1 Department of Medicine, University of Chicago, Chicago, IL; 2 Sidney Kimmel Cancer Center at Johns Hopkins, Baltimore, MD, USA
Received 28 March 2003; accepted 23 April 2003
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Abstract |
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Flavopiridol, a synthetic flavone that inhibits cell cycle progression, has demonstrated activity in colon cancer in xenografts and in a phase I trial. We evaluated flavopiridol in a phase II trial in patients with previously untreated advanced colorectal cancer (ACRC).
Patients and methods:
Twenty chemotherapy-naïve patients with ACRC received flavopiridol at a dose of 50 mg/m2/day via a 72-h continuous infusion every 14 days. Response was assessed by computed tomography or magnetic resonance imaging every 8 weeks.
Results:
Twenty patients were enrolled; 19 were evaluable for toxicity and 18 for response. There were no objective responses. Five patients had stable disease lasting a median of 7 weeks. The median time to progression was 8 weeks. Median survival was 65 weeks. The principal grade 3/4 toxicities were diarrhea, fatigue and hyperglycemia, occurring in 21%, 11% and 11% of patients, respectively. Other common toxicities included anemia, anorexia and nausea/vomiting.
Conclusions:
Flavopiridol in this dose and schedule does not have single-agent activity in patients with ACRC. Recent preclinical data suggest that flavopiridol enhances apoptosis when combined with chemotherapy. Trials that evaluate flavopiridol in combination with active cytotoxic drugs should help to define the role of this novel agent in ACRC.
Key words: clinical trial, colorectal cancer, flavopiridol
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Introduction |
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Since its discovery in the 1950s, 5-fluorouracil (5-FU) has been the cornerstone for the treatment of advanced colorectal cancer (ACRC). Reported response rates rarely exceed 20% [2]. The addition of irinotecan or oxaliplatin to 5-FU results in significantly higher response rates, but only a modest improvement in overall survival has been achieved [35]. It is clear that new agents with different mechanisms of action need to be identified.
Movement through the cell cycle is regulated by complex and coordinated kinase and phosphatase reactions [69]. A family of potential molecular targets that would explain this phenotype is the cyclin dependent kinase (cdk) family of cell cycle regulatory kinases. cdk1 is an enzyme central to cell cycle progression through G2 into M phase. It interacts with cyclin B and initiates a sequence of phosphorylations and dephosphorylations [10].
Flavopiridol is the first drug considered for clinical development that can disrupt cell cycle regulatory kinases. It is a synthetic flavone that is a potent and direct antagonist of cdk1 activity via competitive inhibition of ATP. This blocks cell cycle progression prior to entry into S or M phase [11]. Flavopiridol alters the normal activity of cdk1, both directly and indirectly, inhibits progression from G2 to M phase and delays progression through S phase [12]. Flavopiridol also directly inhibits cdk2 and cdk4 [13]. Flavopiridol is not cytotoxic to resting cells in vitro, although it reversibly inhibits the growth of dividing tumor cells. Some investigators have observed that flavopiridol can be cytotoxic to some resting cell lines and induce apoptosis in others [1419].
Antitumor activity has been observed in preclinical colorectal cancer models including Colo-205 xenografts [20]. Antitumor activity is schedule dependent; the greatest activity has been achieved with prolonged exposure. In the initial phase I trial reported by Senderowicz et al. [21], using a 72-h continuous infusion of flavopiridol every 2 weeks, the maximum tolerated dose was 50 mg/m2/day; diarrhea was dose-limiting. One patient with colon cancer had a minor response.
The activity observed in colon cancer xenografts and in the phase I trial led us to perform a phase II trial of flavopiridol in previously untreated patients with advanced colorectal cancer.
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Patients and methods |
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Pretreatment evaluation
On study entry, all patients had a complete screening assessment (history, physical examination and blood tests) within 1 week of beginning treatment. Assessment of measurable disease by computed tomography or magnetic resonance imaging was performed within 2 weeks of entry.
Treatment
Flavopiridol was administered at an initial dose of 50 mg/m2/day over 72 h every 2 weeks as three 24-h infusions via a central venous catheter. Patients returned to clinic daily during the administration period to have the drug cassettes changed. Cycles were given every 2 weeks until disease progression occurred. Tumor measurements were obtained every four cycles. Responses required confirmatory scans at 4 weeks.
