Multicenter, Randomized Phase II Trial of Oral CI-1033 for Previously Treated Advanced Ovarian Cancer
http://www.100md.com
《临床肿瘤学》
the Dana Farber Cancer Institute
Massachusetts General Hospital, Boston, MA
Hamilton Cancer Center, Hamilton, Ontario, Canada
Loyola University Medical Center, Chicago, IL
Pavillon L'Hotel-Dieu de Quebec, Quebec City
Princess Margaret Hospital, Canada
ABSTRACT
PURPOSE: To evaluate the antitumor activity and toxicity of two doses of CI-1033 in patients with platinum-refractory or recurrent ovarian cancer, and to determine baseline expression of epidermal growth factor receptor in tumor cells.
PATIENTS AND METHODS: This phase II, open-label clinical trial evaluated CI-1033 in patients with ovarian cancer who failed prior platinum-based therapy. Two oral doses of CI-1033 were evaluated—a 50-mg and a 200-mg oral dose administered daily for 21 days in a 28-day cycle. Patients were evaluated for tumor response and toxicity; in addition, archival baseline tumor samples were analyzed by immunohistochemistry for erbB1 to erbB4 status.
RESULTS: One hundred five eligible patients were treated. Baseline demographic characteristics were balanced in this heavily pretreated patient population. The median number of prior chemotherapy regimens received was four. The most commonly encountered drug-related adverse events for both dose arms were gastrointestinal (diarrhea, nausea, stomatitis) toxicity, asthenia, and rash. No responses were observed. Stable disease was confirmed in 34% and 26% of patients in the 200-mg and 50-mg arms, respectively, and 1-year survival rates were 38.5% and 37.7%, respectively. Baseline erbB3 and erbB4 revealed the highest frequencies of expression, while erbB2 was the lowest.
CONCLUSION: CI-1033 did not show activity in unscreened patients with advanced ovarian cancer. At 50 mg/d, CI-1033 had a more favorable adverse events profile than at 200 mg/d. erbB3 and erbB4 receptors showed the highest expression in tumor samples while erbB2 revealed the least. There appears to be no association between baseline erbB expression and disease stability.
INTRODUCTION
Cancer of the ovaries represents the leading cause of death from gynecologic malignancies, and despite advances in treatment, more than 80% of patients with stage III or IV disease die within 5 years.1 Therapy for advanced ovarian cancer usually consists of surgery followed by a platinum-based chemotherapy regimen, and although most patients respond initially, the majority2,3 relapse and die from progressive disease. Several nonplatinum agents have demonstrated activity in the treatment of recurrent tumor; however, response rates have only been in the 10% to 30% range, with modest duration.4 The discovery and development of anticancer therapies with novel mechanisms of action and their subsequent incorporation into combination regimens should improve outcome in this malignancy. CI-1033, an orally available pan-erbB inhibitor, represents one such novel agent.
CI-1033 is a 4-anilinoquinazoline that acts directly with the adenosine triphosphate binding site of the erbB receptor family member (erbB1 [epidermal growth factor receptor {EGFr}], erbB2 [HER-2/neu], erbB3, and erbB4), resulting in irreversible inhibition of the activation of these receptors and their downstream mitogenic signaling pathways. Overexpression of one or more members of the erbB receptor family of proto-oncogenes occurs with high frequency in human nonhematologic malignancies and has been shown to be a negative prognostic factor associated with more aggressive disease in solid tumors, including ovarian cancer.5-8 erbB1 and erbB2/HER2 receptors have been studied in ovarian cancer. Approximately 30% to 75% of ovarian cancer patients have tumor that overexpress the erbB1 receptor, and 20% to 32% overexpress the erbB2 receptor.9,10 The role of erbB3 and erbB4 receptors in ovarian cancer is less clear, however, clinical studies have demonstrated that overexpression and/or mutation of the erbB3 receptor correlates with a shorter length of survival in ovarian cancer patients.11
In preclinical studies, CI-1033 has been shown to have anticancer activity in vivo against a wide variety of tumor models, including the ovarian cell line SK-OV-3.12 Orally administered CI-1033 has been evaluated in phase I clinical studies in patients with advanced solid tumors.13-16 The maximum-tolerated dose was 220 mg administered daily for 28 days in a 35-day cycle. The most common toxicities were considered mild to moderate in severity and included nausea, vomiting, diarrhea, rash, and stomatitis. About a third of the patients achieved stable disease in a variety of nonhematologic tumor types, including patients with ovarian cancer.
Thus, we elected to initiate a phase II, multicenter, open-label study in North America to investigate the antitumor activity and safety of two doses of CI-1033 in patients with advanced ovarian cancer whose tumors progressed following platinum-based chemotherapy. The 200-mg dose selected is a dose level below the maximum tolerated dose of 220 mg achieved in a phase I trial, and the 50-mg dose selected was the lowest dose in which efficacy was noted from phase I.13 The doses are well above the observed 2-mg dose, in which significant tumor erbB phosphorylation inhibition occurred in phase I tumor samples.
PATIENTS AND METHODS
Study Population
Patients were required to have histologically or cytologically confirmed epithelial ovarian cancer, measurable lesions of at least 2 cm, and have either failed or relapsed (progressed after 6 months) following a platinum-based chemotherapy regimen. Further eligibility requirements were age 18 years; Karnofsky performance status (KPS) of 60 and estimated life expectancy of 3 months; adequate bone marrow, renal, and hepatic function; and a time lapse of 4 weeks from prior cancer therapy. Patients were excluded if they had any of the following: tumor arising from the genital tract other than the ovaries, clinically significant cardiovascular disease, known malabsorption syndrome, previous chemotherapy, radiation or surgery to the metastatic site within 4 weeks of baseline, or a diagnosis of another malignancy within 5 years of study enrollment (except adequately treated carcinoma-in-situ of the cervix or nonmelanomatous skin cancer). Pregnant or lactating women were also excluded. Institutional review boards at each participating site approved the protocol, and informed consent documentation was obtained from each patient.
