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© 2002 American Society for Clinical Oncology Phase I Study of the Cyclin-Dependent Kinase Inhibitor Flavopiridol in Combination With Paclitaxel in Patients With Advanced Solid TumorsByFrom the Department of Medicine, Division of Solid Tumor Oncology, Gastrointestinal Oncology Section, Memorial Sloan-Kettering Cancer Center, New York, NY; and Quintiles, Kansas City, MO. Address reprint requests to Gary K. Schwartz, MD, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021; email: schwartg{at}mskcc.org
PURPOSE: Preclinical studies indicate that the cyclin-dependent kinase inhibitor flavopiridol potentiates the induction of apoptosis by paclitaxel, provided paclitaxel is followed by flavopiridol. We therefore designed a phase I clinical trial of sequential paclitaxel and flavopiridol. PATIENTS AND METHODS: Paclitaxel was administered at a fixed dose, as either a 24- or 3-hour infusion on day 1, followed by a 24-hour infusion of flavopiridol on day 2. Doses of flavopiridol were escalated in successive cohorts according to a modified Fibonacci design. Flavopiridol pharmacokinetics were obtained on all patients. RESULTS: Dose-limiting neutropenia developed with 24-hour paclitaxel doses of 135 and 100 mg/m2 and flavopiridol doses of 10 and 20 mg/m2, respectively. With 3-hour paclitaxel at 100 mg/m2, flavopiridol could be escalated to 70 mg/m2 without dose-limiting toxicity. With 3-hour paclitaxel next escalated to 135 mg/m2, dose-limiting neutropenia and pulmonary toxicity occurred when flavopiridol was escalated to 94 mg/m2. This did not correlate with any change in flavopiridol or paclitaxel pharmacokinetics. At a 3-hour paclitaxel dose of 175 mg/m2, dose-limiting pulmonary toxicity occurred in only one patient at flavopiridol doses under 94 mg/m2. Clinical activity was observed in patients with esophagus, lung, and prostate cancer, including patients who had progressed on paclitaxel. CONCLUSION: The recommended phase II doses will be a 3-hour infusion of paclitaxel at 175 mg/m2 on day 1 followed by a 24-hour infusion of flavopiridol at 70 mg/m2 on day 2. Flavopiridol dose escalations to 80 mg/m2 are possible. At these doses, toxicities are manageable and clinical activity is promising.
FLAVOPIRIDOL (L86-8275) is a synthetic flavone. It is identical to a compound obtained by derivation from Dysoxylum binectiferum, a plant indigenous to India.1 Even though its exact mechanism of action remains unknown, it is the first anticancer agent to enter clinical trials as a potent inhibitor of the cyclin-dependent kinases (CDKs). Inhibition of CDK2 and CDK4 has been reported with concentrations that inhibit enzymatic activity by 50% (IC50) in the 100-nmol/L range.2 It also directly inhibits CDK1 enzymatic activity with an inhibitory constant (KI) for adenosine triphosphate (ATP) of 41 nmol/L and inhibits CDK1 phosphorylation.3,4 Although it exhibits a relative selectivity for the CDKs, it is still not specific for this class of enzymes. It has been reported to inhibit protein kinase C at an IC50 of 6 µmol/L, cyclic adenosine monophosphate–dependent protein kinase at an IC50 of 145 µmol/L, and epidermal growth factor–receptor kinase at an IC50 of 25 µmol/L.3 It has been reported to suppress the transcription of cell cycle–specific genes, including cyclin D1,5 block human immunodeficiency virus Tat transactivation and viral replication through inhibition of positive transcription elongation factor b,6 and inhibit glycogen phosphorylase.7 The activation of the CDKs is required for transit of the cell between the different phases of the cell cycle, whether it is G1 to S or G2 to M. Thus, flavopiridol, as a direct inhibitor of the CDKs, has been found at nanomolar concentrations to induce a block in cell cycle progression at the G1-S and G2-M interfaces. Exposure of MDA-MB-468 human breast cancer cells to flavopiridol for 72 hours induces cell cycle arrest.8 In other cell lines it has been shown to induce apoptosis.9,10 Phase I trials with single-agent flavopiridol have been completed at both the University of Wisconsin and the National Cancer Institute.11,12 Because the best activity in tumor xenografts was demonstrated with repeated drug treatment, a 72-hour continuous intravenous schedule was selected for the phase I clinical trial. The 3-day flavopiridol treatment was repeated every 2 weeks. The dose-limiting toxicity was secretory diarrhea at a flavopiridol dose of 62.5 mg/m2/d. The diarrhea could be controlled with loperamide or cholestyramine and further dose escalations were possible with antidiarrheal prophylaxis. In the presence of antidiarrheal prophylaxis, 78 mg/m2/d could be administered without dose-limiting diarrhea. Other acute grade toxicities included anorexia, fatigue, hypotension, fever, tumor pain, dermatitis, nausea/vomiting, and hyperbilirubinemia. The recommended phase II dose for flavopiridol was 50 mg/m2/d for 3 days in the absence of antidiarrheal prophylaxis and 78 mg/m2/d with antidiarrheal prophylaxis. At these two maximum-tolerated doses (MTDs), mean plasma flavopiridol concentrations could be achieved that inhibited the CDKs in vitro. In the phase I clinical trials, clinical activity was observed in a variety of solid tumors including renal and gastric cancer. On the basis of this, a series of phase II clinical trials were initiated in renal, gastric, colon, and prostate cancer using a 72-hour infusion of flavopiridol administered every 14 days at a starting dose of 50 mg/m2/d, in the absence of antidiarrheal prophylaxis. Despite the encouraging phase I results, phase II studies using this dose and schedule have been essentially negative in advanced solid tumor malignancies.13-16 They have also been remarkable for exceptional toxicity including diarrhea, venous thrombosis, and even sudden death. There was no hematologic toxicity. The reason for this degree of nonhematologic toxicity is unclear, although it may be related to the dosing and schedule of the drug selected for these studies. Despite the negative outcome obtained with single-agent flavopiridol at these doses and with this schedule, these results do not exclude other promising new directions for the drug. One of the most hopeful directions for drug development with flavopiridol is in combination with chemotherapy. Flavopiridol has been shown to significantly enhance the induction of apoptosis by chemotherapy and decrease clonogenicity.17-20 