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Cancer Therapy: Clinical |
Authors' Affiliations: 1 Greenebaum Cancer Center and 2 School of Pharmacy, University of Maryland, Baltimore, Maryland; and 3 Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, Maryland
Requests for reprints: Martin J. Edelman, University of Maryland Greenebaum Cancer Center, 22 South Greene Street, Baltimore, MD 21201. Phone: 410-328-2703; Fax: 410-328-0805; E-mail: medelman{at}umm.edu.
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Abstract |
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Patients and Methods: Patients with advanced solid tumors, good performance status, normal organ function, and no potentially curative therapy were eligible for the trial. Carboplatin was escalated from an area under the curve (AUC) of 3 to an AUC of 5. UCN-01 was escalated from 50 to 90 mg/m2.
Results: Twenty-three patients with advanced solid tumors (20 with prior platinum treatment) received a total of 60 cycles of therapy. Full doses of both agents (carboplatin AUC 5, UCN-01 90 mg/m2 in cycle 1, 45 mg/m2 in subsequent cycles) could be administered. The major toxicity noted was hypotension, which could be abrogated with the use of saline prehydration and posthydration. No responses were seen; however, seven patients were able to receive more than two courses of therapy. Of note, two of three patients with refractory, progressive small cell lung cancer were able to receive six cycles of therapy without evidence of progression. One patient experienced resolution of paraneoplastic syndrome of inappropriate antidiuretic hormone. The pharmacokinetic variables Cmax and t1/2 of the 3 h infusion were essentially identical to those previously observed when UCN-01 was administered over 72 h. The average t1/2 for cycle 1 was 506 ± 301 h, and the mean Cmax for all dose levels was >30 µmol/L. The mean AUC over the dosing interval for each dose level ranged from 
6,000 to 9,000 µmol/L h. Thus, the AUC of UCN-01 after the 3 h infusion was lower than was observed after a 72 h infusion.
Conclusion: The regimen of carboplatin and UCN-01 (administered as a 3 h infusion) was well tolerated. Further development of this combination, particularly in small cell lung cancer, is warranted.
Several phase I trials of UCN-01 have been conducted. In a phase I trial of patients with refractory neoplasms, UCN-01 was administered as a 72-h continuous i.v. infusion every 14 days. The starting dose was 1.8 mg/m2 every 24 h (10). Pharmacokinetic data gathered from several patients revealed that the t1/2 of UCN-01 in humans is much longer (300-1,200 h) than that found in rats and mice. Because of this difference, the dosing schedule was amended. The initial cycle remained as a 72 h continuous i.v. infusion; however, the dose in the second and subsequent cycles was reduced to one half the total dose of the first course by shortening the infusion time to 36 h while maintaining the same dose rate. Dose escalation reached 53 mg/m2/24 h, at which point five of eight patients developed hyperglycemia (
grade 3), two of whom experienced significant nausea and vomiting (>grade 3). These events were considered dose limiting and, as a result, the maximum tolerated dose and recommended phase II dose for UCN-01 were defined at 42.5 mg/m2/24 h on a 72/36-h schedule.
In a second National Cancer Institute–sponsored phase I trial, UCN-01 was originally administered as a 3 h i.v. infusion every 4 weeks to patients with advanced solid tumors and chronic lymphoproliferative disorders. The infusion duration was then shortened from 3 to 2 h, and eventually to 1 h for subsequent dose levels to develop a more convenient administration schedule for this agent. The most frequent adverse events were grade 1 to 2 nausea, vomiting, hyperglycemia, and hypotension. Hypotension during, or shortly after, the infusion was dose limiting at 95 mg/m2 when UCN-01 was administered over 1 h. The recommended dose of UCN-01 as a short infusion is 95 mg/m2 over 3 h for the first course and 47.5 mg/m2 over 3 h for the second and subsequent courses (11).
A Japanese trial also evaluated a short infusion of UCN-01. The agent was administered by 3-h infusion every 3 weeks. Thirty-two patients were enrolled on 12 dose levels over the dose range of 65 to 120 mg/m2. At the maximum administered dose of 120 mg/m2, dose-limiting toxicities (DLT) were hypotension, nausea/vomiting, hypoxemia, hyperglycemia, hyperamylasemia, elevated transaminases, and hyperbilirubinemia (12). At this dose and schedule, maximum concentration and area under the curve (AUC) graphs are similar to those achieved on the 72-h schedule.
