Phase I study of flavopiridol with oxaliplatin and fluorouracil/leucovorin in advanced solid tumors Journal Article

Authors: Rathkopf, D.; Dickson, M. A.; Feldman, D. R.; Carvajal, R. D.; Shah, M. A.; Wu, N.; Lefkowitz, R.; Gonen, M.; Cane, L. M.; Dials, H. J.; Winkelmann, J. L.; Bosl, G. J.; Schwartz, G. K.
Article Title: Phase I study of flavopiridol with oxaliplatin and fluorouracil/leucovorin in advanced solid tumors
Abstract: Purpose: Flavopiridol, a cyclin-dependent kinase inhibitor, has promising clinical activity when combined with chemotherapy. Preclinical data indicate that flavopiridol enhances oxaliplatin- and fluorouracil (5FU)-induced apoptosis in a sequence-dependent manner. Experimental Design: We conducted a phase I trial of flavopiridol + FOLFOX (folinic acid, 5FU, and oxaliplatin) for advanced solid tumors. Flavopiridol was administered every 2 weeks with oxaliplatin before 5FU, based on sequence-dependent growth inhibition. Flavopiridol pharmacokinetics and p53 status were evaluated. Results: Forty-eight patients were treated on study. With dose escalation of oxaliplatin (85 mg/m<sup>2</sup>) and 5FU (2,400 mg/m<sup>2</sup>), dose-limiting toxicities included hyponatremia, thrombocytopenia, and neutropenia. 5FU was subsequently reduced to allow for dose escalation of flavopiridol. Dose-limiting toxicities with escalation of flavopiridol were nausea, vomiting, and neutropenia. The maximum tolerated dose was 70 mg/m<sup>2</sup> flavopiridol, 85 mg/m<sup>2</sup> oxaliplatin, and 1,800 mg/m<sup>2</sup> 5FU continuous infusion over 48 hours. Clinical activity was noted in platinum-refractory germ cell tumors: 3 of 9 (33%) evaluable patients showed a partial response on imaging and 7 of 10 (70%) had a decline in serum tumor markers. Responses were also observed in pancreatic, gastric, and sweat gland tumors. Flavopiridol pharmacokinetics had significant interpatient variability. At the maximum tolerated dose, tumor samples were p53 mutant (&gt;30% positive cells) for responders and p53 wild-type for nonresponders. Conclusions: Flavopiridol with FOLFOX is a safe and tolerable regimen. Promising clinical activity was seen across tumor types. Encouraging results in the platinum-refractory germ cell tumor population has prompted a phase II trial that is currently open for accrual. © 2009 American Association for Cancer Research.
Keywords: adult; clinical article; aged; middle aged; clinical trial; fatigue; neutropenia; fluorouracil; advanced cancer; diarrhea; drug withdrawal; solid tumor; pancreas cancer; neoplasms; melanoma; apoptosis; breast cancer; nausea; thrombocytopenia; vomiting; antineoplastic combined chemotherapy protocols; lung cancer; continuous infusion; protein p53; cancer resistance; drug dose escalation; drug hypersensitivity; febrile neutropenia; lymphocytopenia; neuroendocrine tumor; hyponatremia; head and neck cancer; folinic acid; colon cancer; tumor suppressor protein p53; stomach cancer; flavonoids; flavopiridol; piperidines; maximum tolerated dose; phase 1 clinical trial; oxaliplatin; anus cancer; esophagus cancer; cyclin-dependent kinases; rectum cancer; organoplatinum compounds; germ cell tumor; leucovorin; liposarcoma; nephroblastoma; desmoplastic small round cell tumor; sweat gland carcinoma; small intestine cancer; vater papilla carcinoma
Journal Title: Clinical Cancer Research
Volume: 15
Issue: 23
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2009-12-01
Start Page: 7405
End Page: 7411
Language: English
DOI: 10.1158/1078-0432.ccr-09-1502
PUBMED: 19934304
PROVIDER: scopus
PMCID: PMC2787644
Notes: --- - "Cited By (since 1996): 2" - "Export Date: 30 November 2010" - "CODEN: CCREF" - "Source: Scopus"
Altmetric Score
MSK Authors
  1. Gary Schwartz
    358 Schwartz
  2. Mithat Gonen
    701 Gonen
  3. Richard D Carvajal
    133 Carvajal
  4. Darren Richard Feldman
    171 Feldman
  5. Manish Shah
    174 Shah
  6. Dana Elizabeth Rathkopf
    142 Rathkopf
  7. Nian Wu
    30 Wu
  8. Mark Andrew Dickson
    77 Dickson
  9. George Bosl
    255 Bosl