A phase I study of flavopiridol in combination with gemcitabine and irinotecan in patients with metastatic cancer

Houman M. Fekrazad, Claire F. Verschraegen, Melanie Royce, Harriet O. Smith, Fa Chyi Lee, Ian Rabinowitz

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Background: Flavopiridol (HMR 1275) is a synthetic flavone with antineoplastic properties through inhibition of cyclin-dependent kinase inhibitor. Flavopiridol synergizes in a sequence-dependent fashion with chemotherapy. Major adverse events of flavopiridol in single agent phase I studies are secretory diarrhea, neutropenia, thrombosis, and fatigue. Patients and Methods: Patients with advanced solid tumors were treated with gemcitabine 800 mg/m2 and irinotecan 80 mg/m2 on day 1, followed by flavopiridol, starting dose of 30 mg/m2 on day 2 with increment of 15 mg/m2 per dose level, repeated on days 8 and 9 for the first 6 patients (3-week cycle), and then repeated on days 15 and 16 for the remainder patients (4-week cycle). The protocol had to be amended for inability to redose after 1 week. Results: Fourteen women and 7 men with advanced solid tumors were enrolled. The median age was 51 years and the median number of prior chemotherapies was 3 (0-9). Neutropenic sepsis (1 patient), grade 3 diarrhea (1 patient), and neutropenia (2 patients) preventing retreatment on day 8 were observed among the 6 subjects treated on the first schedule. The recommended phase II dose of flavopiridol was 45 mg/m2 in combination with irinotecan and gemcitabine every 2 weeks. Dose-limiting toxicities were electrolyte imbalance with fatigue (1 patient), and renal failure and dyspnea with hypoxia (1 patient each), seen at 45 and 60 mg/m2 doses, respectively. The most common side effects were fatigue (81%), nausea (71%), diarrhea (67%), transient myelosuppression (43%), and vomiting (24%). Conclusions: The every 2 week dosing is well tolerated with a phase II recommended dose of 45 mg/m2 of flavopiridol in combination with irinotecan (80 mg/m2) and gemcitabine (800 mg/m2).

Original languageEnglish (US)
Pages (from-to)393-397
Number of pages5
JournalAmerican Journal of Clinical Oncology: Cancer Clinical Trials
Volume33
Issue number4
DOIs
StatePublished - Aug 2010

Fingerprint

irinotecan
alvocidib
gemcitabine
Neoplasms
Fatigue
Diarrhea
flavone
Neutropenia
Drug Therapy
Retreatment
Cyclin-Dependent Kinases

Keywords

  • Chemotherapy combination
  • Cyclin-dependent kinase inhibitor
  • Flavopiridol
  • Phase I

ASJC Scopus subject areas

  • Oncology
  • Cancer Research
  • Medicine(all)

Cite this

A phase I study of flavopiridol in combination with gemcitabine and irinotecan in patients with metastatic cancer. / Fekrazad, Houman M.; Verschraegen, Claire F.; Royce, Melanie; Smith, Harriet O.; Lee, Fa Chyi; Rabinowitz, Ian.

In: American Journal of Clinical Oncology: Cancer Clinical Trials, Vol. 33, No. 4, 08.2010, p. 393-397.

Research output: Contribution to journalArticle

Fekrazad, Houman M. ; Verschraegen, Claire F. ; Royce, Melanie ; Smith, Harriet O. ; Lee, Fa Chyi ; Rabinowitz, Ian. / A phase I study of flavopiridol in combination with gemcitabine and irinotecan in patients with metastatic cancer. In: American Journal of Clinical Oncology: Cancer Clinical Trials. 2010 ; Vol. 33, No. 4. pp. 393-397.
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AU - Fekrazad, Houman M.

AU - Verschraegen, Claire F.

AU - Royce, Melanie

AU - Smith, Harriet O.

AU - Lee, Fa Chyi

AU - Rabinowitz, Ian

PY - 2010/8

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AB - Background: Flavopiridol (HMR 1275) is a synthetic flavone with antineoplastic properties through inhibition of cyclin-dependent kinase inhibitor. Flavopiridol synergizes in a sequence-dependent fashion with chemotherapy. Major adverse events of flavopiridol in single agent phase I studies are secretory diarrhea, neutropenia, thrombosis, and fatigue. Patients and Methods: Patients with advanced solid tumors were treated with gemcitabine 800 mg/m2 and irinotecan 80 mg/m2 on day 1, followed by flavopiridol, starting dose of 30 mg/m2 on day 2 with increment of 15 mg/m2 per dose level, repeated on days 8 and 9 for the first 6 patients (3-week cycle), and then repeated on days 15 and 16 for the remainder patients (4-week cycle). The protocol had to be amended for inability to redose after 1 week. Results: Fourteen women and 7 men with advanced solid tumors were enrolled. The median age was 51 years and the median number of prior chemotherapies was 3 (0-9). Neutropenic sepsis (1 patient), grade 3 diarrhea (1 patient), and neutropenia (2 patients) preventing retreatment on day 8 were observed among the 6 subjects treated on the first schedule. The recommended phase II dose of flavopiridol was 45 mg/m2 in combination with irinotecan and gemcitabine every 2 weeks. Dose-limiting toxicities were electrolyte imbalance with fatigue (1 patient), and renal failure and dyspnea with hypoxia (1 patient each), seen at 45 and 60 mg/m2 doses, respectively. The most common side effects were fatigue (81%), nausea (71%), diarrhea (67%), transient myelosuppression (43%), and vomiting (24%). Conclusions: The every 2 week dosing is well tolerated with a phase II recommended dose of 45 mg/m2 of flavopiridol in combination with irinotecan (80 mg/m2) and gemcitabine (800 mg/m2).

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KW - Phase I

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