Phase I ClinicalTrial of STA-4783 in Combinationwith Paclitaxel in Patients with Refractory SolidTumors

STA-4783 is a new compound that markedly enhances the therapeutic index of paclitaxel against human tumor xenograft models. A phase I clinical trial was undertaken to determine the maximum tolerated dose, toxicity profile, and pharmacokinetics of STA-4783 in combination with paclitaxel. Adultswith refractory solid tumors concurrently received STA-4783 and paclitaxel as a 3-h i.v. infusion at starting doses of 44 and135mg/m, respectively. After increasingpaclitaxel to175mg/m, the STA-4783 dosewas escalated as permitted by dose-limiting toxicity during the first 21-day cycle.  Thirty-five patients were treated with eight dose levels of STA-4783/paclitaxel. In patients receiving175mg/m paclitaxel, the incidence of severe toxicity increasedwith escalation of the STA-4783 dose above 263 mg/m, and 438 mg/m was the maximum tolerated dose. All toxicities were typical of paclitaxel, with neutropenia, mucositis, and myalgia/arthralgia being dose limiting. Partial responses were achieved in one patient with Kaposi’s sarcoma and another with ovarian cancer that progressed during prior treatment with paclitaxel. STA-4783 exhibited linear pharmacokinetics characterized by rapid elimination from plasma (biological half-life, 1.06F 0.24 h) and a low steady-state apparent volume of distribution (25.1F8.1L/m).The total body clearance of paclitaxel decreased significantly with escalation of the STA-4783 dose.  The STA-4783/paclitaxel combination was well tolerated with a toxicity profile similar to single-agent paclitaxel. Enhanced systemic exposure to paclitaxel resulting from a dose-dependent interaction with STA-4783 was associated with increased toxicity. Objective responses in twoheavily pretreatedpatients, bothwith taxane exposure, have encouraged further clinical evaluation of this regimen. Introduction of the taxanes, paclitaxel, and docetaxel into clinical use has notably improved the treatment of patients with various solid tumors. In particular, both drugs have significant single-agent activity against metastatic breast cancer, advanced ovarian cancer, and advanced non–small cell lung cancer (1–3). Efficacy against ovarian cancer and non–small cell lung cancer is enhanced considerably when the taxanes are combined with cisplatin or carboplatin (2, 3). Taxane-platinum regimens are currently considered to be one of the preferred options for first-line treatment of these diseases. Unfortunately, despite the important advances that have been achieved with taxane-based chemotherapy in treatment outcomes, these regimens are generally not curative, as disease progression occurs eventually in all patients with advanced ovarian cancer and non–small cell lung cancer (2, 3). As with any other cytotoxic chemotherapeutic agent, the potential effectiveness of the taxanes is limited by the severity and frequency of host toxicities that occur at sufficiently high doses. Neutropenia is the principal dose-limiting toxicity (DLT) of both clinically approved taxanes. Peripheral neuropathy, arthralgia, and myalgia are also significant complications (4). Ongoing efforts to further optimize the taxane-platinum regimens may improve tolerability, but it is unlikely that clinical efficacy can be significantly enhanced. This stimulated interest in identifying compounds that could favorably modulate the antiproliferative activity of paclitaxel against tumor cells without affecting host toxicity, thereby effectively increasing the therapeutic index of the drug. N-malonyl-bis(N ¶methyl-N ¶-thiobenzoylhydrazide) (STA-4783; Fig. 1) is a compound that exhibits these characteristics. It was originally identified by empirically screening for compounds that Cancer Therapy: Clinical Authors’ Affiliations: Beth Israel Deaconess Medical Center; Dana-Farber Cancer Institute; Massachusetts General Hospital; Dana-Farber/Harvard Cancer Center, Boston, Massachusetts; and Synta Pharmaceuticals Corp., Lexington, Massachusetts Received 4/20/06; revised10/18/06; accepted10/20/06. Grant support: Synta Pharmaceuticals Corp. (Lexington, MA). The costs of publication of this article were defrayed in part by the payment of page charges.This article must therefore be hereby marked advertisement in accordance with18 U.S.C. Section1734 solely to indicate this fact.  A. Berkenblit andJ.P. Eder contributed equally to this work. Preliminary results of this studywere presented at theAACR-EuropeanOrganization for Research and Treatment of Cancer-National Cancer Institute International Conference on MolecularTargets and Cancer Therapeutics, November 17-21, 2003, Boston, Massachusetts and at the 24th Annual Meeting of the American Society of Clinical Oncology, May13-17, 2005, Orlando, Florida. Requests for reprints: Jeffrey G. Supko, Massachusetts General Hospital, 55 Fruit Street, Room GRJ1025, Boston, MA 02114.  ; E-mail: jsupko@partners.org.  American Association for Cancer Research. doi:10.1158/1078-0432.CCR-06-0964 www.aacrjournals.org Clin Cancer Res 2007;13(2) January15, 2007 584 Research. on April 19, 2017.  Preclinical studies done at the Southern Research Institute (Birmingham, AL) showed that the growth of human tumor xenografts in CD-1 nude mice is unaffected by treatment with STA-4783 alone. In contrast, administering STA4783 in combination with paclitaxel dramatically enhanced the antitumor activity achieved with single-agent paclitaxel, in a dose-dependent manner, without increasing host toxicity. Synergistic activity with paclitaxel was shown against human tumor xenografts of breast cancer, lung cancer, and lymphoma cell lines. In addition, the number of animals with sustained tumor-free regressions after completing treatment was significantly greater in groups that received the STA-4783/paclitaxel combination compared with treatment with paclitaxel alone. The underlying mechanism responsible for the synergistic effect of STA-4783 on the antitumor activity of paclitaxel remains to be elucidated, although preliminary experiments suggest that it may be related to enhanced immune-mediated cytotoxicity. However, the effect is not simply a consequence of a pharmacokinetic interaction because the plasma pharmacokinetics of paclitaxel in mice was found to be unaffected by coadministration of STA-4783. This report describes the results of the first phase I clinical trial of STA-4783. The study was designed to identify the maximum tolerated dose (MTD) of STA-4783 when given concurrently with the standard 175 mg/m dose of paclitaxel as a 3-h i.v. infusion, repeated every 21 days, in adult patients with refractory solid tumors. Additional objectives of the study were to characterize the pharmacokinetic behavior of STA-4783 in humans and to assess whether it has any effect on the plasma pharmacokinetics of paclitaxel when coadministered. Materials andMethods Patient selection. Patients with histologically confirmed solid tumors that were metastatic or unresectable and for which no standard therapy existed were eligible for this study. They were required to be at least 18 years old, have an Eastern Cooperative Oncology Group performance status of 0 to 2, and have a life expectancy of >12 weeks. Acceptable hematologic (absolute neutrophil count z1,500 cells/AL, platelet count z100,000/AL), hepatic (aspartate aminotransferase and alanine aminotransferase V2.5 times the upper limit of normal, normal total bilirubin), and renal (serum creatinine <1.5 mg/dL or measured creatinine clearance >50 mL/min) function as well as an electrocardiogram without evidence of clinically significant conduction abnormalities or active ischemia were required. Patients with a history of treated brain metastases that were clinically stable for at least 4 weeks were eligible. Conditions resulting in exclusion from the study included any of the following: baseline neuropathy grade z2, history of significant neurologic problems, treatment with approved or investigational anticancer agents or radiation within 4 weeks (6 weeks for chloroethylnitrosoureas or mitomycin C), prior high-dose chemotherapy with autologous stem cell rescue or bone marrow transplantation, history of severe allergic reaction to taxanes, current pregnancy or breast-feeding, and an uncontrolled intercurrent medical condition or psychiatric illness that would limit compliance with study requirements. Patients whose tumors had progressed during previous treatment with a taxane were not excluded, although the efficacy of the STA-4783/paclitaxel combination has not been evaluated in taxaneresistant tumor models. The protocol for this clinical trial was approved by the Dana-Farber/Harvard Cancer Center (Boston, MA) Scientific Review Committee and Institutional Review Board. Patients signed a written informed consent document satisfying all institutional, state, and federal requirements as a condition of registration into the study. Drug administration. Paclitaxel (Bristol-Meyers Squibb Co., Wallingford, CT) was obtained from commercial sources as the standard dosage form for injection. STA-4783 was provided by Synta Pharmaceuticals (Lexington, MA) as 75 and 300 mg of a dry powder, free of excipients, in 50 mL vials. Because of the poor water solubility of STA4783, the drug was reconstituted by adding Paclitaxel Injection USP [sterile solution containing 6 mg paclitaxel, 527 mg of purified Cremophor EL, and 49.7% (v/v) dehydrated alcohol, USP in each mL] directly into a single STA-4783 vial. The paclitaxel/STA-4783 doses (mg/m) are reducible to whole number ratios, ranging from 4:1 to 1:3 at each dose level to be evaluated, allowing the precise volume of Paclitaxel Injection USP required to prepare any dose to be readily determined. The vial was manually shaken and placed in an ultra