Annals of Oncology Advance Access originally published online on November 10, 2005
Annals of Oncology 2006 17(2):334-340; doi:10.1093/annonc/mdj076
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© 2005 European Society for Medical Oncology
Phase I trial of UCN-01 in combination with topotecan in patients with advanced solid cancers: a Princess Margaret Hospital Phase II Consortium study
1 Princess Margaret Hospital Phase II Consortium, Cancer Therapy Evaluation Program; 2 National Cancer Institute, Bethesda, Maryland, USA
* Correspondence to: Dr S. J. Hotte, Juravinski Cancer Centre at Hamilton Health Sciences, 699 Concession Street, Hamilton, Ontario, Canada L8V 5C2. Tel: +1-905-387-9495, ext. 64602; Fax: +1-905-575-6326; E-mail: sebastien.hotte{at}hrcc.on.ca
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Abstract |
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Background: 7-Hydroxystaurosporine (UCN-01) inhibits serine–threonine kinases including the Ca2+ and phospholipid-dependent protein kinase C (PKC), CDKs 2, 4, 6, Chk-1 and PDK1. UCN-01 mediates distinct effects in vitro/in vivo: cell cycle arrest in G1, abrogation of G2 arrest by inhibiting chk1, induction of apoptosis and potentiation of cytotoxicity of S-phase-active chemotherapeutics including the topoisomerase 1 inhibitor topotecan (T). This phase I study was designed to determine the maximal tolerated dose (MTD), recommended phase 2 dose (RPTD), toxicity profile, pharmacokinetics and antitumor activity of T and UCN-01 in patients with refractory solid tumors.
Design: Both agents were administered every 21 days intravenously through central venous access in escalating doses to eligible patients. On day 1, following antiemetic prophylaxis with dexamethasone and a serotonin type 3(A) receptor (5HT3) inhibitor, UCN-01 was infused over 3 h, followed by T infused over 30 min. On days 2–5, patients received T only. UCN-01 doses were reduced by 50% in cycles 2 and beyond because of its prolonged half-life.
Results: Thirty-three patients were entered in three cohorts: Dose Level (DL) 1 (UCN-01 70 mg/m2, T 0.75 mg/m2), three patients; DL 2 (UCN-01 70 mg/m2, T 1.0 mg/m2), 24 patients; DL 3 (UCN-01 90 mg/m2, T 1.0 mg/m2), six patients. All but three patients were PS 0 or 1, median age was 54 years (range, 29–72), 91% were female. Primary tumor types: ovary/peritoneal (23 patients), colon (three patients), salivary gland (two patients), others (five patients). All patients were eligible for adverse event (AE) analysis and 22 patients were eligible for survival and tumor response analysis. Two of six patients had dose limiting toxicity (DLT) at DL 3 (grade 3 N/V; grade 4 neutropenia with infection). One DLT was seen in one patient at DL 2, consisting of grade 4 leukopenia. This cohort was expanded and no further DLTs were observed. Most common drug-related AEs were mild (grade 1–2). Non-hematological grade 3–4 AEs consisted of transient hyperglycemia (4), infection (3), coagulation, fatigue, hypotension, nausea (2), hypomagnesemia, vomiting, headache (1). Hematologic toxicities occurred in 100% of patients. Grade 3–4 hematologic abnormalities included neutropenia (16, including three with infection), leukopenia (11), lymphopenia (7), thrombocytopenia (5). Best response for 22 evaluable patients was PD (8), SD for at least six cycles (12), PR (1: carcinoma of ovary, dose level 2) and one not assessable. Pharmacokinetic analysis confirmed the prolonged half-life of UCN-01 of 
15 days.
Conclusions: DLT was observed at DL 3 and RPTD was determined to be DL 2. To date, this combination has been relatively well tolerated with some preliminary evidence of efficacy. A phase II study of this combination in patients with ovarian cancer is underway.