Pretreatment evaluation included a medical history and physical examination, CBC, differential and platelet count, serum chemistries and coagulation profile, abdominopelvic imaging scan or pelvic examination, chest x-ray, ECG, and ejection fraction evaluation with either multigated acquisition (MUGA) or echocardiogram (ECHO). Follow-up studies included physical examinations, CBCs, differential and platelet counts, serum chemistries, ECHO or MUGA, and imaging procedures or pelvic examinations (every 8 weeks).
Original diagnostic tumor specimens or other more recent tumor tissue biopsy material, if available, were collected either as paraffin-imbedded tissue or unstained slides. These materials were assessed for levels of erbB1 to erbB4 by quantitative immunohistochemistry (IHC) methods.
Treatment
Pfizer Global Research and Development, Ann Arbor Laboratories, supplied CI-1033 in 5- and 50-mg capsules. Patients were randomly assigned to receive either a 50-mg or 200-mg daily dose for 21 days in a 28-day cycle. Dose reductions in increments of 25 mg in the 200-mg arm, and 10 mg in the 50-mg arm were allowed if the patient developed any grade 4 hematologic toxicity or grade 3 nonhematolgoic toxicity or other intolerable toxicities, at the discretion of the treating investigator.
Random assignment was further stratified by number of prior chemotherapy regimens (1 v 2) and progression-free interval following platinum-based chemotherapy (< 6 v 6 months).
Response and Toxicity Criteria
Response Evaluation Criteria in Solid Tumors (RECIST)17 were used to evaluate antitumor response. A complete response (CR) was defined as complete disappearance of all measurable and assessable disease, no new lesions, no disease-related symptoms, and no evidence of nonassessable disease maintained for at least 4 weeks. A partial response (PR) was defined as a decrease of 30% in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD, and no unequivocal progression of nontarget lesions maintained for 4 weeks. Progression of disease (PD) was defined as an increase of 20% in the sum of the LD of the target lesions from the smallest sum LD recorded since the beginning of therapy or the appearance of one or more new lesions or unequivocal progression of existing nontarget lesions. Patients with stable disease (SD) were those not meeting the criteria for CR, PR, or PD during the first 8 weeks after the start of treatment. Toxicities were assessed according to the National Cancer Institute Common Toxicity Criteria, version 2.0.
Statistical Methods and Study Design
This open-label, single-agent, multicenter study evaluated two dose levels of CI-1033. Efficacy parameters included 1-year progression-free survival (PFS) rate, overall response rate, duration of overall response, and survival. No statistical comparisons between treatment arms were made. Based on binomial distribution, a target sample size of 45 patients per treatment group gives a 90% power to detect a difference between 5% and 20% 1-year PFS rate, assuming a one-sided type I error rate of 5%.
Assessment of Biomarkers
A centralized reference laboratory (IMPATH Inc, Los Angeles, CA) performed IHC staining and analysis on formalin-fixed paraffin-embedded specimens using histopathologic semiquantitaive scale and the H-score method to assess erbB markers. Fifty-six archival tumor samples were analyzed. Samples were tested for erbB1, erbB2, erbB3, and erbB4.
Expression was assessed using a standard histopathologic semiquantitative scale that scored staining as 0 (absent staining), 1 + (slight staining in at least 10% of cells), 2 + (moderate staining in at least 10% of cells), or 3 + (marked staining in at least 10% of cells). In addition, the H-score method18 was also used to demonstrate expression and calculated based on the total number of malignant cells in each field and the number of cells stained at each intensity. The average percentage positive was calculated, and the following formula was applied:
An H-score between 0 and 300 was obtained, where 300 was equal to 100% of tumor cells stained strongly (3+).
RESULTS
Patients
Fifty-three and fifty-two patients with platinum-refractory or recurrent ovarian cancer or primary peritoneal cancer were randomly assigned to the 50-mg and 200-mg groups, respectively, between December 2001 and May 2002. Rapid accrual of patients in this multicenter study accounted for overenrollment. All 105 patients were assessable for safety. Two patients in the 200-mg arm with unknown primary disease were not assessed for efficacy.
The baseline characteristics of the 105 patients randomly assigned to the study are presented in Table 1. The groups were well balanced for age, menopausal status, race, performance status, previous therapy, and primary tumor site. The median KPS was 90. More than 75% of patients had advanced disease at baseline (International Federation of Gynecology and Obstetrics [FIGO] stage III or IV), and approximately 85% of patients had received two or more previous chemotherapy regimens.
Extent of Exposure
A total of 146 cycles were administered to the 53 patients treated in the 50-mg arm, and 138 cycles were given to the patients treated in the 200-mg arm. The median number of cycles in each arm was two (50-mg range, 1 to 12 cycles; 200-mg range, 1 to 18 cycles). Details of exposure to study treatment are given in Table 2.
Efficacy
Time to progression and duration of survival are shown in Figure 1. The 1-year PFS was 0.0% in the 50-mg treatment group and 9.0% (95% CI, 2.4 to 21.1) in the 200-mg group. Censoring occurred in each treatment group (nine and 14 patients in the 50-mg and 200-mg treatment groups, respectively) due to patients who withdrew from the study before progressing. The median survival was 252 days (95% CI, 197 to 380) for the 50-mg group and 274 days (95% CI, 200 to 386) for the 200-mg group (Fig 1). The 1-year survival rate was 37.7% (95% CI, 25.1 to 50.3) and 38.5% (95% CI, 25.7 to 51.1) for the 50-mg and 200-mg groups, respectively.
No CRs or PRs were observed (Table 2). Twenty-six percent and 34% percent of patients at 8 weeks, and 7.5% and 14.0% of patients at 16 weeks had SD in the 50-mg and 200-mg treatment groups, respectively.
