1 British Columbia Cancer Agency-Vancouver Cancer Center, Vancouver, BC; 2 London Regional Cancer Center, London, ON; 3 Jewish General Hospital, McGill, Montreal, PQ; 4 British Columbia Cancer Agency-Fraser Valley Cancer Center, Surrey, BC; 5 University Health Network, Ontario Cancer Institute/Princess Margaret Hospital, Toronto, ON; 6 AstraZeneca Canada, Mississauga, ON; 7 National Cancer Institute of Canada Clinical Trials Group, Kingston, ON, Canada
Received 29 July 2002; revised 12 December 2002; accepted 14 January 2003
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Abstract |
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ZD0473 is a new generation platinum compound with activity against a wide range of human tumor cell lines and xenografts, including carboplatin- and cisplatin-resistant lines. A phase II study of ZD0473 in advanced breast cancer was initiated by the National Cancer Institute of Canada Clinical Trials Group.
Patients and methods:
Women with metastatic breast cancer, measurable disease, an Eastern Cooperative Oncology Group performance status of up to two, and a maximum of one prior cytotoxic agent for recurrent disease were enrolled and treated at 120 mg/m2 every 3 weeks. After 13 patients were enrolled, the dose was increased to 150 mg/m2 on the basis of emergent data from studies ongoing at the time.
Results:
Thirty-three women were evaluable for toxicity and 26 patients for response. Toxicity was mainly hematological with grade 3/4 thrombocytopenia in 12 of 20 patients (60%) treated at 150 mg/m2 and grade 3 thrombocytopenia in three of 13 patients (23%) at 120 mg/m2. Grade 3/4 neutropenia occurred in 15 patients (75%) at 150 mg/m2 and two patients (10%) at 120 mg/m2. Non-hematological toxicities were generally mild or moderate. There was one partial response seen for a response rate of 3.8% (95% confidence interval 0.1% to 19.5%) and stable disease in 15 patients.
Conclusion:
ZD0473 has minor activity as a single agent in metastatic breast cancer. Combinations with other drugs including docetaxel are ongoing and may be of interest.
Key words: breast cancer, phase II studies, platinum, ZD0473
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Introduction |
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Platinum agents have been shown to have activity in untreated or minimally pretreated breast cancer while showing poor efficacy in heavily pretreated women. Studies at non-myeloablative doses in both untreated and treated patients report a wide range of response rates ranging from 0% to 53% for cisplatin and carboplatin [16]. Due to toxicity and a wide variety of other active options, these drugs have not been extensively used in breast cancer. Recently, however, with the preclinical finding of synergy between platinums and Herceptin" (trastuzumab) in patients overexpressing human epidermal growth factor receptor 2 (HER2), there has been renewed interest in these agents [79]. A phase II trial in advanced breast cancer of single agent cisplatin and Herceptin" confirmed clinical activity and acceptable toxicity [10]. Two phase II trials using a combination of docetaxel, Herceptin" and cisplatin or carboplatin have reported 76% and 71% response rates, respectively, and with these encouraging results adjuvant studies have been initiated [11, 12]. This interest has sparked enthusiasm for new platinum compounds.
ZD0473 is a new platinum analog that was specifically developed to overcome platinum resistance [13, 14]. It appears to have a different DNA sequence specificity compared with cisplatin and circumvents acquired resistance mediated by changes in uptake and retention, DNA repair and reduced glutathionine uptake [15]. Like other platinum analogs, ZD0473 causes cell death by the formation of covalent cross-links that interfere with DNA replication and transcription and lead to cell death [16]. ZD0473 was tested against a panel of three sensitive and five platinum-resistant human ovarian carcinoma cell lines in culture. Against the sensitive cell lines (41M, CH1, A2780) ZD0473 showed similar potency to carboplatin but its potency was intermediate between cisplatin and carboplatin against the resistant cell lines. The data demonstrated that ZD0473 retained activity in the three cell line pairs where the mechanisms of resistance were variable, including due to reduced drug uptake in the 41McisR, due to enhanced DNA repair in the DH1cisR, and due to uptake, repair and increased glutathione levels in the A2780cisR. ZD0473 was tested in other cell lines including colorectal cancer and breast cancer and found to be active [14, 1618].