Key words: Clinical trial, cyclin-dependent kinase modulator, human, staurosporine analogs
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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UCN-01 (7-hydroxystaurospaurine) (Figure 1) is a selective inhibitor of a number of serine–threonine kinases, including the Ca2+- and phospholipid-dependent protein kinase C (PKC) and cell-cycle-specific kinases including cyclin-dependent kinases (CDKs) 2, 4 and 6, Chk1 kinase and, most recently, PDK1 [1
–3]. It was selected for clinical development because of its potent antiproliferative activity in vitro (IC50 25 nM) in the NCI human tumor cell screen against several cell lines (especially renal) and its antineoplastic activity in several xenograft systems [reviewed in 4 and 5]. While UCN-01 is a potent inhibitor of certain PKC isoenzymes, the precise mechanism of action for its antitumor activity is still not fully understood. In preclinical studies, UCN-01 causes arrest of cell cycle progression at G1/S phase and/or abrogation of arrest at G2 phase at concentrations that reduce PKC activity [reviewed in 5]. G1 arrest may be induced through inhibition of PDK1 and/or inhibition of CDKs. Abrogation of the G2 checkpoint arrest in the presence of DNA damage is independent of p53 status and may be due to the inhibition of Chk1 [6]. Preclinical studies have suggested that Chk1 is the molecular mediator of G2 checkpoint abrogation by UCN-01 and may be an important mechanism of synergy seen when UCN-01 is combined with DNA-damaging agents [6–8].
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Induction of apoptosis by UCN-01 has been reported in various human cell lines [9
–15]. The arrest of cells at the G1 and abrogation of G2 cell cycle phases are unusual among antitumor agents, the majority of which cause DNA damage, tubulin binding, S/G2 phase arrest, or act as anti-metabolites [16]. It may be possible to exploit this unusual characteristic of UCN-01 to design more effective antitumor therapies through novel combination drug regimens.
Phase I studies of UCN-01 evaluating schedules of 72 h and 3 h intravenous infusions have been completed [17–19]. Pharmacokinetic data from the first patients administered UCN-01 revealed that the agent binds tightly to human 
-1 acid glycoprotein (hAGP) resulting in a long half-life of several weeks, small volume of distribution at steady state and low systemic clearance. To prevent drug accumulation, doses were reduced by half after the first cycle with both schedules. For the 72 h schedule, the cycle 1 recommended phase II dose (RPTD) of UCN-01 is 42.5 mg/m2/day for 3 days during cycle 1 and the same dose per day for 1.5 days for subsequent cycles. For the 3 h schedule, the cycle 1 RPTD is 90 mg/m2 over 3 h during cycle 1. Significant toxicities seen with this agent include hyperglycemia with metabolic acidosis, pulmonary dysfunction, nausea, vomiting and hypotension. The mean total salivary concentration, which was evaluated as a surrogate measure of ‘free’ drug, was 111 nmol/l of UCN-01, within the range predicted to inhibit PDK1 and Chk1 [17]. More recently, studies that evaluated UCN-01 in combination with other cytotoxic agents have also been published [20,21]. In these trials, cisplatin [20] and fluorouracil (FU) [21] were combined with UCN-01 given as a 72 h infusion. Toxicities similar to those observed with single-agent UCN-01 were seen but other unique toxicities such as arrhythmias and syncope were also seen. In the study by Kortmansky and colleagues [20], pre-treatment and post-treatment tumor biopsies showed that UCN-01 successfully inhibited the checkpoint kinase Chk1.
Topotecan hydrochloride is a camptothecin (CPT) analog, which has shown significant anticancer effects inhibiting the nuclear enzyme topoisomerase I. Cytotoxicity of this agent is predominantly exerted during the S phase of the cell cycle. Although topoisomerase I is expressed throughout the cell cycle, cells in S phase are 1000 times more sensitive than cells in G1 or G2 phase to the cytotoxicity of CPTs reflecting the need for DNA replication for drug efficacy [22].
Synergic interactions between UCN-01 and cytotoxic agents have been seen in preclinical studies using these agents with a range of UCN-01 concentrations (20–150 nM) [23]. Preclinical studies with UCN-01 and topoisomerases have suggested synergy with UCN-01 and this interaction does not appear to be sequence dependent [24]. Potentiation of cytotoxicity of topoisomerase I poisons by concurrent and sequential treatment with UCN-01 involves disparate mechanisms resulting in either p53-independent clonogenic suppression or p53-dependent mitotic catastrophe [23–25]. Synergy may be due to induction of double-stranded DNA breaks and abrogation of the G2 checkpoint precluding their repair [26]. Interestingly in this study, the epithelial cell line was not affected. The authors concluded that UCN-01 can inhibit CPT-induced S-phase arrest in tumor cells defective in p53 function and can enhance CPT-induced cytotoxicity in a synergic manner. Results from phase I studies have suggested that free drug concentrations of UCN-01 in the range that can enhance in vitro toxicity of clinical agents in human tumor cell lines can be obtained with doses close to the single agent RPTD [17]. There are pros and cons in the two strategies used to develop biomodulators: whether to fix the dose of the cytotoxic and escalate the modulator or whether to fix the dose of the modulator and fix the dose of the cytotoxic. As a result of preclinical and single-agent phase studies, this phase I study was designed to evaluate the UCN-01-biomodulating effects of topotecan's cytotoxicity using dose levels close to the UCN-01 RPTD with escalating doses of topotecan to ensure that concentrations of UCN-01 would be in a range predicted from preclinical studies to act synergically with topotecan.