Patients were stratified based on the number of prior chemotherapy regimens received for their ovarian cancer (1 v 2) and progression-free interval following prior platinum therapy (< 6 v 6 months), and an analysis of these subgroups was conducted. Combined, the treatment groups demonstrated a proportionally poorer 1-year survival rates as the number of prior chemotherapy exposure increased. Overall, a clinically significant difference in 1-year survival was observed, estimates were 52%, 48%, and 42% in patients who received one, two, or three prior regimens, respectively. In addition, a clinically significance difference in 1-year survival of 37% was noted in patients who progressed within 6-months of prior platinum treatment, versus 42% in patients who had a duration of response of 6 months before progression following prior platinum treatment.
Toxicity
Adverse events (AEs) deemed at least possibly related to CI-1033 by the investigators are described. Clinically significant differences in toxicities between the two doses were observed. Overall, the percentages of patients reporting AEs and serious AEs were higher in the 200-mg treatment group than in the 50-mg treatment group. In addition, patients treated in the 200-mg treatment group had a higher observed incidence of grade 3 AEs (36 patients; 69.2%) compared with the 50-mg treatment group (16 patients; 30.2%). Only one patient (1.9%) in each dose arm reported drug-associated toxicity of grade 4 severity. The most commonly reported toxicities observed for patients in the 200-mg treatment group were stomatitis, diarrhea, rash, nausea, and vomiting, and for patients in the 50-mg treatment group, toxicities included diarrhea, nausea, asthenia, rash, and stomatitis (Table 3).
Fourteen patients (26.9%) in the 200-mg arm and 11 patients (20.8%) in the 50-mg arm discontinued treatment due to AEs; approximately half were due to a drug-associated toxicity. Across both treatment groups, the most frequent AEs leading to discontinuation were diarrhea, asthenia, and abdominal pain.
While deaths due to PD were reported, two patients died during the study due to an AE. One patient on the 50-mg treatment group had extensive metastasis to the liver, peritoneum, pelvic sidewall, and omentum at baseline, and was admitted to the hospital on day 18 with diarrhea, severe tenesmus, and chills. Based on further examination, the patient showed diffuse inflammatory changes in the abdomen and appearance consistent with bowel erosion by metastatic disease, perforation, and superinfection. The patient's condition deteriorated; the patient died on study day 19. In the opinion of the investigator, the patient's death was due to the diarrhea, sepsis, and bowel perforation, which were possibly related to CI-1033. One patient in the 200-mg treatment group died due to sepsis on day 68, considered by the investigator to be unrelated to CI-1033.
There were no reports of drug-related increase in serum creatinine or liver transaminases during treatment, nor were there any changes in pulmonary function or significant decrease in ejection fraction. Sixteen and thirteen patients in the 50-mg and 200-mg arms, respectively, had a baseline and end-of-treatment evaluation of left ventricular ejection fraction (LVEF). Only one patient, randomly assigned to the 200-mg arm, had a decrease in LVEF to below 50% (baseline = 60% and end of treatment = 49%); however, the interpretation of this result is confounded by the fact that ECHO was used for the baseline assessment, and MUGA, for the end-of-treatment assessment. In the 50-mg cohort, four patients had an asymptomatic decrease of 10% in LVEF. One patient who had a decline from 73% to 58% had an intervening myocardial infarction between the two LVEF assessments. In the 200-mg arm, three patients were noted to have asymptomatic decreases of 10% in LVEF.
Dose Reductions
Twenty-six patients (49.1%) in the 200-mg treatment group required at least one dose reduction. Toxicities requiring dose reductions included gastrointestinal side effects (diarrhea, vomiting, and mucositis), rash/acne, and asthenia. No patients required dose reductions in the 50-mg treatment group.
Biomarkers
An important concept in the development of targeted therapies is the activation status of the targeted pathway. It is expected that in order to have a meaningful therapeutic effect, tumor cells must rely on the pathway targeted, and therefore have evidence of signaling through that pathway. Therefore, we evaluated the level of expression of all four subtypes of erbB in patients' archived tumor samples. A total of 56 archival tumor samples were analyzed for IHC expression of erbB1 to erbB4 by a centralized reference laboratory (Fig 2). As shown, erbB3 exhibited the highest frequency of positive erbB status, 2+ or 3+ (41 of 56 samples), while erbB2 demonstrated the lowest expression (two of 54 samples), and erbB4 demonstrated the next most frequent expression, with 25 samples showing at least 2+ staining.
In addition, 49 of 54 samples showed multiple receptor expression (Fig 3), with the erbB3 subreceptor demonstrating the most frequently expressed subreceptor in combination with other erbB receptors. Furthermore, 50% of the samples had simultaneous expression of at least three receptors, with the erbB3 subreceptor again being the most frequently expressed. There was no relationship between tumor expression of any of the subtypes of erbB receptors and disease stabilization, or overall survival.
DISCUSSION
This multicenter, randomized trial conducted in North America evaluated the efficacy and safety of daily oral doses of 50 mg and 200 mg of CI-1033 administered for 21 days in a 28-day cycle in patients with advanced ovarian cancer. A major aim of the study was to identify the optimal dose for patients in this setting. In the 49 patients analyzed for efficacy and treated with CI-1033 at 200 mg/d, the SD rate was 34%, median PFS was 2.2 months, and median overall survival was 9.1 months. Although there were no CRs or PRs, the rate of SD and the median PFS were similar to results in other trials of tyrosine kinase inhibitors in advanced ovarian cancer. Bookman et al,19 evaluated trastuzumab, an erbB2/HER2 inhibitor, in patients with recurrent or refractory ovarian carcinoma who expressed HER2 and reported a response rate (RR) of 7.3%, SD of 39%, and median PFS of 2.0 months. Similarly, Schilder et al20 noted minimal activity of gefitinib, an erbB1 inhibitor given to patients with recurrent ovarian cancer, and reported an RR of 6.7% and a 6-month progression-free interval of 15%. A phase II evaluation of OSI-774 (an oral antagonist of EGFR-TK) in patients with advanced ovarian carcinoma who were refractory to taxane and/or platinum, was presented at the 2001 Annual Meeting of the American Society of Clinical Oncology.21 Thirty-four patients received the drug, with three patients (9%) evaluated as having a PR and three (9%) as having SD after 8 weeks of treatment.
