Phase I trial of two schedules of vincristine, oral irinotecan, and temozolomide (VOIT) for children with relapsed or refractory solid tumors

A children's oncology group phase I consortium study

Lars M. Wagner, John P. Perentesis, Joel M Reid, Matthew M. Ames, Stephanie L. Safgren, Marvin D. Nelson, Ashish M. Ingle, Susan M. Blaney, Peter C. Adamson

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

Background. In preclinical models, temozolomide, and vincristine are additive or synergistic with irinotecan. We examined this three-drug combination in children with relapsed solid tumors. Patients received orally administered irinotecan together with temozolomide and vincristine on two different schedules, using cefixime to reduce irinotecan-associated diarrhea. Methods. Oral irinotecan was given daily on days 1-5 and 8-12 (Schedule A), or on days 1-5 (Schedule B). Temozolomide was given on days 1-5, with vincristine 1.5 mg/m2 administered on days 1 and 8 (Schedule A) or day 1 (Schedule B) in 21-day courses. Results. On Schedule A, the maximum tolerated dose of oral irinotecan was 35 mg/m2/day combined with temozolomide 100 mg/m 2/day and vincristine on days 1 and 8. Dose-limiting toxicities in 4 of 12 patients included hepatotoxicity, abdominal pain, anorexia, hypokalemia, and thrombocytopenia at 50 mg/m2/day. Using Schedule B, 0 of 6 patients experienced dose-limiting toxicity (DLT) at the highest doses studied of oral irinotecan 90 mg/m2/day, temozolomide 150 mg/m 2/day x 5, and vincristine on day 1. First-course and cumulative toxicity was greater with Schedule A. UGT1A1*28 genotype did not correlate with DLT. At the irinotecan dose of 90 mg/m2/day, the mean SN-38 AUCinf was 63 ng/ml hr. Activity was seen in sarcoma patients, and overall eight patients received ≥6 courses. Conclusions. The 5-day schedule of VOIT was well tolerated and provided SN-38 exposures similar to those achieved with intravenous IRN. Activity on this and prior studies suggests a potential role for VOIT in a spectrum of childhood solid tumors.

Original languageEnglish (US)
Pages (from-to)538-545
Number of pages8
JournalPediatric Blood and Cancer
Volume54
Issue number4
DOIs
StatePublished - Apr 2010

Fingerprint

irinotecan
temozolomide
Vincristine
Appointments and Schedules
Neoplasms
Cefixime

Keywords

  • Cefixime
  • Oral irinotecan
  • SN-38
  • Temozolomide
  • Vincristine

ASJC Scopus subject areas

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

Cite this

Phase I trial of two schedules of vincristine, oral irinotecan, and temozolomide (VOIT) for children with relapsed or refractory solid tumors : A children's oncology group phase I consortium study. / Wagner, Lars M.; Perentesis, John P.; Reid, Joel M; Ames, Matthew M.; Safgren, Stephanie L.; Nelson, Marvin D.; Ingle, Ashish M.; Blaney, Susan M.; Adamson, Peter C.

In: Pediatric Blood and Cancer, Vol. 54, No. 4, 04.2010, p. 538-545.

Research output: Contribution to journalArticle

Wagner, Lars M. ; Perentesis, John P. ; Reid, Joel M ; Ames, Matthew M. ; Safgren, Stephanie L. ; Nelson, Marvin D. ; Ingle, Ashish M. ; Blaney, Susan M. ; Adamson, Peter C. / Phase I trial of two schedules of vincristine, oral irinotecan, and temozolomide (VOIT) for children with relapsed or refractory solid tumors : A children's oncology group phase I consortium study. In: Pediatric Blood and Cancer. 2010 ; Vol. 54, No. 4. pp. 538-545.
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abstract = "Background. In preclinical models, temozolomide, and vincristine are additive or synergistic with irinotecan. We examined this three-drug combination in children with relapsed solid tumors. Patients received orally administered irinotecan together with temozolomide and vincristine on two different schedules, using cefixime to reduce irinotecan-associated diarrhea. Methods. Oral irinotecan was given daily on days 1-5 and 8-12 (Schedule A), or on days 1-5 (Schedule B). Temozolomide was given on days 1-5, with vincristine 1.5 mg/m2 administered on days 1 and 8 (Schedule A) or day 1 (Schedule B) in 21-day courses. Results. On Schedule A, the maximum tolerated dose of oral irinotecan was 35 mg/m2/day combined with temozolomide 100 mg/m 2/day and vincristine on days 1 and 8. Dose-limiting toxicities in 4 of 12 patients included hepatotoxicity, abdominal pain, anorexia, hypokalemia, and thrombocytopenia at 50 mg/m2/day. Using Schedule B, 0 of 6 patients experienced dose-limiting toxicity (DLT) at the highest doses studied of oral irinotecan 90 mg/m2/day, temozolomide 150 mg/m 2/day x 5, and vincristine on day 1. First-course and cumulative toxicity was greater with Schedule A. UGT1A1*28 genotype did not correlate with DLT. At the irinotecan dose of 90 mg/m2/day, the mean SN-38 AUCinf was 63 ng/ml hr. Activity was seen in sarcoma patients, and overall eight patients received ≥6 courses. Conclusions. The 5-day schedule of VOIT was well tolerated and provided SN-38 exposures similar to those achieved with intravenous IRN. Activity on this and prior studies suggests a potential role for VOIT in a spectrum of childhood solid tumors.",
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T1 - Phase I trial of two schedules of vincristine, oral irinotecan, and temozolomide (VOIT) for children with relapsed or refractory solid tumors