Patients who developed grade 3 or 4 non-hematological toxicity (with the exception of alopecia, nausea and vomiting, or diarrhea) or grade 4 hematological toxicity lasting more than 3 days were dose reduced to 40 mg/m2/day at the next cycle. Patients who experienced nausea and vomiting or diarrhea could be retreated at the same dose with appropriate anti-emetic or anti-diarrheal therapy. The next course of therapy was not administered until all toxicities returned to baseline. If this did not occur despite optimal prophylaxis, subsequent cycles were given at a dose of 40 mg/m2/day. Continued toxicity required dose reduction to 30 mg/m2/day. Patients who did not experience grade 3/4 toxicity after the initial two cycles could receive dose escalation to 60 mg/m2/day, and if this was well tolerated, to 75 mg/m2/day, at the discretion of the treating physician and the principal investigator.
Response and toxicity criteria
The ECOG criteria for tumor response in measurable disease were employed. Complete response (CR) was defined as complete disappearance of all clinically detectable malignant disease for at least 4 weeks. Partial response (PR) was defined as 50% decrease in tumor size (product of longer diameter by the perpendicular diameter) for at least 4 weeks, without increase in any area of malignant disease or any new areas. Progressive disease (PD) was defined as a
25% increase over initial measurements in the sum of the product of the two largest perpendicular diameters of measurable lesions, a
50% increase in size of the product of diameters if only one lesion was available, or appearance of any new malignant lesions. Stable disease (SD) was designated for all patients not qualifying for CR, PR or PD.
Toxicity was graded according to standard National Cancer Institute Common Toxicity Criteria.
Statistical methods
Accrual proceeded using a standard two-stage design. Twelve patients were to be entered in the first stage. If one or more patients had an objective response or SD lasting 6 months, then 25 additional patients would be accrued for a total of 37 patients. The primary objective of this study was to determine the activity of flavopiridol in ACRC and to define toxicity in this patient population. Activity was calculated as the proportion of patients with responsive disease and the 95% confidence interval (CI) for response. As flavopiridol may be a cytostatic agent and prolonged (
6 months) stabilization of measurable disease may have clinical benefit, such stabilization was also considered for evaluation. Time to progression was calculated using the method of Kaplan and Meier [22].
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Results |
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Patient characteristics are summarized in Table 1. The median age was 68 years (range 4280). The median WHO performance status was 0 (range 01). There were 11 men and nine women. Thirteen patients had colon cancer and seven had rectal cancer. Eighty per cent of patients had liver metastases. Most patients were chemotherapy naïve; only 35% had received adjuvant chemotherapy. Six patients had received prior radiotherapy.
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There were no objective responses. Five patients (28%) experienced SD lasting a median of 7 weeks (range 715) as their best response. The remaining 13 patients had PD. The median time to progression of the evaluable patients was 8 weeks (range 730). The median overall survival was 65 weeks (range 4156). Accrual to the study was terminated early due to lack of efficacy.
Toxicity
Nineteen patients were evaluable for toxicity. The maximal toxicities are listed in Table 2. Hematological toxicity was mild. No grade 3/4 hematological toxicities were observed. Grade 2 thrombocytopenia developed in 21% of patients and grade 2 anemia in 5%.
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Discussion |
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Although flavopiridol in this dose and schedule does not appear to have single-agent activity in patients with colorectal cancer, it may be worthwhile to examine flavopiridol as a chemotherapy-modulating agent in this disease. There is schedule-dependent cytotoxic synergy in vitro when 5-FU is administered after flavopiridol [23]. Flavopiridol can potentiate apoptosis induced by mitomycin in gastric cancer cell lines [24]. Of greater interest in colorectal cancer, flavopiridol augments apoptosis induced by irinotecan in resistant colon cancer cell lines. Sequential treatment with irinotecan followed by flavopiridol results in significant tumor regression, including CRs, in a mouse xenograft model [25]. Motwani et al. [25] observed that single-agent irinotecan causes transient cell cycle arrest, while the addition of flavopiridol activates caspase-3, cleaves inhibitors of apoptosis such as p21 and sensitizes cells to undergo cell death. Preliminary evidence of antitumor activity has been observed in a phase I trial of irinotecan followed by flavopiridol [26]. A phase II trial of this combination in patients with advanced colorectal cancer is in development.
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Acknowledgements |
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Footnotes |
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