In our findings in this heavily pretreated patient population, a median survival of 9 months is comparable to that seen for other cytotoxic agents. For example, Bookman et al22 reported a median survival of 47 weeks with the use of topotecan for the treatment of advanced epithelial ovarian cancer. Likewise, Rose et al23 reported with etoposide a median survival of 10.8 months in patients with platinum-sensitive and refractory disease.
With respect to safety, drug-related AEs were similar in type of reaction for both doses and consisted mainly of GI toxicities, skin reaction, and asthenia, but the incidence of AEs, dose modification, and withdrawal was significantly lower in the 50-mg/d group than in the 200-mg/d group. In particular, GI toxicity in the higher dose was pronounced compared with the lower dose, and was the most likely cause for dose reduction.
Because CI-1033 targets all four members of the erbB family, including erbB2, there is at least a theoretical possibility that it, too, may be associated with an increased risk of cardiac toxicity, as has been reported with trastuzumab.24 Although some patients have been noted to experience asymptomatic decreases in LVEF after treatment with CI-1033, the significance of these findings remains to be seen given the limitations of the experimental conditions and the techniques employed. It should be noted that there was no evidence of cardiac muscle damage seen in the preclinical toxicology studies of CI-1033.
Overall, the 200-mg/d dose may have had a slightly better SD rate, time to progression, and 1-year survival, but it was much less tolerated than the 50-mg/d dose. Although the differences between the two doses were not considered to be clinically significant, results from phase I studies with CI-1033 in solid tumor have suggested a dose response correlation with efficacy at doses higher than the 200-mg/d as presented in this study, suggesting that a higher but intolerable dose may be needed to achieve adequate response.
Baseline tumor biopsies were not required for testing of erbB expression in this study. Instead, archived tumor specimens available from either an original diagnostic or, preferably, a more recent biopsy, were assessed. Expression levels of erbB were assessed in these specimens for investigation for possible associations with antitumor response. While expression levels of markers could not be assumed to reflect baseline expression at the time of CI-1033 treatment, we reasoned that observing an association, nonetheless with antitumor outcome, could provide a useful and efficient method of screening patients for target enrichment purposes in future studies.
Baseline tumor samples in this study revealed high expression of erbB3 and erbB4 and low expression of erbB1 and erbB2. Overall, 73% and 45% of samples showed 2+ or 3+ erbB3 and erbB4 expression, respectively, and only 27% and 3.5% of tumor samples exhibited erbB1 and erbB2 expression, respectively. Similar erbB2 expression data in ovarian tissue have been reported.19 In addition, multiple subreceptor expression was noted in 78% of tumor cells, with erbB3 showing it to be the most frequently expressed subreceptor when in combination with other receptors.
The clinical application of epidermal growth factor receptor inhibitors in the management of ovarian cancer poses both challenges and opportunities. Studies that predate the current study have also yielded underwhelming results. One conclusion might be that given such poor response rates, these agents will have a limited role in the management of ovarian cancer. However, despite a dismal showing there are several points to consider. Patients enrolled onto these studies have generally had advanced refractory disease. In the current study, more than 85% of the patients studied had more than two prior regimens, while 53% to 55% of patients had more than four prior regimens. In all, a heavily pretreated population constituted the majority of patients in this trial. Of interest would be the application of such compounds in low-volume or marker-only (elevated CA125) recurrent disease.
Extrapolating from the data utilizing trastuzumab and cytotoxic therapy, the combination of chemotherapy and epidermal growth factor receptor inhibitors may result in synergistic interaction. It is important to note that there are varied responses with such combinations. Two large trials have been completed in chemotherapy-naive patients with stage III and IV non–small-cell lung cancer, noting that the addition of ZD1839 did not demonstrate any increase in tumor response rates, time to progression, or overall survival beyond that of chemotherapy alone.25
Nevertheless, given the well-documented pathway interactions (ie, crosstalk) that regulate apoptosis and metastasis, targeting several of the critical pathways may enhance the role of these agents. Several studies are currently examining the cooperative inhibitory effect of small molecules directed at the epidermal growth factor receptor, with monoclonal antibodies directed against HER2. Novel compounds are currently being explored that block the association of HER2 with other members of the EGFR family, the result being inhibition of two major signal pathways, MAP kinase and PI3 kinase.
Future studies should concentrate on the identification of markers that predict response to EGFR inhibitors. They should incorporate analysis of EGFR expression, levels of phosphorylated MAP kinases and active AKT. Gene expression profiling may also identify predictors of response to this class of compounds.
Although the common tendency is to enroll advanced patients in trials with novel compounds, we are faced with agents that might best serve a different population. One option would be to consider these agents as maintenance therapy after initial therapy in patients that are in a complete clinical remission. Currently, there are protocols aimed at describing the role of these agents in small-volume disease or in patients with an asymptomatic rise in CA125.
Additionally, careful attention to clinical design, with appropriate end points and eligibility criteria, will eventually define the role of these agents in the management of patients with these malignancies. Although CA125 was collected in this study, response was not defined according to the serum CA125. Recent reports by Grolund et al have suggested that the CA125 response criteria are better prognostic tools than RECIST in patients with recurrent disease. Future trials, given these recent data, may revisit their response evaluation methods.26
In summary, this study demonstrated that CI-1033 given as single agent had no clinically relevant activity in a heavily pretreated patient population with ovarian cancer. The 50-mg/d dose had a more favorable safety profile and better tolerability than the 200-mg/d dose, and the majority of baseline tumor samples expressed at least one type of erbB receptor, with the erbB3 and erbB4 subreceptors showing the highest frequency of overexpression, and the erbB2 showing the least.
Authors' Disclosures of Potential Conflicts of Interest
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Acknowledgment
We acknowledge the assistance of Xin Huang and Jeff Robbins for statistical analysis, the nurses for patient care, and data managers for study coordination.
