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Journal of Clinical Oncology, Vol 22, No 17 (September 1), 2004: pp. 3507-3516 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.09.016 Randomized, Placebo-Controlled Study of Oregovomab for Consolidation of Clinical Remission in Patients With Advanced Ovarian CancerFrom the David Geffen School of Medicine at UCLA, University of California at Los Angeles, CA; University of Virginia, Charlottesville, VA; US Oncology, Texas Oncology PA, Dallas, TX; State University of New York Upstate Medical University, Syracuse, NY; Florida Hospital Cancer Institute, Orlando; Florida Gynecologic Oncology, Ft Myers, FL; Swedish Tumor Institute, Seattle, WA; Unither Pharmaceuticals, Wellesley Hills, MA; and University of Pittsburgh, Pittsburgh, PA Address reprint requests to Jonathan S. Berek, MD, MMSc, David Geffen School of Medicine at UCLA, University of California at Los Angeles, Division of Gynecologic Oncology, 24-137 UCLA Center for the Health Sciences, 10833 Le Conte Ave, Los Angeles, CA 90095-1740; e-mail: jberek{at}mednet.ucla.edu
PURPOSE: To assess oregovomab as consolidation treatment of advanced ovarian cancer and refine the immunotherapeutic strategy for subsequent study. PATIENTS AND METHODS: Patients with stage III/IV ovarian cancer who had a complete clinical response to primary treatment were randomly assigned to oregovomab or placebo administered at weeks 0, 4, and 8, and every 12 weeks up to 2 years or until recurrence. The primary end-point was time to relapse (TTR). RESULTS: One hundred forty-five patients were treated with oregovomab (n = 73) or placebo (n = 72). For the population overall, median TTR was not different between treatments at 13.3 months for oregovomab and 10.3 months for placebo (P = .71). Immune responses were induced in most actively treated patients. This was associated with prolonged TTR. Quality of life was not adversely impacted by treatment. Adverse events were reported with similar frequency in oregovomab and placebo groups, indicating a benign safety profile. A long-term survival follow-up is ongoing. Cox analysis of relapse data identified significant factors: performance status, CA-125 before third cycle, and baseline CA-125. Further evaluation identified a subpopulation with favorable prognostic indicators designated as the successful front-line therapy (SFLT) population. For the SFLT population, TTR was 24.0 months in the oregovomab group compared with 10.8 months for placebo (unadjusted hazard ratio of 0.543 [95% CI, 0.287 to 1.025]), a hypothesis-generating observation. CONCLUSION: Consolidation therapy with oregovomab did not significantly improve TTR overall. A set of confirmatory phase III studies has been initiated to determine whether the SFLT population derives benefit from oregovomab treatment.
Ovarian cancer is the fifth most frequent cause of cancer death in women and the leading cause of gynecologic cancer death in the United States.1 Almost 75% of women with epithelial ovarian cancers are discovered to have disseminated intra-abdominal disease at the time of their initial diagnosis. Extensive surgical resection followed by intensive platinum-based combination chemotherapy results in a high rate of initial response, including complete clinical and radiologically confirmed responses. Even so, a distressingly high percentage of those women with a complete response will eventually experience relapse.2 Although there are many active agents for the treatment of women with relapsed ovarian cancer, there is no predictably curative therapy, especially for those with multisite relapse. There is universal interest in additional therapy after complete remission that might delay or prevent relapse. Since there is no consistently effective or accepted standard for consolidation therapy, all programs are investigational in nature. Because patients are clinically free of disease, investigational therapies ideally should also carry minimal toxicity and not adversely impact the patient's quality of life, although this should be balanced against ultimate survival benefit. Interventions that can complement the effect of standard front-line therapy and prolong the disease-free interval in patients with advanced ovarian cancer represent an unmet medical need. If such interventions have minimal toxicity, they would be of value even in the absence of a demonstrated survival benefit. The study reported here uses an alternative strategy, using active stimulation of the immune system at a time of minimal disease burden (no clinically detectable disease in a population statistically likely to have residual disease). The current study uses a xenotypic monoclonal antibody targeting the tumor antigen CA-125. It has been demonstrated that the antibody induces altered antigen processing of this otherwise poorly immunogenic glycoprotein, thus making CA-125 a target for immune recognition and tumor-directed immunity. The nature of endogenous immune regulation, however, likely modulates the beneficial clinical translation of induced immunity. Adequate appreciation of this influence may be critical to the ultimate success of immunotherapeutic treatment strategies for cancer.3 CA-125 is a surface mucin-like glycoprotein antigen that is expressed