Phase I studies of ZD0473 defined a maximum tolerated dose of 150 mg/m2 when administered as a 23 h infusion every 4 weeks with a dose-limiting toxicity of thrombocytopenia and febrile neutropenia. Other toxicities were mild and nephrotoxicity was unusual. Pharmacokinetics showed a linear relationship between the dose and myelosuppression. As well, the trial suggested that patients who were less heavily pretreated tolerated 150 mg/m2 without excessive toxicity. The recommended phase II dose (RP2D) was 120 mg/m2.
Using an RP2D of 120 mg/m2 given as a 2-h infusion every 3 weeks, the National Cancer Institute of Canada Clinical Trials Group (NCIC-CTG) initiated a multicenter phase II study of ZD0473 (IND 129) in patients with advanced or metastatic breast cancer.
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Patients and methods |
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All patients were assessed at baseline with a history, physical examination, hematology and chemistry panel, diagnostic imaging of their disease and had baseline toxicity assessment before being enrolled with the NCIC-CTG central office.
Body surface area was assessed using actual height and weight. Patients in the initial cohort were treated with a dose of ZD0473 120 mg/m2 given as an i.v. infusion over 2 h. Later patients accrued were treated at a starting dose of 150 mg/m2 as this dose was shown to be tolerable in other phase II studies [19, 20]. As ZD0473 is a platinum compound and known to be emetogenic, the prophylactic use of antiemetics including 5-hydroxytryptamine type 3 receptor antagonists was recommended. Patients in the 120 mg/m2 cohort who experienced no drug-related toxicity that was grade 2 were increased to a dose of 150 mg/m2 for the second and subsequent cycles given at 3-week intervals. Doses were reduced for hematological toxicity that included nadir counts of granulocytes <0.5 x 109/l for
7 days or platelet counts of <10 x 109/l as well as delays on the basis of counts on the day of treatment. Doses were also decreased or delayed for non-hematological toxicity including changes in the creatinine clearance.
Patients were assessed for toxicity every 3 weeks and for response every second cycle. Treatment was discontinued for progressive disease (PD), unacceptable toxicity, a diagnosis of intercurrent illness that would affect assessments, or if requested by the patient.
Response was defined by the RECIST (Response Evaluation Criteria in Solid Tumors) criteria [21]. Measurable lesions were defined as those that could be accurately measured in at least one dimension of 20 mm by conventional imaging or physical examination or
10 mm by spiral CT. Lesions not meeting these criteria (i.e. too small) were followed as non-target lesions. All measurable lesions up to a maximum of 10 were considered target lesions and were recorded and measured at baseline and follow-up visits. Complete response (CR) was defined as the disappearance of all clinical and radiological evidence of tumor (both target and non-target). Partial response (PR) was at least a 30% decrease in the sum of the longest diameter (LD) of target lesions taking as a reference the baseline LD. Stable disease (SD) was defined as neither sufficient shrinkage to qualify for PR, nor sufficient increase to qualify for PD. PD was at least a 20% increase in the sum of LDs of measured lesions taking as references the smallest sum of LDs recorded since treatment started, or the appearance of one or more new lesions. The response duration was the time that CR or PR was first met to the first date of PD. SD duration was the time from the start of therapy to the date of progression. The same method measuring target lesions was used for all assessments.
Statistical plan
In order to minimize the expected number of patients treated in the event that the treatment proved either disappointing or very successful, a two-stage design was planned for patient accrual. After 15 patients were accrued in this design the results were assessed and it was planned that if an extreme result with poor efficacy was observed (defined as a <5% response rate), the study would be terminated. If better results were observed, a maximum of 30 patients would be accrued. Therefore if there were no responses in the first 15 patients no others would be accrued. If one or more responses were observed in this cohort, an additional 15 evaluable patients would be accrued as this could represent a response rate of 20%, which would make the regimen of interest to the oncology community [22, 23].
