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© 2002 American Society for Clinical Oncology Phase I Clinical and Pharmacokinetic Study of Flavopiridol Administered as a Daily 1-Hour Infusion in Patients With Advanced NeoplasmsByFrom the Center for Cancer Research, Developmental Therapeutics Program, and Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda; Science Applications International Corporation–Frederick, National Cancer Institute, Frederick, MD; and Aventis Pharmaceuticals, Bridgewater, NJ. Address reprint requests to Adrian M. Senderowicz, MD, Molecular Therapeutics Unit, Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bldg 30, Rm 211, 30 Convent Dr, Bethesda, MD 20892; email: asenderowicz{at}dir.nidcr.nih.gov
PURPOSE: To define the maximum-tolerated dose (MTD), dose-limiting toxicity, and pharmacokinetics of the cyclin-dependent kinase inhibitor flavopiridol administered as a daily 1-hour infusion every 3 weeks. PATIENTS AND METHODS: Fifty-five patients with advanced neoplasms were treated with flavopiridol at doses of 12, 17, 24, 30, 37.5, and 52.5 mg/m2/d for 5 days; doses of 50 and 62.5 mg/m2/d for 3 days; and doses of 62.5 and 78 mg/m2/d for 1 day. Plasma sampling was performed to characterize the pharmacokinetics of flavopiridol with these schedules.
RESULTS: Dose-limiting neutropenia developed at doses CONCLUSION: The recommended phase II doses of flavopiridol as a 1-hour infusion are 37.5 mg/m2/d for 5 days, 50 mg/m2/d for 3 days, and 62.5 mg/m2/d for 1 day. Flavopiridol as a daily 1-hour infusion can be safely administered and can achieve concentrations in the micromolar range, sufficient to inhibit cyclin-dependent kinases in preclinical models. Further studies to determine the optimal schedule of flavopiridol as a single agent and in combination with chemotherapeutic agents are underway.
Cyclin-dependent kinases (CDKs) are important cell cycle regulators whose catalytic subunits require association with cyclin proteins for activation.1 Theoretically, the disruption of cell cycle progression by inhibition of CDK activity is a promising anticancer strategy.2 Flavopiridol is the first selective but pan-CDK inhibitor to enter clinical trials. Its antiproliferative effect is mediated by a number of mechanisms, including the induction of cell cycle arrest at the G1-S or G2-M phases from the direct inhibition of CDK1, CDK2, and CDK43-7; depletion of cyclin D18,9; apoptosis9-19; and antiangiogenesis.20-22 In preclinical models, flavopiridol is cytostatic in colon and prostate cancer xenografts when given over a protracted schedule,23 forming the basis for the administration of flavopiridol as a 72-hour continuous intravenous infusion (CIV) in two phase I trials.24,25 In the study conducted at the National Cancer Institute (NCI), the maximum-tolerated dose (MTD) was 50 mg/m2/d for 3 days with secretory diarrhea as the dose-limiting toxicity (DLT) observed at 62.5 mg/m2/d for 3 days.24 With antidiarrheal prophylaxis using loperamide and cholestyramine, a second MTD was defined at 78 mg/m2/d for 3 days. A partial response was observed in a patient with renal cell cancer (RCC) and three patients experienced minor responses (less than 50% tumor reduction) for more than 6 months. A second CIV phase I trial defined the MTD at 40 mg/m2/d for 3 days where the DLT was also diarrhea.25 One complete response was seen in a patient with gastric cancer. With these encouraging results, several phase II trials of flavopiridol administered as a 72-hour CIV at 50 mg/m2/d were initiated. A phase II trial in patients with metastatic RCC yielded a 6% response rate.26 In patients with advanced gastric cancer, previously untreated metastatic non–small-cell lung cancer, and metastatic colorectal cancer, there were no major objective responses, but some disease stabilization was observed.27-29 In preclinical models of hematopoietic tumors, regression of tumor can be observed when flavopiridol is administered intravenously as a bolus for 5 days (7.5 mg/kg/d), achieving plasma concentrations between 7 and 9 µmol/L.12 Similarly, tumor regression occurs in head and neck xenografts when flavopiridol is given intraperitoneally for 5 days (5 mg/kg/d), with evidence of apoptosis and decreased cyclin D1 protein expression.9 Therefore, we postulated that flavopiridol administered as a 1-hour infusion would result in higher serum drug concentrations and possibly lead to an alternate strategy for drug use. We report our experience of administering flavopiridol as a daily infusion for 5 days, 3 days, and 1 day every 3 weeks.