The current study sought to build upon these preclinical observations by enrolling patients who have advanced solid cancers to this novel combination of topotecan and UCN-01.
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patients and methods |
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patient eligibility
Patients 18 years of age or older with malignant solid tumors refractory to conventional therapy or for whom no effective therapy exists were eligible. Patients with ovarian cancer had to have received at least one course of platinum-based therapy. Each platinum course was counted as one line of therapy. No restrictions were put on the number of previous chemotherapy regimens but patients could not have received prior topotecan. Patients must have completed any prior radiotherapy or surgery at least 4 weeks before study entry and patients must have recovered from the toxic effects of any prior therapy. Patients had no more than 40% of their bone marrow irradiated and had either progressive or evaluable disease outside the field or progression post-radiation therapy.
Patients had adequate performance status of ECOG 0, 1 or 2; life expectancy of at least 12 weeks; normal bone marrow and organ function defined as absolute neutrophil count of >1500/µl, platelets > 100 000/µl, total bilirubin equal to or below the upper limit of normal (ULN), AST and/or ALT <2.5 times ULN, creatinine no higher than ULN or creatinine clearance >50 ml/min/1.73 m2. Patients were excluded if they had known brain metastases; a history of other active malignancy in the past 5 years with the exception of adequately treated cervical carcinoma in situ and non-melanomatous skin cancers; or a serious medical condition. Because of the effects of UCN-01 on serum glucose levels, patients with insulin-dependent diabetes mellitus were excluded. Pregnant or breastfeeding women were also excluded. Participants gave informed consent before they entered the study, and the study was approved by the local research ethics committees of all participating centers.
therapy
Study treatment was administered on an outpatient basis and both agents were given intravenously. Because of the potential for venous irritation from UCN-01, a central venous catheter was inserted before initiation of therapy. On the first day of each cycle, both UCN-01 and topotecan were given. On days 2–5, patients received only topotecan. On day 1, patients received emesis prophylaxis with intravenous dexamethasone 4 mg and a serotonin type 3(A) receptor (5HT3) antagonist along with saline hydration with 1 l normal saline. UCN-01 was administered as a 3 h infusion followed by topotecan given intravenously over 30 min. On days 2–5, topotecan was administered as a 30 min intravenous infusion without routine antiemetic prophylaxis. Because of its prolonged half-life, the UCN-01 dose was reduced by 50% for cycles 2 and beyond. UCN-01 was supplied by the National Cancer Institute, Division of Cancer Treatment and Diagnosis, Cancer Therapy Evaluation Program (CTEP). Cycle length was defined as 3 weeks or 21 days and treatment was continued until disease progression, unacceptable toxicity, patient's refusal or physician's decision.
toxicity assessment and dose reductions
Toxicity was graded according to National Cancer Institute Common Toxicity Criteria, version 2. No dose interruption or modification was made for grade 1 non-hematologic toxicity. Doses were reduced for hematologic and other toxicities. In the event of a grade 3 or 4 hematologic toxicity, only topotecan was reduced. In the event of a grade 4 non-hematologic toxicity, both topotecan and UCN-01 were reduced. Dose adjustments were made according to the system showing the greatest degree of toxicity. Doses that were reduced for toxicity were not re-escalated. The treatment of a patient could be postponed for up to 2 weeks if he/she had not recovered from hematologic and/or non-hematologic toxicity at the beginning of a cycle (day 1). Treatment was restarted immediately after recovery; that is, neutrophils 
1.5 x 109/l, platelets 100 x 109/l, and recovery from non-hematologic toxicities. A patient was discontinued from the study if the beginning of a given cycle was postponed due to toxicity for more than 2 weeks, unless approved by the CTEP drug monitor.
assessment of response
Patients were evaluated for response every 6 weeks and responses were classified according to criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee [27].
pharmacokinetics
No interaction that would alter topotecan pharmacokinetics based on known mechanisms of metabolism and clearance were anticipated and hence, no pharmacokinetic studies of topotecan were undertaken. However, additional clinical pharmacokinetic study of UCN-01 was warranted and was undertaken in this trial.
