Department of Medicine, Section of Hematology and Oncology, University of Chicago Medical Center, University of Chicago Cancer Center and the University of Chicago Phase II Network, Chicago, IL, USA
Received 12 December 2001; revised 16 September 2002; accepted 22 October 2002
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Abstract |
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The aim of this study was to evaluate feasibility and tolerability of the three-drug combination of paclitaxel, ifosfamide and carboplatin (TIC) in patients with advanced non-small-cell lung cancer. The specific objectives of the study were: (i) to define the dose-limiting toxicities (DLTs) and the maximum-tolerated dose of ifosfamide administered as part of the combination; and (ii) to determine the overall response rate and overall survival of patients treated with this regimen.
Patients and methods:
Patients with untreated, stage IIIB (pleural effusion) or stage IV non-small-cell lung cancer were enrolled in one of three cohorts. Patients received paclitaxel 200 mg/m2 as a 1-h infusion on day 1 with carboplatin at an area under the concentrationtime curve (AUC) of 6 mg·min/ml on day 2. For dose level I, ifosfamide was administered at a dose of 2 g/m2 on days 1 and 2. For dose levels II and III, the dose of ifosfamide was decreased to 1.5 g/m2 on days 1 and 2 and the dose of carboplatin was decreased to AUC 5 mg·ml/min. Therapy for dose levels I and III included filgrastim support (5 µg/kg/day), which was initiated on day 3 and continued until after day 11 or until an absolute neutrophil count >10 000/µl. Treatment cycles were repeated every 21 days. Once the phase II dose was established, a full cohort of patients received therapy at this dose level to examine further the regimens activity and tolerability.
Results:
Neutropenia was the DLT encountered for dose levels I and II. No DLT was encountered in the initial six patients treated at dose level III, and therefore this dose level was declared the recommended phase II dose. A total of 49 patients were treated at the recommended phase II dose. The predominant non-hematological toxicity encountered with this triplet regimen was cumulative peripheral neuropathy. Of the 65 eligible patients enrolled in this study, 17 (26%) responded. There were 15 patients with partial responses (23%), two with regression, and 26 with stabilization of disease (40%). Median progression-free and overall survival were 4.8 and 9.4 months, respectively.
Conclusions:
The combination TIC is well-tolerated. This triplet regimen produced response and survival rates in advanced non-small-cell lung cancer similar to those of other current combination chemotherapy regimens.
Key words: carboplatin, ifosfamide, non-small-cell lung cancer, paclitaxel
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Introduction |
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Based on the results of the trials comparing doublet and single drug regimens, it may be hypothesized that triplet combinations may be more efficacious than doublet combinations. Therefore, one strategy to improve systemic therapy for advanced NSCLC is to combine three agents with known activity. Such three-drug combinations would ideally utilize drugs that have non-overlapping mechanisms of action and toxicity profiles. Although the triplet regimens studied in the 1980s appeared no more active than doublet combinations [9, 10], the availability of new agents with novel mechanisms of action provides a new opportunity to develop and evaluate new triplet combinations.
Ifosfamide is a potential drug to combine with an active doublet. Phase II studies demonstrated that single-agent ifosfamide administered by various schedules produces response rates of 1529%, with median survival times of 57 months [11, 12]. Ifosfamide has been used in various combination regimens to treat NSCLC, including carboplatin-based regimens. At the University of Chicago, we have investigated the administration of ifosfamide in combination with paclitaxel or vinorelbine in NSCLC [13, 14]. In a phase I study, we identified the maximum-tolerated dose (MTD) of ifosfamide to be 1.6 g/m2/day on days 13 when given in combination with paclitaxel 250 mg/m2 over either 24 h or 3 h on day 2. The regimen included filgrastim support on days 411 or until neutrophil recovery. Neutropenia was the dose-limiting toxicity (DLT) and the regimen was well-tolerated. The response rate was 20%, with all responses noted at paclitaxel doses of 200 mg/m2 or higher. The National Cancer Institute of Canada clinical trials group undertook a phase I dose escalation study to determine the maximum doses of paclitaxel and ifosfamide which could be administered without growth factor support [15]. The DLT of the regimen was neutropenia and recommended doses for phase II study were paclitaxel 225 mg/m2 as a 3-h infusion and ifosfamide 4 g/m2 as a 1-h infusion every 3 weeks. The Cancer and Leukemia Group B (CALGB) undertook a randomized phase II study to evaluate further the efficacy and toxicity of the University of Chicago ifosfamidepaclitaxel doublet in advanced NSCLC [16]. In this large phase II trial, the response rate was 36% and median survival time was 8.5 months. The incidence of neutropenia, the predominant toxicity encountered, was considered acceptable.