The primary toxicities of UCN-01 have been severe hyperglycemia, nausea, and vomiting. It would therefore be difficult to attempt combination of this drug with highly emetogenic therapy such as cisplatin or with drugs requiring steroid premedication such as the taxanes. Carboplatin, although showing more hematologic toxicity than cisplatin, is markedly less emetogenic and neuropathic. It has been shown to produce comparable results with cisplatin in several malignancies, including ovarian and lung cancer. Hence, it is logical to evaluate the combination of carboplatin and UCN-01 in the hopes of preserving the potentially synergistic activity without the additive toxicity. In vitro data showed that the interaction of platinum and UCN-01 was optimal when the platinum preceded administration of UCN-01 (8). Therefore, platinum was to be administered before beginning the UCN-01 infusion. A 3 h infusion schedule would allow for outpatient administration and greatly facilitate the use of this agent in the clinic. Based on the in vitro data of synergy with platinum agents and prior studies indicating that a 3 h schedule of UCN-01 administration was both feasible and comparable with more prolonged infusions, we undertook a phase I trial of carboplatin and UCN-01 administered over 3 h.
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Patients and Methods |
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2, had histologically confirmed malignancy that was metastatic or unresectable, and for which standard curative or palliative measures did not exist or were no longer effective.
At least 4 weeks must have elapsed since prior chemotherapy or radiation therapy, or 6 weeks if the last regimen included 1,3-bis(2-chloroethyl)-1-nitrosourea or mitomycin C. Patients were required to have an anticipated life expectancy of >12 weeks, and normal marrow and organ function was defined as an absolute neutrophil count >1,500 cells/mm3, platelets >100,000/mm3, total bilirubin within institutional limits, aspartate aminotransferase/alanine aminotransferase <2.5x the institutional upper limit of normal, and serum creatinine within normal institutional limits or a measured creatinine clearance of >60 mL/min/1.73 m2 for patients with elevated serum creatinine. Patients were required to have measurable or evaluable disease. Diabetic patients were excluded due to possible risk of hyperglycemia. Initially, patients with a history of cardiovascular disease or prior mediastinal irradiation were excluded. However, the study was modified to allow such patients to participate if they were asymptomatic and had a measured ejection fraction of 50%. Patients with brain metastases were also initially excluded but later allowed to participate if the metastases were asymptomatic (or previously treated and now asymptomatic) and did not require corticosteroid or antiseizure therapy. These modifications were made to expand the potential patient pool to include populations for whom this treatment would be of potential interest (i.e., lung cancer and other thoracic malignancies). Written informed consent was required, and the study was approved by the Institutional Review Board of the University of Maryland before enrollment of the first patient.
Drug administration. Drugs were administered at the levels specified in Table 1 . Three patients were treated in each cohort and escalation to the next cohort occurred if there were no DLT noted in the first cycle. If one of three patients experience first-course DLT, up to three more patients were to be started at that same dose level. If two or more patients experience first-course DLT, no further patients are started at that dose. The maximum tolerated dose is the highest dose level where none of six or one of six patients experience DLT. Patients who were not evaluable for toxicity were to be replaced. The study was to conclude if doses of carboplatin and UCN-01 (i.e., dose level 5) could be achieved in the absence of DLT. Patients were allowed to receive up to six cycles of therapy.
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Dose modifications, toxicity, and response assessment. DLT was defined as drug attributable grade 3 or worse nonhematologic and any grade 4 hematologic toxicity. The National Cancer Institute Common Toxicity Criteria version 2.0 was used to grade toxicity. Inability to receive treatment as scheduled (i.e., >2 weeks delay) was also considered dose limiting. Patients who were delayed in therapy but eventually recovered were allowed to continue to receive therapy at a lower dose if they seem to be deriving benefit from the compound. UCN-01 doses were modified for hematologic toxicity with a 25% dose reduction for febrile neutropenia or absolute neutrophil count <500 for >5 days. In addition, 25% dose reductions of UCN-01 were mandated for grade 2 hyperglycemia, gastrointestinal toxicity, or pulmonary toxicity. The drug was held if grade 3 toxicity was encountered and could be re-administered with a 50% dose reduction only after return to grade 1. Carboplatin was adjusted for myelosuppression with a 25% dose reduction for febrile neutropenia or absolute neutrophil count <500 for >5 days or for a platelet nadir in the prior course of <50,000. Tumor response was assessed every two cycles using the Response Evaluation Criteria in Solid Tumors (RECIST).