on more than 95% of all nonmucinous stage III/IV epithelial ovarian carcinomas and occurs at elevated levels in the serum of patients with ovarian cancer.4 Increased CA-125 serum levels have also been observed in men and women with a variety of malignancies (carcinomas of the pancreas, lung, colon, and other gastrointestinal tumors), as well as with benign tumors. It is also found in normal secretions of women (breast milk, normal cervical mucus, and amniotic fluid), in the serum of some women with endometriosis and leiomyomata and during menstruation, and in the serum during the first trimester of pregnancy. It is normally expressed during early fetal development, implying a role in normal growth and development. Its sequence and structure was recently published, but its function is not well elucidated.5-8 The predictive value of following serial changes in serum levels of CA-125 for screening of asymptomatic women is currently under study. In the setting of known stage III or IV epithelial ovarian cancers, serologic changes in CA-125 levels have been commonly accepted as a useful marker to monitor response to therapy and for surveillance of those women who achieve remission. Oregovomab (OvaRex monoclonal antibody [MAb]-B43.13; Unither Pharmaceuticals, Wellesley Hills, MA) is an immunotherapeutic agent for investigational use in the immunotherapy of patients with ovarian adenocarcinomas expressing the tumor-associated antigen CA-125. The active component of oregovomab is the modified murine MAb-B43.13, an IgG1k subclass immunoglobulin. MAb-B43.13 binds with high affinity (1.16 x 1010/M) to CA-125.
Oregovomab behaves as an active immunotherapeutic agent through a unique mechanism.9-11 The processing of CA-125 complexed with oregovomab-B43.13 is altered from the immune recognition of CA-125 alone by the mechanisms that have been well characterized.12,13 The CA-125-B43.13 complex binds to antigen-presenting cells such as macrophages and dendritic cells more readily than either antibody or tumor antigen alone. Multiple receptors have been implicated, including the Fc This report summarizes the results of a randomized study conducted in the United States. The study was designed without preliminary experience with the antibody as consolidation therapy of advanced ovarian cancer. A separate consolidation study was conducted in Canada, which could have formed the basis for early product registration based on a combined meta-analysis of the two studies if the outcome was compelling.15 These studies did not meet their primary end points. As a consolidation therapy, oregovomab has been developed with markers of biologic activity but without a distinct surrogate marker of efficacy. The current study has provided a body of data used to identify evidence of an effect from which to design confirmatory studies.
Patient Selection Women at least 18 years of age with recently diagnosed International Federation of Gynecology and Obstetrics stage III or IV ovarian cancer (histologically proven epithelial adenocarcinoma of ovarian, tubal, or peritoneal origin) who had complete clinical response to their primary treatment (surgery and neoadjuvant platinum-based chemotherapy) were specific candidates for the study. Patients could have undergone only one attempt at surgical resection (debulking) and were required to have at least microscopic residual disease after surgery. Complete clinical response after chemotherapy was defined as normal physical examination, no conclusive evidence of residual tumor by computed tomography (CT) of the abdomen and pelvis, normal chest x-ray, and normal serum CA-125 level (  35 U/mL). Patients were required to receive their first dose of the study medication within 10 weeks of completing primary chemotherapy. Patients must have had a performance status of 2 on the Eastern Cooperative Oncology Group scale or  60% on the Karnofsky scale with an expected survival of at least 6 months. Not all women who achieved remission with front-line treatment were eligible to volunteer for this study. Patients with known allergy to murine proteins, documented anaphylactic reaction to any drug, recognized immunodeficiency disease, or active autoimmune disease and those who had previously received murine monoclonal antibodies for diagnostic or therapeutic purposes, who had received immunotherapy of any type within the past 6 weeks, or who were receiving treatment with immunosuppressive therapy were ineligible. Also excluded were patients with compromised hematopoietic function (hemoglobin < 80 g/L, lymphocyte count < 300 x 106/L, neutrophil count < 1 x 109/L, or platelet count < 100 x 109/L), hepatic dysfunction (bilirubin > 1.5 times the upper normal limit), severe renal dysfunction (serum creatinine > 140 µmol/L), significant cardiovascular abnormalities, active infection causing fever, or concurrent malignancy. Patients who had received more than one prior regimen of chemotherapy or who had received whole abdomen, abdominopelvic, or pelvic radiotherapy, surgery, or chemotherapy within the previous 4 weeks were also excluded. The study protocol was approved by the institutional review board for each participating study center, and written informed consent was obtained from all patients before study participation.