Patients Patients were eligible if they had refractory tumors for which no standard therapy was available, were  18 years old, and had an Eastern Cooperative Oncology Group performance status of  2. The requirements for adequate organ function included an absolute granulocyte count 1,000/µL, platelets 75,000/µL, total bilirubin 1.5 times the upper limit of normal, AST and ALT 2.5 times the upper limit of normal, and creatinine 1.5 mg/dL. No prior chemotherapy or radiotherapy was allowed within 4 weeks of study entry (6 weeks for prior nitrosourea or mitomycin and 8 weeks for prior UCN-01). Patients were excluded if they had brain metastasis, a myocardial infarction during the previous 6 months, New York Heart Association class II to IV heart disease, unstable or newly diagnosed angina pectoris, or coagulopathy requiring anticoagulation. The protocol was approved by the institutional review board of the NCI. All patients gave written informed consent.
Dosage and Dose Escalation The starting dose of flavopiridol, 12 mg/m2 given as a 1-hour infusion daily for 5 days every 3 weeks, was one half the toxic low dose in rats (24 mg/m2/d). When the MTD was achieved, the protocol was modified in an effort to achieve higher peak plasma concentrations, by shortening the number of treatments to 3 days, with an initial daily dose of 50 mg/m2/d. As this regimen also yielded lower than potentially desired peak concentrations of flavopiridol compared with preclinical models, the schedule of administration was decreased to 1 day every 3 weeks at a starting dose of 62.5 mg/m2. A minimum of three patients was entered for each dose level unless DLT was observed. If one instance of DLT occurred among the three patients, up to three additional patients were treated at that dose level. Thus, the MTD (or recommended phase II dose) was defined as one dose level below that which produced two instances of DLT during cycle 1 and the level at which no more than one of six patients experienced DLT.
Drug Administration
Pretreatment and Follow-Up Studies
Pharmacokinetic Studies Flavopiridol plasma concentrations were determined using a validated high-performance liquid chromatography assay. Briefly, 1 mL of acetonitrile was added to 0.25 mL of plasma and vortexed for 30 seconds. The samples were centrifuged at 10,000 rpm for 5 minutes at 4°C. The supernatant was transferred to a glass tube and evaporated to dryness at 40°C under air. The sample was reconstituted with 200 µL mobile phase and vortexed and 150 µL of specimen was injected onto a Waters Nova-Pak C18 column (Waters Corporation, Milford, MA). A gradient profile consisted of ammonium acetate (0.05 mol/L, pH 4.2) and methanol (containing 0.025 mol/L ammonium acetate) and a flow rate of 1 mL/min was used with a total run time of 21 minutes. Flavopiridol had an eluting time of 9.8 minutes and was detected with ultraviolet absorbance at 268 nm. The lower limit of quantitation for the peak area was 40 ng/mL (approximately 90 nmol/L). Pharmacokinetic parameters were analyzed by compartmental methods using ADAPT II Version 4 (Biomedical Simulations Resource, Los Angeles, CA). A two-compartment open linear model best fit the data. The terminal elimination rate constant of flavopiridol was determined using linear regression. The area under the curve (AUC) was calculated using the linear trapezoidal method extrapolated to infinity.
General Fifty-six patients were enrolled between August 1998 and January 2001 and 55 patients were assessable for toxicity. One patient with non-Hodgkin’s lymphoma was withdrawn before receiving treatment because he developed spinal cord compression requiring emergent radiation therapy. All patients had received prior therapy, 16 had prior chemotherapy only, five had prior immunotherapy only, and 17 had prior radiotherapy. Patient demographics are listed in Table 1. A total of 195 courses of flavopiridol were administered with a median number of three cycles per patient (range, one to 15 cycles). There are no patients who remain on study.