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Results |
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Toxicity
Hematological toxicity was significant with several patients experiencing grade 3/4 thrombocytopenia and/or granulocytopenia and this was more severe at the 150 mg/m2 dose, although the median nadir counts were similar for both starting dose levels. Hematological toxicity is summarized in Table 2. The duration of the granulocyte nadirs were similar for both doses, ranging from 5 to 42 days for the 120 mg/m2 dose and 15 to 36 days for the higher dose with a day to median nadir count of 15 and 20 days, respectively. Despite these decreases in the granulocyte counts there were no cases of febrile neutropenia or infection. The platelet nadirs occurred at a median of day 15 for both doses and ranged from 7 to 26 days. There was no consistent trend in grade of hematological toxicity with number of prior regimens, although chemo-naive patients appeared to experience less severe hematological toxicity (Table 3).
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At the lower dose of ZD0473, 77% of the patients received more than 90% of the planned dose intensity. Only one patient treated in the initial cohort of 120 mg/m2 was escalated to the 150 mg/m2 in cycle 2. Only 55% of patients at the 150 mg/m2 dose received more than 90% of the planned dose intensity. At 120 mg/m2 there was only one dose reduction for hematological toxicity on cycle 6 and five patients requiring delays on 12 cycles, with nine resulting from hematological toxicity. At the 150 mg/m2 dose there were two patients requiring reductions and nine patients in 15 cycles requiring delays, all due to hematological toxicity.
Seventeen patients went off the study for objective evidence of PD, seven for symptomatic progression, seven for toxicity and two for physician-related decisions. At the lower dose one patient went off study for grade 2 nausea and one for grade 3 nausea, vomiting and anorexia. The other five patients who discontinued for toxicity were all treated at the 150 mg/m2 dose; treatments were discontinued in four patients due to hematological toxicity (one each for grade 2 and 3 thrombocytopenia or neutropenia) while one patient was taken off study due to grade 3 nausea.
Response
Only one PR (at ZD0473 120 mg/m2) was seen in this patient population, in a patient at the 120 mg/m2, and no CRs. This is a response rate of 3.8% (95% confidence interval 0.1% to 19.5%). Fifteen patients had SD and 10 had PD. The duration for the PR was 5.2 months and for SD was a median of 3.9 months with a range of 1.114.1 months.
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Discussion |
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In this trial of ZD0473 given every 3 weeks, we observed a low response rate and significant toxicity. Although there are always concerns that small phase II studies may bias for or against results, the 4% response rate is not of adequate interest to proceed with further testing. Nor is it worthwhile considering if there were problems in patient selection, tumor assessments, tumor heterogeneity or other factors, which may have resulted in this disappointing result. With five centers participating we must assume that the patients were representative of metastatic breast cancer and our result reflects true activity.
As well, there was significant hematological toxicity, which made treatment delivery difficult and may preclude against easily combining ZD0473 with other active agents. There are multiple causes for poor hematological tolerance in a breast cancer population including prior radiotherapy, marrow involvement and previous adjuvant chemotherapy. However, in this setting prolonged marrow toxicity and in particular thrombocytopenia are of concern.
This study demonstrates the difficulty of predicting an RP2D. With the usual patient population in phase I studies, there may be a tendency to initiate phase II studies in less heavily pretreated patients at inadequate doses and this may prejudice the results if indeed a dose response is associated with activity. In this trial, however, the dose was escalated, there were adequate numbers of patients at the higher dose, and activity was not sufficient to be of interest. As well, the higher dose was definitely associated with both increased toxicity and difficulties in delivering full dose intensity.
There was an attempt to limit the number of patients enrolled if the activity was disappointing. As the response was seen in the first cohort, enrollment continued and the design did not effectively protect against the total accrual. The power that was required in the statistical proposal calculated that this enrollment was necessary to avoid accepting the null hypothesis incorrectly.
In summary, the response rate seen in this trial of ZD0473 given as a 3-weekly i.v. infusion at a dose of 120 or 150 mg/m2 was lower than anticipated. Further trials of this agent in metastatic breast cancer are unlikely to be of interest unless there is good preclinical evidence of a synergistic augmentation of activity with another agent. However, combinations of ZD0473 and other active agents may be of interest in other types of malignancy. As couplets of platinum agents and taxanes are standard therapy in a number of malignancies, the NCIC is currently conducting a study of ZD0473 and docetaxel, to assess the combination in the clinical setting. Other such studies may determine the therapeutic role of this new agent.
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Acknowledgements |
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Footnotes |
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References |
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