Treatment Schedule Patients remained in the infusion clinic for 1 full hour after administration of study medication to monitor for the possible occurrence of symptoms of anaphylaxis.
Evaluations Patients were assessed for disease progression during the study by physical examination and CT scan for measurable or assessable disease every 3 months until recurrence (CT evaluations every 6 months after year 1). The detection of recurrence of disease was defined as unequivocal identification of new intraperitoneal lesions (eg, in the omentum) not previously seen or the presence of a retroperitoneal lesion on CT scan greater than 2 x 2 cm, which was not seen on a previous scan. If a lesion less than 2 x 2 cm was detected, a follow-up CT scan was performed at intervals of not greater than 12 weeks or sooner if specific clinical symptoms dictated. In addition, histologic or cytologic proof of relapse (eg, malignant pleural effusion or ascites) was also acceptable evidence of disease relapse. As mandated by the US Food and Drug Administration and incorporated into the informed consent, clinicians were blinded to CA-125 to avoid possible bias in determination of relapse. Determination of disease progression was validated by independent review by an End Point Monitoring Board (EMB). The EMB determination was used for analysis. CA-125 was not used to determine clinical relapse by the EMB. Other assessments conducted during the study included performance status and vital signs evaluations, administration of the QOL questionnaire, and hematology and clinical chemistry laboratories.
Statistical Methods Secondary efficacy end points included overall survival, immune response, and changes over time in QOL. Survival was estimated using Kaplan-Meier methods. The global health status and global QOL scales from the EORTC QLQ-C30 were scored by the patient from 1 (very poor) to 7 (excellent); scores were standardized using a linear transformation so that the resulting values ranged from 0 to 100. Although designated a phase II study with the United States Food and Drug Administration, the study aimed to demonstrate a definitive treatment effect based on the surrogate end point of TTR, a phase III-type parameter. This end point was chosen because it was not feasible to demonstrate objective response rates based on tumor shrinkage in a consolidation setting in the absence of measurable baseline disease. The study was designed to permit further exploration of the data if necessary to define the proper use of the product as a consolidation therapy for confirmation in future studies.
Patients A total of 147 patients were recruited and randomly assigned onto the study between April 1998 and February 2000; 145 patients were treated at 32 study sites in the United States, including 73 patients (50.3%) who were treated with oregovomab and 72 patients (49.7%) who were treated with placebo. Two patients withdrew from study participation before treatment. Premature discontinuations were infrequent: five patients (3.4%) discontinued because of toxicity (oregovomab, n = 1; placebo, n = 4), and eight patients (5.5%) requested to withdraw (oregovomab, n = 5; placebo, n = 3). Patient characteristics for the two treatment groups are listed in Table 1. The 145 women with advanced ovarian cancer enrolled and treated in this study ranged in age from 28 to 80 years. The majority of patients in both treatment groups had stage III disease with serous histopathology; carboplatin and paclitaxel were used as front-line therapy in more than 98% of patients. Characteristics were similar in both treatment groups.