NOTES
Supported by Pfizer Global Research and Development, Department of Clinical Oncology, Ann Arbor, MI.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Massachusetts General Hospital, Boston, MA
Hamilton Cancer Center, Hamilton, Ontario, Canada
Loyola University Medical Center, Chicago, IL
Pavillon L'Hotel-Dieu de Quebec, Quebec City
Princess Margaret Hospital, Canada
ABSTRACT
PURPOSE: To evaluate the antitumor activity and toxicity of two doses of CI-1033 in patients with platinum-refractory or recurrent ovarian cancer, and to determine baseline expression of epidermal growth factor receptor in tumor cells.
PATIENTS AND METHODS: This phase II, open-label clinical trial evaluated CI-1033 in patients with ovarian cancer who failed prior platinum-based therapy. Two oral doses of CI-1033 were evaluated—a 50-mg and a 200-mg oral dose administered daily for 21 days in a 28-day cycle. Patients were evaluated for tumor response and toxicity; in addition, archival baseline tumor samples were analyzed by immunohistochemistry for erbB1 to erbB4 status.
RESULTS: One hundred five eligible patients were treated. Baseline demographic characteristics were balanced in this heavily pretreated patient population. The median number of prior chemotherapy regimens received was four. The most commonly encountered drug-related adverse events for both dose arms were gastrointestinal (diarrhea, nausea, stomatitis) toxicity, asthenia, and rash. No responses were observed. Stable disease was confirmed in 34% and 26% of patients in the 200-mg and 50-mg arms, respectively, and 1-year survival rates were 38.5% and 37.7%, respectively. Baseline erbB3 and erbB4 revealed the highest frequencies of expression, while erbB2 was the lowest.
CONCLUSION: CI-1033 did not show activity in unscreened patients with advanced ovarian cancer. At 50 mg/d, CI-1033 had a more favorable adverse events profile than at 200 mg/d. erbB3 and erbB4 receptors showed the highest expression in tumor samples while erbB2 revealed the least. There appears to be no association between baseline erbB expression and disease stability.
INTRODUCTION
Cancer of the ovaries represents the leading cause of death from gynecologic malignancies, and despite advances in treatment, more than 80% of patients with stage III or IV disease die within 5 years.1 Therapy for advanced ovarian cancer usually consists of surgery followed by a platinum-based chemotherapy regimen, and although most patients respond initially, the majority2,3 relapse and die from progressive disease. Several nonplatinum agents have demonstrated activity in the treatment of recurrent tumor; however, response rates have only been in the 10% to 30% range, with modest duration.4 The discovery and development of anticancer therapies with novel mechanisms of action and their subsequent incorporation into combination regimens should improve outcome in this malignancy. CI-1033, an orally available pan-erbB inhibitor, represents one such novel agent.
CI-1033 is a 4-anilinoquinazoline that acts directly with the adenosine triphosphate binding site of the erbB receptor family member (erbB1 [epidermal growth factor receptor {EGFr}], erbB2 [HER-2/neu], erbB3, and erbB4), resulting in irreversible inhibition of the activation of these receptors and their downstream mitogenic signaling pathways. Overexpression of one or more members of the erbB receptor family of proto-oncogenes occurs with high frequency in human nonhematologic malignancies and has been shown to be a negative prognostic factor associated with more aggressive disease in solid tumors, including ovarian cancer.5-8 erbB1 and erbB2/HER2 receptors have been studied in ovarian cancer. Approximately 30% to 75% of ovarian cancer patients have tumor that overexpress the erbB1 receptor, and 20% to 32% overexpress the erbB2 receptor.9,10 The role of erbB3 and erbB4 receptors in ovarian cancer is less clear, however, clinical studies have demonstrated that overexpression and/or mutation of the erbB3 receptor correlates with a shorter length of survival in ovarian cancer patients.11
In preclinical studies, CI-1033 has been shown to have anticancer activity in vivo against a wide variety of tumor models, including the ovarian cell line SK-OV-3.12 Orally administered CI-1033 has been evaluated in phase I clinical studies in patients with advanced solid tumors.13-16 The maximum-tolerated dose was 220 mg administered daily for 28 days in a 35-day cycle. The most common toxicities were considered mild to moderate in severity and included nausea, vomiting, diarrhea, rash, and stomatitis. About a third of the patients achieved stable disease in a variety of nonhematologic tumor types, including patients with ovarian cancer.
Thus, we elected to initiate a phase II, multicenter, open-label study in North America to investigate the antitumor activity and safety of two doses of CI-1033 in patients with advanced ovarian cancer whose tumors progressed following platinum-based chemotherapy. The 200-mg dose selected is a dose level below the maximum tolerated dose of 220 mg achieved in a phase I trial, and the 50-mg dose selected was the lowest dose in which efficacy was noted from phase I.13 The doses are well above the observed 2-mg dose, in which significant tumor erbB phosphorylation inhibition occurred in phase I tumor samples.
PATIENTS AND METHODS
Study Population
Patients were required to have histologically or cytologically confirmed epithelial ovarian cancer, measurable lesions of at least 2 cm, and have either failed or relapsed (progressed after 6 months) following a platinum-based chemotherapy regimen. Further eligibility requirements were age 18 years; Karnofsky performance status (KPS) of 60 and estimated life expectancy of 3 months; adequate bone marrow, renal, and hepatic function; and a time lapse of 4 weeks from prior cancer therapy. Patients were excluded if they had any of the following: tumor arising from the genital tract other than the ovaries, clinically significant cardiovascular disease, known malabsorption syndrome, previous chemotherapy, radiation or surgery to the metastatic site within 4 weeks of baseline, or a diagnosis of another malignancy within 5 years of study enrollment (except adequately treated carcinoma-in-situ of the cervix or nonmelanomatous skin cancer). Pregnant or lactating women were also excluded. Institutional review boards at each participating site approved the protocol, and informed consent documentation was obtained from each patient.
