A phase II study to determine the efficacy and tolerability of intravenous ZD9331 in heavily pretreated patients with ovarian cancer

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Gynecologic Oncology 91 (2003) 318 –325

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A phase II study to determine the efficacy and tolerability of intravenous ZD9331 in heavily pretreated patients with ovarian cancer J.S. Rader,a,* D. Clarke-Pearson,b M. Moore,c L. Carson,d R. Holloway,e M.-S. Kao,f I. Wiznitzer,g and E.C. Douglassh a

Washington University School of Medicine, St. Louis, MO, USA b Duke University Medical Center, Durham, NC, USA c Georgia Cancer Specialists, Decatur, GA, USA d University of Minnesota, Minneapolis, MN, USA e Walt Disney Memorial Cancer Institute, Orlando, FL, USA f St. Louis University School of Medicine, St. Louis, MO, USA g Midwest Cancer Research Group, Skokie, IL, USA h AstraZeneca, Wilmington, DE, USA Received 11 December 2002

Abstract Background. This Phase II, multicenter, open-label study was conducted to assess the efficacy and tolerability of ZD9331, a novel direct-acting thymidylate synthase inhibitor, in heavily pretreated patients with ovarian cancer. Methods. The study recruited 44 women with ovarian cancer or primary peritoneal cancer previously treated with platinum therapy and paclitaxel and with progressive disease after, or intolerance to, topotecan administered as the most recent therapy. ZD9331 was administered as an intravenous infusion at 130 mg/m2 on Days 1 and 8 of 3-week cycles, until objective evidence of disease progression. A cutoff date of 3 months after the last patient received the first dose was set for data collection. Results. Patients received a mean of 3.3 cycles of ZD9331 and a total of 143 cycles were administered. Among the 42 patients evaluated for best overall tumor response, one achieved a complete response and two achieved a partial response, giving an objective tumor response rate of 7%. The complete response occurred at Day 15 of Cycle 2 in a patient receiving ZD9331 as her eighth-line therapy. Seven patients had stable disease, giving a disease control rate of 23%. Thirty-one patients (71%) had disease progression and the median time to progression was 53 days. Most patients (89%) experienced drug-related adverse events, most commonly nausea (73%), vomiting (48%), and neutropenia (50%). Six patients (14%) were withdrawn from treatment due to adverse events. Conclusions. The preliminary evidence of efficacy and acceptable tolerability of ZD9331 in this heavily pretreated population with ovarian cancer warrants further investigation, especially in a less heavily pretreated patient population. © 2003 Elsevier Inc. All rights reserved.

Introduction Ovarian cancer occurs predominantly in postmenopausal women and is the fifth most common cause of female cancer deaths in the United States and the most common cause of

* Corresponding author. Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Washington University School of Medicine, Box 8064, 4911 Barnes-Jewish Hospital Plaza, St. Louis, MO 63110. E-mail address: [email protected] (J.S. Rader). 0090-8258/$ – see front matter © 2003 Elsevier Inc. All rights reserved. doi:10.1016/S0090-8258(03)00491-8

death from gynecological cancer [1,2]. As the onset of ovarian cancer is hard to detect, by the time the cancer is diagnosed 70% of cases have progressed to an advanced stage [3]. The long-term prognosis is poor, with a 5-year survival rate of 50% of all cases and 29% for advancedstage disease [4,5]. Advanced disease is managed by surgical intervention and aggressive chemotherapy. Since the early 1990s treatment regimens have been principally platinum-based (cisplatin or carboplatin) combinations; however, responses are usually short-lived and even in long-term survivors there