Time-to-Disease Relapse and Prognostic Factors Figure 1 displays the Kaplan-Meier analyses of TTR based on data obtained for the ITTm population of 145 patients. The median TTR was 13.3 months in the oregovomab group and 10.3 months in the placebo group; the results were not significantly different (P = .71; log-rank test). The unadjusted hazard ratio (oregovomab/placebo) was 0.927 (95% CI, 0.621 to 1.383) and the adjusted hazard ratio incorporating all predetermined relevant covariates was 0.881 (95% CI, 0.578 to 1.349). Values less than 1 reflect reduced risk for the oregovomab group. Levels of CA-125 before cycle 3 and at baseline before first antibody administration were the most relevant factors influencing clinical outcome in this data set.
CA-125 at Time of Relapse To avoid potential bias in the clinical diagnosis of relapse, CA-125 values were blinded to clinical investigators, and clinical relapse was determined on the basis of clinical and radiographic findings only. Figure 2 shows the distribution of CA-125 values that were obtained closest to actual clinical diagnoses of recurrence for all patients in the study. The data reveal that recorded CA-125 values were similar in both treatment groups at the time of clinical relapse, indicating that recurrent ovarian cancer expressed CA-125 similarly in the presence or absence of oregovomab. It is noteworthy that clinical recurrence occurred in both the presence and the absence of elevated CA-125 in either group.
Immune Response Scatterplots of the time course of HAMA and Ab2 response to oregovomab treatment are provided in Figures 3 and 4, respectively. Antibody response increased in the majority of patients treated with oregovomab by the third infusion (week 8) and reached a plateau in response to the fourth infusion (week 32). The pattern was similar for both HAMA and Ab2. The magnitude of individual patient response was highly variable, ranging from less than 200 to greater than 100,000 ng/mL for HAMA and from less than 50 to greater than 1,000 ng/mL for Ab2. The percentage of patients achieving a HAMA level of greater than 5,000 ng/mL was 58.9% and an Ab2 level of greater than 100 ng/mL was 67.1%. These levels have previously been defined as robust for the purposes of assessing clinically relevant immune responses.19
TTR by Immune Response Patients generating robust immune responses were assessed for TTR relative to those patients not achieving such a response and to the placebo-treated population. TTR for oregovomab-treated patients included in the ITTm population who exhibited a robust Ab2 response (cutoff of 100 ng/mL) was 18.8 months (95% CI, 12.7 to 24.5 months), compared with 6.1 months (95% CI, 2.5 to 7.7 months) for Ab2 nonresponders and 10.3 months (95% CI, 7.4 to 18.1 months) for placebo.
Other Efficacy Parameters The global health status and global QOL scale scores at baseline and as a last value available on study are depicted in Figure 5. Mean QOL scores were similar for both global scales at both time points for the oregovomab and placebo groups, indicating that treatment with oregovomab did not adversely affect QOL over the duration of the study, when patients are clinically free of disease and enjoying optimal QOL.
Toxicities All patients were evaluated for safety. The most frequently reported adverse events assessed as related to study treatment are presented in Table 2 by severity and treatment group. The primary toxicities were nonhematologic in nature and included pain, asthenia, and headache; the reported frequency of these events was similar in the oregovomab and placebo groups. Gastrointestinal toxicities, primarily reports of nausea and diarrhea, were also recorded with similar frequency between the two treatment groups. There was no pattern of grade 3 or 4 toxicity attributable to either treatment, and many of the events were most likely attributable to underlying malignancy-related pathology. As reflected in Table 2, several potentially treatment-related grade 3 or 4 events were reported in the active group, whereas none were reported in placebo. Review of these data identifies five patients (7% of the oregovomab group) who experienced symptoms categorized as severe in intensity on a scale of mild, moderate, and severe by site investigators and at least possibly attributed to study treatment. These include two patients with parasthesia, two patients with intermittent diarrhea, and one patient with abdominal and shoulder pain occurring as a prodrome to recurrence. This does not reflect a pattern suggestive of a unifying underlying treatment-associated process but deserves observation in future studies. Notably, infusions were well tolerated, and there was not a distinctive pattern of hypersensitivity-related signs or symptoms, despite multiple administrations of oregovomab in the presence of serum HAMA. Mild to moderate back pain in the oregovomab group may be reflective of an oregovomab-mediated process; however, the low incidence and overlap of this reported event between treatment groups leaves even this observation ambiguous. Oregovomab administration was not problematic for patient or infusion center staff.