Blood samples for pharmacokinetic analysis were collected in heparinized tubes before treatment and at 1.5, 3 (end of infusion), 4, 6, 48, 96 and 504 h (before the second cycle of treatment) after the start of UCN-01 infusion [28, 29]. They were centrifuged at 3000 g for 15 min at room temperature. Plasma samples was separated and stored at –20°C until analysis.
Plasma UCN-01 concentrations were determined using high-performance liquid chromatography (HPLC) with fluorescence detection. Briefly, pre-chilled 1.0 ml acetonitrile was mixed with 0.2 ml of plasma and the internal standard (straurosporine), vortexed and centrifuged at 4000 g for 30 min at 4°C. The supernatant was transferred and vacuum dried. Each sample was reconstituted with 0.4 ml of the mobile phase, and injected on to the HPLC system. Throughout processing, samples were kept in an ice–water bath and protected from light. Separation of the analytes was achieved at ambient temperature using an Alltima C18 column (100 x 4.6 mm ID, 3 µM particles) (Alltech Associates Inc., Deerfield, IL, USA) protected by a Waters mBondapak C18 guard column (Milford, MA, USA). The mobile phase consisted of acetonitrile–0.05 M potassium phosphate buffer (47.5:52.5, v/v) with the pH adjusted to 5.9 with 0.2% triethylamine, and the flow rate was set at 1.0 ml/min. The detector was set at an excitation wavelength of 310 nm and an emission wavelength of 410 nm. Retention times were 6.4 and 10.6 min for UCN-01 and straurosporine, respectively. The method was validated from 0.05 to 12.5 mg/ml. Pharmacokinetic parameters were calculated according to non-compartmental methods using WinNonlin Version 4.1 (Pharsight Corp, Mountain View, CA, USA).
statistical considerations
The primary objective of this study was to determine the maximal tolerated doses (MTDs) of the combination of UCN-01 and topotecan to choose a RPTD, and to determine the safety and tolerability of this combination in patients with advanced cancer. Secondary objectives were to determine the relationship between clinical and pharmacokinetic effects of UCN-01 in combination with topotecan and to assess for preliminary evidence of efficacy.
Three patients were initially treated at each dose level. If no DLT were encountered in any of the three patients in cycle 1, dose escalation was allowed. If one of the three patients experienced a DLT, three more patients were to be enrolled at the same dose level and if none of these three additional patients experienced a DLT, dose escalation was allowed. The RPTD of this drug combination was to be defined as the next lower dose level below the one in which >1/3 patients or 2/6 patients experience DLT. Three additional patients were entered at the MTD if only three patients were previously treated at that dose level. DLT was defined as any grade 3 or 4 non-hematologic toxicity or any grade 4 hematologic toxicity lasting more than 7 days. Complete blood counts (CBCs) were carried out weekly.
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results |
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patients and treatment
Thirty-four patients were accrued to the phase I study at three centres in Canada. Patients were enrolled on to one of three dose levels (Table 1). Intra-patient dose escalation was not allowed. One patient at dose level 2 withdrew from the study after being registered but before receiving any treatment and needed to be replaced. This patient will be excluded from the statistical analysis. The first 22 evaluable patients were accrued to the phase I study exclusively, and the final 11 patients accrued to the phase I study but evaluable for response evaluation in a phase II trial of this treatment combination in patients with ovarian carcinomas. As a result, information on objective tumor response and patient survival will be restricted to those 22 patients enrolled to the phase I study alone, while adverse event information will be reported on all patients.
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Patient characteristics are listed in Table 2. All patients had measurable disease. Thirty of 33 patients were female and the mean age was 54.8 years (range 29.8–72.9 years). Most patients had a performance status of ECOG 0 or 1. As expected for most phase I studies, patients were reasonably heavily pretreated with a median of two regimens (range 0–5 regimens). Patients with a diagnosis of ovarian cancer were either refractory or resistant to a platinum agent (i.e. relapsed/progressed on or within 6 months of receiving a platinum compound).
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Three patients received a total of 11 cycles of treatment at dose level 1, consisting of 70 mg/m2 of UCN-01 and 0.75 mg/m2 of topetecan. Twenty-four patients received a total of 104 cycles of treatment at dose level 2, consisting of 70 mg/m2 of UCN-01 and 1.00 mg/m2 of topetecan. Six patients received a total of 19 cycles at dose level 3, consisting of 90 mg/m2 of UCN-01 and 0.75 mg/m2 of topetecan.
toxicity
Treatment was generally well tolerated with an expected side-effect profile for the two agents. The most common adverse events experienced were anemia, leukopenia, neutropenia, lymphopenia and fatigue. All patients experienced hematologic toxicity, especially leukopenia and neutropenia, which are likely effects of the topotecan. Hyperglycemia, hypotension, nausea and/or vomiting, fatigue, constipation and alopecia were observed in at least 50% of patients. Most of these toxicities are likely secondary to UCN-01. Non-hematologic adverse events are described in Table 3 and hematologic adverse events are listed in Table 4.