Plasma and saliva pharmacokinetics. Blood (7 mL) was collected into heparinized tubes for determination for UCN-01 concentrations with each treatment cycle. Samples were obtained immediately before and at 0.5, 1, 2, and 3 h after the start of the infusion. Following the infusion, samples were drawn at 2, 4, 8, 24, and 48 h and at 7 and 21 days after the end of the infusion. Immediately after blood collection, samples were centrifuged at 10,000 xg for 10 min and plasma was removed, aliquoted into two cryogenic vials, and flash frozen in liquid nitrogen. Saliva was obtained concurrently with each blood draw. Immediately after saliva collection, samples were transferred into a cryogenic vial and flash frozen in liquid nitrogen. Plasma and saliva concentrations were determined using a previously published reverse-phase high-performance liquid chromatography assay method (13). The pharmacokinetic variables of UCN-01 in plasma and saliva were determined by a model-independent approach using WinNonlin v4.1 (Pharsight Corporation; ref. 14). Pharmacokinetic variables estimated include the maximum observed plasma or saliva concentration (Cmax), terminal eliminations half-life (t1/2) calculated as (ln2/
z), and area under the plasma or saliva concentration versus time curve (AUC) calculated using the linear trapezoidal method and extrapolated to infinity (AUC0-
) by dividing the concentration at last measurable time point by the terminal elimination rate constant (z). The volume of distribution at steady-state (Vss) was calculated as follows:
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is the area under the first moment curve from time zero to infinity. The pretreatment pharmacokinetic plasma sample was used for the determination of 
1-acid glycoprotein (AAG) plasma concentrations at each cycle. AAG concentration was determined using a radial immunoassay. AAG is the major protein binding UCN-01 in human plasma. Prior studies have documented that knowledge of patient-specific AAG binding is critical to understanding the pharmacokinetics of UCN-01 (15). |
Results |
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Nineteen patients received more than one course of therapy and therefore could potentially receive modified doses for toxicity. No patient underwent a dose modification. In one case, a patient on cohort 3 with heavily pretreated non–small cell lung cancer (prior chemoradiotherapy and prior chemotherapy for malignant disease) experienced persistent thrombocytopenia after four courses of treatment and could not be receive further protocol chemotherapy.
All but one patient had measurable disease. No measurable responses were seen. However, seven patients received more than two cycles, indicating disease stability. Of note, two of three patients with small cell lung cancer received six cycles, implying disease stabilization. The first patient, enrolled on cohort 2, was initially treated with cisplatin/etoposide and hyperfractionated radiation for limited-stage disease. He received additional cisplatin/etoposide when he developed radiographic progression (>50% increase) in his mediastinum. Although he initially responded, he radiographically progressed within 90 days and was then referred for treatment with carboplatin/UCN-01. The second patient, enrolled on cohort 4, was initially treated on a clinical trial for limited-stage disease with induction chemotherapy of paclitaxel, topotecan, and etoposide followed by carboplatin/etoposide and concurrent radiation. The patient experienced a complete response but relapsed within 90 days with severe hyponatremia (sodium, 123) and radiographic progression. Hyponatremia was attributed to the paraneoplastic syndrome of inappropriate antidiuretic hormone and was treated with fluid restriction and demeclocycline. The patient was then enrolled on study and was successfully withdrawn from demeclocycline. Both patients ceased therapy due to receiving the maximum permissible cycles of treatment rather than for disease progression. Following withdrawal of therapy, both patients progressed in previously known areas of disease within 60 days. An attempt to re-treat one of the patients with carboplatin/UCN-01 was unsuccessful.
Pharmacokinetics. Adequate samples for pharmacokinetic analysis were available from 21 of the 23 patients. Two patients did not have adequate sampling due to early withdrawal for either disease progression or toxicity. Plasma samples for pharmacokinetic analysis were obtained for one complete cycle for 21 patients, whereas 17 patients completed two cycles, 7 patients completed four cycles, and 3 patients completed six cycles. Six of the seven patients who completed four cycles had data amenable to pharmacokinetic analysis. The plasma and saliva pharmacokinetic variables are presented in Tables 5
and 6
. A representation of the mean plasma concentration versus time curves for cycles one and two is presented in Fig. 1
. The maximum plasma concentrations of UCN-01 observed at cycle 1 were 31.1 ± 16.1 µmol/L (n = 3) at 50 mg/m2, 35.0 ± 5.99 µmol/L (n = 4) at 70 mg/m2, and 36.3 ± 15.8 µmol/L (n = 15) at 90 mg/m2. Due to the small sample size and high variability, dose proportionality was not assessed. Maximum plasma concentrations achieved were in the range of 20 to 40 µmol/L (9.65-19.3 µg/mL) and the terminal elimination half-life was long and variable ranging from 113 to 1,090 h for individual patients in cycle 1. Plasma AAG levels were measured on the 1st day of cycles 1 and 2. AAG levels measured before UCN-01 ranged from 87 to 221 mg/dL with a mean of 144 mg/dL. For those patients that completed two cycles of therapy, the plasma AAG levels were 144 ± 43 and 158 ± 48 mg/dL for cycles 1 and 2, respectively. The mean AAG levels for each dose level are presented in Table 6. The relationship between AAG levels and Cmax and Vss calculated from the first dose of UCN-01 is presented in Fig. 2
. As displayed in Fig. 2, the association between plasma AAG and Cmax or Vss shows a positive correlation between Cmax and plasma AAG level and an inverse correlation between Vss and plasma AAG level.