Further Exploration of Explanatory Factors A Cox proportional hazards model analysis was performed on TTR data; significant factors from the model included performance status (hazard ratio = 0.62), log (base 10) CA-125 before the third cycle (hazard ratio = 2.64), and baseline CA-125 (hazard ratio = 1.04). For this analysis, hazard ratios greater than 1.0 indicate a shorter time to relapse for larger values of the prognostic factor. These hazard ratios indicate that a 10-fold increase in CA-125 at precycle 3 and at baseline would yield 164% and 48% increase in risk of relapse, respectively. The results of the Cox analysis were consistent with prognostic factors as described in the literature,20-22 although surgical outcome was not significant in the model. The hazard ratio for residual disease 2 cm was 0.74 (P = .249), a nonsignificant outcome that may be reflective of the high percentage of patients with favorable surgical outcomes in this study. Data from other studies with oregovomab have suggested that favorable surgical outcomes are important to the therapeutic outcome achieved. Specifically, patients with less favorable surgical outcomes have been reported not to respond favorably to oregovomab consolidation treatment.25,23 The current study points to the importance of response to chemotherapy in the period 3 to 6 months before randomization as reflected in CA-125 assessments before cycle 3 of front-line therapy and at randomization after front-line treatment. It is noteworthy that the percentage of patients with residual disease greater than 2 cm was 15.1% in the oregovomab group and 26.4% in the placebo group, which is suggestive of a possible imbalance that might favor the oregovomab group. As an exploratory exercise, we have evaluated results for a patient subpopulation with prognostic indicators related to residual disease and CA-125 levels (as an indicator of disease burden and chemoresponsiveness)21 to reflect the results of Cox modeling and a possible demographic imbalance. The population is designated as the successful front-line therapy (SFLT) population and describes a balanced population that may be more likely to respond clinically to immunologic stimulation.
The SFLT population represents that subset of patients who met the following criteria at study entry: microscopic or small diameter ( Figure 6 presents the results of the Kaplan-Meier analysis of TTR based on the SFLT population (n = 67); approximately 46% of patients enrolled in each treatment group qualified for this patient subset. Median TTR was 24.0 months for patients treated with oregovomab (n = 34) and 10.8 months for placebo-treated patients (n = 33). The unadjusted hazard ratio for this population was 0.543 (P = .0596; 95% CI, 0.287 to 1.025). The adjusted hazard ratio using the protocol-defined risk factors still relevant for the subset population—namely, presence of ascites, residual disease, performance status, and pretreatment CA-125 values at cycle 3 front-line therapy and just before first oregovomab administration—was 0.474 (P = .0261; 95% CI, 0.246 to 0.915). The heterogeneous population not meeting the SFLT criteria was also assessed in the same analyses. The unadjusted hazard ratio for this group was 1.316 (P = .3102; 95% CI, 0.774 to 2.237) and the adjusted hazard ratio was 1.298 (P = .3853; 95% CI, 0.720 to 2.338).
TTR for the SFLT population was also explored in the context of immune induction using Ab2 as the categoric factor. For the SFLT population, median TTR was 28.2 months (95% CI, 18.8 to not estimated) for the Ab2 responder group, 6.4 months (95% CI, 2.5 to not estimated) for the nonresponder group, and 10.8 months (95% CI, 7.3 to 20.6) for placebo.