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remains a continued risk of relapse [6]. More recently, improved response rates and prolonged survival periods have been observed with the taxane compound paclitaxel [7,8]. The development of new and effective agents is a priority in the treatment of ovarian cancer and appropriate second- and third-line therapies such as topotecan are now emerging. Nevertheless, novel treatments are still required to improve the outcome for the large number of patients who relapse after receiving the most effective currently available platinum- or topotecan-based regimens [7,9]. ZD9331 is a novel, direct-acting antifolate developed by a process of rational structural design. ZD9331 acts by inhibiting thymidylate synthase, an enzyme critical to DNA synthesis and a regulator of proliferation. It is actively transported into cells by the reduced folate carrier, which is expressed to a greater extent in tumor cells than in normal cells [10]. Furthermore, in vitro data suggest that cellular uptake of ZD9331 may in part be mediated by the ␣-folate receptor [11], a receptor that is highly expressed in ovarian cancer cells [12]. Polyglutamation is not required for the activity of ZD9331 as is the case for some antifolates [13]. Consequently, this antifolate may be active against tumors with low folylpolyglutamate synthetase levels [13,14], a common resistance mechanism to thymidylate synthase inhibitors such as raltitrexed [15] or the dihydrofolate reductase inhibitor methotrexate [16]. ZD9331 has a broad spectrum of activity in a number of tumor types. Initial results from Phase I/II studies indicated that ZD9331 is active in a range of solid tumors, including pancreatic, breast, and colorectal cancers [17–19]. Phase I studies also suggested that ZD9331 is active in ovarian cancer [20,21] and combinations of ZD9331 with topotecan [22] and carboplatin [23] have also shown activity in patients with relapsed ovarian cancer. This Phase II study was conducted to assess the efficacy and tolerability of ZD9331 in heavily pretreated patients with ovarian cancer as part of an extensive clinical program.

Methods This was a Phase II, multicenter, open-label study of intravenous (iv) ZD9331 for the treatment of heavily pretreated ovarian cancer. The study was conducted in accordance with the Declaration of Helsinki, with the approval of institutional review boards or ethical committees, and with the written informed consent of all patients. Patients The first patient was recruited to the study on 26 May 1999 and data cutoff was 17 March 2000. The study population comprised women aged ⱖ18 years with histologically or cytologically confirmed epithelial ovarian cancer or

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primary peritoneal cancer. Patients had received prior platinum therapy and paclitaxel alone or in combination and had progressive disease after, or intolerance to, topotecan (5-day iv regimen) administered as the most recent therapy. Other inclusion criteria were as follows: life expectancy ⬎ 12 weeks; ⱖ1 measurable lesion, accurately measured ⱖ1 dimension, with the longest diameter ⱖ20 mm with conventional techniques or ⱖ10 mm with spiral computerized tomography (CT) scan; and Karnofsky performance status ⱖ60. Patients were excluded if they had the following: neutrophils ⬍ 1.5 ⫻ 109/liter and/or platelets ⬍ 100 ⫻ 109/liter, serum bilirubin ⱖ1.5 times the upper limit of reference range (ULRR) and/or alanine aminotransferase (ALT) or aspartate aminotransferase (AST) (⬎5 times the ULRR), creatinine clearance ⬍ 60 mL/min (Cockcroft–Gault formula), current intestinal obstruction, any evidence of severe or uncontrolled systemic disease, concomitant use of folic acid, any metastasis to the central nervous system, pregnancy, breastfeeding, any severe concurrent condition, other malignancies known to be active within the previous 5 years, any unresolved toxicity from previous anticancer therapy, extensive radiotherapy in the 6 weeks prior to the first dose or any surgery or chemotherapy in the 4 weeks prior to the first dose, previous treatment with a Phase I experimental agent or more than one previous Phase II experimental agent, or previous myeloablative chemotherapy with stem cell or autologous bone marrow rescue. Treatment Patients received ZD9331 130 mg/m2 administered as a 30-min iv infusion on Days 1 and 8 of a 3-week cycle. An interval of at least 21 days had to occur between the first doses of each cycle. The dose of ZD9331 was calculated based on the patient’s body surface area. If the patient’s weight fluctuated by ⬎10% (not due to ascites) from that previously measured, the dose of ZD9331 was recalculated. The maximum body surface area was 2.0 m2 irrespective of the patient’s size. Patients were scheduled to continue treatment until a predetermined cutoff date of 3 months after the last patient received the first dose. After the cutoff date, treatment could be continued until there was objective evidence of disease progression or until another event necessitating withdrawal occurred. Dosing criteria: Day 1 On Day 1 of subsequent cycles, patients were required to have a neutrophil count of ⱖ1.5 ⫻ 109/liter, a platelet count of ⱖ75 ⫻ 109/liter, serum creatinine ⬍1.25 times the ULRR, and a total bilirubin concentration of ⬍1.5 times the ULRR. Treatment could be delayed for up to 14 days in order for a patient to meet these criteria; if the criteria were not met after this time, the patient was withdrawn from the study. Treatment cycles could also be delayed for up to 14