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Discussion |
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TopAbstractPatients and MethodsResultsDiscussionReferences |
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In this trial, we have shown that UCN-01 can be safely administered as a 3 h infusion and achieve comparable Cmax and t1/2 as the 72 h infusion (10). The recommended maximum tolerated dose for single agent UCN-01 administered as a 72 h infusion was 42.5 mg/m2/d equivalent to 127.5 mg/m2 total dose each cycle, with one half of the initial dose administered each cycle thereafter every 4 weeks. At that dose, the Cmax of UCN-01 was 36.4 µmol/L (23.3-51.3 µmol/L) or 17.6 µg/mL (11.2-24.8 µg/mL). In the current study, a similar Cmax of 35.0 ± 5.99 µmol/L [median 35.8 (range 27.2-41.8)] or 16.9 ± 2.89 µg/mL [median 17.4 (range 13.1-20.1)] was achieved with a 3 h infusion after administration of 70 mg/m2, followed by one half the initial dose every 3 weeks. However, due to the higher dose and longer interval for the dosing cycle for the 72 h infusion study, the overall exposure over one cycle in the previous study was substantially greater (median 21,212 µmol/L h) than in the present study [median 8.447 µmol/L h (mean 8,320 µmol/L h) at the 70 mg/m2 dose level]. The t1/2 of UCN-01 was similar to the previous study as well. In the current investigation, the t1/2 overall was 506 ± 301 h [median 407 (range 106-1,714)], whereas the previously reported half-life was 622 h (143-3,879 h). It is universally accepted that only drug that is free to pass from the plasma to the site of action can exert the pharmacologic effect. Because UCN-01 is highly bound to the plasma protein AAG, early investigation focused on the determination of unbound concentrations of UCN-01 and also saliva concentrations of UCN-01 as a surrogate for the unbound concentrations. Because the pharmacologic activity of UCN-01 in vitro has been associated with concentrations >10 nmol/L, saliva concentrations above that level are presumed to be representative of potentially therapeutic concentrations. Thus, salivary sampling presumptively confirmed tissue penetration of the agent at levels similar to those seen with the single agent over 72 h. For example, using the 72 h infusion, mean maximum salivary concentration at the maximum tolerated dose (42.5 mg/m2/d) was 111 nmol/L (60.1-280.4 nmol/L), or 53.6 ng/mL (29.0-135.3 ng/mL), and in the current study at the 70 mg/m2 dose level the mean maximum saliva concentration was 130 ± 59.7 nmol/L (6,237 ± 28.8 ng/mL). Considerable variability in maximum plasma saliva concentrations was seen, which in part could be due to the pitfalls of collecting adequate saliva samples. An additional finding of this clinical trial was the correlation between Vss and plasma AAG level. There was also a corresponding correlation between the plasma UCN-01 Cmax and plasma AAG level. As depicted in Fig. 2, it is evident that the UCN-01 plasma Cmax is greater in patients with a higher circulating AAG level and as would be expected form that finding the Vss was inversely correlated with the plasma AAG level. Because UCN-01 is extremely highly bound to plasma a correlation between UCN-01 Cmax and circulating AAG might be expected. Our results are consistent with those of Sparreboom et al. (18) who reported that as individual values for AAG increased, values for clearance of UCN-01 decreased, suggesting nonlinearity in the pharmacokinetics of UCN-01. However, nonlinearity was not seen in the pharmacokinetics of the unbound concentrations at the peak plasma concentration of UCN-01. These results suggest that extensive binding to AAG may explain the small volume of distribution and slow systemic clearance of UCN-01 and indicate that measurement of total UCN-01 concentrations in plasma is a less than ideal surrogate for that of the pharmacologically active fraction unbound drug.
