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/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.

©2011 AACR.

Figures

Figure 1

Pharmacokinetic dose-ranging for Cmax (top) and AUC (bottom) of safingol. Cmax and AUC for each patient studied are plotted against safingol dose. Diamonds represent doses of safingol given alone. Circles represent doses of safingol given with cisplatin.

Figure 2

(A) Pharmacodynamics of sphingosine-1-phophate (S1P) in peripheral blood. The mean S1P levels 1 hour and 4 hours after safingol treatment are shown, with patients grouped by safingol dose cohort. S1P levels are normalized to the pre-treatment S1P levels for each cohort with standard error bars shown. (B) Safingol plasma concentration over time for the patients treated at or near the MTD. Safingol doses of 750–930 mg/m2 were administered. Plasma levels were measured beginning at the end of safingol infusion (time = 0).

Figure 3

Regression of pulmonary and hepatic metastases from a patient with adrenal cortical carcinoma, 16 weeks after a treatment with safingol and cisplatin.