Dose Escalation and Dose-Limiting Toxicity The dose escalation scheme is summarized in Table 2. No first-course DLT was noted at the levels of 12, 17, 24, or 30 mg/m2/d for 5 days with the exception of a reversible, asymptomatic grade 3 occurrence of hypophosphatemia at the level of 30 mg/m2/d for 5 days, which was considered unrelated to drug, as it was associated with diarrhea (Table 3). At the 52.5-mg/m2/d dose level, four of five patients had DLT, including grade 4 neutropenia, grade 3 fatigue, and grade 3 hypotension with grade 3 hypoalbuminemia.
The first significant toxicity of grade 4 neutropenia, grade 3 ileus, and grade 4 anorexia occurred at the level of 52.5 mg/m2/d for 5 days in a patient with metastatic colon cancer and ascites who had a history of extensive abdominal operations. The patient developed diffuse abdominal pain and increased abdominal girth on day 3 of cycle 1. Radiographic examination showed evidence of a small bowel obstruction. The patient responded to supportive care, which included nasogastric tube decompression and paracentesis, and fully recovered by day 17. At this dose level, another patient experienced grade 3 hypotension and grade 3 hypoalbuminemia. Two additional patients were accrued to the level of 52.5 mg/m2/d for 5 days, with one experiencing grade 4 neutropenia and one with grade 3 fatigue. It was therefore considered that the MTD had been exceeded and three additional patients were added to the previous dose level of 37.5 mg/m2/d for 5 days, where a patient with metastatic nasopharyngeal carcinoma experienced grade 3 tumor pain and grade 4 fatigue that were attributed to disease progression. Seven additional patients were enrolled at 37.5 mg/m2/d for 5 days for further pharmacokinetic analysis and a patient with metastatic gallbladder cancer developed grade 3 deep vein thrombosis (DVT). Only one of 13 patients experienced DLT during cycle 1. Thus, 37.5 mg/m2/d was defined as the recommended phase II dose (RPD) for flavopiridol administered as a daily 1-hour infusion for 5 days.
Pharmacokinetic determinations suggested that the schedule might be optimized with respect to peak concentration by changing the infusion schedule to 50 mg/m2/d for 3 days. Two patients treated with flavopiridol at 62.5 mg/m2/d for 3 days experienced DLT of grade 4 neutropenia, thus defining this dose level as surpassing the MTD (Table 4). Although these two occurrences of granulocytopenia clearly defined the level at which the MTD had been surpassed, grade 3 elevation in hepatic transaminases and grade
We subsequently analyzed the utility of a 1-day dosing schedule every 3 weeks starting at the dose of 62.5 mg/m2/d. Two of six patients treated with 78 mg/m2/d for 1 day had grade 4 neutropenia during cycle 1. Three more patients were then enrolled at the level of 62.5 mg/m2/d for 1 day and one patient developed grade 4 neutropenia, whereas another patient had reversible grade 3 hyperglycemia. On the basis of these results, the RPDs of flavopiridol are 50 mg/m2/d and 62.5 mg/m2/d where flavopiridol is administered for 3 consecutive days and 1 day, respectively.
Hematologic Toxicities
Gastrointestinal Toxicities
Biochemical Toxicities Seven patients developed grade 2 isolated hyperbilirubinemia that resolved within 48 hours. Of note, at the level of 62.5 mg/m2/d for 3 days (above the RPD), one patient had an isolated transient increase in total bilirubin to a peak value of 2 mg/dL on day 7 of cycle 1 with normalization 4 days later. Another patient with esophageal cancer developed an increase in total bilirubin (baseline = 0.6 mg/dL) that reached 3.4 mg/dL on day 9 of the first cycle with a transient elevation in the hepatic transaminases around day 3.
Proinflammatory Syndrome
Other Clinical Toxicities Five patients (9%) experienced thrombotic events during cycle 1 or 2, and their relationship to flavopiridol is unclear. Three instances of lower extremity DVTs and two catheter-related thromboses occurred. One patient on the daily for 5 days schedule at the RPD was diagnosed with a right lower extremity DVT after completing 3 days of the first cycle. Therapy was discontinued and the patient was treated with low-molecular-weight heparin. Three weeks later, the patient was found unresponsive. A computed tomographic scan revealed ischemic lesions and a magnetic resonance imaging scan showed several areas of infarction. An autopsy could not be obtained and her death could have occurred secondary to multiple emboli, although long after the clearance of flavopiridol. No other arterial thrombotic events were observed.