This randomized, double-blind, placebo-controlled clinical study was designed to measure the efficacy of oregovomab in delaying the recurrence of disease after laparotomy and platinum-based combination chemotherapy, with secondary goals to evaluate safety, QOL, immunologic parameters, and impact on survival. A total of 145 patients were randomly assigned to this study and treated with oregovomab (73 patients) or placebo (72 patients). This study did not meet its primary end point, showing no difference in TTR between placebo and oregovomab groups, which is a disappointment for the management of advanced ovarian cancer patients who complete front-line treatment without evidence of disease. The strategy to mobilize endogenous immune responses targeting CA-125 and its associated neoplastic cellular source is of significant clinical interest; however, based on this study, immune regulatory and clinical factors may limit general applicability of the approach. The identification of a population (46% of the enrolled subjects) that experienced prolonged disease-free intervals similar to that recently reported for a consolidation strategy with paclitaxel24 is of great interest if it can be confirmed prospectively. The toxicity associated with consolidation chemotherapies being assessed for ovarian cancer seem to be avoided by the use of an antibody-based immune modulation. The identified population seems to be well balanced for known factors that influence outcomes in a stage III/IV ovarian cancer population; however, unappreciated factors may have biased the results in favor of treatment. If the subpopulation that has been identified in the detailed analysis of this protocol is confirmed to exhibit prolonged time to progression in the ongoing confirmatory studies, this protocol will prove to have been successful.
As a randomized study powered to detect a difference in efficacy outcomes, a demonstration of advantage in TTR, an end point characteristic of a phase III study, was sought. In the absence of this achievement, the study serves an important scientific function in permitting identification of a refined population that may have benefited from treatment that can be further evaluated. To better understand clinically identifiable factors that may be of relevance to the treatment strategy, exploration of baseline factors that significantly influenced TTR was conducted using Cox proportional hazards model methodology. In this analysis, several prognostic factors were identified as significant determinants of TTR. The most influential factors were related to the outcome of the patient's initial front-line treatment course, as reflected in CA-125 levels before cycle 3 of chemotherapy and at study baseline before antibody treatment. These factors and residual disease after primary surgery are consistent with those reported in the literature20,21,25,26 and reflect a population perhaps more likely to respond clinically to an immune modulatory intervention. As patients were referred for the protocol after front-line therapy, available data characterizing the population were less than in a typical front-line protocol where data are collected as they are generated. CA-125 before cycle 3 worked as a stratification factor on the study, ensuring availability of the parameters for analysis. Exploratory analyses were then conducted on a patient subset based on these factors; 67 patients (46%) of the overall population were included in this SFLT patient subset. In this subset, TTR was measured at 24.0 months for oregovomab-treated patients and at 10.8 months for placebo-treated patients. This finding is consistent with expectations of what population might best respond to immune modulatory consolidation and thus generates a hypothesis for clinical confirmation. The SFLT is a clinically defined group representing a set of concurrent parameters, namely, optimal surgical outcome ( It is noteworthy that CA-125 values were not different in the oregovomab-treated population as compared with the placebo-treated population at the time of clinical relapse. CA-125 values were blinded to investigators and the End Point Monitoring Board, so CA-125 did not contribute to the diagnosis of relapse. Presence of oregovomab in the serum may interfere with CA-125 measurement (data not shown); however, by sampling CA-125 at a time when oregovomab is not present in the serum, this interference can be avoided. Oregovomab has a serum half-life of approximately 48 hours and is cleared more rapidly on subsequent administrations when HAMA is present. Furthermore, serum samples for CA-125 measurements were obtained before oregovomab administration throughout the study, at least 4 weeks beyond the previous infusion. Serum HAMA also interferes with some commercial CA-125 assays. CA-125 was measured using an Abbott assay platform that uses a sheep anti-CA125 antibody to detect serum CA-125. This assay has recently been demonstrated to be reliable in the presence of interfering HAMA (P. Catomeris, PhD, FCACB, Lab Services