of 1,000 and 1,250 mg/m2 on days 1 and 8 and MTA at doses of 200, 300, 400, 500, and 600 mg/m2, given 90 minutes after gemcitabine on day 1. Courses were repeated every 3 weeks. Because the day 8 dose of gemcitabine was reduced or omitted in 57% of courses due to neutropenia, 21 patients (group II) were treated on an alternate schedule, with MTA administered on day 8 rather than day 1. This group received 85 treatment courses (median, four; range, one to 10 courses). RESULTS: The most common and dose-limiting toxicity was neutropenia. Other toxicities included nausea, fatigue, rash, and elevated hepatic transaminases. The maximum-tolerated dose was gemcitabine/MTA 1,000/500 mg/m2 for group I and 1,250/500 mg/m2 for group II. Thirteen objective responses were documented (colorectal cancer, n = 3; non–small-cell lung cancer, n = 3; cholangiocarcinoma, n = 2; ovarian carcinoma, n = 2; mesothelioma, n = 1; breast cancer, n = 1; and adenocarcinoma of unknown primary site, n = 1). Gemcitabine had no effect on the disposition of MTA. CONCLUSION: The gemcitabine/MTA combination is broadly active and warrants further evaluation. The sequence of gemcitabine administered on days 1 and 8 with MTA administered on day 8 is better tolerated and is recommended for further study at doses of gemcitabine/MTA 1,250/500 mg/m2.