Based upon the known activity and the good tolerability of the doublets paclitaxelcarboplatin and paclitaxelifosfamide in NSCLC, we investigated the three drug combination of paclitaxel, carboplatin and ifosfamide (TIC). A phase I study was first undertaken to determine the maximum dose of ifosfamide that could be administered with carboplatin and paclitaxel. The regimen was designed to deliver paclitaxel and carboplatin at doses within the known range of single-agent activity with escalation of the ifosfamide dose [17]. When the maximum dose of ifosfamide was established for the combination, a separate phase II study was undertaken to evaluate the efficacy and tolerability of this triplet combination in NSCLC. This report describes the results of both studies.
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Patients and methods |
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Before study entry, all patients underwent evaluation consisting of a complete history and physical examination; electrocardiogram; chest roentgenogram; chest and upper abdomen computed tomography (CT) scan; brain CT scan or magnetic resonance imaging; and bone scan.
Treatment
Protocol treatment consisted of ifosfamide administered intravenously over 2 h on days 1 and 2. Intravenous mesna was given concomitantly with the ifosfamide and then again 4 and 8 h following ifosfamide on days 1 and 2. At the conclusion of the ifosfamide infusion on day 1, paclitaxel 200 mg/m2 was administered intravenously as a 1-h infusion. Following the ifosfamide infusion on day 2, carboplatin at an area under the concentrationtime curve (AUC) of 6 mg·min/ml [19] was administered intravenously over 1-h. Six and 12 h before each paclitaxel dose, the patient received dexamethasone 20 mg by mouth. All patients received diphenhydramine 50 mg and ranitidine 50 mg (or equivalent H2-blocker) intravenously before each paclitaxel dose. Prophylactic antiemetic support with ondansetron 24 mg was recommended and other antiemetics were used at the discretion of the treating physician. Treatment cycles were administered every 21 days. For this study, the paclitaxel dose was fixed and the doses of ifosfamide and carboplatin were de-escalated as shown in Table 1. For dose levels I and III, prophylactic filgrastim support of 5 µg/kg/day was initiated on day 4 and continued until WBC >10 000/µl after day 11. Each patient was assigned treatment at a particular dose level at the time of registration and no within-patient dose escalation was permitted.
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For dose levels I and III, which included prophylactic granulocyte colony-stimulating factor, hematological DLT was defined as: grade 4 thrombocytopenia or neutropenia of >5 day duration, neutropenic fever [as defined by absolute neutrophil count (ANC) 500 cells/µl and fever of
38.2°C], or the need for platelet transfusion, or failure to achieve recovery to grade
1 toxicity by day 21. For dose level II, DLT was defined as grade 4 thrombocytopenia of >5 days duration or need for platelet transfusion; or neutropenic fever; or grade 4 neutropenia of any duration. Any non-hematological toxicity of grade
3 was considered dose-limiting if of >7 days duration.
Dose modifications
Dose modification of the paclitaxel, ifosfamide and carboplatin doses was specified for myelosuppression, nephrotoxicity, neurotoxicity and hepatic dysfunction. Therapy was delayed 1 week for inadequate hematological recovery (ANC <1800/µl or platelet count <100 000/µl) by day 22. In these instances, if recovery occurred before day 42, no dose reduction was utilized for the subsequent cycle of chemotherapy. If recovery was delayed beyond 42 days, protocol therapy was discontinued. Dose reduction was required for neutropenic fever requiring hospitalization, nadir thrombocytopenia with platelet count 25 000/µl, or neutropenia with ANC <500/µl lasting >4 days. If grade 2 or 3 neurotoxicity developed, therapy was held until resolution to grade
1 then resumed, if medically appropriate, with a dose reduction of all three drugs by 25%. Patients who developed grade 4 neurotoxicity discontinued protocol therapy.
Assessment of response and toxicity
Toxicities were assessed at least once during each treatment cycle and graded according to the CALGB toxicity criteria. Complete blood counts were performed at least twice weekly. Serum chemistry and liver function tests were obtained before each cycle of chemotherapy. Patients were monitored weekly throughout treatment by physical examination and recording of toxic effects.