In particular, flavopiridol has been shown to enhance the induction of apoptosis by mitomycin and paclitaxel in human breast and gastric cancer cell lines. In the case of paclitaxel, this effect is highly sequence dependent such that paclitaxel must precede flavopiridol in order to achieve this effect.17 In the presence of paclitaxel, flavopiridol activates the common final executioner of the apoptotic cascade, caspase-3, which is only minimally induced by paclitaxel alone. This effect could be maintained in vitro with either 3-hour or 24-hour paclitaxel exposures, provided the interval between the start of paclitaxel and the initiation of flavopiridol was fixed at 24 hours. Furthermore, the enhancement of paclitaxel-induced apoptosis was achieved with a 24-hour flavopiridol exposure. Exposure of the tumor cells to flavopiridol for 48 or 72 hours after paclitaxel did not result in any further enhancement of apoptosis. Because prolonged 72-hour infusions of flavopiridol have been associated with considerable clinical toxicity, it is therefore possible that shorter infusions may be used to avoid these toxicities and to allow potentiation of chemotherapy. On the basis of these laboratory studies, we initiated a phase I clinical trial in which patients were treated with a fixed dose of paclitaxel on day 1 followed by escalating doses of flavopiridol given as a 24-hour infusion on day 2.
Patient Selection Adult patients (  18 years old) with histologically confirmed solid tumor that was refractory to standard therapy (or for which there is no standard therapy) were eligible for the study. The patient had to be off all previous chemotherapy, immunotherapy, or radiotherapy for 4 weeks before study entry (6 weeks for nitrosoureas and for mitomycin). A performance status of more than 60% on the Karnofsky scale was required. Prior paclitaxel therapy was allowed.
Required laboratory tests included an adequate hematopoietic function, defined as having a total WBC count greater than or equal to 3,500/mm3, a total absolute neutrophil count (ANC) greater than 1,500/mm3, and a platelet count greater than or equal to 100,000/mm3. The patient was required to have adequate renal function, defined as having a serum creatinine less than or equal to 1.5 mg/dL; adequate hepatic function, defined as having a total serum bilirubin less than or equal to 1.5 mg/dL; serum AST and ALT levels less than 2.5 times the upper institutional limit of normal; and because of potential pulmonary toxicity, adequate pulmonary function, defined as having a diffusing capacity The protocol was reviewed and approved by the Institutional Review Board of Memorial Sloan-Kettering Cancer Center. Written, informed consent was obtained from each patient.
Treatment Plan Because of potential hemodynamic effects, vital signs, including blood pressure, heart rate, and respiratory rate, were to be measured every 15 minutes during the first hour of the flavopiridol infusion and hourly thereafter for the following 3-hour period for the first two cycles of therapy. For the first cycle, they were also to be monitored at the completion of the 24-hour flavopiridol infusion. Routine laboratory studies including a complete blood count with differential and platelets, liver and renal function, and electrolytes with blood glucose were to be obtained on the day of therapy and weekly thereafter. Treatment responses were to be evaluated after two cycles. Standard World Health Organization response criteria were used. The initial dose of flavopiridol was 10 mg/m2/d, which represented 20% of the MTD from the phase I single-agent trial (50 mg/m2/d).12 Flavopiridol doses were to be escalated by 100% between cohorts until 53 mg/m2 or until any one patient developed grade 3 or greater toxicity of any type attributable to the combination of flavopiridol and paclitaxel. Subsequent dose escalations of flavopiridol were to be by 33% until the MTD was reached. At the MTD, the plan was to define an intermediate dose of flavopiridol with paclitaxel fixed at 175 mg/m2. If unexpected toxicity was observed with flavopiridol and with paclitaxel as a 24-hour infusion, two different treatment plans were to be considered: (1) if dose-limiting toxicity was observed in the first cohort of patients with paclitaxel at 135 mg/m2 over 24 hours and flavopiridol at 10 mg/m2 over 24 hours, the plan was to reduce the paclitaxel dose to 100 mg/m2 over 24 hours and resume flavopiridol dose escalations, starting at 10 mg/m2; and (2) if flavopiridol could not be escalated above 20 mg/m2 with either 135 or 100 mg/m2 of paclitaxel over 24 hours, the plan was then to change paclitaxel to a 3-hour infusion at 100 mg/m2 on day 1 and flavopiridol starting 21 hours later administered as a 24-hour infusion on day 2. Dose-limiting toxicity (DLT) was defined as the occurrence of grade 4 hematologic toxicity; grade 3 or 4 nonhematologic toxicity, including diarrhea despite optimal antidiarrheal prophylaxis; or failure of thrombocytopenia or any of the nonhematologic toxicities to recover fully within 21 days after causing a dose delay, or failure of the ANC to return to more than 1,500/mm3 within 21 days after causing a dose delay. Optimal antidiarrheal therapy was to consist of administration of Questran one packet bid to qid and loperamide (Imodium) one capsule every 4 hours while awake and every 2 hours if diarrhea occurred while on flavopiridol. Minimums of three patients were to be followed for at least one complete cycle (or 3 weeks in the absence of a dose delay) of therapy before the trial could escalate to the next dose. If none of the three patients experienced DLT as described above, then new patients were to be entered at the next higher flavopiridol dose level. The dose level was to be escalated in successive cohorts of patients, provided no DLT was observed. If one instance of DLT was observed among the initial three patients treated at a dose level, an additional three patients were to be treated at that dose level, with no further DLT, in order that dose escalation could proceed. If two instances of DLT were observed at a dose level, the MTD had been surpassed, and an intermediate dose level of flavopiridol was to be evaluated. In the clinical setting of stable or responding disease, patients could continue treatment after experiencing a DLT with the flavopiridol dose reduced to one lower level, once all unacceptable toxicity had completely resolved.