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Table 1 Criteria for dose modification (as percentage of baseline dose) based on the presence or absence of hematological and nonhematological toxicity (Day 1, cycle 1)a Nonhematological toxicities (diarrhea Grade 1 to 4; mucositis Grade 3 to 4; Rash Grade 3 to 4)b CTC grade Hematological toxicity (neutrophils or platelets)b

Grade Grade Grade Grade Grade

0 1 2 3 4

Grade 0 (mg/m2) (%)

Grade 1 (mg/m2) (%)

Grade 2 (mg/m2) (%)

Grade 3 (mg/m2) (%)

Grade 4 (mg/m2) (%)

162.5 (125) 162.5 (125) 130.0 (100) 130.0 (100) 97.5 (75)

130.0 (100) 130.0 (100) 130.0 (100) 130.0 (100) 97.5 (75)

130.0 (100) 130.0 (100) 130.0 (100) 97.5 (75) 97.5 (75)

97.5 (75) 97.5 (75) 97.5 (75) 97.5 (75) 65.0 (50)

97.5 (75) 97.5 (75) 65.0 (50) NT NT

Abbreviations: CTC, common toxicity criteria; NT, no further treatment with ZD9331. If toxicity recurred at same or worse grade, dose was reduced to 65.0 mg/m2; if dose was already 65.0 mg/m2 and toxicity recurred, no further treatment was given. The toxicity was considered as an adverse event and cause for withdrawal of the patient. b Observed at any time within the previous cycle. a

days for unresolved diarrhea, mucositis, rash, or Grade 3/4 elevated ALT and AST levels. Clinical laboratory assessments were performed at least weekly until the patient met the dosing criteria or withdrew from the study. For patients with Grade 4 neutropenia or thrombocytopenia, hematological assessments were performed at least twice weekly. At each cycle, the Day 1 dose of ZD9331 could be modified according to predetermined guidelines based on the presence or absence of hematological or nonhematological toxicity during the previous treatment cycle (Table 1). The dose could be increased to a maximum of 125% of the initial dose or decreased to a minimum of 50% of the initial dose. ZD9331 dose could also be modified on the basis of deteriorating renal function as indicated by creatinine clearance values. If creatinine clearance was ⱖ 60 mL/min the dose given was 130 mg/m2 (100%), if between 40 and 60 mL/min the dose given was 97.5 mg/m2 (75%), if between 25 and 40 mL/min the dose was 65.0 mg/m2 (50%), and if creatinine clearance was less than 25 mL/min, no further treatment with ZD9331 was given. Dosing criteria: Day 8 The dose of ZD9331 on Day 8 was not administered if the patient’s neutrophil count fell by ⱖ 50% from Day 1, the neutrophil count was ⬍ 1.5 ⫻ 109/liter, or the platelet count was ⬍75 ⫻ 109/liter. The total bilirubin concentration and other liver function tests were also rechecked prior to dosing on Day 8 in patients with abnormal liver function results on Day 1 of the cycle, and the Day 8 dose was omitted in patients with total bilirubin ⬎1.5 times the ULRR. If two dose reductions had previously occurred (based on a neutrophil count reduction ⱖ 50% from Day 1) and the dose had been reduced to 65 mg/m2, it was not necessary to discontinue treatment based solely on a further 50% drop in neutrophil count from baseline, as long as the count was ⬎1.0 ⫻ 109/liter at Day 8. The Day 8 dose could be delayed for up to 14 days to allow