Pretreatment evaluation included a medical history and physical examination, CBC, differential and platelet count, serum chemistries and coagulation profile, abdominopelvic imaging scan or pelvic examination, chest x-ray, ECG, and ejection fraction evaluation with either multigated acquisition (MUGA) or echocardiogram (ECHO). Follow-up studies included physical examinations, CBCs, differential and platelet counts, serum chemistries, ECHO or MUGA, and imaging procedures or pelvic examinations (every 8 weeks).
Original diagnostic tumor specimens or other more recent tumor tissue biopsy material, if available, were collected either as paraffin-imbedded tissue or unstained slides. These materials were assessed for levels of erbB1 to erbB4 by quantitative immunohistochemistry (IHC) methods.
Treatment
Pfizer Global Research and Development, Ann Arbor Laboratories, supplied CI-1033 in 5- and 50-mg capsules. Patients were randomly assigned to receive either a 50-mg or 200-mg daily dose for 21 days in a 28-day cycle. Dose reductions in increments of 25 mg in the 200-mg arm, and 10 mg in the 50-mg arm were allowed if the patient developed any grade 4 hematologic toxicity or grade 3 nonhematolgoic toxicity or other intolerable toxicities, at the discretion of the treating investigator.
Random assignment was further stratified by number of prior chemotherapy regimens (1 v 2) and progression-free interval following platinum-based chemotherapy (< 6 v 6 months).
Response and Toxicity Criteria
Response Evaluation Criteria in Solid Tumors (RECIST)17 were used to evaluate antitumor response. A complete response (CR) was defined as complete disappearance of all measurable and assessable disease, no new lesions, no disease-related symptoms, and no evidence of nonassessable disease maintained for at least 4 weeks. A partial response (PR) was defined as a decrease of 30% in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD, and no unequivocal progression of nontarget lesions maintained for 4 weeks. Progression of disease (PD) was defined as an increase of 20% in the sum of the LD of the target lesions from the smallest sum LD recorded since the beginning of therapy or the appearance of one or more new lesions or unequivocal progression of existing nontarget lesions. Patients with stable disease (SD) were those not meeting the criteria for CR, PR, or PD during the first 8 weeks after the start of treatment. Toxicities were assessed according to the National Cancer Institute Common Toxicity Criteria, version 2.0.
Statistical Methods and Study Design
This open-label, single-agent, multicenter study evaluated two dose levels of CI-1033. Efficacy parameters included 1-year progression-free survival (PFS) rate, overall response rate, duration of overall response, and survival. No statistical comparisons between treatment arms were made. Based on binomial distribution, a target sample size of 45 patients per treatment group gives a 90% power to detect a difference between 5% and 20% 1-year PFS rate, assuming a one-sided type I error rate of 5%.
Assessment of Biomarkers
A centralized reference laboratory (IMPATH Inc, Los Angeles, CA) performed IHC staining and analysis on formalin-fixed paraffin-embedded specimens using histopathologic semiquantitaive scale and the H-score method to assess erbB markers. Fifty-six archival tumor samples were analyzed. Samples were tested for erbB1, erbB2, erbB3, and erbB4.
Expression was assessed using a standard histopathologic semiquantitative scale that scored staining as 0 (absent staining), 1 + (slight staining in at least 10% of cells), 2 + (moderate staining in at least 10% of cells), or 3 + (marked staining in at least 10% of cells). In addition, the H-score method18 was also used to demonstrate expression and calculated based on the total number of malignant cells in each field and the number of cells stained at each intensity. The average percentage positive was calculated, and the following formula was applied:
An H-score between 0 and 300 was obtained, where 300 was equal to 100% of tumor cells stained strongly (3+).
RESULTS
Patients
Fifty-three and fifty-two patients with platinum-refractory or recurrent ovarian cancer or primary peritoneal cancer were randomly assigned to the 50-mg and 200-mg groups, respectively, between December 2001 and May 2002. Rapid accrual of patients in this multicenter study accounted for overenrollment. All 105 patients were assessable for safety. Two patients in the 200-mg arm with unknown primary disease were not assessed for efficacy.
The baseline characteristics of the 105 patients randomly assigned to the study are presented in Table 1. The groups were well balanced for age, menopausal status, race, performance status, previous therapy, and primary tumor site. The median KPS was 90. More than 75% of patients had advanced disease at baseline (International Federation of Gynecology and Obstetrics [FIGO] stage III or IV), and approximately 85% of patients had received two or more previous chemotherapy regimens.
Extent of Exposure
A total of 146 cycles were administered to the 53 patients treated in the 50-mg arm, and 138 cycles were given to the patients treated in the 200-mg arm. The median number of cycles in each arm was two (50-mg range, 1 to 12 cycles; 200-mg range, 1 to 18 cycles). Details of exposure to study treatment are given in Table 2.
Efficacy
Time to progression and duration of survival are shown in Figure 1. The 1-year PFS was 0.0% in the 50-mg treatment group and 9.0% (95% CI, 2.4 to 21.1) in the 200-mg group. Censoring occurred in each treatment group (nine and 14 patients in the 50-mg and 200-mg treatment groups, respectively) due to patients who withdrew from the study before progressing. The median survival was 252 days (95% CI, 197 to 380) for the 50-mg group and 274 days (95% CI, 200 to 386) for the 200-mg group (Fig 1). The 1-year survival rate was 37.7% (95% CI, 25.1 to 50.3) and 38.5% (95% CI, 25.7 to 51.1) for the 50-mg and 200-mg groups, respectively.
No CRs or PRs were observed (Table 2). Twenty-six percent and 34% percent of patients at 8 weeks, and 7.5% and 14.0% of patients at 16 weeks had SD in the 50-mg and 200-mg treatment groups, respectively.