Subjects could proceed with treatment if, on the day of scheduled treatment, the ANC was
Drug Supply Paclitaxel (Taxol; Bristol-Meyers Squibb Co, New York, NY) was commercially available as a fully reconstituted sterile solution in a 30-mg vial at a concentration of 6 mg/mL in 5-mL ampules in polyethoxylated castor oil (Cremophor EL) 50% and dehydrated alcohol, USP, 50%. The appropriate dose of paclitaxel was withdrawn from the ampule and further diluted with either 0.9% sodium chloride or 5% dextrose injection. Doses were prepared before use because of the concentration-dependent stability of paclitaxel, and the total dose was administered through a standard 0.22-µm filter.
Pharmacokinetics
Biologic Monitoring
Patient Characteristics Table 1 lists the patient characteristics. Forty-eight patients with advanced solid tumors were treated with the combination of paclitaxel and flavopiridol. One patient received paclitaxel on day 1, withdrew consent before receiving the first treatment of flavopiridol on day 2, and was not considered assessable for toxicity or response to the combination therapy. The median age was 51 years (range, 21 to 77 years), and the median Karnofsky performance status was 90% (range, 70% to 90%). There were 32 men and 16 women. The cancers treated and patient numbers included sarcoma (12), stomach (eight), esophagus (seven), colon (four), prostate (four), pancreas (three), rectum (two), lung (two), liver (two), head and neck (one), carcinoid (one), small bowel (one), and melanoma (one). Forty-four patients had received prior chemotherapy (92%), and 21 patients had received prior radiotherapy (44%). There were also 12 patients who had received prior paclitaxel (25%).
Hematologic Toxicities Table 2 lists the hematologic toxicities for the first cycle of therapy. In the first cohort of patients treated with paclitaxel 135 mg/m2 over 24 hours on day 1 and 10 mg/m2 of flavopiridol as a 24-hour infusion on day 2, each patient developed DLT (grade 4 neutropenia). The median WBC count and ANC were 0.8 x 103/mm3 and 0.1 x 103/mm3, respectively. This was first noted on day 7 after therapy and had resolved by day 14. One patient was admitted for treatment of neutropenic fever, but no source of infection could be detected. This patient had no prior chemotherapy.
We believed this degree of toxicity was related to the dose of paclitaxel. Therefore, the dose of paclitaxel was reduced to 100 mg/m2 over 24 hours on day 1 with flavopiridol maintained at 10 mg/m2 over 24 hours on day 2. At this dose level, there was no dose-limiting hematologic toxicity and flavopiridol was next escalated to 20 mg/m2 with paclitaxel fixed at 100 mg/m2 over 24 hours. However, with this dose escalation there was again dose-limiting (grade 4) neutropenia in two of six patients with a median ANC nadir of 0.6 x 103/mm3 (range, 0.2 to 1.7 x 103/mm3). The nadir counts were noted on day 7 after therapy and persisted until day 21. Neither patient developed neutropenia fever despite this prolonged nadir. Both patients were re-treated with a reduced paclitaxel dose of 80 mg/m2, with the flavopiridol dose maintained at 20 mg/m2. With this reduced dose of paclitaxel, both patients were re-treated without dose-limiting neutropenia. An examination of paclitaxel levels, starting after completion of the 24-hour flavopiridol infusion on day 2, indicated that the mean plasma levels of paclitaxel were not significantly different with flavopiridol doses of 10 or 20 mg/m2 at a fixed paclitaxel dose of 100 mg/m2 over 24 hours (data not shown). Similarly, flavopiridol concentrations ranged from 23 to 46 nmol/L and were not greater than expected from historical data, at these respective doses.12 In this clinical trial, one of our clinical targets was to achieve a standard paclitaxel dose of 175 mg/m2. Therefore, rather than further reducing the dose of paclitaxel to less than 100 mg/m2 over 24 hours, we elected to change the duration of the paclitaxel infusion from 24 hours to 3 hours so as to try to mitigate the myelosuppression. This was also decided on the basis of preclinical studies indicating that the enhancement of paclitaxel-induced apoptosis by flavopiridol could also be achieved with 3-hour rather than 24-hour paclitaxel exposure, provided the paclitaxel was given on day 1 and the flavopiridol was started 21 hours later for 24 hours on day 2. Starting with cohort 4, patients were then treated with paclitaxel as a 3-hour infusion, at a fixed dose of 100 mg/m2 on day 1, and with flavopiridol on day 2, at a starting dose of 20 mg/m2. As shown in Table 3, with this modification to the paclitaxel schedule, we were able to escalate the dose of flavopiridol to 70 mg/m2 without dose-limiting hematologic toxicities (cohort 7). Therefore, in cohort 8, we elected to increase the paclitaxel dose to 135 mg/m2 over 3 hours and resume the flavopiridol dose escalation starting at 70 mg/m2 over 24 hours.