Director, MDS Pharma Services Central Lab, personal communication, February, 2002). Most importantly, inspection of Fig 2 reveals that in all groups, clinical relapse occurred over a 100-fold range of CA-125 values from less than 10 to greater than 1,000 U/mL. CA-125 levels can be followed in patients with ongoing oregovomab treatment; however, CA-125 values may not relate directly to clinical recurrence on an individual patient basis. The data do not suggest that oregovomab treatment led to selection of CA-125 nonproducing tumors (antigen escape), although additional observations are required to fully address this issue. Immune responses were induced in most patients as measured by the generation of HAMA or Ab2 antibodies, with more than 60% of the patients who received oregovomab having robust antibody responses. The population of patients generating robust immune responses was noted to have favorable clinical outcomes as assessed by TTR. Median TTR for the Ab2 responder group in the SFLT population was 28.2 months, compared with 6.4 months for those oregovomab-treated patients who did not generate a robust response. Similar results were obtained for HAMA in the ITTm population consistent with previous studies, suggesting that both HAMA and Ab2 are correlated with improved clinical outcome.10 Survival data were immature at the time of the primary analysis. Overall, there were no differences in the survival curves; however, the high percentage of censored patients in the analysis makes further comment on this parameter premature. The primary reported adverse events occurring during treatment were nonhematologic in nature and were typical of a population of patients with history of prior abdominal surgery and ovarian cancer, and included pain, asthenia, headache, nausea, arthralgia, myalgia, back pain, and abdominal pain. The reported frequency of these events was similar in the oregovomab and placebo groups. The low frequency of clinically significant hypersensitivity reactions is notable, given the high frequency of treatment-related immune responses observed in the actively treated patients. This may be a result of the low-dose of antibody at each infusion (2 mg) and the fact that it is diluted and infused slowly over 20 minutes. Similar doses of antibody given for radiodiagnostic imaging are given by IV bolus, and typical therapeutic antibodies are administered in doses ranging several orders of magnitude above the oregovomab dose. The current study used a xenotypic monoclonal antibody to mobilize immunity. Although detailed immunologic assays were not incorporated into this clinical study, recently reported correlative studies from other oregovomab studies14,27 suggest that IV infusion of oregovomab meaningfully activates several important immune pathways, including B- and T-cell responses to oregovomab, CA-125, and autologous tumor. Success in confirmatory protocols will establish a clinical application for an immune modulatory approach to be used after front-line surgery and chemotherapy in the treatment of patients with advanced ovarian cancer. QOL was not adversely impacted by treatment with oregovomab. The results of the EORTC QLQ-C30 did not change meaningfully during the survey period, and the changes noted were similar between the oregovomab and placebo groups. During the time period after first-line chemotherapy and pending first clinical relapse, patients experience a favorable clinical period before their inevitably deteriorating disease course. For that reason, it is important that any additional intervention not adversely impact QOL, especially if a survival outcome is not established. Any prolongation of the disease-free period with preserved life quality is highly clinically meaningful for patients facing palliative interventions at relapse. Furthermore, a longer progression-free interval may provide for improved response rates to second-line therapy.28 Prolongation of progression-free survival in a subpopulation of ovarian cancer patients will prove to be relevant if the observation can be reproduced prospectively. This study provides the basis for the confirmatory randomized, phase III clinical trials currently enrolling patients in multiple centers in the United States.
The following authors or their immediate family members have 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. Received more than $2,000 a year from a company for either of the last 2 years: Birgit C. Schultes, Unither Pharmaceuticals; Christopher F. Nicodemus, Unither Pharmaceuticals.
We thank John Balser, and Barbara Balser, for their analyses, editorial contribution, and critical review; Jessica Suttle for her assistance with the manuscript; and the clinical investigators who participated in the multicenter program.
Supported by AltaRex Corp, Edmonton, Alberta, Canada, and United Therapeutics Corp, Silver Spring, MD. Presented at the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 3, 2003. Authors' disclosures of potential conflicts of interest are found at the end of this article.