Responses
Pharmacokinetics
There was no correlation between the occurrence of diarrhea and the maximum concentration (Cmax) of flavopiridol. There was an increasing correlation observed between the occurrence of diarrhea and the AUC of flavopiridol (Fig 2) as the length of the infusion was shortened (r = 0.34, 0.48, and 0.67 on the 5-day, 3-day, and 1-day schedules, respectively). Also, the mean AUC values increased as the duration of treatment administration was reduced. With respect to neutropenia, there appeared to be a moderate correlation with the occurrence of neutropenia and the Cmax, particularly on the 1-day schedule (r = 0.76). There was no significant correlation with neutropenia as a function of AUC.
In this phase I trial of flavopiridol administered as a daily 1-hour infusion, we have reached the following conclusions: (1) neutropenia was a dose-limiting toxicity observed at doses 52.5 mg/m2/d; (2) higher peak plasma concentrations (range, 1.67 to 4.77 µmol/L) were achieved compared with the 72-hour CIV schedule (however, the plasma concentrations of flavopiridol achieved at the RPDs were somewhat lower than the concentrations in the preclinical models associated with an apoptotic response and tumor regression [7 to 9 µmol/L])12; and (3) administration of more dose over a shorter time period did result in some (3 v 5 days), but not a proportional (1 day v 3 days) increase in median Cmax. The RPDs of flavopiridol administered as a 1-hour infusion are 37.5 mg/m2/d for 5 days, 50 mg/m2/d for 3 days, and 62.5 mg/m2/d for 1 day. Neutropenia was the principal DLT (with no episodes complicated by neutropenic fever) and was not observed in the initial 72-hour CIV phase I trial. This finding is not entirely unexpected, as examination of preclinically observed lesions in rats and dogs by histopathology reveal atrophy of bone marrow and lymphoid depletion in the spleen and thymus. In animal models that underwent implantation with hematopoietic human cell lines that were treated with 5 mg/kg of intravenous bolus flavopiridol for 5 days, reversible leukopenia was observed.12 Myelosuppression may have occurred because higher drug concentrations were transiently achieved when flavopiridol was administered as a 1-hour infusion. Although initially characterized as a cytostatic agent,3 subsequent studies have revealed that in certain cell types, particularly hematologic neoplasm models, flavopiridol has a cytotoxic outcome.10,11,14
With the exception of nausea and vomiting, which were more prominent on this trial and required routine premedication with antiemetics, nonhematologic toxicities similar to the 72-hour infusional schedule were observed.24 Although bismuth subsalicylate was implemented with the hypothesis that it would bind flavopiridol and prevent its action on the intestinal mucosa, it is not clear whether this was helpful in ameliorating the diarrhea. The proinflammatory syndrome was seen and recent studies have correlated this with an increase in interleukin-6 detected in a substantial fraction of patients treated on the original 72-hour CIV trial (Senderowicz, unpublished results). Other laboratory abnormalities common to both schedules of administration were reversible lymphocytopenia in which no obvious clinical infectious complications arose and hyperglycemia in patients with a history of diabetes mellitus or borderline glucose control. Hyperglycemia occurred at or below the MTD in our 72-hour CIV trial (in 303 total courses of flavopiridol administered at Transient hyperbilirubinemia was recorded in several patients, possibly reflecting shared glucuronidation pathways by flavopiridol and bilirubin. A study in rat liver has shown that flavopiridol undergoes glucuronidation.33 An analysis of blood samples from patients on the phase II RCC trial quantified flavopiridol and flavopiridol glucuronide, suggesting that a patient’s ability for glucuronidation may be related to the risk of developing diarrhea.34 In a more recently reported experiment, the metabolism of flavopiridol was investigated in rat and human liver microsomes and identified the UDP-glucuronosyltransferases 1A1 and 1A9 as the enzymes responsible for flavopiridol glucuronidation.35 Venous thromboses, which were seen in several trials of 72-hour CIV, also occurred with the daily 1-hour infusion schedule. In patients with catheter-related or isolated thrombi without major life-threatening dysfunction, the flavopiridol was continued with concurrent anticoagulation and no further complications occurred. The 72-hour CIV phase I trial reported five cases of catheter-related clots and one patient who had a myocardial infarction 10 days after the second treatment.24 There were six instances of DVT (two related to venous access devices) and three arterial