There was no dose-limiting hematologic toxicity until flavopiridol was escalated to 94 mg/m2 (cohort 9). At this dose level, two patients developed grade 4 neutropenia but without fever on day 7 after therapy. The median ANC nadir was 0.6 x 103/mm3 with a range of 0.2 to 2.8 x 103/mm3. This was not associated with lymphopenia. The neutropenic counts had resolved by day 14. With flavopiridol reduced to an intermediate dose of 80 mg/m2 (cohort 10), no dose-limiting hematologic toxicity was observed. Because we desired to achieve a paclitaxel dose of 175 mg/m2, we next elected to decrease the flavopiridol dose by one level to 70 mg/m2 over 24 hours. With paclitaxel at a dose of 175 mg/m2, we were able to escalate flavopiridol from 70 to 80 mg/m2 without dose-limiting hematologic toxicity (cohort 12). Because of the hematologic toxicity observed with flavopiridol of 94 mg/m2, as well as the nonhematologic toxicity observed with this flavopiridol dose, we elected not to continue with further dose escalations of flavopiridol.
Common Nonhematologic Toxicity
An unsuspected nonhematologic toxicity developed with paclitaxel 135 mg/m2 as a 3-hour infusion and flavopiridol at 94 mg/m2 (cohort 9). In this cohort, in whom we also saw dose-limiting hematologic toxicity, there was also dose-limiting pulmonary toxicity. At this level, one patient developed grade 3 and two patients developed grade 4 pulmonary toxicity. This was characterized as acute pleuritic chest pain that started within 24 hours of completing the flavopiridol infusion. Two of these patients had grade 2 hypotension that was rapidly reversible with discontinuation of the flavopiridol and one of these patients had dose-limiting grade 3 nausea that responded to antiemetics. These acute pulmonary episodes were remarkable for normal ECG and arterial blood gases. Evaluations for pulmonary embolism, including venous perfusion studies, were negative in all patients. Two (one with small-cell lung cancer and the other with metastatic colon cancer to the lung) of the three patients recovered to baseline within 24 to 48 hours of these episodes. The third patient with metastatic hepatoma and a prior history of mediastinal radiotherapy for non-Hodgkin’s lymphoma developed deteriorating arterial blood gases with worsening oxygen saturations despite increasing supplemental oxygen. Her chest x-ray revealed new bilateral pleural effusions with ground-glass infiltrates. She was placed on high doses of corticosteroids and antibiotics. A thoracentesis revealed an "exudative" pleural fluid with negative cytology. A lung biopsy specimen indicated slightly thickened alveolar septa, which was considered nonspecific. Pulmonary function tests showed only a mild restrictive ventilatory defect with an otherwise normal diffusion capacity (86% of predicted). She was ultimately discharged after a 14-day hospitalization. This patient elected not to receive further treatment with reduced doses of flavopiridol. However, one of the two other patients elected to continue therapy with the flavopiridol dose reduced to 80 mg/m2. At this reduced dose, he was safely treated without recurrent pulmonary toxicity. Three other patients were treated with paclitaxel at 135 mg/m2 and flavopiridol at 80 mg/m2 without pulmonary toxicity, although mild fatigue (grade 2) and diarrhea (grade 1 and 2) were observed. With paclitaxel dose escalations to 175 mg/m2 (cohort 11), one of six patients developed reversible, grade 4 pulmonary toxicity with 70 mg/m2 flavopiridol. Subsequent pulmonary function tests indicated a normal study. Interestingly, this patient was re-treated with the same dose of flavopiridol (70 mg/m2) but with a reduced dose of paclitaxel (135 mg/m2, cohort 8) and did not develop a comparable reaction. Three other patients in cohort 11 also reported grade 1 dyspnea at the end of their infusions of flavopiridol that was completely reversible within 24 hours. Grade 1 fatigue was also common to all patients at this level. In contrast, with flavopiridol escalated to 80 mg/m2 with 175 mg/m2 of paclitaxel (cohort 12), only one patient noted mild dyspnea (grade 1).
Cumulative hematologic and nonhematologic toxicities associated with 3-hour paclitaxel and subsequent 24-hour infusions of flavopiridol are listed in Table 5. As indicated, the pattern of toxicities was similar to that which was observed with only one cycle of combination therapy. Diarrhea and fatigue were not appreciably increased despite repeated treatments. Sixteen patients were re-treated with 70 mg/m2 of flavopiridol and paclitaxel doses ranging from 100 to 175 mg/m2. Four patients who had no pulmonary reactions with cycle 1 of therapy developed mild and reversible pulmonary toxicity (grade 1 to 2) with cycle 2. These episodes were independent of underlying lung abnormality. Nine patients were re-treated with 80 mg/m2 of flavopiridol and paclitaxel doses ranging from 135 to 175 mg/m2 and only one episode of grade 2 dyspnea was noted. In fact, with 175 mg/m2 of paclitaxel (cohort 12), one patient remained on study for 28 cycles and another for 10 cycles without developing any evidence of pulmonary toxicity. Cumulative neutropenia requiring dose reduction was observed in only one patient (cohort 11). The incidence of neurosensory changes, which were characterized as a peripheral neuropathy without motor weakness, also appeared more prominent with repeated therapy, especially with flavopiridol doses of
Pharmacokinetics and Surrogate Studies Flavopiridol and paclitaxel pharmacologic assays were performed for all patients for paclitaxel doses of 100 and 135 mg/m2 for both 3-hour and 24-hour infusions on day 1, with flavopiridol given as a 24-hour infusion at doses of 10, 20, 40, 53, 70, 80, and 94 mg/m2. A total of 352 plasma samples were available for analysis and 43 samples were excluded because the flavopiridol concentrations were below the limits of detection (< 5 ng/mL). Because of the sparse sampling design, modeling of individual plasma concentration–time profiles was difficult. A plot of plasma flavopiridol concentration versus time for one of the patients treated with 94 mg/m2 of flavopiridol in cohort 9 is shown in Fig 1. Individual estimates of the pharmacokinetic parameters were obtained from predicted flavopiridol pharmacokinetics for this population. As indicated, the observed plasma levels closely approximate those that were predicted from the two-compartment model.
