Cynthia Uehara

A Phase I Clinical Trial of Darinaparsin in Patients with Refractory Solid Tumors

Purpose: Darinaparsin, an organic arsenic, targets essential cell survival pathways. We determined the dose-limiting toxicity (DLT) and maximum tolerated dose of darinaparsin in patients with advanced cancer. Experimental Design: Patients with solid malignancies refractory to conventional therapies were treated with i.v. darinaparsin daily for 5 days every 4 weeks. The starting dose (78 mg/m2) escalated to 109, 153, 214, 300, 420, and 588 mg/m2. A conventional “3 + 3” design was used. Results: Forty patients (median age, 61.5 years; median number of prior therapies, 5) received therapy; 106 cycles were given (median, 2; range, 1-12). Twenty patients reported no drug-related toxicities. No DLTs were reported at a dose of <420 mg/m2. At 588 mg/m2, two of four patients developed DLTs, including grade 3 altered mental status and ataxia. Of four patients treated at the de-escalated dose of 500 mg/m2, one developed similar toxicities. De-escalating the dose to 420 mg/m2 (n = 8) resulted in two neurologic DLTs. Further de-escalation to 300 mg/m2 (n = 3) resulted in no drug-related toxicities. Arsenic plasma levels peaked on treatment day 3, plateaued on day 5, and returned to baseline on day 7. Plasma levels varied within cohorts but increased with increasing doses. The median plasma arsenic half-life was 16.2 hours. Seven (17.5%) patients had stable disease for ≥4 months (median, 6; range, 4-11), including 4 of 17 with colorectal and 2 of 3 with renal cancer. Conclusions: The recommended dose for phase II trials is 300 mg/m2 i.v. given daily for 5 days every 4 weeks.

Phase I clinical trial of MPC-6827 (Azixa), a microtubule destabilizing agent, in patients with advanced cancer

MPC-6827 (Azixa) is a small-molecule microtubule-destabilizing agent that binds to the same (or nearby) sites on β-tubulin as colchicine. This phase I study was designed to determine the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), and pharmacokinetics (PK) of MPC-6827 in patients with solid tumors. Patients with advanced/metastatic cancer were treated with once-weekly, 1- to 2-hour intravenous administration of MPC-6827 for 3 consecutive weeks every 28 days (1 cycle). Dose escalation began with 0.3, 0.6, 1, and 1.5 mg/m2, with subsequent increments of 0.6 mg/m2 until the MTD was determined. A 3 + 3 design was used. Pharmacokinetics of MPC-6827 and its metabolite MPI-0440627 were evaluated. Forty-eight patients received therapy; 79 cycles were completed (median, 1; range, 1–10). The most common adverse events were nausea, fatigue, flushing, and hyperglycemia. The DLT was nonfatal grade 3 myocardial infarction at 3.9 mg/m2 (1/6 patients) and at 4.5 mg/m2 (1/7 patients). The MTD was determined to be 3.3 mg/m2 (0/13 patients had a DLT). Five (10.4%) of the 48 patients achieved stable disease (Response Evaluation Criteria in Solid Tumors) for 4 months or greater. MPC-6827 has a high volume of distribution and clearance. Half-life ranged from 3.8 to 7.5 hours. In conclusion, MPC-6827 administered intravenously over 2 hours at a dose of 3.3 mg/m2 once weekly for 3 weeks every 28 days was safe in patients with heavily pretreated cancer. Clinical trials with MPC-6827 and chemotherapy are ongoing. Mol Cancer Ther; 9(12); 3410–9. ©2010 AACR.

Phase I Clinical Trial Outcomes in 93 Patients with Brain Metastases: The MD Anderson Cancer Center Experience

Purpose: Patients with brain metastases are often excluded from clinical trials, but it is unclear whether they pose an enhanced risk. Experimental Design: We reviewed the records of 1,181 consecutive patients, with and without brain metastases, treated in our Phase I Clinical Trials Program. Results: Ninety-three patients had brain metastases at the time of referral. Their median age was 54 years; median follow-up, 8 months. The rates of stable disease ≥ 4 months, partial response, and complete response combined in patients with and without brain metastases were 17% and 27%, respectively (P = 0.03). Although the median survival of patients with brain metastases was shorter than that of patients without brain metastases (7.5 vs. 10.3 months; P = 0.002), in multivariate analysis, the presence of brain metastases was not an independent factor predicting survival. There was no difference in time-to-treatment failure (1.74 vs. 1.84 months, respectively; P = 0.61) or in grade 3 and 4 toxicity rates (including neurologic; 12% vs. 10%, respectively; P = 0.77) between patients with and without brain metastases. Conclusions: The rates of survival and response of patients with brain metastases were lower than those for other patients in the phase I setting, but the presence of brain metastases was not an independent prognostic factor predicting survival, indicating that other covariates that coexist with brain metastases were more significant. Time-to-treatment failure for patients with brain metastases was not decreased, nor was the incidence of serious adverse effects (including neurologic toxicity) increased, suggesting that these patients should be eligible for early clinical trials. Clin Cancer Res; 17(12); 4110–8. ©2011 AACR.

