A phase I study with CRx-026, a novel dual action agent, in patients (pts) with advanced solid tumors

Abstract

3073 Background: CRx-026 contains two active pharmaceutical ingredients which, when combined, synergistically blocks cancer cell division by inhibiting two critical elements of the cancer cell’s mechanism for dividing. One component of CRx-026, chlorpromazine, inhibits hsEg5/KSP, a mitotic kinesin essential for centrosome separation. The other component, pentamidine, is reported to inhibit PRL phosphatases, which play an important role in regulating mitotic progression and proper chromosome separation. The objectives of this Phase I study were to assess the dose limiting toxicities (DLTs), to determine the maximum tolerated dose (MTD), and to describe the pharmacokinetics (PK) of CRx-026 in patients with advanced solid tumors. Methods: 18pts with metastatic cancer whose tumors had progressed on at least one prior therapy were enrolled in escalating dose-level (DL) cohorts in a ‘3+3’ design. The pts received CRx-026 by infusion daily for 5 consecutive days. After a 16-day therapy-free interval (one cycle) the treatment was repeated. Evaluation for response was performed every 2 cycles. EKG monitoring and PK analysis were done during cycle one only. Results: Standard Phase I eligibility criteria were required for patient entry. The pts (median age: 61yrs; 13M/5F) were treated at 4DLs: DL1 (7pts); DL2 (3pts); DL3 (6pts); DL4 (2pts). WHO PS: 0 (7pts.), 1 (11pts.). The DLTs included one dystonic reaction and one supraventricular tachycardia at DL4. The other common toxicity was somnolence which occurred during the infusion but this was not dose limiting. No CRs or PRs have been observed to date. 6pts have shown stable disease ranging from 4–8+ cycles. The median duration on study showed a trend toward longer duration at higher dose levels. The MTD for this trial is DL 3. The PK profile of CRx-026 was linear over the dose range studied. The PK parameters of the components of CRx-026 did not appear to differ from known literature values indicating an absence of drug-drug interactions. Conclusions: CRx-026 represents a different approach to hitting a pattern of targets in cancer cells. CRx-026 can be safely given in pts with advanced cancer. DL3 is the recommended Phase II dose on this schedule to assess its clinical activity. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration CombinatoRx CombinatoRx CombinatoRx CombinatoRx