A summary of the flavopiridol pharmacokinetics for patients treated with 53 to 94 mg/m2 of flavopiridol and with either 100 or 135 mg/m2 is shown in Table 6 (cohorts 6 to 10). With paclitaxel fixed at 100 mg/m2 and with the dose of flavopiridol escalated from 53 mg/m2 to 70 mg/m2 (cohorts 6 and 7), there was a trend in favor of an increasing maximal drug concentration (Cmax) that did not reach statistical significance. This may reflect the small sample size. However, a comparison of the pharmacokinetics between 53 mg/m2 and 94 mg/m2 (cohorts 6 and 9) reveals an approximate two-fold increase on the Cmax that achieved statistical significance (P < .002).
In view of the hematologic and pulmonary toxicity observed in cohort 9 with 135 mg/m2 of paclitaxel administered over 3 hours on day 1 followed by 94 mg/m2 of flavopiridol on day 2, we carefully compared the flavopiridol pharmacokinetics in this cohort with cohorts 8 and 10, which used the same paclitaxel dose and schedule but with flavopiridol at reduced doses of 70 and 80 mg/m2, respectively. As shown in Table 6, despite increasing doses of flavopiridol, with a fixed dose of 3-hour paclitaxel at 135 mg/m2, there was no significant change in the mean Cmax for flavopiridol when administered at 70, 94, and 80 mg/m2 (cohorts 8, 9, and 10). These results would indicate that despite the increasing doses of flavopiridol, the significant toxicity observed with 94 mg/m2 of flavopiridol could not be explained by a significant increase in flavopiridol pharmacokinetics. In fact, at the 94-mg/m2 dose for flavopiridol (cohort 9), there was an unexpected decrease in the area under the curve (AUC) for flavopiridol that was statistically significant (P = .005) when compared with 80 mg/m2 (cohort 10). This decrease in AUC with 94 mg/m2 flavopiridol appears secondary to an approximate two-fold increase in the mean clearance adjusted for body surface area at this level. The increase in adjusted clearance with 94 mg/m2 of flavopiridol is statistically significant when compared with all other doses (eg, P = .006 for flavopiridol 80 mg/m2 v 94 mg/m2). The reason for this decrease in the adjusted clearance with 94 mg/m2 of flavopiridol remains unclear but needs to be validated in other studies. Paclitaxel levels were also obtained for these cohorts, but only beginning at the completion of the 24-hour flavopiridol infusion on day 2. Therefore, complete paclitaxel pharmacokinetics starting with the day 1 treatment are not available. Nevertheless, a comparison of mean paclitaxel levels with 70 to 94 mg/m2 of flavopiridol, taken up to 48 hours after the completion of flavopiridol, indicated no significant change in paclitaxel levels. Therefore, the increased hematologic and pulmonary toxicity observed with 94 mg/m2 of flavopiridol could not be explained by increases in paclitaxel pharmacokinetics.
On the basis of prior knowledge of the pharmacokinetics of flavopiridol in cancer patients (NCI-sponsored phase I studies), a two-compartment infusion model was selected for the population pharmacokinetics. Because of the sparse sampling design, modeling of individual plasma concentration–time profiles was difficult. A plot of plasma flavopiridol concentration versus time for one of the patients treated with 94 mg/m2 of flavopiridol in cohort 9 is shown in Fig 1. Individual estimates of the pharmacokinetic parameters were obtained from predicted flavopiridol pharmacokinetics for this population. As indicated, the observed plasma levels closely approximate those that were predicted from the two-compartment model. Population pharmacokinetics for the entire patient population was also calculated and was adjusted to a flavopiridol dose of 80 mg/m2/d given as a 24-hour infusion. From this analysis, the population estimated clearance was 6.23 mL/h/m2, and the steady-state volume of distribution was 168 L/m2. The population terminal half-life was 21.7 hours, the Cmax was 737 nmol/L, and the AUC(0- Flavopiridol has been reported to induce apoptosis in chronic lymphocytic leukemia cells and is cytotoxic to noncycling human lung cancer cells.10,23 Therefore, we hypothesized that normal circulating lymphocytes could serve as a source for surrogate markers of flavopiridol-induced apoptosis. There was no evidence of induction of apoptosis by flavopiridol by either terminal deoxynucleotidyl transferase or 7-aminoactinomycin D labeling with flow cytometry. This was also confirmed in selected patients for molecular markers of apoptosis, including the absence of poly(ADP-ribose)polymerase cleavage and the failure to induce caspase-3 activation (data not shown). We now understand that lymphocytes, which are noncycling cells, are poor markers of treatment-induced apoptosis.