Assessment of response to protocol therapy was performed after every two cycles of therapy. A complete response (CR) was defined as the complete clinical and radiological disappearance of tumor without the appearance of new lesions. A partial response (PR) was characterized as a reduction by at least 50% of the products of the longest perpendicular diameters of all measurable lesions. A PR also required that there was no growth of other lesions or the appearance of new lesions over at least 28 consecutive days. Stable disease (SD) was defined as a decrease in the sum of the products of two perpendicular diameters of all measured lesions by <50% or an increase by <25% after a minimum of two cycles of therapy. Progressive disease was characterized as an increase in the product of the longest diameters of measured lesion by 25%, or the appearance of new lesions. Regression of evaluable lesions was defined as a definite decrease in tumor size agreed upon by two independent investigators [including one radiologist (T. C.)] and no new lesions for >8 weeks.
Those patients who achieved SD or response after two cycles of therapy continued to receive protocol-specified therapy until disease progression, unacceptable toxicity, or the patients desire to discontinue therapy.
Phase II study statistical planning and analysis
The primary objective of the phase II portion of the study was to test the null hypothesis that the overall response rateamong patients evaluable for response (see definition above)is less than 0.15 versus the alternative that it is at least 0.35. The study was performed in two stages, with 19 evaluable patients being enrolled during the first stage. If more than three of the first 19 patients responded, then an additional 25 evaluable patients were to be enrolled, for a total of 44. Only if 11 or more responses were observed were we to reject the null hypothesis. This design limited the probabilities of type I () and type II (ß) error to 0.05 and 0.10, respectively, and minimized the expected sample size if the true response rate is 0.15 [20].
In addition to the hypothesis test described above, the overall response rate (combining CR, PR and disease regression among patients without measurable disease) was computed using all enrolled patients, and a 95% confidence interval (CI) was constructed based on the binomial distribution but ignoring the multi-stage nature of the design. Progression-free survival (defined as the time from registration until progression or death from any cause) and survival (also from date of registration) curves were estimated for all enrolled patients using the KaplanMeier method, and approximate 95% CIs were computed using the method described by Kalbfleisch and Prentice [21]. CIs for the median survival times were obtained as described in Bookmeyer and Crowley [22].
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Results |
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Phase I dose escalation and determination of MTD
A total of 16 patients were treated during the phase I study. Table 1 lists the dose de-escalation schema and the number of patients treated at each dose level, while Table 2 summarizes the hematological toxicity encountered during cycle 1. Out of the eight patients who received treatment at dose level I, three experienced grade 4 neutropenia during cycle 1, although by duration it was not dose-limiting. When cumulative thrombocytopenia was noted in three patients treated at this dose level, dosing delays and dose reductions were necessary. Because of this severe cumulative thrombocytopenia, this dose level was not considered feasible and a dose de-escalation was undertaken. For subsequent dose levels the ifosfamide and carboplatin doses were decreased in an attempt to cumulative thrombocytopenia. The paclitaxel dose was maintained in subsequent dose levels to ensure delivery of this agent at a known level of single-agent activity. Delivery of the regimen was attempted without prophylactic growth factor support in dose level II.
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Phase II study of the TIC regimen
A total of 49 patients received protocol therapy at the recommended phase II dose. The total number of cycles administered was 201 with the median number of cycles delivered per patient was four (range one to eight). Only 9% of all cycles were delayed to allow hematological toxicity to recover.
Overall toxicity
The total number of treatment cycles administered to patients enrolled in the phase I and II portions of the trial was 278. Table 3 summarizes the hematological toxicity encountered during cycle 1 for patients enrolled in the phase I portion of the study. The maximum hematological toxicity experienced for all patient during all courses of therapy is listed by dose level in Table 4. Overall the hematological toxicity encountered in patients treated at the recommended phase II dose was mild with only 14% experiencing grade 4 neutropenia of any duration and only one patient developing neutropenic fever. Cumulative thrombocytopenia was noted with this regimen with typical onset after four cycles of therapy.
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Response and survival
Among the first 19 patients treated in the phase II study who were evaluable for response, six had PRs and thus an additional 25 evaluable patients were enrolled. However, out of these 44 total patients only 10 responses (all partial) were observed, and thus we cannot reject the null hypothesis that the true response rate is less than 0.15. Four additional patients with non-measurable disease and one additional patient with measurable disease were treated during the phase II study for a total of 49. The responses for all 65 patients treated are shown in Table 6, separately by dose level. The overall response rate (including two responses by patients without measurable disease) for all 65 patients was 0.26 (95% CI 0.160.39). Twenty-six patients (40%) had SD.