Patients were stratified based on the number of prior chemotherapy regimens received for their ovarian cancer (1 v 2) and progression-free interval following prior platinum therapy (< 6 v 6 months), and an analysis of these subgroups was conducted. Combined, the treatment groups demonstrated a proportionally poorer 1-year survival rates as the number of prior chemotherapy exposure increased. Overall, a clinically significant difference in 1-year survival was observed, estimates were 52%, 48%, and 42% in patients who received one, two, or three prior regimens, respectively. In addition, a clinically significance difference in 1-year survival of 37% was noted in patients who progressed within 6-months of prior platinum treatment, versus 42% in patients who had a duration of response of 6 months before progression following prior platinum treatment.
Toxicity
Adverse events (AEs) deemed at least possibly related to CI-1033 by the investigators are described. Clinically significant differences in toxicities between the two doses were observed. Overall, the percentages of patients reporting AEs and serious AEs were higher in the 200-mg treatment group than in the 50-mg treatment group. In addition, patients treated in the 200-mg treatment group had a higher observed incidence of grade 3 AEs (36 patients; 69.2%) compared with the 50-mg treatment group (16 patients; 30.2%). Only one patient (1.9%) in each dose arm reported drug-associated toxicity of grade 4 severity. The most commonly reported toxicities observed for patients in the 200-mg treatment group were stomatitis, diarrhea, rash, nausea, and vomiting, and for patients in the 50-mg treatment group, toxicities included diarrhea, nausea, asthenia, rash, and stomatitis (Table 3).
Fourteen patients (26.9%) in the 200-mg arm and 11 patients (20.8%) in the 50-mg arm discontinued treatment due to AEs; approximately half were due to a drug-associated toxicity. Across both treatment groups, the most frequent AEs leading to discontinuation were diarrhea, asthenia, and abdominal pain.
While deaths due to PD were reported, two patients died during the study due to an AE. One patient on the 50-mg treatment group had extensive metastasis to the liver, peritoneum, pelvic sidewall, and omentum at baseline, and was admitted to the hospital on day 18 with diarrhea, severe tenesmus, and chills. Based on further examination, the patient showed diffuse inflammatory changes in the abdomen and appearance consistent with bowel erosion by metastatic disease, perforation, and superinfection. The patient's condition deteriorated; the patient died on study day 19. In the opinion of the investigator, the patient's death was due to the diarrhea, sepsis, and bowel perforation, which were possibly related to CI-1033. One patient in the 200-mg treatment group died due to sepsis on day 68, considered by the investigator to be unrelated to CI-1033.
There were no reports of drug-related increase in serum creatinine or liver transaminases during treatment, nor were there any changes in pulmonary function or significant decrease in ejection fraction. Sixteen and thirteen patients in the 50-mg and 200-mg arms, respectively, had a baseline and end-of-treatment evaluation of left ventricular ejection fraction (LVEF). Only one patient, randomly assigned to the 200-mg arm, had a decrease in LVEF to below 50% (baseline = 60% and end of treatment = 49%); however, the interpretation of this result is confounded by the fact that ECHO was used for the baseline assessment, and MUGA, for the end-of-treatment assessment. In the 50-mg cohort, four patients had an asymptomatic decrease of 10% in LVEF. One patient who had a decline from 73% to 58% had an intervening myocardial infarction between the two LVEF assessments. In the 200-mg arm, three patients were noted to have asymptomatic decreases of 10% in LVEF.
Dose Reductions
Twenty-six patients (49.1%) in the 200-mg treatment group required at least one dose reduction. Toxicities requiring dose reductions included gastrointestinal side effects (diarrhea, vomiting, and mucositis), rash/acne, and asthenia. No patients required dose reductions in the 50-mg treatment group.
Biomarkers
An important concept in the development of targeted therapies is the activation status of the targeted pathway. It is expected that in order to have a meaningful therapeutic effect, tumor cells must rely on the pathway targeted, and therefore have evidence of signaling through that pathway. Therefore, we evaluated the level of expression of all four subtypes of erbB in patients' archived tumor samples. A total of 56 archival tumor samples were analyzed for IHC expression of erbB1 to erbB4 by a centralized reference laboratory (Fig 2). As shown, erbB3 exhibited the highest frequency of positive erbB status, 2+ or 3+ (41 of 56 samples), while erbB2 demonstrated the lowest expression (two of 54 samples), and erbB4 demonstrated the next most frequent expression, with 25 samples showing at least 2+ staining.
In addition, 49 of 54 samples showed multiple receptor expression (Fig 3), with the erbB3 subreceptor demonstrating the most frequently expressed subreceptor in combination with other erbB receptors. Furthermore, 50% of the samples had simultaneous expression of at least three receptors, with the erbB3 subreceptor again being the most frequently expressed. There was no relationship between tumor expression of any of the subtypes of erbB receptors and disease stabilization, or overall survival.
DISCUSSION
This multicenter, randomized trial conducted in North America evaluated the efficacy and safety of daily oral doses of 50 mg and 200 mg of CI-1033 administered for 21 days in a 28-day cycle in patients with advanced ovarian cancer. A major aim of the study was to identify the optimal dose for patients in this setting. In the 49 patients analyzed for efficacy and treated with CI-1033 at 200 mg/d, the SD rate was 34%, median PFS was 2.2 months, and median overall survival was 9.1 months. Although there were no CRs or PRs, the rate of SD and the median PFS were similar to results in other trials of tyrosine kinase inhibitors in advanced ovarian cancer. Bookman et al,19 evaluated trastuzumab, an erbB2/HER2 inhibitor, in patients with recurrent or refractory ovarian carcinoma who expressed HER2 and reported a response rate (RR) of 7.3%, SD of 39%, and median PFS of 2.0 months. Similarly, Schilder et al20 noted minimal activity of gefitinib, an erbB1 inhibitor given to patients with recurrent ovarian cancer, and reported an RR of 6.7% and a 6-month progression-free interval of 15%. A phase II evaluation of OSI-774 (an oral antagonist of EGFR-TK) in patients with advanced ovarian carcinoma who were refractory to taxane and/or platinum, was presented at the 2001 Annual Meeting of the American Society of Clinical Oncology.21 Thirty-four patients received the drug, with three patients (9%) evaluated as having a PR and three (9%) as having SD after 8 weeks of treatment.
