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537.Full.Pdf Vol. 3, 537-543, April 1997 Clinical Cancer Research 537 A Pilot Clinical/Pharmacological Study of the Protein Kinase C-specific Inhibitor Safingol Alone and in Combination with Doxorubicin Gary K. Schwartz,1 David Ward, Leonard Saltz, INTRODUCTION Ephraim S. Casper, Tara Spiess, Eillen Mullen, PKC2 is a phospholipid-dependent serine/threonine kinase that plays a pivotal role in many of the signal transduction events Jim Woodworth, Robert Venuti, Peter Zervos, related to tumorigenesis. Activation of cell surface receptors by Anne-Mane Storniolo, and David P. Kelsen extracellular molecules such as growth factors and hormones can Department of Medicine, Division of Solid Tumor Oncology, stimulate phosphatidylinositol turnover, leading to elevated levels Gastrointestinal Oncology Section, Memorial Sloan-Kettering Cancer of inositol triphosphate and sn-l,2-diacylglycerol, the endogenous Center, New York, New York 10021 [G. K. S., L. S., E. S. C., T. S., E. M., D. P. K.], and Eli Lilly Research Lab, Indianapolis, Indiana ligand that activates PKC (1 , 2). These extracellular signaling 46285 [D. W., J. W., R. V., P. Z., A-M. S.] molecules, as well as their receptors, are altered in their effect by cellular oncogenes, and diacylglycerol is known to be elevated in cells transformed by ras, sis, and src (3). In addition, activation of ABSTRACT PKC leads to the expression of nuclear proto-oncogenes (e.g., myc, We performed a pilot clinical trial with safingol (L- fos, cis, and fins) associated with cellular proliferation. PKC is threo-dihydrosphingosine), a protein kinase C-specific in- activated by phorbol esters, such as phorbol myristate acetate, hibitor that potentiates the effect of doxorubicin (DOX) in which are potent tumor promoters in mouse skin (4). Increased tumor-bearing animals. Safingol was initially administered tumorigenicity also correlates with overexpression of certain PKC as a 1-h infusion at escalating doses. Fourteen days later, isoforms in Nil-I 3T3 cells inoculated into nude mice (5). The patients received the same dose of safingol in combination involvement of PKC in so many aspects of aberrant growth regu- with a fixed dose of DOX. The combination was repeated at lation suggests that the modulation of PKC activity might be an 3-week intervals. Safingol dose levels ranged from 15 to 120 effective target for anticancer therapy. mg/m2. The plasma levels achieved at the final dose level Safingol (Fig. 1), the L-threo enantiomer of dihydrosphin- were comparable to those associated with potentiation of gosine, is a PKC-specific inhibitor that inhibits PKC enzyme ac- DOX in animals. The mean Cmax and area under the curve tivity in micromolar concentrations (6). In vitro studies of safingol for safingol at the 120 mg/m2 dose level were 1040 ± 196 have demonstrated reversal of multidrug resistance in DOX-resist- ng/ml and 1251 ± 317 mg x h/mI, respectively. The mean ant cell lines (7, 8). Safmgol has also been shown to increase the plasma half-life for safmgol was 3.97 ± 2.51 h, the mean activity of DOX and other chemotherapeutic agents, including estimated clearance was 3140 ± 765 mI/mm, and the mean mitomycin C, by enhancing chemotherapy-induced apoptosis, even volume of distribution was of 995 ± 421 liters. Coadminis- in tumor cell lines that were resistant to chemotherapy by virtue of tration of a fixed dose of DOX did not significantly change a mutation in p53 (6). In vivo, as a single agent, safingol has shown the pharmacokinetics of safingol, nor did increasing doses of little direct antitumor activity. However, in a series of murine tumor safingol significantly affect the pharmacokinetics of DOX. models and human tumor xenografts, safingol has been shown to Minor responses were observed in three patients with pan- significantly modulate the antitumor effect of DOX and cisplatin creatic cancer and one patient with angiosarcoma of the (9, 10). This was achieved without an increase in chemotherapy- induced bone marrow suppression or major organ toxicity (i.e., scalp. This pilot Phase I study indicates that the protein ear or kidney). In these studies, nontoxic serum levels of safingol could kinase C inhibitor safingol can be given safely with 45 be attained at concentrations associated with inhibition of PKC mg/rn2 of DOX at a dose that is potentially pharmacologi- enzyme activity (1 1). cally active without dose-limiting toxicity. Because the in vivo activity of safingol appeared to be greatest when combined with chemotherapy and because this was associated with established serum safingol levels, we per- formed a pilot clinical study of safingol and DOX with phar- macological end points designed to determine whether we could Received 6/4/96; revised 12/18/96; accepted 12/30/96. 