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

Clin Cancer Res. 2011 Apr 15;17(8):2484-92. doi: 10.1158/1078-0432.CCR-10-2323. Epub 2011 Jan 21.

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/m(2) was reduced in cohort 4 to 60 mg/m(2) 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/m(2) over 120 minutes C 60 mg/m(2), 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 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/m(2) and C 60 mg/m(2), every 3 weeks.

Publication types

  • Clinical Trial, Phase I
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Area Under Curve
  • Cisplatin / administration & dosage
  • Cisplatin / adverse effects
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Fatigue / chemically induced
  • Female
  • Humans
  • Lymphopenia / chemically induced
  • Lysophospholipids / blood
  • Lysophospholipids / metabolism
  • Male
  • Metabolic Clearance Rate
  • Middle Aged
  • Neoplasms / drug therapy*
  • Neoplasms / pathology
  • Phosphotransferases (Alcohol Group Acceptor) / antagonists & inhibitors
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism
  • Sphingosine / administration & dosage
  • Sphingosine / adverse effects
  • Sphingosine / analogs & derivatives
  • Sphingosine / blood
  • Sphingosine / metabolism
  • Sphingosine / pharmacokinetics
  • Treatment Outcome

Substances

  • Lysophospholipids
  • sphingosine 1-phosphate
  • Phosphotransferases (Alcohol Group Acceptor)
  • sphingosine kinase
  • Sphingosine
  • safingol
  • Cisplatin