events in the phase II RCC study.26 In the phase II gastric carcinoma trial, five patients developed catheter-related thromboses in the upper extremity.27 There were seven thrombotic events in the metastatic non–small-cell lung carcinoma trial, including four clots related to a catheter, two episodes of DVT in the lower extremity, and a pulmonary embolism (intermediate probability).28 Treatment with flavopiridol was continued in most patients while receiving concomitant anticoagulation. The relationship between flavopiridol and increased thrombosis has not been definitively established but should be considered in selecting patients for treatment with flavopiridol. The pharmacokinetic data demonstrate that patients at the RPDs on the 5-day, 3-day, and 1-day schedules achieved median peak plasma flavopiridol concentrations of 1.7 µmol/L, 3.2 µmol/L, and 3.9 µmol/L, respectively. These were lower than the peak concentrations described in preclinical models, which resulted in significant tumor regressions. However, the micromolar concentrations achieved in this trial were substantially higher than the median peak level (271 nmol/L) at the RPD (50 mg/m2/d for 3 days) on the infusional schedule. Thus, bolus administration schedules as used here might reasonably be considered if efforts to exploit the proapoptotic activity of the drug are to be undertaken. The median half-life of flavopiridol on the daily 1-hour schedule was shorter than on the infusional schedule (3.5 v 11.6 hours). There was also no evidence of enterohepatic circulation on this trial (whereas postinfusion peaks in the plasma concentration of flavopiridol were observed on the 72-hour CIV schedule24). The peak plasma concentrations did not differ significantly on the three different schedules. The plasma clearance and half-life did not change as higher daily doses were given over a shorter period of time. As the duration of the infusion decreased, an increasing correlation was noted between the AUC of flavopiridol and grade of diarrhea. This may impact the decision to choose a particular schedule where this toxicity is minimized. The AUC and clearance were comparable between the 1-hour infusion and 72-hour CIV schedule (data not shown). The AUC in mice at a dose of 5 mg/kg/d for 5 days was comparable to the AUC of flavopiridol administered over 1 hour at the dose of 37.5 mg/m2/d for 5 days (Stinson, unpublished results). Although induction of apoptosis was reported to occur at micromolar concentrations in preclinical models, the plasma level necessary for this activity may not be possible in humans because of toxicity. Conversely, future studies with these regimens might profit considerably by assessing indices of apoptosis before and after treatment if feasible, as this could conceivably contribute to the impression of disease stabilization and clinical response. Several phase II trials of flavopiridol as monotherapy given as a 72-hour CIV in solid malignancies have been completed.26-29 Although nanomolar concentrations of flavopiridol were achieved on these studies, which are the targeted concentrations for inhibition of CDKs in vitro, minimal clinical activity as defined by conventional response criteria was observed. Several phase II trials of single-agent flavopiridol administered as a daily 1-hour infusion in patients with chronic lymphocytic leukemia, mantle-cell lymphoma, melanoma, soft tissue sarcoma, RCC, head and neck cancer, and endometrial cancer are ongoing or completed.36 In addition, the role of flavopiridol as a modulator of chemotherapy is being explored. The optimal schedule of flavopiridol (72-hour CIV, 24-hour CIV, 1-hour infusion) either alone or in combination with standard chemotherapy has not been determined and is currently being studied.37 Flavopiridol as a 1-hour infusion seems to be safe in patients, although the incidence and demographics of thrombotic phenomena after exposure to flavopiridol need to be quantified more clearly, and the mechanism for this potentially serious adverse event is yet to be elucidated. Hematologic toxicity and nausea and vomiting at higher doses were observed, and had not been seen in the infusional trial. The achievement of micromolar concentrations of flavopiridol, sufficient to inhibit CDKs in vitro, is encouraging and provides a basis for further evaluation of this schedule, alone and in combination with traditional cytotoxic agents.
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37. Schwartz GK, O’Reilly E, Ilson D, et al: Phase I study of the cyclin-dependent kinase inhibitor flavopiridol in combination with paclitaxel in patients with advanced solid tumors. J Clin Oncol 20: 2157-2170, 2002 Submitted January 11, 2002; accepted June 14, 2002.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
