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Table 1 Dose limiting toxicity and maximum grade of all hepatic toxicities for all 15 patients enrolled on NANT 2004–04

From: Probable fatal drug interaction between intravenous fenretinide, ceftriaxone, and acetaminophen: a case report from a New Approaches to Neuroblastoma (NANT) Phase I study

Total dose of IV fenretinide # patients enrolled (# evaluable for dose escalation) Patient Age at study entry (years) Fenretinide peak level Course 1 (μM) Dose Limiting Toxicity Total number courses/Hepatic toxicities (maximum grade (Gr) across all courses received ) Ceftriaxone during or after fenretinide Acetaminophen during or after fenretinide
Level 1: 640 mg/m2/day 3 (3) 7.9 30.5 None 6 courses: Gr 2 AST, Gr 2 hypoalbuminemia, Gr 1 hyperbilirubinemia 3 days during Course 6  
8.5 17.2 None 1 course: Gr 1 hypoalbuminemia, Gr 1 AST   1 dose 2 days after Course 1
24 30.1 None 2 courses; none   
Level 2: 770 mg/m2/day 3 (3) 4.2 40.7 None 30 courses: Gr. 3 ALT, Gr 3 AST, Gr. 2 hypoalbuminemia, Gr 1 alkaline phosphatase. Got dose level 1 for courses 26–30 due to delayed platelet recovery course 25.   20 doses starting after completion of Course 14
4.4 70.2 None 4 courses; Grade 1 AST   
5 39.4 Gr 3 hypoalbuminemia* 1 course: Gr 3 AST, Gr 3 hypoalbuminemia*   
Level 3: 925 mg/m2/day 7 ( 6 ) 6.7 36.3 None 2 courses: Gr. 1 ALT, Gr 1 AST, Gr. 1 hypoalbuminemia   4 doses during Course 3
5.2 38.4 None 6 courses; Gr 1 AST, Gr 1 hypoalbuminemia, Gr 2 hyperbilirubinemia 2 days during Course 1  
9.7 60.7 Gr 4 hypertriglyceridemia due to error in drug infusion 1 course: Not evaluable for dose escalation due to error in drug infusion with 24 hour dose given over 12 hours; Gr 1 hypoalbuminemia, Gr 2 hyperbilirubinemia   
11.4 33.0 Pseudotumor cerebri 1 course: Gr 3 ALT, Gr 2 AST   
11 29.1 None 1 course; Gr 1 ALT, Gr 2 AST, Gr 1 hypoalbuminemia   
5.3 23.7 None 2 courses: Gr 1 AST   
12.6 45.0 None 2 courses; Gr 1 ALT, Gr 2 AST   
Level 4: 1110 mg/m2/day 2 (2) 5.5 83.3 Gr 4 epistaxis related to multi organism non-neutropenic bacteremia during course 5 5 courses: Gr 1 ALT, Gr 2 AST, Gr 2 hypoalbuminemia, Gr 1 alkaline phosphatase 4 days starting 9 days after completion of Course 5  
7.2 110.9 Fatal hepatic failure, renal failure, and hypotension** 1 course (subject of this case report): Gr 5 liver dysfunction/failure (clinical), Gr 4 ALT, Gr 4 AST, Gr 4 hyperbilirubinemia; Gr 3 hypoalbuminemia; Gr 1 alkaline phosphatase 3 days starting 4th day of the infusion 9 doses starting 4th day of the infusion
Level 3a: 925 mg/m2/day 2 (0) 6.7 14.17# None 2 courses: Gr 1 ALT/Gr 1 AST   
7.8 21.93# None 5 courses:Gr 1 AST, Gr 1 hypalbuminemia, Gr 1 alkaline phosphatase   
  1. *Patient enrolled with Grade 1 hypoalbuminemia, resolved from asymptomatic Grade 3 to Grade 2 by day 27 of course; Grade 1 by Day 31 (definition of DLT was resolution to Grade 1 by Day 28). Dose level not expanded since not considered clinically significant & protocol amended to exclude metabolic abnormalities as DLT. ** Subsequent Gr 4 acidosis, colitis, disseminated intravascular coagulation, enteritis, hypoxia, and hemorrhage; Gr 3 encephalitis as described in the text. # Both patients had course 1 infusion interrupted for hypertriglyceridemia and dose reduced by 50% to complete course 1 and for subsequent courses.