The pharmacokinetics of UCN-01 has been reported in five other clinical trials (10, 11, 19–21). Including the present study, UCN-01 has been administered as a 72 h infusion in three prior trials and as a 3 h infusion in three other studies. The concentrations achieved at the maximum tolerated UCN-01 dose presented here, 90 mg/m2, the maximum plasma concentration, overall drug exposure and half-life are similar across the clinical trials. Because similar plasma concentrations and overall exposure can be achieved with the shorter 3 h infusion at a dose of 90 mg/m2 total dose over 3 h compared with 45 mg/m2/d (total dose 130 mg/m2) over 72 h with an improved toxicity profile, the shorter infusion would be recommended for further investigation. It is not known whether the therapeutic effect of UCN-01 is associated with Cmax or total exposure (AUC); however, the proposed mechanism of action of UCN-01 suggests that intermittent high concentrations should produce the desired antitumor effect.
The primary toxicity observed was hypotension, which could be easily overcome by the use of aggressive saline prehydration and posthydration. In addition, the agent can be safely administered with full doses of carboplatin.
Although tumor responses as defined by RECIST were not seen, there was clear evidence of patient benefit in the form of disease stability for seven patients. Interestingly, several patients had received prior platinum agents within the past 90 days. Two of the patients demonstrating benefit (both receiving the full six courses of therapy) had radiographically and symptomatically progressive, chemotherapy-refractory small cell lung cancer. One patient who experienced severe syndrome of inappropriate antidiuretic hormone could be withdrawn from demeclocycline without ill effect. The efficacy of this combination is of particular interest given prior in vitro data demonstrating that this combination may be particularly attractive small cell lung cancer, a disease in which p53 and Rb abnormalities are almost universal. In both p53 wild-type and mutated cell lines, it was critically important for the platinum agent to precede administration of UCN-01 (22). Cell killing was most pronounced in lines with both disrupted p53 and Rb function. This was felt to be a consequence of abrogation of S and G2 checkpoint arrest shifting the balance to cell death from DNA repair (8).
The combination of UCN-01 has also been attempted with cisplatin. Lara et al. (20) combined UCN-01 administered as a 72 h continuous i.v. infusion with escalating doses of cisplatin. Severe toxicities, including death, were noted at relatively low doses of cisplatin, aborting the trial. It is unclear whether these toxicities were a consequence of the prolonged infusion time or additive toxicity with cisplatin. Other combination regimens of UCN-01 using 3 h infusions with chemotherapy in advanced solid tumors have been better tolerated. Hotte et al. (21) showed that a 3 h infusion of UCN-01 combined with topotecan was well tolerated and had a promising level of activity in ovarian cancer.
In summary, this study shows the ability to safely administer UCN-01 in combination with carboplatin in the outpatient setting. Disease stabilization was observed in heavily pretreated patients, indicating that this combination is potentially active and worthy of further evaluation. In particular, evaluation of this combination in less heavily pretreated patients with small cell lung cancer is warranted.
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Footnotes |
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Note: Preliminary results of this study were published in Proceedings of the American Society of Clinical Oncology 2003.
Received 7/24/06; revised 2/ 5/07; accepted 2/16/07.
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References |
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1-acid glycoprotein. Cancer Res 1998;58:3248–53.1-acid glycoprotein on the clinical pharmacokinetics of 7-hydroxystaurosporine. Clin Cancer Res 2004;10:6840–6.This article has been cited by other articles:
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  S. Romagnoli, E. Fasoli, V. Vaira, M. Falleni, C. Pellegrini, A. Catania, M. Roncalli, A. Marchetti, L. Santambrogio, G. Coggi, et al. Identification of Potential Therapeutic Targets in Malignant Mesothelioma Using Cell-Cycle Gene Expression Analysis Am. J. Pathol., March 1, 2009; 174(3): 762 - 770. [Abstract] [Full Text] [PDF]
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 C. Marminon, F. Anizon, P. Moreau, B. Pfeiffer, A. Pierre, R. M. Golsteyn, P. Peixoto, M.-P. Hildebrand, M.-H. David-Cordonnier, O. Lozach, et al. Rebeccamycin Derivatives as Dual DNA-Damaging Agents and Potent Checkpoint Kinase 1 Inhibitors Mol. Pharmacol., December 1, 2008; 74(6): 1620 - 1629. [Abstract] [Full Text] [PDF]
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