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 with 18 U.S.C. Section 1734 solely to 2 The abbreviations used are: PKC, protein kinase C; DOX, doxorubi- indicate this fact. I To whom requests for reprints should be addressed, at Department of cm; PT, prothrombin; P’FT, partial thromboplastin; CBC, complete Medicine, Division of Solid Tumor Oncology, Gastrointestinal Oncol- blood count; DLT, dose-limiting toxicity; HPLC, high-performance ogy Section, Memorial Sloan-Kettering Cancer Center, New York, NY liquid chromatography; AUC, area under the curve; HNTD, highest 10021. Phone: (212) 639-8324; Fax: (212) 717-3320. nontoxic dose. Downloaded from clincancerres.aacrjournals.org on September 28, 2021. © 1997 American Association for Cancer Research. 538 Safingol Alone and in Combination with Doxorubicin QH CH3(CH2)1 4AyOH U U- NH2 Day# 1 14 35 Fig. 1 Safingol (L-threo-dihydrosphingosine). I Safingol (infusion over I hour) Doxorubicin (bolus) achieve nontoxic levels of safingol in serum associated with Fig. 2 Treatment scheme of Phase I study for safingol/DOX. Patients chemopotentiation of DOX in animals. were treated in cohorts of three to six patients with safingol on day 1. If there was no acute toxicity, they were again treated with the same dose of safingol on day 14, followed in 1 h by a fixed dose of DOX. If there PATIENTS AND METHODS was no dose-limiting toxicity, they could then be retreated with the same Patients. Patients treated as part of this clinical trial had to combination at the same doses 21 days later (day 35). Subsequent meet the following criteria. All patients had to be 18 years of age cohorts were treated with an increased dose of safingol according to the same treatment scheme and with the DOX dose fixed at all safingol dose with histologically confirmed carcinoma by the Pathology Depart. levels. ment of Memorial Hospital. Patients had to have cancer refractory to standard therapy (or for which there was no standard therapy) and not curable by surgery or radiation therapy. A Karnofsky performance status 60% with a life expectancy of at least 12 measurement of all measurable disease, as well as signs and weeks was required. Previously treated patients were accepted. symptoms. Pretreatment laboratory studies included a CBC, They may not, however, have received myelosuppressive chemo- platelet count, differential, biochemical screening profile, serum therapy or radiation therapy to major bone marrow-containing creatinine, PT, P’fl’, chest X-ray, and urinalysis, and serum areas within the previous 4 weeks (6 weeks for prior nitrosurea or pregnancy test for females. Radiological studies with measure- mitomycin C), and they must have recovered from the marrow ment of the tumor indicator lesion(s) were performed as clini- toxic effects of prior chemotherapy and radiation. cally indicated. Pretreatment gated pool heart scan at rest and a All patients must have had a WBC count 4000/p.l, a total 12-lead EKG were required. neutrophil count 1500/p.l, a platelet count l50,000/p.l, and a Safingol Administration. Safingol is the non-proprie- hemoglobin l0 g/dl, and a normal PT/FIT prior to starting tary name for the L-threo enantiomer of dihydrosphingosine. therapy. Normal renal function (serum creatinine l.5 mg/dl) and The chemical name is (2S,3S)-2-amino-l,3-octadecanediol; the normal hepatic function (serum bilirubin, l.5 mg/dl; serum as- Eli Lilly Research Laboratory code number is SPC-100270; and partate aminotransferase and alkaline phosphatase levels 2.5 safingol is a white to off-white crystalline solid with a molecular times the upper limit of normal) were required. Patients with weight of 301.50. The molecular formula is C18H39N02. documented bone metastases and an elevated alkaline phosphatase Safingol was supplied by Eli Lilly Research Lab (Indian- >25 times the upper limit of normal were eligible for the study if apolis, Indiana) as a 0.5% (5 mg/mI) emulsion, which was all other liver function tests were within the above-specified limits. diluted with 5% dextrose in water to achieve a 0.5 mg/ml A normal resting gated pool heart scan with an ejection fraction solution for administration. The lipid emulsion contained soy- 50% was required. Patients were required to have no prior history bean oil, Pluronic F-68 (NF), cholesterol (NF), a-tocopherol of cardiac arrhythmia requiring therapy (other than chronic atrial (USP), glycerin (USP), water, and HC1. The vials were stored fibrillation). Patients with a history of a myocardial infarction under at 2-8#{176}Cand were for single-use only. The appropriate within 6 months prior to study entry were excluded. Prior DOX amount of safingol was diluted in 5% dextrose in water to treatment was allowed as long as the prior lifetime cumulative dose achieve the desired concentration. The diluted emulsion was ofDOX did not exceed 280 mg/m2. Good peripheral venous access stored at room temperature and was administered within 12 h of was required; otherwise central access via a Mediport or Broviac dilution when stored diluted in either polyvinyl chloride bags or catheter was required.
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