Response to Therapy
Flavopiridol has completed a series of single-agent phase II trials in patients with advanced solid tumors. In these studies, flavopiridol was administered as a 72-hour infusion every 14 days at a starting dose of 40 to 50 mg/m2/d. Because of persistent fatigue, severe diarrhea, or venous thromboses, flavopiridol on this 3-day schedule was difficult to tolerate for the majority of patients. In a phase II study of patients with gastric cancer, these toxicities on the 72-hour schedule prompted earlier than anticipated restaging CT scans in many patients.14 Whereas the plan was to reevaluate patients after four cycles of treatment, the median number of treatment cycles received on this study was 3.4. In addition, there was a remarkable lack of tumor response in this study and in other reports of patients with solid tumors treated on this 72-hour single-agent schedule.13-16 The reasons for this are unclear. In the gastric cancer trial, mean peak total flavopiridol concentrations ranged between 248 and 810 nmol/L.14 The predicted free plasma concentrations of flavopiridol are believed to constitute approximately 10% of the total drug. This would imply that maximal free plasma concentrations of 25 to 80 nmol/L were achieved. These later free concentrations should have been sufficient to inhibit at least CDK1 kinase activity, which has KI for ATP of 41 nmol/L. Nevertheless, in this phase II trial there was no correlation between plasma drug levels, response, or toxicity. In view of these essentially negative clinical results, we elected to develop flavopiridol in combination with chemotherapy on the basis of laboratory data indicating that flavopiridol significantly enhances the induction of apoptosis by chemotherapy and decreases clonogenicity in vitro.17-20 When flavopiridol is used as a modulator of chemotherapy-induced apoptosis, much shorter durations of drug exposure (ie, 24 hours) are necessary to achieve this effect. For this reason, we selected a 24-hour infusion of flavopiridol to combine with paclitaxel in this phase I trial. This resulted in a different pattern of toxicities. Fatigue and diarrhea, which were dose-limiting in the single-agent studies, were essentially observed as grade 1 and 2 toxicities with paclitaxel and 24-hour flavopiridol. In addition, venous and arterial thromboses, which were observed in several phase II single-agent studies, were nonexistent on the 24-hour schedule. Bone and tumor pain were observed with both 24- and 72-hour schedules. On the single-agent phase I trial with the 72-hour flavopiridol infusion, dose-limiting hypotension and acute hyperglycemia were observed.12 The median onset for hypotension was 2 days (range, 1 to 6 days) and increased with dose such that at 98 mg/m2/d and 122.5 mg/m2/d for 3 days, 100% of patients had grade 2 or greater hypotension.12 In this study with 3-hour paclitaxel and 24-hour flavopiridol, grade 2 hypotension was only observed in two of six patients at the 94-mg/m2 level. This difference between the studies may reflect less aggressive hemodynamic monitoring with the 24-hour schedule, a 24-hour flavopiridol dose that never exceeded 94 mg/m2, or differences in the pattern of toxicity between a 24- and a 72-hour flavopiridol schedule. Hyperglycemia secondary to the corticosteroid premedications was noted before paclitaxel therapy, but this did not seem to be exacerbated by the subsequent 24-hour flavopiridol infusion. Instead, the DLTs for the combination of paclitaxel and flavopiridol were hematologic (neutropenia) and pulmonary. With 24-hour paclitaxel, hematologic toxicity developed with low doses of flavopiridol, such that the flavopiridol dose could not be escalated to 20 mg/m2 with a paclitaxel dose of 100 mg/m2. This may have reflected the extensive prior chemotherapy in this phase I population. However, two of these patients had not received prior chemotherapy, and yet they still developed grade 4 neutropenia. With the 3-hour paclitaxel schedule, grade 4 neutropenia was observed with 135 mg/m2 of paclitaxel and 94 mg/m2 of 24-hour flavopiridol (cohort 9). Interestingly, one of these patients had also received no prior chemotherapy, suggesting that the hematologic effects may be secondary to the drug combination rather than to the paclitaxel alone. The pulmonary toxicity, which also developed in cohort 9 with a flavopiridol dose of 94 mg/m2, was quite dramatic and completely unexpected on the basis of the prior experience with single-agent 72-hour flavopiridol. An extensive pulmonary and cardiac work-up was negative in all patients. A bronchoscopy in one patient was nondiagnostic. All patients recovered completely from the event and one even went on to be treated at a lower flavopiridol dose without pulmonary toxicity. Therefore, the effect appears to be dose related, but a correlation with the pharmacologic studies could not be established. All three patients with grade 3 and 4 pulmonary toxicity at this dose level did have some form of pulmonary abnormality, including primary lung cancer, metastatic colon cancer to the lung, or a history of prior mediastinal radiotherapy. The most severe pulmonary reaction occurred in the patient with a history of mediastinal radiation. Cardiac tamponade in the setting of prior mediastinal radiation was reported in one patient on the phase I single-agent study at a dose of 122.5 mg/m2/d for 3 days.12 This patient had no evidence of cardiac tamponade by ECG or standard radiologic criteria. Pulmonary function tests performed at the onset of this reaction showed only mild restrictive lung disease and a normal diffusion capacity by our institution’s standards. Although a baseline test is not available for comparison, routine pulmonary function tests with exclusion criteria for low (< 60%) diffusion capacity would not have excluded this patient from the study. Dose-limiting pulmonary toxicity was not observed with 80 mg/m2 of flavopiridol in combination with either 135 mg/m2 (cohort 10) or 175 mg/m2 (cohort 12) of paclitaxel. It was still dose-limiting in one patient treated with 70 mg/m2 of flavopiridol and 175 mg/m2 of paclitaxel (cohort 11). In contrast, this patient had no known pulmonary disease. Grade 1 or 2 dyspnea was noted at lower levels of flavopiridol (20 and 53 mg/m2). At the time of occurrence, these were believed related to the patient’s underlying metastatic disease