Phase I dose-finding study of weekly docetaxel followed by flavopiridol for patients with advanced solid tumors Journal Article

Authors: Fornier, M. N.; Rathkopf, D.; Shah, M.; Patil, S.; O'reilly, E.; Tse, A. N.; Hudis, C.; Lefkowitz, R.; Kelsen, D. P.; Schwartz, G. K.
Article Title: Phase I dose-finding study of weekly docetaxel followed by flavopiridol for patients with advanced solid tumors
Abstract: Purpose: Flavopiridol is a cyclin-dependent kinase inhibitor that enhancesd ocetaxel-induced apoptosis in a sequence-specific manner. In vivo, docetaxel must precede flavopiridol by at least 4 h to induce this effect. We conducted a phase I trial of weekly, sequential docetaxel followed 4 h later by flavopiridol in patientsw ith advanced solid tumors. Experimental Design: Docetaxel at a fixed dose of 35 mg/m2 was administered over 30 min, followed 4 h later by escalating doses of flavopiridol, ranging from 20 to 80 mg/m 2 in successive cohorts, administered weekly over 1h. This schedule was repeated for 3 weeks of each 4-week cycle. Results: Twenty-seven evaluable patients were enrolled. The combination was well tolerated, with one dose-limiting toxicity occurring at flavopiridol 70 mg/m2 (grade 3 mucositis) and one dose-limiting toxicity at 80 mg/m2 (grade 4 neutropenia). We observed 1 complete response in a patient with pancreatic carcinoma and 4 partial responses in pancreatic (1), breast (2), and ovarian (1) cancer patients. Stable disease was seen in 10 patients. Pharmacokinetic studies showed Cmax ranging from 1.49 ± 0.69 μmol/L (flavopiridol 20 mg/m2) to 4.54 ± 0.08 μmol/L (flavopiridol 60 mg/m2) in cycle 1. Conclusions: Treatment with weekly, sequential docetaxel followed by flavopiridol is an effective and safe regimen at all flavopiridol dose levels. The pharmacokinetic data indicate that concentrations of flavopiridol that enhance the effects of docetaxel both in vitro and in vivo can be achieved. Clinical activity is encouraging, even in patients who have received a prior taxane and in patients with gemcitabine-refractory metastatic pancreatic cancer. © 2007 American Association for Cancer Research.
Keywords: adult; clinical article; controlled study; treatment outcome; treatment response; aged; middle aged; clinical trial; drug tolerability; fatigue; neutropenia; paresthesia; advanced cancer; area under the curve; diarrhea; drug potentiation; drug withdrawal; side effect; solid tumor; gemcitabine; cancer patient; neoplasms; multiple cycle treatment; ovary cancer; breast cancer; anemia; blood toxicity; mucosa inflammation; nausea; vomiting; antineoplastic combined chemotherapy protocols; drug administration schedule; dexamethasone; antineoplastic activity; drug resistance, neoplasm; docetaxel; irinotecan; arthralgia; drug dose escalation; drug hypersensitivity; dyspnea; febrile neutropenia; hyperglycemia; pancreas carcinoma; drug synergism; lung embolism; thrombosis; flavonoids; flavopiridol; piperidines; taxoids; maximum tolerated dose; phase 1 clinical trial; hand foot syndrome; deoxycytidine; sinus tachycardia; lacrimation
Journal Title: Clinical Cancer Research
Volume: 13
Issue: 19
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2007-10-01
Start Page: 5841
End Page: 5846
Language: English
DOI: 10.1158/1078-0432.ccr-07-1218
PUBMED: 17908977
PROVIDER: scopus
Notes: --- - "Cited By (since 1996): 27" - "Export Date: 17 November 2011" - "CODEN: CCREF" - "Source: Scopus"
Altmetric Score
MSK Authors
  1. Sujata Patil
    382 Patil
  2. Clifford Hudis
    838 Hudis
  3. Gary Schwartz
    358 Schwartz
  4. Archie Tse
    34 Tse
  5. Monica Nancy Fornier
    136 Fornier
  6. Manish Shah
    174 Shah
  7. Dana Elizabeth Rathkopf
    142 Rathkopf
  8. Eileen O'Reilly
    316 O'Reilly
  9. David P Kelsen
    332 Kelsen