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No DLT was observed among the first three patients at dose level 1, thus dose level 2 was opened. The second patient at dose level 2 experienced grade 4 leukopenia and grade 3 neutropenia during cycle 1. Dose level 2 was expanded to six patients and no additional DLTs were observed. At dose level 3, the second patient entered experienced grade 3 nausea and grade 3 vomiting during cycle 1, and the fourth patient experienced a grade 4 febrile neutropenic event during cycle 1. Thus, dose level 2 was defined as the MTD and was expanded. One patient experienced grade 4 hyperglycemia during cycle 1, but no other DLTs were observed. Thus, the RPTD for this treatment combination was determined to be dose level 2, consisting of 70 mg/m2 of UCN-01 and 1.00 mg/m2 of topotecan.
pharmacokinetics of UCN-01
Limited pharmacokinetic studies of UCN-01 were undertaken. Blood sampling was performed on days 1, 3, 5 and 22. Sufficient data were available for pharmacokinetic analysis in 22 patients at the 70 mg/m2 dose level and five patients at the 90 mg/m2 dose level. Pharmacokinetic parameters are summarized in Table 5. A prolonged mean half-life of over 15 days and a maximal concentration of 14.1 µg/ml and 15.8 µg/ml were observed for the 70 mg/m2 and 90 mg/m2 dose levels, respectively. There was large inter-subject variation in pharmacokinetic parameters and little difference in pharmacokinetic parameters was observed between these two dose levels.
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response and survival
Two of the three patients accrued to dose level 1 had stable disease (one completed six cycles of treatment and the other was removed during cycle 3 due to clinical progression, and died shortly after removal from treatment). Of the six patients accrued to dose level 3, two patients had stable disease (one for four cycles and the other for nine cycles), three patients had disease progression and one died before a response evaluation could occur. One patient had adenocarcinoma of the parotid gland with no prior systemic treatment and the other had stage 4 papillary serous adenocarcinoma of the ovary and was found to be platinum resistant following carboplatinum and paclitaxel.
At dose level 2, there were 13 evaluable patients. Patient 5, a female with advanced adenocarcinoma of the ovary diagnosed as stage 3C 30 months before study entry, had stable disease after cycle 2, a confirmed partial response at cycle 4 and completed eight cycles before being removed from treatment. Before coming on to the study, she had received carboplatinum and paclitaxel with complete response followed by carboplatin and gemcitabine, carboplatin alone and and an investigational agent with a best response of stable disease. This patient was alive at last known contact 17.5 months after first being treated. Eight patients had objective stable disease at cycle 2 (one patient had symptomatic progression after cycle 2, two patients had disease progression in cycles 3 and 4, and one patient was removed from treatment at cycle 4 due to complicating disease and progressed 4 months post-cycle 4). Four of the eight patients had adenocarcinoma of the ovary or primary peritoneal carcinoma and one patient each had colorectal cancer, squamous cell cancer of the cervix and adenocarcinoma of the parotid gland. Of the four patients who completed six cycles in stable disease, two later died (1 week later and 6 months later), one progressed 6 months post-cycle 6 and remains alive 9 months post-cycle 6, and one patient progressed 4 months post-cycle 6 and remains alive 1 year post-cycle 6. Four patients had disease progression after two cycles.
Seven patients are still alive and median overall survival is estimated to be 8.3 months (95% CI 6.7–NA). Survival at 6 months is estimated to be 67.6% (50.5–90.6%) and at 1 year to be 37.3% (21.0–66.1%). The overall survival plot is shown in Figure 2. Six of the 13 patients accrued to dose level 2 are still alive with a median follow-up time of 6.9 months (range 4.2–17.6 months). Using the Kaplan–Meier method, median survival was estimated to be 8.9 months (95% CI 5.0–NA). Survival at 6 months was estimated to be 67.7% (46.0–99.7%) and at 1 year to be 42.3% (21.8–82.0%) for those patients accrued to dose level 2. One patient at dose level 3 is still alive 13.7 months post-treatment.