to their lung. However, in retrospect, these could have been because of a reaction to either flavopiridol or to the flavopiridol/paclitaxel combination. These results would suggest that underlying pulmonary disease may predispose patients to this reaction, but the occurrence of this reaction in patients with no known pulmonary disease would also suggest that this could still represent an idiosyncratic process. A similar pulmonary reaction was reported in at least one patient in the NCI phase I study of single-agent flavopiridol on the 72-hour schedule at a dose of 35 mg/m2/d.12 This was attributed to the patient’s underlying disease, but may in fact have been a pulmonary toxicity from flavopiridol itself. This reaction appears similar to that which has been reported with biologic modifiers and may represent a cytokine-mediated effect. The induction of acute-phase reactants has been reported as part of a proinflammatory syndrome in the 72-hour single-agent phase I trial of flavopiridol.12 Acute-phase reactants were not measured in this study, and therefore the cause of this process remains undefined. The effect of flavopiridol on cytokine release and expression is currently under investigation at the NCI. Relative to the tumor responses observed, it is interesting that antitumor effects were observed with 3-hour paclitaxel and flavopiridol doses of 53 to 80 mg/m2, whereas with 24-hour paclitaxel, clinical activity was observed with flavopiridol doses of only 10 to 20 mg/m2. It is conceivable that longer exposure of tumor cells to paclitaxel will result in a greater number of cells arresting in mitosis, making them more susceptible to even low doses of flavopiridol. This hypothesis is currently being tested in the laboratory. Nevertheless, in terms of clinical development, the 3-hour paclitaxel schedule provides a more convenient paclitaxel schedule and allows us to achieve a standard paclitaxel dose of 175 mg/m2. With this dose and schedule, clinical activity was observed with manageable toxicity. The peak concentrations of flavopiridol achieved on this study with paclitaxel are also similar to those reported on the phase I trial of flavopiridol administered as a single agent over 72 hours. For example, on this trial with 94 mg/m2 of flavopiridol as a 24-hour infusion, we achieved a median peak plasma concentration of 570 nmol/L (range, 428 to 776 nmol/L). On the 72-hour single-agent study, with a similar 24-hour dose of 98 mg/m2/d for 3 days, the median peak flavopiridol level was 556 nmol/L (range, 281 to 954 nmol/L). This examination of historical data would also support the observation that the prior administration of paclitaxel did not affect the peak concentrations of subsequent flavopiridol. However, the only way to fully exclude such an interaction would be to first study a patient with monotherapy and then re-treat the same patient with the drug combination. We elected not to pursue this study design because of the lack of single-agent activity with flavopiridol alone. On the basis of the pattern of hematologic and nonhematologic toxicities of the study, we would recommend a phase II study of paclitaxel at 175 mg/m2 over 3 hours on day 1, followed by a starting dose of flavopiridol at 70 mg/m2 over 24 hours on day 2. Dose escalations of flavopiridol to 80 mg/m2 also seem possible without significant DLT. With 70 mg/m2 of flavopiridol, we achieved a mean peak plasma flavopiridol concentration of 629 nmol/L (range, 414 to 906 nmol/L). Again, assuming a 10% free drug concentration, this should have been sufficient to inhibit CDK1 kinase, which has a KI for ATP of 41 nmol/L. Inhibition of CDK1 kinase with 300 nmol/L flavopiridol after paclitaxel therapy has been shown to accelerate mitotic exit and enhances paclitaxel-induced apoptosis.17 Whether this is sufficient to inhibit CDK1 activity in vivo is unknown. Tests to determine the degree of CDK1 inhibition by flavopiridol in human tissues will require serial tumor biopsy specimens of patients undergoing therapy. We, in fact, had hoped to test this as part of this clinical trial. Unfortunately, we were unable to obtain serial tumor biopsy specimens from patients and cannot draw any conclusions regarding the effect of flavopiridol on specific tumor targets. Further analysis of the pharmacokinetic studies indicated that the clearance of flavopiridol increased with increasing body surface area. In view of this, clearances were normalized to body surface area at each flavopiridol dose. As shown in Table 6, with clearance normalized in this fashion, the clearances were similar in all the cohorts tested, except for cohort 9, in which patients were treated with 94 mg/m2 of flavopiridol. In this cohort, there was a statistically significant increase in the normalized clearance. This increase in clearance was not related to the dose of paclitaxel. Instead, with a fixed paclitaxel dose of 135 mg/m2, there was a dramatic decrease in flavopiridol clearance, but only as the flavopiridol dose was increased from 80 to 94 mg/m2. Although this could be related to small sample size, it is possible that at a threshold dose the clearance of flavopiridol is increased. The exact mechanism for the increased clearance of flavopiridol at 94 mg/m2 remains unknown. The major mechanism of flavopiridol metabolism is glucuronidation. Flavopiridol is transformed in the liver to flavopiridol glucuronide and excreted in the bile.24 Enterohepatic circulation of flavopiridol has also been proposed.25 This, in fact, has been cited to explain the intermittent spikes in flavopiridol plasma levels observed during prolonged infusions and the occurrence of postinfusional peaks after discontinuation of the therapy.12 We did not observe this effect in our patient population. This may have been undetected in the postinfusional setting because of sparse plasma sampling or differences in the methodology for flavopiridol determinations. The role of renal clearance for flavopiridol also remains untested, although urinary recovery of flavonoids after soy consumption has been reported.26 Unfortunately, we did not test for flavopiridol glucuronide, nor did we measure for flavopiridol in the urine. Therefore, we are unable to measure the metabolic clearance of flavopiridol in this study. One striking difference between this trial with 24-hour infusion flavopiridol and other trials with prolonged (72-hour) infusions of flavopiridol is the absence of dose-limiting diarrhea. It has been reported that the degree of diarrhea correlates with the degree of glucuronidation of flavopiridol. In a series of 22 renal cancer patients treated with flavopiridol for 72 hours, patients with extensive glucuronidation did not develop diarrhea, whereas those patients who exhibited low glucuronidation did develop diarrhea.27 Interestingly, the pharmacokinetics of flavopiridol glucuronide on the 72-hour renal cancer study indicated that the metabolite accumulated from 23 to 47 hours and reached a plateau from 47 to 71 hours. This would suggest that glucuronidation on our study is probably not the critical determinant for the absence of significant diarrhea. Nevertheless, measurements of flavopiridol glucuronide should be included in future clinical trials using 24-hour infusions of the drug. Clinical activity has been observed in patients with a wide range of malignancies. This was particularly impressive in patients with adenocarcinoma of the gastroesophageal junction. Although paclitaxel is an active single agent in esophageal cancer, CRs with single-agent therapy are rare and the median duration of response for partial responses is 17 weeks (range, 7 to 58 weeks).28 In this study, we observed patients with esophageal cancer who achieved a CR that was durable for over a year and an MR in a patient who remained on study for 19.6 months. There was also a suggestion that treatment with a prior taxane did not exclude the possibility of a clinical response when re-treated with paclitaxel and flavopiridol. This is consistent with the in vitro data, indicating activity for this drug combination in human gastroesophageal cell lines, which were resistant to the induction of apoptosis by paclitaxel alone.17 In view of this, a phase II study to evaluate the combination of paclitaxel and flavopiridol in paclitaxel-refractory esophagus cancer has been initiated. Even though flavopiridol has yet to find its place as a single agent in the treatment of solid tumors, it still holds promise as an agent for potentiating the effect of chemotherapy. In addition to paclitaxel, preclinical studies indicate that flavopiridol will enhance the induction of apoptosis by mitomycin, docetaxel, vinorelbine, irinotecan, cisplatin, and gemcitabine.17-20,29,30 A phase I trial, with paclitaxel and flavopiridol at these recommended phase II doses, indicates that cisplatin can be added up to a dose of 50 mg/m2 without DLT.31 Phase I drug combinations with flavopiridol and these other agents are either being planned or are underway. For many of these agents, especially paclitaxel, this effect is highly sequence dependent such that paclitaxel therapy must come before flavopiridol in order to induce this effect. Laboratory studies indicate that pretreatment with flavopiridol will induce a G1 arrest that will prevent cycling cancer cells from entering the M phase of the cell cycle, where they are susceptible to the effect of paclitaxel. The result of this is to antagonize the paclitaxel effect.17 However, when paclitaxel precedes flavopiridol, there is activation of caspases, the putative executioners of programmed cell death that are only minimally activated with paclitaxel alone. In view of this sequence specificity, every flavopiridol-based combination needs to be carefully evaluated in the laboratory in order to determine the optimal drug sequence. The failure to induce chemotherapy-induced apoptosis remains one of the major obstacles to successful chemotherapy. This has severely limited the activity of many of the agents in clinical use today. The introduction of flavopiridol, as a modulator of chemotherapy-induced apoptosis, offers a new direction in cancer therapy. This study indicates that with a 24-hour infusion of flavopiridol the toxicities, which characterized the prolonged 72-hour schedule, can be considerably reduced, and nanomolar levels, associated with CDK inhibition, can be achieved. In fact, 1-hour infusions of flavopiridol are now being tested.32 In these trials, low micromolar concentrations of flavopiridol have been attained with acceptable toxicity. It is apparent that with a change in schedule, the toxicities of flavopiridol can be ameliorated and favorable pharmacokinetics can be maintained. However, the ultimate test of this drug as a potentiator of chemotherapy will still require clinical proof that flavopiridol with chemotherapy is superior to chemotherapy alone. This will require carefully designed phase II trials in chemotherapy-refractory diseases, evidence of reversal of resistance in chemotherapy failures, or randomized phase III trials with chemotherapy in the presence or absence of flavopiridol.
Supported by grant nos. R01 CA67819 and U01 69856 04 from the National Cancer Institute, Bethesda, MD.
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Ajani JA, Ilson DH, Daugherty K, et al: Activity of Taxol in patients with squamous cell carcinoma and adenocarcinoma of the esophagus. J Natl Cancer Inst 86: 1086-1091, 1994 29. Schwartz GK, Farsi K, Maslak P, et al: Potentiation of apoptosis by flavopiridol on mitomycin-c treated gastric and breast cancer cells. Clin Cancer Res 3: 1467-1472, 1996[Abstract] 30. Motwani M, Li X, Schwartz GK: Docetaxel and Navelbine induced apoptosis is enhanced by flavopiridol (Flavo) in breast cancer cells and is sequence dependent. Proc Am Assoc Cancer Res 41: 142, 2000 (abstr 912) 31. Schwartz GK, Kaubisch A, Saltz L, et al: Phase I trial of sequential paclitaxel and cisplatin in combination with the cyclin dependent kinase inhibitor flavopiridol in patients with advanced solid tumors. Proceedings of the AACR-NCI-EORTC International Conference, Washington, DC, November 16-19, 1999, p 26 (abstr 122) 32. Senderowicz A, Messman R, Arbuck S, et al: A phase I trial of 1 hour flavopiridol, a novel cyclin dependent kinase inhibitor, in patients with advanced neoplasms. Proc Am Soc Clin Oncol 19: 204a, 2000 (abstr 796) Submitted February 23, 2001; accepted January 28, 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
341.2 for the free base form of flavopiridol and m/z = 344.0 
, Observed; —, predicted. Flavopiridol samples were obtained at serial time points as described in Patients and Methods. These values closely approximate those predicted from the two-compartment model.
) was 12,841 ng/h/mL. 
