The purpose of this bridging phase I study was to characterize the toxicity, pharmacokinetics, and antitumor effects of a capsule formulation of DRF-1042, a novel camptothecin analog, in refractory solid tumor patients. DRF-1042 was given daily for 5 consecutive days for 2 weeks, repeated every 3 weeks at 81 mg/m(2). Adverse events were monitored following NCI-CTC. Blood samples were processed for bioanalysis using a validated high-performance liquid chromatography method. The pharmacokinetics of lactone and total (lactone + carboxylate) forms was determined on days 1 and 12 using a noncompartmental pharmacokinetic method. Pharmacokinetic data with the capsule formulation were compared with previously reported pharmacokinetic parameters with a suspension formulation. Efficacy was evaluated by applying World Health Organization criteria. Six patients received 10 courses of therapy. Thrombocytopenia and diarrhea were dose-limiting toxicities. The upper limit of the area under the curve of DRF-1042 (lactone and total) with the capsule formulation was higher than a suspension formulation at a similar dose on day 1 (lactone: capsule = 8.53 microMxh, suspension = 5.33 microMxh; total: capsule = 393 microMxh, suspension = 176 microMxh) and day 12 (lactone: capsule = 22.1 microMxh, suspension = 6.1 microMxh; total: capsule = 1302 microMxh, suspension = 309 microMxh). The upper limit of the area under the curve of DRF-1042 (lactone and total) was higher under fed conditions (lactone = 15.9 microMxh, total = 605 microMxh) relative to fasted conditions (lactone = 8.53 microMxh, total = 393 microMxh) on day 1. One patient experienced stable disease. The toxicity and pharmacokinetics of the capsule correlated well with the suspension. The recommended phase II dose is 81 mg/m(2).

Mutations in the Bcr-Abl kinase domain (KD) are a major cause for acquired resistance to imatinib (IM) treatment and have been associated with progression and poor prognosis in chronic myeloid leukemia patients. The present study includes 63 patients resistant to standard imatinib dose of 400 mg according to ELN guidelines. Direct sequencing method is used for mutational analysis. The present study revealed 15 exonic mutations in 46.03 % of patients; among them, seven cases (24.13 %) had multiple mutations. Mutations were found to be higher in sokal high- (45.0 %) and intermediate- (68.42 %) compared to low-risk (29.16 %) group. Mutations were observed in 38.09 % of patients with EUTOS (European Treatment and Outcome Study) high risk and in 50.0 % with low risk. The frequency of mutations was 50.0 % in advanced phase, 47.36 % in late chronic-phase, and 43.33 % in chronic-phase patients. 42.10 % of patients with primary resistance and 52.0 % with secondary resistance had mutations. P-loop and T315I mutations were associated with poor survival in advanced phase patients (85.71 %) (P = 0.03). No significant variation was observed with Bcr-Abl transcript levels between the patients with the presence or absence of mutations (P = 0.73). Bcr-Abl levels were found to be significantly elevated in P-loop and T315I mutation carriers (P = 0.001) and also in T315I mutation-positive patients (P = 0.01). P-loop mutations and T315I are frequent in advanced phases and strongly associated with poor prognosis and survival. Hence, the identification of mutations in IM-resistant CML patients will help in treatment optimization with 2nd- or 3rd-generation tyrosine kinase inhibitors (TKIs).

The objective of this study was to characterize the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), pharmacokinetics, and antitumor effects of DRF-1042, a novel camptothecin analog, in refractory solid tumor patients. DRF-1042 was given for 5 consecutive days for 2 weeks, repeated every 3 weeks at 1.5 to 270 mg/m(2). Adverse events were monitored following NCI-CTC. Pharmacokinetics of lactone and total forms were determined using validated high-performance liquid chromatography (HPLC) and noncompartmental methods. Efficacy was evaluated applying World Health Organization (WHO) criteria. The 1st course was used to determine DLT and MTD. Twenty-five patients received 73 courses of therapy. Myelosuppression and diarrhea were DLTs. MTD was 120 mg/m(2)/day. AUC increased approximately linearly with dose. The t(1/2) for lactone and total forms was 9.9 and 29 hours, respectively. AUCs correlated significantly with nadir leucopenia and grade 4 diarrhea. Two complete responses (CRs) and 2 partial responses (PRs) were observed. In addition, 4 stable diseases were observed. The recommended phase II dose is 80 mg/m(2)/day.

BACKGROUND: There is general belief that patients who enrolled on a clinical trial have better outcomes compared to those who are treated outside of a trial. We analyzed if there was a 'trial effect' for patients with advanced non-small cell lung cancer (NSCLC) treated with chemotherapy. MATERIALS AND METHODS: A retrospective analysis of cohorts of patients with advanced NSCLC who received chemotherapy inside and outside of a clinical trial were analyzed for response rates (RR), progression free survival (PFS), overall survival (OS), 1 and 2 year survival. RESULTS: There were 194 patients who received chemotherapy of which, 54 were on a clinical trial and 140 outside of it. For the whole group, the RR, median PFS, OS, one and two-year survivals were 35.4%, six months (range, 2-70), seven months (range, 2-72), 29.8% and 9.7% respectively. The differences in RR and PFS of patients who were treated inside and outside of a clinical trial were not signifi cant (P=0.6164, 0.0881). The differences in median OS and one-year survivals between the groups were signifi cant (P=0.0052, 0.022). For the whole group, patients who received II line chemotherapy had better OS (P≤0.0001). More patients in the trial group received II line chemotherapy (P=0.0004).The difference in the median OS between the groups continued to be signifi cant even after patients who received II line chemotherapy were censored (P=0.0437). CONCLUSION: Patients with advanced NSCLC who were treated inside of a clinical trial had better OS compared to those who were treated outside of it.

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