for recovery of severe toxicity between Days 1 and 8 and for up to 3 days for convenience, as long as the timing of subsequent doses was planned to maintain the minimum intervals of 7 days between doses and 21 days between cycles. If a Day 8 dose was given, it had to be the same dose as that given on Day 1. If a Day 8 dose was omitted, there had to be a minimum 25% dose reduction on Days 1 and 8 of subsequent cycles. Assessments All evaluations were performed in the intent-to-treat population (in patients who received ⱖ1 dose of ZD9331). The primary efficacy endpoint was objective tumor response in the intent-to-treat population. The revised World Health Organization Response Evaluation Criteria in Solid Tumors (WHO-RECIST; May 1999) definitions were used to determine a patient’s best overall tumor response [24]: a complete response (CR) is the disappearance of all target and nontarget lesions and no new lesions; a partial response (PR) is a ⱖ30% decrease from baseline in the sum of the longest diameter (LD) of target lesions and no progression of nontarget lesions and no new lesions; stable disease (SD) is where there is neither sufficient shrinkage to qualify for PR (in target lesions) nor sufficient increase to qualify for progression (target and nontarget lesions), taking as a reference the smallest sum LD since the start of treatment and no new lesions; disease progression (DP) is defined as ⱖ20% increase in the sum of LD of target lesions taking as a reference the smallest sum LD recorded since the start of treatment or the appearance of one or more lesions; and symptomatic deterioration is the global deterioration of health status requiring discontinuation of treatment with objective evidence of DP. As many as 10 target lesions were selected at screening and monitored by the investigator during the study. The lesions had to be accurately measurable in ⱖ1 dimension, with the longest diameter ⱖ 20 mm with conventional techniques or ⱖ 10 mm

J.S. Rader et al. / Gynecologic Oncology 91 (2003) 318 –325 Table 2 Baseline characteristics and previous chemotherapy regimens in 44 patients treated with ZD9331 Characteristics Mean age, years (range) Mean weight, kg (range) Race, N (%) White African American Karnofsky performance status, N (%) Range 60–80 Range 90–100 Primary tumor site, N (%) Ovary Other abdomen Stage, N (%) Locally advanced disease Distant metastases Number of previous chemotherapy regimens, N (%) 2 3 ⬎3 Response to most recent platinum regimen, N (%) Platinum-refractory Platinum-resistant Platinum-sensitive Not recorded

57.8 (36–80) 73.1 (50.0–113.4) 42 (96) 2 (5) 15 (34) 29 (66) 40 (91) 4 (9) 41 (93) 20 (46) 13 (30) 12 (27) 19 (43) 13 (30) 24 (55) 6 (14) 1 (2)

N ⫽ number of patients.

with spiral CT scan. The baseline objective tumor assessment was performed within 3 weeks before the first dose of ZD9331. At baseline all patients had a CT scan of the abdomen/pelvis performed, and tumor response was evaluated at baseline, after the first two cycles, after four cycles and after every subsequent three cycles of treatment, and at withdrawal from the study. Repeat evaluations were obtained at least 4 weeks after apparent attainment of partial or complete response. Patients who withdrew from the study for reasons other than DP continued to be monitored every 9 weeks until progression occurred. Secondary endpoints were the median time to progression, defined as the interval from the date of registration until the date of documented DP; the disease control rate, defined as the percentage of patients who achieved a CR or PR response or SD for ⱖ 6 weeks; and the median duration of response, defined as the interval from the date of registration until the date of documented DP, for those patients who responded. Adverse events (AEs), hematology, biochemistry, weight, 12-lead ECG, and vital signs were assessed during the study and AEs, hematology, and biochemistry continued to be monitored for up to 30 days after the last dose of ZD9331.

Results

and were therefore included in the intent-to-treat population. Baseline characteristics are summarized in Table 2. Approximately 70% of the study population had received ⱖ three previous chemotherapy regimens, and two patients received ZD9331 as their eighth-line treatment. After their most recent platinum regimen, 13 patients (30%) were platinum-refractory (progression or no response on platinum therapy or progression after an initial responses), 24 patients (55%) were platinum-resistant (CR or PR on platinum therapy lasting for ⬍6 months), 6 patients (14%) were platinum-sensitive (CR or PR on platinum therapy lasting for ⱖ 6 months), and 1 patient (2%) was not categorized. The most common analgesic medications taken on entry and during the study were paracetamol, oxycodone, hydrocodone, and ibuprofen. The most common therapies required for prophylaxis of toxicity during the study were the antiemetics granisetron (12 patients), prochlorperazine (9 patients), and ondansetron (8 patients). At the cutoff date, 6 patients (14%) remained in the study. DP was the most common reason for withdrawal prior to the cutoff date, affecting 24 of the 38 withdrawn patients (63%). Patients received a mean of 3.3 cycles of ZD9331 (range 1–10), and a total of 143 cycles were administered. Efficacy Among 42 patients evaluable for tumor response, 1 patient achieved a CR and 2 patients achieved a PR, giving an objective tumor response rate of 7% (Table 3). Tumor response was not recorded in two patients. The CR occurred in a patient receiving ZD9331 as eighth-line therapy and was achieved at Day 15 of Cycle 2 and maintained until the last recorded observation at Day 7 of Cycle 4. The patient had previously received both paclitaxel- and platinum-based combination regimens and was platinum-resistant. CT scans for this patient at baseline and following two cycles of chemotherapy are shown in Fig. 1. Two patients had a best overall tumor response of partial response with ZD9331 as