T2 - A children's oncology group phase I consortium study

AU - Wagner, Lars M.

AU - Perentesis, John P.

AU - Reid, Joel M

AU - Ames, Matthew M.

AU - Safgren, Stephanie L.

AU - Nelson, Marvin D.

AU - Ingle, Ashish M.

AU - Blaney, Susan M.

AU - Adamson, Peter C.

PY - 2010/4

Y1 - 2010/4

N2 - Background. In preclinical models, temozolomide, and vincristine are additive or synergistic with irinotecan. We examined this three-drug combination in children with relapsed solid tumors. Patients received orally administered irinotecan together with temozolomide and vincristine on two different schedules, using cefixime to reduce irinotecan-associated diarrhea. Methods. Oral irinotecan was given daily on days 1-5 and 8-12 (Schedule A), or on days 1-5 (Schedule B). Temozolomide was given on days 1-5, with vincristine 1.5 mg/m2 administered on days 1 and 8 (Schedule A) or day 1 (Schedule B) in 21-day courses. Results. On Schedule A, the maximum tolerated dose of oral irinotecan was 35 mg/m2/day combined with temozolomide 100 mg/m 2/day and vincristine on days 1 and 8. Dose-limiting toxicities in 4 of 12 patients included hepatotoxicity, abdominal pain, anorexia, hypokalemia, and thrombocytopenia at 50 mg/m2/day. Using Schedule B, 0 of 6 patients experienced dose-limiting toxicity (DLT) at the highest doses studied of oral irinotecan 90 mg/m2/day, temozolomide 150 mg/m 2/day x 5, and vincristine on day 1. First-course and cumulative toxicity was greater with Schedule A. UGT1A1*28 genotype did not correlate with DLT. At the irinotecan dose of 90 mg/m2/day, the mean SN-38 AUCinf was 63 ng/ml hr. Activity was seen in sarcoma patients, and overall eight patients received ≥6 courses. Conclusions. The 5-day schedule of VOIT was well tolerated and provided SN-38 exposures similar to those achieved with intravenous IRN. Activity on this and prior studies suggests a potential role for VOIT in a spectrum of childhood solid tumors.

AB - Background. In preclinical models, temozolomide, and vincristine are additive or synergistic with irinotecan. We examined this three-drug combination in children with relapsed solid tumors. Patients received orally administered irinotecan together with temozolomide and vincristine on two different schedules, using cefixime to reduce irinotecan-associated diarrhea. Methods. Oral irinotecan was given daily on days 1-5 and 8-12 (Schedule A), or on days 1-5 (Schedule B). Temozolomide was given on days 1-5, with vincristine 1.5 mg/m2 administered on days 1 and 8 (Schedule A) or day 1 (Schedule B) in 21-day courses. Results. On Schedule A, the maximum tolerated dose of oral irinotecan was 35 mg/m2/day combined with temozolomide 100 mg/m 2/day and vincristine on days 1 and 8. Dose-limiting toxicities in 4 of 12 patients included hepatotoxicity, abdominal pain, anorexia, hypokalemia, and thrombocytopenia at 50 mg/m2/day. Using Schedule B, 0 of 6 patients experienced dose-limiting toxicity (DLT) at the highest doses studied of oral irinotecan 90 mg/m2/day, temozolomide 150 mg/m 2/day x 5, and vincristine on day 1. First-course and cumulative toxicity was greater with Schedule A. UGT1A1*28 genotype did not correlate with DLT. At the irinotecan dose of 90 mg/m2/day, the mean SN-38 AUCinf was 63 ng/ml hr. Activity was seen in sarcoma patients, and overall eight patients received ≥6 courses. Conclusions. The 5-day schedule of VOIT was well tolerated and provided SN-38 exposures similar to those achieved with intravenous IRN. Activity on this and prior studies suggests a potential role for VOIT in a spectrum of childhood solid tumors.

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