Phase 1 trial and pharmacokinetic study of the oral platinum analog satraplatin in children and young adults with refractory solid tumors including brain tumors

Srivandana Akshintala, Leigh Marcus, Katherine E. Warren, Robert F. Murphy, Tristan M. Sissung, Anjali Srivastava, Wendy J. Goodspeed, Anne Goodwin, Carmen C. Brewer, Christopher Zalewski, Kelly A. King, Aerang Kim, William D. Figg, Brigitte C. Widemann

Research output: Contribution to journalArticle

Abstract

Background: Based on pre-clinical and clinical activity in adult refractory tumors, and absence of significant neuro-, nephro-, or oto-toxicity, we conducted a pediatric phase 1 trial to determine the toxicities, maximum tolerated dose (MTD), and pharmacokinetics of satraplatin, an oral platinum analogue, in children and young adults with refractory solid tumors. Procedure: Satraplatin was administered orally once daily on days 1-5 of a 28-day cycle at dose level (DL) 1 (60mg/m2/dose), and DL2 (80mg/m2/dose). Toxicities, responses, satraplatin pharmacokinetics, and pharmacogenomic expression of specific DNA repair genes were evaluated. Results: Nine patients received 1-15 cycles (median=2). The MTD was exceeded at DL2 with delayed prolonged myelosuppression as dose-limiting toxicity (DLT) in 2/4 patients. At DL1, 0/5 patients had DLTs. Common non-DLTs included myelosuppression, gastrointestinal toxicities, fatigue, headache, liver enzyme elevation, and electrolyte abnormalities. No significant neuro-, nephro-, or oto-toxicity was observed. No objective responses were observed but 2 patients experienced prolonged disease stabilization (---6-15 cycles). Satraplatin exposure (day 1 plasma ultrafiltrate area under the curve) was similar at DL1 and DL2. A strong correlation between estimated creatinine clearance and satraplatin pharmacokinetic parameters (clearance, area under the curve, and peak concentration) was observed. Conclusions: The MTD of oral satraplatin in children with solid tumors was 60mg/m2/dose daily ×5 days every 28 days, which is lower than the adult recommended dose of 80-120mg/m2/dose. The toxicity profile was similar to adults and delayed myelosuppression was the DLT. No significant neuro-, nephro- or oto-toxicities were observed. Pediatr Blood Cancer 2015;62:603-610.

Original languageEnglish (US)
Pages (from-to)603-610
Number of pages8
JournalPediatric Blood and Cancer
Volume62
Issue number4
DOIs
StatePublished - Apr 1 2015
Externally publishedYes

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Platinum
Brain Neoplasms
Young Adult
Pharmacokinetics
Maximum Tolerated Dose
Neoplasms
Area Under Curve
Pharmacogenetics
DNA Repair
Electrolytes
Fatigue
Headache
satraplatin
Creatinine
Pediatrics
Liver
Enzymes
Genes

Keywords

  • Pediatric
  • Phase 1 trial
  • Satraplatin
  • Solid tumors

ASJC Scopus subject areas

  • Oncology
  • Pediatrics, Perinatology, and Child Health
  • Hematology

Cite this

Phase 1 trial and pharmacokinetic study of the oral platinum analog satraplatin in children and young adults with refractory solid tumors including brain tumors. / Akshintala, Srivandana; Marcus, Leigh; Warren, Katherine E.; Murphy, Robert F.; Sissung, Tristan M.; Srivastava, Anjali; Goodspeed, Wendy J.; Goodwin, Anne; Brewer, Carmen C.; Zalewski, Christopher; King, Kelly A.; Kim, Aerang; Figg, William D.; Widemann, Brigitte C.

In: Pediatric Blood and Cancer, Vol. 62, No. 4, 01.04.2015, p. 603-610.

Research output: Contribution to journalArticle

Akshintala, S, Marcus, L, Warren, KE, Murphy, RF, Sissung, TM, Srivastava, A, Goodspeed, WJ, Goodwin, A, Brewer, CC, Zalewski, C, King, KA, Kim, A, Figg, WD & Widemann, BC 2015, 'Phase 1 trial and pharmacokinetic study of the oral platinum analog satraplatin in children and young adults with refractory solid tumors including brain tumors', Pediatric Blood and Cancer, vol. 62, no. 4, pp. 603-610. https://doi.org/10.1002/pbc.25344
Akshintala, Srivandana ; Marcus, Leigh ; Warren, Katherine E. ; Murphy, Robert F. ; Sissung, Tristan M. ; Srivastava, Anjali ; Goodspeed, Wendy J. ; Goodwin, Anne ; Brewer, Carmen C. ; Zalewski, Christopher ; King, Kelly A. ; Kim, Aerang ; Figg, William D. ; Widemann, Brigitte C. / Phase 1 trial and pharmacokinetic study of the oral platinum analog satraplatin in children and young adults with refractory solid tumors including brain tumors. In: Pediatric Blood and Cancer. 2015 ; Vol. 62, No. 4. pp. 603-610.
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AU - Marcus, Leigh

AU - Warren, Katherine E.

AU - Murphy, Robert F.

AU - Sissung, Tristan M.

AU - Srivastava, Anjali

AU - Goodspeed, Wendy J.

AU - Goodwin, Anne

AU - Brewer, Carmen C.

AU - Zalewski, Christopher

AU - King, Kelly A.

AU - Kim, Aerang

AU - Figg, William D.

AU - Widemann, Brigitte C.

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N2 - Background: Based on pre-clinical and clinical activity in adult refractory tumors, and absence of significant neuro-, nephro-, or oto-toxicity, we conducted a pediatric phase 1 trial to determine the toxicities, maximum tolerated dose (MTD), and pharmacokinetics of satraplatin, an oral platinum analogue, in children and young adults with refractory solid tumors. Procedure: Satraplatin was administered orally once daily on days 1-5 of a 28-day cycle at dose level (DL) 1 (60mg/m2/dose), and DL2 (80mg/m2/dose). Toxicities, responses, satraplatin pharmacokinetics, and pharmacogenomic expression of specific DNA repair genes were evaluated. Results: Nine patients received 1-15 cycles (median=2). The MTD was exceeded at DL2 with delayed prolonged myelosuppression as dose-limiting toxicity (DLT) in 2/4 patients. At DL1, 0/5 patients had DLTs. Common non-DLTs included myelosuppression, gastrointestinal toxicities, fatigue, headache, liver enzyme elevation, and electrolyte abnormalities. No significant neuro-, nephro-, or oto-toxicity was observed. No objective responses were observed but 2 patients experienced prolonged disease stabilization (---6-15 cycles). Satraplatin exposure (day 1 plasma ultrafiltrate area under the curve) was similar at DL1 and DL2. A strong correlation between estimated creatinine clearance and satraplatin pharmacokinetic parameters (clearance, area under the curve, and peak concentration) was observed. Conclusions: The MTD of oral satraplatin in children with solid tumors was 60mg/m2/dose daily ×5 days every 28 days, which is lower than the adult recommended dose of 80-120mg/m2/dose. The toxicity profile was similar to adults and delayed myelosuppression was the DLT. No significant neuro-, nephro- or oto-toxicities were observed. Pediatr Blood Cancer 2015;62:603-610.

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