Table 3 Objective tumor response and best overall tumor response in the intentto-treat population (N ⫽ 44) receiving ZD9331 130 mg/m2 administered as a 30-min iv infusion on Days 1 and 8 of 3-week cycles No. of patients (%) (N ⫽ 44)a Objective tumor response Complete or partial response Best overall tumor responseb Complete response Partial response Stable disease Disease progression Symptomatic deterioration a

The study recruited 44 patients from 19 centers in the United States, and all received at least one dose of ZD9331

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Response not recorded in two patients. Based on the WHO-RECIST criteria. N ⫽ number of patients.

b

3 (7) 1 (2) 2 (5) 7 (16) 31 (71) 1 (2)

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Fig. 1. CT scans (A) at baseline and (B) following two cycles of treatment with ZD9331 in the 42-year-old patient who had a CR.

fifth-line treatment (Day 22 of Cycle 9 and Day 19 of Cycle 2, respectively) (Table 3). They had both previously received paclitaxel- and platinum-based regimens and one was platinum-resistant and the other platinum-refractory. All three patients have subsequently relapsed. Thirty-one patients (71%) had DP with a median time to progression of 53 days. Disease control was achieved in 10 patients (23%). That is, in addition to the 3 objective tumor responders, 7 patients had a best overall tumor response of SD. The previous types of chemotherapy received by the patients experiencing disease control are shown in Table 4. Of the 7 patients with SD, 3 received ZD9331 as third-line treatment, 1 as fourth-line, 2 as fifth-line, and 1 as eighthline treatment. The median duration of response could not be analyzed due to the small number of patients with a response.

Tolerability AEs occurred in all but one patient (98%), although this resulted in withdrawal from treatment in only 6 patients (14%). The most common AEs were anemia (42 patients; 95%), nausea (39 patients; 89%), vomiting (29 patients; 66%), leukopenia (29 patients, 66%), and neutropenia (26 patients; 59%) (Table 5). Increased ALT or AST were each experienced by 26 patients (59%). AEs reported in the highest proportion of therapy cycles were nausea, vomiting, neutropenia, abdominal pain, asthenia, and anorexia. Drugrelated AEs were experienced by 89% (39/44) of patients. Nausea (32 patients; 73%), neutropenia (22 patients; 50%), and vomiting (21 patients; 48%) were the most frequently reported drug-related AEs. Seventeen patients (39%) experienced serious AEs, most

Table 4 Previous types of chemotherapy treatment received by the patients experiencing disease control with ZD9331 treatment Patient

Response to ZD9331a

Previous chemotherapy treatments

1

CR

2

PR

3

PR

4 5 6 7 8 9 10

SD SD SD SD SD SD SD

Paclitaxel/cisplatin (1 cycle); cisplatin (1 cycle); paclitaxel/carboplatin (3 cycles); cisplatin/topotecan (1 cycle); paclitaxel/carboplatin (5 cycles); investigational agent (1 cycle); topotecan (6 cycles) Paclitaxel/carboplatin (6 cycles); paclitaxel/carboplatin (2 cycles); cisplatin/cyclophosphamide (3 cycles); topotecan (6 cycles) Gemcitabine/paclitaxel/carboplatin (8 cycles); paclitaxel/carboplatin (2 cycles); investigational agent (3 cycles); topotecan (4 cycles) Paclitaxel/cisplatin (6 cycles); topotecan (3 cycles) Paclitaxel/cisplatin (2 cycles); Paclitaxel/carboplatin (4 cycles); paclitaxel (10 cycles); topotecan (5 cycles) Paclitaxel/carboplatin (7 cycles); topotecan (2 cycles) Cisplatin/cyclophosphamide (6 cycles); paclitaxel (11 cycles); carboplatin/cyclophosphamide (3 cycles); topotecan (4 cycles) Paclitaxel/carboplatin (6 cycles); paclitaxel (4 cycles); topotecan (9 cycles) Paclitaxel/carboplatin (6 cycles); topotecan (11 cycles) Paclitaxel/carboplatin (6 cycles); paclitaxel/carboplatin (4 cycles); paclitaxel (1 cycle); gemcitabine (3 cycles); paclitaxel/cisplatin (3 cycles); topotecan (5 cycles); topotecan (6 cycles)

