A phase I clinical trial of safingol in combination with cisplatin in advanced solid tumors Journal Article
| Authors: | Dickson, M. A.; Carvajal, R. D.; Merrill, A. H. Jr; Gonen, M.; Cane, L. M.; Schwartz, G. K. |
| Article Title: | A phase I clinical trial of safingol in combination with cisplatin in advanced solid tumors |
| Abstract: | Purpose: Sphingosine 1-phosphate (S1P) is an important mediator of cancer cell growth and proliferation. Production of S1P is catalyzed by sphingosine kinase 1 (SphK). Safingol, (L-threo-dihydrosphingosine) is a putative inhibitor of SphK. We conducted a phase I trial of safingol (S) alone and in combination with cisplatin (C). Experimental Design: A 3 + 3 dose escalation was used. For safety, S was given alone 1 week before the combination. S + 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. Doselimiting 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 μmol/L and maintained levels greater than and equal to 5 μmol/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. © 2011 AACR. |
| Keywords: | adult; clinical article; controlled study; treatment response; aged; fatigue; cisplatin; advanced cancer; area under the curve; dose response; drug dose reduction; drug safety; monotherapy; side effect; solid tumor; treatment duration; antineoplastic activity; alanine aminotransferase blood level; aspartate aminotransferase blood level; drug dose escalation; hyponatremia; liver metastasis; lung metastasis; cancer regression; maximum plasma concentration; maximum tolerated dose; phase 1 clinical trial; safingol; enzyme blood level; sphingosine kinase 1 |
| Journal Title: | Clinical Cancer Research |
| Volume: | 17 |
| Issue: | 8 |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2011-04-15 |
| Start Page: | 2484 |
| End Page: | 2492 |
| Language: | English |
| DOI: | 10.1158/1078-0432.ccr-10-2323 |
| PROVIDER: | scopus |
| PMCID: | PMC3078945 |
| PUBMED: | 21257722 |
| DOI/URL: | |
| Notes: | --- - "Export Date: 23 June 2011" - "CODEN: CCREF" - "Source: Scopus" |
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