In our findings in this heavily pretreated patient population, a median survival of 9 months is comparable to that seen for other cytotoxic agents. For example, Bookman et al22 reported a median survival of 47 weeks with the use of topotecan for the treatment of advanced epithelial ovarian cancer. Likewise, Rose et al23 reported with etoposide a median survival of 10.8 months in patients with platinum-sensitive and refractory disease.
With respect to safety, drug-related AEs were similar in type of reaction for both doses and consisted mainly of GI toxicities, skin reaction, and asthenia, but the incidence of AEs, dose modification, and withdrawal was significantly lower in the 50-mg/d group than in the 200-mg/d group. In particular, GI toxicity in the higher dose was pronounced compared with the lower dose, and was the most likely cause for dose reduction.
Because CI-1033 targets all four members of the erbB family, including erbB2, there is at least a theoretical possibility that it, too, may be associated with an increased risk of cardiac toxicity, as has been reported with trastuzumab.24 Although some patients have been noted to experience asymptomatic decreases in LVEF after treatment with CI-1033, the significance of these findings remains to be seen given the limitations of the experimental conditions and the techniques employed. It should be noted that there was no evidence of cardiac muscle damage seen in the preclinical toxicology studies of CI-1033.
Overall, the 200-mg/d dose may have had a slightly better SD rate, time to progression, and 1-year survival, but it was much less tolerated than the 50-mg/d dose. Although the differences between the two doses were not considered to be clinically significant, results from phase I studies with CI-1033 in solid tumor have suggested a dose response correlation with efficacy at doses higher than the 200-mg/d as presented in this study, suggesting that a higher but intolerable dose may be needed to achieve adequate response.
Baseline tumor biopsies were not required for testing of erbB expression in this study. Instead, archived tumor specimens available from either an original diagnostic or, preferably, a more recent biopsy, were assessed. Expression levels of erbB were assessed in these specimens for investigation for possible associations with antitumor response. While expression levels of markers could not be assumed to reflect baseline expression at the time of CI-1033 treatment, we reasoned that observing an association, nonetheless with antitumor outcome, could provide a useful and efficient method of screening patients for target enrichment purposes in future studies.
Baseline tumor samples in this study revealed high expression of erbB3 and erbB4 and low expression of erbB1 and erbB2. Overall, 73% and 45% of samples showed 2+ or 3+ erbB3 and erbB4 expression, respectively, and only 27% and 3.5% of tumor samples exhibited erbB1 and erbB2 expression, respectively. Similar erbB2 expression data in ovarian tissue have been reported.19 In addition, multiple subreceptor expression was noted in 78% of tumor cells, with erbB3 showing it to be the most frequently expressed subreceptor when in combination with other receptors.
The clinical application of epidermal growth factor receptor inhibitors in the management of ovarian cancer poses both challenges and opportunities. Studies that predate the current study have also yielded underwhelming results. One conclusion might be that given such poor response rates, these agents will have a limited role in the management of ovarian cancer. However, despite a dismal showing there are several points to consider. Patients enrolled onto these studies have generally had advanced refractory disease. In the current study, more than 85% of the patients studied had more than two prior regimens, while 53% to 55% of patients had more than four prior regimens. In all, a heavily pretreated population constituted the majority of patients in this trial. Of interest would be the application of such compounds in low-volume or marker-only (elevated CA125) recurrent disease.
Extrapolating from the data utilizing trastuzumab and cytotoxic therapy, the combination of chemotherapy and epidermal growth factor receptor inhibitors may result in synergistic interaction. It is important to note that there are varied responses with such combinations. Two large trials have been completed in chemotherapy-naive patients with stage III and IV non–small-cell lung cancer, noting that the addition of ZD1839 did not demonstrate any increase in tumor response rates, time to progression, or overall survival beyond that of chemotherapy alone.25
Nevertheless, given the well-documented pathway interactions (ie, crosstalk) that regulate apoptosis and metastasis, targeting several of the critical pathways may enhance the role of these agents. Several studies are currently examining the cooperative inhibitory effect of small molecules directed at the epidermal growth factor receptor, with monoclonal antibodies directed against HER2. Novel compounds are currently being explored that block the association of HER2 with other members of the EGFR family, the result being inhibition of two major signal pathways, MAP kinase and PI3 kinase.
Future studies should concentrate on the identification of markers that predict response to EGFR inhibitors. They should incorporate analysis of EGFR expression, levels of phosphorylated MAP kinases and active AKT. Gene expression profiling may also identify predictors of response to this class of compounds.
Although the common tendency is to enroll advanced patients in trials with novel compounds, we are faced with agents that might best serve a different population. One option would be to consider these agents as maintenance therapy after initial therapy in patients that are in a complete clinical remission. Currently, there are protocols aimed at describing the role of these agents in small-volume disease or in patients with an asymptomatic rise in CA125.
Additionally, careful attention to clinical design, with appropriate end points and eligibility criteria, will eventually define the role of these agents in the management of patients with these malignancies. Although CA125 was collected in this study, response was not defined according to the serum CA125. Recent reports by Grolund et al have suggested that the CA125 response criteria are better prognostic tools than RECIST in patients with recurrent disease. Future trials, given these recent data, may revisit their response evaluation methods.26
In summary, this study demonstrated that CI-1033 given as single agent had no clinically relevant activity in a heavily pretreated patient population with ovarian cancer. The 50-mg/d dose had a more favorable safety profile and better tolerability than the 200-mg/d dose, and the majority of baseline tumor samples expressed at least one type of erbB receptor, with the erbB3 and erbB4 subreceptors showing the highest frequency of overexpression, and the erbB2 showing the least.
Authors' Disclosures of Potential Conflicts of Interest
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Acknowledgment
We acknowledge the assistance of Xin Huang and Jeff Robbins for statistical analysis, the nurses for patient care, and data managers for study coordination.
NOTES
Supported by Pfizer Global Research and Development, Department of Clinical Oncology, Ann Arbor, MI.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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