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discussion |
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The combination of UCN-01 and topotecan was generally well tolerated in this population of patients with advanced cancer. As expected, side effects encountered with this combination were similar to those expected with each agent alone. DLT was a combination of non-hematologic side effects such as nausea and vomiting, and hematologic toxicity. The main toxicities observed in phase I studies of single-agent UCN-01 as a 3 h infusion have been hypotension, fatigue, nausea and vomiting and hyperglycemia [18
, 19]. Most of these were also observed commonly in this study. Hypotension was uncommon in this study, and this may have been secondary to protocol-directed prehydration with normal saline when UCN-01 was given. Similarly, severe hyperglycemia was not observed but patients with pre-existing insulin-dependent diabetes mellitus were excluded from the trial. Other commonly occurring adverse events were hematologic in origin as would be expected with topotecan administration. All patients experienced leukopenia and neutropenia and a considerable number of patients had grade 3 or greater toxicity. Redkar and collaborators [30] have suggested that UCN-01 may have had a cytoprotective effect with regard to hyperproliferative normal cells and described experiments where in vitro interaction between UCN-01 and topotecan was tested in normal murine bone marrow cells and an antagonistic interaction between the two drugs was observed, as opposed to an at least additive interaction on tumor cells. Although we cannot conclude that UCN-01 potentiated the hematologic toxicity of topotecan, it appears very unlikely that UCN-01 has a protective effect against topotecan-induced bone marrow toxicity. In contrast to other combination studies of UCN-01 with other cytotoxic agents, patients in our trial tolerated treatment reasonably well [20, 21]. For example, Lara and colleagues [21] observed significant toxicity including grade 3 creatinine elevation, grade 3 atrial fibrillation and grade 5 sepsis with respiratory failure at relatively modest doses of cisplatin (30 mg/m2). Similarly, Kortmansky and colleagues [20] observed unique toxicities such as arrhythmia and syncope. For both these trials, hyperglycemia was particularly difficult to manage. Whether these issues pertain particularly to the prolonged infusion schedule will warrant further study. Because of its very long half-life, prolonged infusions may not be necessary or advantageous, as short infusions such as the 3 h infusion used in this study could distribute drug to peripheral tissues and it has been suggested that dose intensity (mg/m2/h) and toxicity may be better with this shorter schedule [31].
In keeping with single-agent phase I studies of UCN-01 [17–19], the drug was found to have a very prolonged half-life, in large part due to extensive protein binding [17]. Other pharmacokinetic parameters were similar to when UCN-01 is used alone and hence topotecan does not appear to substantially affect the kinetic profile of UCN-01.
In the study by Kortmansky and colleagues [20], some evidence of possible efficacy and the ability to overcome resistance was observed. No responses were seen but a number of patients, most of whom had received prior FU experienced stable disease for a median of 4 months. In our study, we saw encouraging clinical activity with this combination with one partial response and a number of patients with disease stabilization. Topotecan has modest activity in women with advanced ovarian cancer. It was therefore appropriate that a large number of patients enrolled to this study had this diagnosis, especially since an extension of the trial specifically accrued patients with ovarian cancer, to obtain a better toxicity profile in this population in preparation for a phase II study that is now ongoing.
As was anticipated, evidence of possible synergy was observed. The identification of enhanced myelosuppression at doses of topotecan lower than the ones when the agent is administered as a single agent suggests that there may be enhanced toxicity of the agent in the presence of UCN-01. Whether this will also result in enhanced antitumor activity will require additional study. Lower doses in combination, if agents truly act synergically on cancer cells does not necessarily mean that the lower doses decrease or negate their potency. Further clinical evaluation will help address this question.
In summary, the combination of UCN-01 and topotecan at clinically relevant doses for either agent was shown to have an acceptable toxicity profile in patients with advanced solid malignancies. The pharmacokinetic profile of UCN-01 did not appear to be significantly different than when used as a single agent. Encouraging suggestions of possible efficacy were observed, especially in patients with ovarian cancer. A phase II study is currently underway through this Consortium to better evaluate this combination in women with ovarian cancer who have progressed on or after platinum-based therapy.
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Acknowledgements |
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This study was previously presented in part at the 2003 AACR meeting in Washington, DC, and at the 2003 NCI-AACR-EORTC meeting in Boston, Massachusetts.
This study has been supported by a clinical trials contract from the US National Cancer Institute, #N01-CM-1701.
Received for publication December 2, 2004. Revision received October 12, 2005. Accepted for publication October 13, 2005.
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References |
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