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Discussion |
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This phase I/II trial demonstrates the feasibility of administering the TIC triplet regimen to patients with advanced NSCLC. In this phase I/II study, neutropenia was the DLT and prophylactic filgrastim support was necessary in order to maintain dose intensity. The recommended phase II dose of ifosfamide is 1.5 g/m2 administered on days 1 and 2 with paclitaxel 200 mg/m2 (1-h infusion) on day 1 and carboplatin AUC 5 mg·min/ml on day 2. The regimen also included mesna given concomitantly with the ifosfamide then again 4 and 8 h following ifosfamide. In a phase I study of this triplet combination in patients with resistant small-cell lung cancer reported by van Putten et al. [24], MTD of ifosfamide was 2000 mg/m2 given in combination with paclitaxel 175 mg/m2 and carboplatin AUC 6 mg·min/ml on day 1 of a 21-day cycle. The DLT reported in the van Putten trial was thrombocytopenia.
Our large phase II experience confirms the feasibility of delivering TIC at doses that are active, with an acceptable level of toxicity. Cumulative myelosuppression of leukopenia and thrombocytopenia was encountered at all dose levels studied. The predominant non-hematological toxicity of the regimen, peripheral neuropathy, was moderate-to-severe in 25% of patients. This triplet regimen was active in advanced NSCLC and produced an overall response rate of 26% and a median survival time of 9.4 months. The efficacy of this regimen compares favorably with results reported from randomized trials evaluating the newer doublet chemotherapy regimens [68], and is similar to those reported for other recent trials at our institution [13, 14, 25]. However, this regimen with this level of activity is not considered sufficient for further investigation. In addition, the need for prophylactic growth factor which is not cost-effective and beneficial in NSCLC limited its further utility.
Other trials investigating other triplet regimens in NSCLC have been completed. The combination of paclitaxel, gemcitabine and carboplatin has been studied in several phase II trials. Studies from the University of Colorado Cancer Center and the Sarah Cannon Cancer center indicated that full doses of these agents could be delivered [26, 27]. Kelly et al. [26] reported a response rate of 26% and a 1-year survival rate of 33%. Results of the Sarah Cannon trial [27] were more favorable, with a response rate of 48% with a reported 1-year survival of 47%. Hainsworth et al. [28] have evaluated the combination of paclitaxel, carboplatin and vinorelbine in a phase II trial where the regimen produced an overall response rate of 35% and 1-year survival rates of 43%. Comella et al. [29, 30] have conducted a trial evaluating the triplet regimen of gemcitabine, vinorelbine and cisplatin. They reported interim analysis results of a randomized phase III trial investigating this triplet combination and noted a median survival time of 48 weeks. Preliminary results of a randomized trial undertaken by the Spanish Lung Cancer Group [31] comparing a cisplatin-based three-drug regimen with a cisplatin doublet combination showed more favorable median survival times for the triplet regimen, 40.8 versus 44.8 weeks. A second trial comparing paclitaxelcarboplatingemcitabine with paclitaxelcarboplatin also favored longer survival with the three-drug regimen, 7.8 versus 10.5 months, although the difference was not statistically significant [32]. Preliminary analysis of a randomized phase II trial completed by Thompson and colleagues [33] has shown comparable survival between the two- and three-drug regimens, although results of the phase III analysis are awaited. Although the results of our phase I/II experience and other phase II trials suggest that triplet therapy might be more efficacious than doublet therapy, randomized trials are necessary to confirm superiority.
Another potential strategy for developing more active therapies is to add molecularly targeted agents to standard doublet chemotherapy approaches. Recent advances in the understanding of the biology of lung cancer and other tumors have led to the development of various novel therapies directed at tumor-specific targets. The potential combination of standard chemotherapy and these new drugs is attractive given their different mechanisms of action and toxicity profiles. Several phase I, II and III trials in patients with NSCLC are in progress to examine the feasibility and efficacy of regimens that combine targeted therapies with cytotoxic chemotherapy. A recently reported randomized phase II trial evaluated the triplet combination of anti-vascular endothelial growth factor antibody with carboplatin and paclitaxel in patients with advanced NSCLC [34]. Several other trials are underway to combine novel cellular therapies, which target receptor tyrosine kinase growth factor receptors with cytotoxic chemotherapy. It is hoped that the combination of standard chemotherapy and targeted therapies will result in improved outcomes for patients with NSCLC. These approaches appear more promising for advanced NSCLC and therefore we are no longer pursuing classic cytotoxic triplet combinations.
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Acknowledgements |
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Footnotes |
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References |
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