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A Phase I Clinical Trial of Safingol in Combination with Cisplatin in Advanced Solid Tumors

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A Phase I Clinical Trial of Safingol in Combination with Cisplatin in Advanced Solid Tumors Published OnlineFirst January 21, 2011; DOI: 10.1158/1078-0432.CCR-10-2323 Clinical Cancer Cancer Therapy: Clinical Research A Phase I Clinical Trial of Safingol in Combination with Cisplatin in Advanced Solid Tumors Mark A. Dickson1, Richard D. Carvajal1, Alfred H. Merrill, Jr.3, Mithat Gonen2, Lauren M. Cane1, and Gary K. Schwartz1 Abstract Purpose: Sphingosine 1-phosphate (S1P) is an important mediator of cancer cell growth and pro- liferation. Production of S1P is catalyzed by sphingosine kinase 1 (SphK). Safingol, (L-threo-dihydro- sphingosine) is a putative inhibitor of SphK. We conducted a phase I trial of safingol (S) alone and in combination with cisplatin (C). Experimental Design: A3þ 3 dose escalation was used. For safety, S was given alone 1 week before the combination. S þ C were then administered every 3 weeks. S was given over 60 to 120 minutes, depending on dose. Sixty minutes later, C was given over 60 minutes. The C dose of 75 mg/m2 was reduced in cohort 4 to 60 mg/m2 due to excessive fatigue. Results: Forty-three patients were treated, 41 were evaluable for toxicity, and 37 for response. The maximum tolerated dose (MTD) was S 840 mg/m2 over 120 minutes C 60 mg/m2, every 3 weeks. Dose- limiting toxicity (DLT) attributed to cisplatin included fatigue and hyponatremia. DLT from S was hepatic enzyme elevation. S pharmacokinetic parameters were linear throughout the dose range with no significant interaction with C. Patients treated at or near the MTD achieved S levels of more than 20 mmol/L and maintained levels greater than and equal to 5 mmol/L for 4 hours. The best response was stable disease in 6 patients for on average 3.3 months (range 1.8–7.2 m). One patient with adrenal cortical cancer had significant regression of liver and lung metastases and another had prolonged stable disease. S was associated with a dose-dependent reduction in S1P in plasma. Conclusions: Safingol, the first putative SphK inhibitor to enter clinical trials, can be safely administered in combination with cisplatin. Reversible dose-dependent hepatic toxicity was seen, as expected from preclinical data. Target inhibition was achieved with downregulation of S1P. The recommended phase II dose is S 840 mg/m2 and C 60 mg/m2, every 3 weeks. Clin Cancer Res; 17(8); 2484–92. Ó2011 AACR. Introduction multiple cellular processes including apoptosis inhibition, cell proliferation, and angiogenesis (2). SphK therefore The role of sphingolipid compounds is increasingly regulates a rheostat, balancing the effects of proapoptotic recognized in cancer. The metabolites ceramide, sphingo- ceramide and proproliferative S1P. Inhibiting SphK and sine, and sphingosine 1-phosphate (S1P) have crucial roles downregulating S1P is thus a rational therapeutic target in in intracellular and extracellular signaling (1). Sphingosine cancer (3). kinase 1 (SphK) catalyzes the phosphorylation of sphin- Safingol (L-threo-dihydrosphingosine) is a potent compe- gosine to form S1P(2). S1P acts downstream as a second titive inhibitor of SphK with a Ki of about 5 mmol/L (4). messenger and via G protein-coupled receptors regulates Safingol is the first SphK inhibitor to enter clinical trials as an anticancer agent. Safingol has significant in vitro antic- ancer activity. It increases the in vitro antitumor effect of various chemotherapeutic agents such as doxorubicin, cis- Authors' Affiliations: 1Melanoma and Sarcoma Service, Department of Medicine; 2Biostatistics Service, Department of Epidemiology and Bios- platin, and mitomycin C by enhancing chemotherapy- tatistics; Memorial Sloan-Kettering Cancer Center, New York, New York; induced apoptosis (5). We have also shown that safingol 3 and Department of Molecular Cell Biology, Georgia Institute of Technol- alone induces cell death by autophagy (6). Although safin- ogy, Atlanta, Georgia gol has limited single-agent activity in vivo, xenograft experi- Corresponding Author: Gary K. Schwartz, Melanoma and Sarcoma Service, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, ments have shown that it can increase the antitumor activity New York, NY 10065. Phone: 212-639-8624; Fax: 212-717-3340; of cisplatin without increasing toxicity (5, 7). The exact E-mail: [email protected] mechanism of its action is, however, uncertain. Safingol has doi: 10.1158/1078-0432.CCR-10-2323 previously been studied extensively as an inhibitor of Pro- Ó2011 American Association for Cancer Research. tein Kinase C (PKC), although the Ki is somewhat higher at 2484 Clin Cancer Res; 17(8) April 15, 2011 Downloaded from clincancerres.aacrjournals.org on September 26, 2021. © 2011 American Association for Cancer Research. Published OnlineFirst January 21, 2011; DOI: 10.1158/1078-0432.CCR-10-2323 Phase I Trial of Safingol and Cisplatin Translational Relevance tory to standard therapy or for which there was no standard therapy. Eligible