Abbreviations: CR, complete response; PR, partial response; SD, stable disease. a Best overall response, based on the WHO-RECIST criteria.

J.S. Rader et al. / Gynecologic Oncology 91 (2003) 318 –325 Table 5 AEs reported by ⬎10% of patients receiving ZD9331 Body system and AE

Whole body Abdominal pain Asthenia Fever Headache Back pain Pain Chills Digestive Nausea Vomiting Anorexia Diarrhea Constipation Dyspepsia Intestinal obstruction Hematological Neutropenia Anemia Leukopenia Thrombocytopenia Metabolic and nutritional Dehydration ALT increased AST increased Hypokalemia Nervous system Dizziness Insomnia Respiratory system Dyspnea Pharyngitis Skin and appendages Rash Pruritus

No. of patients (%) (N ⫽ 44)

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ZD9331. However, 11 patients (25%) died during the 3-month follow-up period. No. of patients with CTC Grade 3 or 4 AE

22 (50) 22 (50) 16 (36) 10 (23) 9 (21) 6 (14) 5 (11)

7 0 1 0 1 0 0

39 (89) 29 (66) 22 (50) 16 (36) 9 (21) 7 (16) 7 (16)

6 6 3 1 0 0 6

26 (59) 42 (95) 29 (66) 21 (48)

16 4 12 7

8 (18) 26 (59) 26 (59) 5 (11)

3 2 1 3

6 (14) 6 (14)

0 0

11 (25) 6 (14)

0 0

10 (23) 5 (11)

0 0

Abbreviations: CTC, common toxicity criteria; AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase.

commonly intestinal obstruction (6 patients; 14%), vomiting (6 patients; 14%), and nausea (5 patients; 11%). Three patients (7%) developed Grade 4 neutropenia, and one of these patients also developed Grade 4 thrombocytopenia. Grade 3 or 4 nonhematological toxicity occurred in 26 patients (60%); Grade 4 events occurring in 10% or more of patients included intestinal obstruction (3 patients). No patients had abnormal biochemistry lab parameters of Grade 4 but 5 patients had Grade 3 abnormalities (ALT, 2 patients; total bilirubin, AST, Alkaline phosphatase, 1 patient each). Half the study population (22 patients; 50%) had a dose delay, reduction, or omission due to toxicity. Of the 143 cycles administered, 47 (33%) were delayed, reduced, or had a dose omitted due to toxicity. The Day 8 dose was omitted due to toxicity in 30 cycles (21%). There were no deaths during the study or within 30 days of the last dose of

