Abstract | PURPOSE: 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.
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Authors | Mark A Dickson, Richard D Carvajal, Alfred H Merrill Jr, Mithat Gonen, Lauren M Cane, Gary K Schwartz |
Journal | Clinical cancer research : an official journal of the American Association for Cancer Research
(Clin Cancer Res)
Vol. 17
Issue 8
Pg. 2484-92
(Apr 15 2011)
ISSN: 1557-3265 [Electronic] United States |
PMID | 21257722
(Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Extramural)
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Copyright | ©2011 AACR. |
Chemical References |
- Lysophospholipids
- sphingosine 1-phosphate
- Phosphotransferases (Alcohol Group Acceptor)
- sphingosine kinase
- Sphingosine
- safingol
- Cisplatin
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Topics |
- Adult
- Aged
- Aged, 80 and over
- Antineoplastic Combined Chemotherapy Protocols
(adverse effects, therapeutic use)
- Area Under Curve
- Cisplatin
(administration & dosage, adverse effects)
- Dose-Response Relationship, Drug
- Drug Administration Schedule
- Fatigue
(chemically induced)
- Female
- Humans
- Lymphopenia
(chemically induced)
- Lysophospholipids
(blood, metabolism)
- Male
- Metabolic Clearance Rate
- Middle Aged
- Neoplasms
(drug therapy, pathology)
- Phosphotransferases (Alcohol Group Acceptor)
(antagonists & inhibitors, metabolism)
- Sphingosine
(administration & dosage, adverse effects, analogs & derivatives, blood, metabolism, pharmacokinetics)
- Treatment Outcome
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