Phase 1 Clinical Trials in 83 Patients With Pancreatic Cancer: The M. D. Anderson Cancer Center Experience

The outcomes of patients with pancreatic cancer treated on early phase clinical trials have not been systematically analyzed. The purpose of this study was to report the presenting characteristics and outcomes of patients with locally advanced or metastatic pancreatic cancer treated on phase 1 clinical trials at a single institution.

Effects of Patupilone on the Pharmacokinetics and Pharmacodynamics of Warfarin in Patients with Advanced Malignancies: A Phase I Clinical Trial

Patupilone is a novel microtubule-targeting cytotoxic agent, which exerts its antitumor effect through microtubule stabilization. Pharmacokinetics, pharmacodynamics, and safety of warfarin when administered concomitantly with patupilone were investigated, and antitumor activity was assessed. This was a phase I, two-center, drug–drug interaction study. In the core phase of the study, treatment consisted of warfarin 20 mg orally (days 1 and 29) and patupilone 10 mg/m2 i.v. (days 8 and 29). Patients benefiting from patupilone treatment continued treatment every 3 weeks (extension phase) until progression of disease, death, or unacceptable toxicity. Seventeen patients were treated (core phase, 17; extension, 9). The geometric mean ratios (comedication/monotherapy) for Cmax and area under the curve0–168 of warfarin were near unity and their 90% confidence intervals were within the equivalence limits of 0.80 and 1.25. The half-life, plasma clearance, and International Normalized Ratio (INR) of warfarin were not affected by patupilone coadministration. The most common adverse events were diarrhea, nausea, vomiting, abdominal pain, anorexia, dehydration, asthenia, and peripheral neuropathy. Five (29.4%) patients experienced grade 3 study drug-related adverse events (diarrhea, 17.6%; increased INR, 11.8%; dehydration, 5.9%; and neutropenia, 5.9%). One patient with triple-negative breast cancer (estrogen receptor, progesterone receptor, and HER2/neu negative) had a partial response (35% decrease in tumor measurements by Response Evaluation Criteria in Solid Tumors), and 11 had stable disease for 6 weeks or more (≥12 weeks, 6 patients). The pharmacokinetics and pharmacodynamics of warfarin were not affected by patupilone coadministration, suggesting that patupilone has no clinically relevant effect on CYP2C9 metabolism. Patupilone showed antitumor activity in triple-negative breast cancer. Mol Cancer Ther; 10(1); 207–17. ©2011 AACR.

Abstract 2771: Clinical outcomes and prognostic factors in 83 patients with pancreatic cancer treated in phase I clinical trials at M.D. Anderson Cancer Center

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Introduction. The outcomes of patients with pancreatic cancer treated on early-phase clinical trials have not been systematically analyzed. The purpose of this study was to report the presenting characteristics and outcomes of patients with locally advanced or metastatic pancreatic cancer treated on phase I clinical trials at a single institution. Patients and Methods. We reviewed the records of consecutive patients with metastatic pancreatic cancer who were treated in the Phase I Clinical Trials Program at The University of Texas M. D. Anderson Cancer Center from November 2004 to March 2009. Data recorded and analyzed included survival, response, and disease characteristics. Results. Eighty-three patients were identified. The median age was 62 years (range, 39-81). There were 40 men and 43 women. The most common metastatic sites were liver (54% of patients), lung (51%), lymph nodes (37%), and peritoneum and omentum (24%). The median number of prior therapies was 2 (range, 0-7). Thirty-two (39%) patients had a history of pancreatectomy. Sixty-seven (81%) patients had ≥1 comorbidity. Of 78 patients evaluable for response, 2 (3%) had a partial response (PR), and 10 (13%) had stable disease (SD) for ≥4 months. With a median follow-up for survivors of 3.7 months, the median survival from presentation in the Phase I Clinic was 5.0 months (95% CI, 3.3-6.2). The median overall survival from diagnosis was 22.1 months (95% CI, 17.9-26.5). The median time to treatment failure (TTF) was 1.5 months (95% CI, 1.3-1.8). In multivariate analysis, independent factors associated with lower rates of PR or SD were liver metastases (p = 0.001) and PS greater than 0 (p = 0.01) (Table 3). Independent factors associated with shorter survival were liver metastases (p = 0.007), calcium ≤ 8.4 mg/nL (p = 0.015), and elevated serum levels of CEA (>6 ng/mL; p = 0.005). Independent factors associated with shorter TTF were history of smoking (p = 0.009), liver metastases (p = 0.001), serum bilirubin levels >1 mg/dL (p = 0.007), and >1 prior therapy (p = 0.002). Conclusions. The median survival in the current study (5 months) compares favorably to the median survival reported with best supportive care (3 months). Our results suggest that phase I clinical trials offer a reasonable therapeutic approach for patients with advanced pancreatic cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2771.