Discussion The aim of this study was to investigate the efficacy and tolerability of ZD9331 in patients with ovarian cancer, who were refractory or resistant to platinum and paclitaxel and resistant or intolerant to topotecan. Previously, in Phase I studies ZD9331 was shown to have encouraging activity against solid tumors, including ovarian cancer. Objective tumor response rate in the current study was 7% and 2 of 44 patients were not evaluable for response. The dosing schedule for ZD9331 was determined from a Phase I dose-escalation study [20]. In this two-stage dose escalation study, dose-limiting toxicity was observed in 3 of 5 patients entered at a dose of 162.5 mg/m2. The maximum tolerated dose was therefore defined as 130 mg/m2 and a dose of 130 mg/m2 administered as a single 30-min iv infusion on Days 1 and 8 of a 3-week cycle was recommended for further studies [20]. The demographic characteristics of the patient population were in line with that seen in clinical practice. Over 70% of patients had received ⱖ3 chemotherapy regimens and the population can therefore be considered heavily pretreated. In particular, two patients received ZD9331 as their eighth-line treatment. Moreover, 85% of patients were either refractory or resistant to their most recent platinum regimen. The results from the primary efficacy endpoint of objective tumor response and the secondary efficacy endpoints of time to progression and disease control provide limited evidence for the clinical activity of ZD9331 in ovarian cancer. ZD9331 demonstrated activity in three patients, if activity is defined as the number of patients showing an objective response. Overall, the objective tumor response rate appeared similar in platinum-refractory and platinumresistant patients, although because of the small number of responders in the study, it is difficult to draw firm conclusions. It is possible that in a less heavily pretreated population higher response rates may be observed. However, a CR was achieved in a platinum-resistant patient who received ZD9331 as her eighth-line treatment, and PRs were noted in two patients (one platinum-refractory and one platinum-resistant) where ZD9331 was fifth-line treatment. Although the majority of patients experienced AEs, only a small proportion of patients (14%) had to be withdrawn from the study due to these events. In line with findings from earlier studies, the most common drug-related AEs were nausea, vomiting, and myelosuppression. Other agents that have been investigated in the secondand third-line treatment of advanced ovarian cancer include paclitaxel, topotecan, and gemcitabine. Results from these studies have been variable and are difficult to compare with the present study, due to the differences in previous treat-

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ments and patient populations included in the studies. However, data from some of the most similar second-/third-line studies are summarized below. In a small study of 28 patients receiving third-line or greater treatment with a weekly paclitaxel regimen for platinum- and/or paclitaxel-resistant ovarian cancer, an objective response rate of 50% was observed [25]. However, in a large randomized crossover study of paclitaxel and topotecan in patients who had progressed following one platinum-based regimen, response rates were lower. In this study, 10% of patients receiving paclitaxel as third-line treatment and 13% of those receiving topotecan experienced objective responses, although longterm survival remained poor [26]. Paclitaxel has been combined with doxorubicin in the treatment of patients with ovarian cancer refractory to cisplatin-cyclophosphamide in an attempt to improve response rate and survival. In a study of 23 patients, 33% achieved objective responses on this regimen; however, median survival was not improved, being 15.5 months in this population [27]. In other studies using topotecan as a treatment for relapsed ovarian cancer response rates ranged between 19 and 33% in platinum-sensitive patients, 14 –18% in platinumresistant patients, and 5–11% in platinum-refractory patients [28]. In a small retrospective analysis, including 34 patients receiving gemcitabine (22 second-line, 11 thirdline, and 1 fourth-line) following surgery and platinum plus paclitaxel-based therapy, objective responses were seen in 27% of patients; however the progression-free interval was short in these patients [29]. Although the response rates in the aforementioned studies may appear higher than those reported here, it should be noted that in addition to being refractory or resistant to platinum and paclitaxel the patients included in our study were possibly a more difficult-to-treat population, also being resistant or intolerant to topotecan. In conclusion, the preliminary evidence of efficacy and acceptable tolerability obtained with ZD9331 in this heavily pretreated population with ovarian cancer warrants further investigation, especially in less heavily pretreated patients.

Acknowledgments We acknowledge the following investigators for their involvement in the trial: Dr. F.A. Bailey (Birmingham, AL), Dr. S.A. Cannistra (Boston, MA), Dr. L.F. Carson (Minneapolis, MN), Dr. J.A. Chapman (Kansas City, KA), Dr. D.L. Clarke-Pearson (Durham, NC), Dr. R.W. Holloway, (Orlando, FL), Dr. A.J. Jacobs (New York, NY), Dr. M.-S. Kao (St. Louis, MO), Dr. J.H. Malfetano (Albany, NY), Dr. M.R. Moore (Atlanta, GA), Dr. W.A. Peters III (Seattle, WA), Dr. S.R. Poliakoff (Miami Beach, FL), Dr. J.L. Powell (Wilmington, NC), Dr. S.E. Sightler (Baton Rouge, LA), Dr. D.L. Spitz (West Palm Beach, FL), Dr. G. Abdulhay (Allentown, PA), Dr. M.A. Finan (New Orleans, LA), Dr. I. Wiznitzer (Skokie, IL). Supported by a grant from AstraZeneca.

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