patients had Karnofsky performance status 3 Sphingolipid metabolites play important roles in of 70% or more, total white blood cell count 3,500/mm or 3 cancer. A balance exists between the proapoptotic more, absolute neutrophil count 1,500/mm or more, 3 sphingolipid ceramide and its proproliferation counter- platelet count of 100,000/mm or more, hemoglobin of part sphingosine 1-phosphate (S1P). Sphingosine 9.5 g/dL or more, haptoglobin 30 mg/dL or more, and kinase 1 (SphK) catalyzes the production of S1P and adequate hepatic and renal function. Patients may have thus regulates this balance. Inhibition of SphK is there- received prior chemotherapy (including cisplatin) but fore a rational therapeutic strategy. We report the first 4 weeks from last dose had to elapse before study entry complete phase I study of a safingol, a putative inhibitor (6 weeks for nitrosoureas and mitomycin C). Patients with of SphK. Safingol was administered alone and, based on central nervous system metastases or a primary central preclinical data, in combination with cisplatin. Safingol nervous system neoplasm were not eligible. can be safely administered at doses that achieve plasma The protocol was approved by the Institutional Review levels consistent with target inhibition. Manageable Board of MSKCC and all patients provided written hepatotoxicity, as predicted from animal models, informed consent. occurred. Administration of safingol and cisplatin was associated with dose-dependent decreases in plasma Treatment plan levels of S1P, consistent with SphK inhibition. Consid- This was an open-label, nonrandomized, dose escalation ering the importance of sphingolipids in inflammation, study to determine the MTD of intravenous safingol when immunity, and cancer, the results could have broad administered 1 hour prior to a standard dose of cisplatin, implication for human disease and treatment. once every 21 days. Groups of 3 to 6 patients were treated sequentially according to the dose escalation in Table 1. Safingol was administered as a 60- to 120-minute IV infusion, depend- 33 mmol/L for PKC than for SphK (8). Inhibition of SphK is a ing on the volume of the dose. Sixty minutes after the plausible mechanism of action based on safingol’s ability to completion of the safingol infusion, cisplatin was given as a increase ceramide levels, alter the S1P/ceramide rheostat, 60-minute infusion. Each treatment cycle lasted 3 weeks, and decrease tumor cell survival (9). except for cycle 1, which lasted 4 weeks. In cycle 1, in order We have previously reported a phase I study of safingol to assess safety and pharmacokinetics, safingol was given in combination with doxorubicin (10). Doses of safingol alone on day 1. Following this, on day 8 of cycle 1, both up to 120 mg/m2 were administered every 3 weeks with no safingol and cisplatin were administered. dose-limiting toxicity (DLT) observed. However, the clin- Because of concerns for hemolysis, urinalysis, haptoglo- ical trial was terminated before the maximum tolerated bin, RBC morphology, and complete blood count (CBC) dose (MTD) could be determined because of insufficient were assessed before and after the first infusion of safingol. drug supply. The only safingol-associated toxicity was a All treatments were administered in the outpatient set- single episode of grade 1 hemolysis. No significant phar- ting and, once assigned to a dose level, intrapatient dose macokinetic interaction with doxorubicin was detected. escalation was not permitted. Further clinical development of safingol was delayed by Toxicity was graded in accordance with the Common drug supply issues and commercial circumstances. Toxicity Criteria version 3.0 (12). DLT was defined as the Recently, however, safingol has gained renewed attention occurrence of grade 4 hematologic toxicity, grade 3 or 4 as a putative inhibitor of SphK (11). We now report the nonhematologic toxicity attributable to the study drug in results of a complete phase I study of safingol in combina- combination with cisplatin, or any delay in treatment of tion with cisplatin. The primary objective of this trial was to determine the MTD of safingol when administered in combination with Table 1. Dose escalation cisplatin in patients with advanced solid tumors. Safingol Cohort Safingol, mg/m2 Cisplatin, mg/m2 N was administered over 60 to 120 minutes, prior to cisplatin dosing. Secondary objectives were to investigate the clinical 160 754 pharmacokinetics of safingol and cisplatin, to study the 2 120 75 3 pharmacodynamics of SphK inhibition, and to obtain 3 240 75 3 preliminary data on the therapeutic activity of this regimen. 4 240 60 6 5 360 60 3 Patients and Methods 6 480 60 3 7 600 60 3 Eligibility 8 750 60 6 Eligible patients were 18 years of age or more with a 9 930 60 6 diagnosis of pathologically confirmed measurable or eva- 10 840 60 6 luable advanced solid tumor, with disease that was refrac- www.aacrjournals.org Clin Cancer Res; 17(8) April 15, 2011 2485 Downloaded from clincancerres.aacrjournals.org on September 26, 2021. © 2011 American Association for Cancer Research.
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