1. American Cancer Society: Cancer Facts & Figures 2003. Atlanta, GA, American Cancer Society, 2003 2. Clarke-Pearson DL, Rodriguez GC, Boente M: Palliative surgery for epithelial ovarian cancer, in Rub SC, Sutton GP (eds): Ovarian Cancer. New York, NY, McGraw-Hill, 1993, pp 351-373 3. Sakaguchi S, Sakaguchi N, Shimizu J, et al: Immunologic tolerance maintained by CD25+CD4+ regulatory T cells: Their common role in controlling autoimmunity, tumor immunity, and transplantation tolerance. Immunol Rev 182:18-32, 2001[CrossRef][Medline] 4. Bast RC Jr, Klug TL, St John E, et al: A radio-immunoassay using a monoclonal antibody to monitor the course of epithelial ovarian cancer. N Engl J Med 309:883-887, 1983[Abstract] 5. Yin BWT, Dnistrian A, Lloyd KO: Ovarian cancer antigen CA125 is encoded by the MUC16 mucin gene. Int J Cancer 98:737-740, 2002[CrossRef][Medline] 6. Fendrick JL, Staley KA, Gee MK, et al: Characterization of CA 125 synthesized by the human epithelial amnion WISH cell line. Tumour Biol 14:310-318, 1993[Medline] 7. O'Brien TJ, Beard JB, Underwood LJ, et al: The CA125 gene: An extracellular superstructure dominated by repeat sequences. Tumour Biol 22:348-366, 2001[CrossRef][Medline] 8. O'Brien TJ, Beard JB, Underwood LJ, et al: The CA125 gene: A newly discovered extension of the glycosylated N-terminal domain doubles the size of this extracellular superstructure. Tumour Biol 23:154-169, 2002[CrossRef][Medline] 9. Noujaim AA, Schultes BC, Baum RP, et al: Induction of CA125-specific B and T cell responses in patients injected with MAb-B43.13: Evidence for antibody-mediated antigen-processing and presentation of CA125 in vivo. Cancer Biother Radiopharm 16:187-203, 2001[CrossRef][Medline] 10. Schultes BC, Baum RP, Niesen A, et al: Anti-idiotype induction therapy: Anti-CA125 antibodies (Ab3) mediated tumor killing in patients treated with OvaRex MAb B43.13 (Ab1). Cancer Immunol Immunother 46:201-212, 1998[CrossRef][Medline] 11. Nicodemus CF, Schultes BC, Hamilton BL: Immunomudulation with antibodies: Clinical application in ovarian cancer and other malignancies. Expert Rev Vaccines 1:35-48, 2002[CrossRef][Medline] 12. Schultes BC, Kuzma M, Agopsowicz K, et al: Antibodies as vaccines: Immune complexes allow for efficient uptake and processing of antigens on MHC class I and II and induce maturation of dendritic cells. FASEB J 16:A334, 2003 (abstr 246.12) 13. Eng H, Kuzma ML, Agopsowicz K, et al: Complexation with murine MAb-B43.13 alters the endocytic trafficking of the mucinous tumor antigen CA125 after uptake by human dendritic cells. Presented at Keystone Symposia, Dendritic Cells: Interfaces with Immunobiology and Medicine, Keystone, CO, March 3-8, 2003 14. Gordon AN, Schultes BC, Gallion H, et al: CA125- and tumor-specific T-cell responses correlates with prolonged survival in oregovomab-treated recurrent ovarian cancer patients. Gynecol Oncol 94:340-351, 2004[CrossRef][Medline]
15. Berek JS, Schultes BC, Nicodemus CF: Biologic and immunologic therapies for ovarian cancer. J Clin Oncol 21:168s-174s, 2003 (suppl 10)
16. Aaronson NK, Ahmedzai S, Bergman B, et al: The European Organization for Research and Treatment of Cancer QLQ-C30: A quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 85:365-376, 1993 17. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958[CrossRef] 18. Cox DR: Regression models and life tables. J R Stat Soc B 34:187-220, 1972 19. Möbus VJ, Baum RP, Bolle M, et al: Immune responses to murine monoclonal antibody-B43.13 correlate with prolonged survival of women with recurrent ovarian cancer. Am J Obstet Gynecol 189:28-36, 2003[CrossRef][Medline] 20. McGuire WP, Rowinsky EK, Rosenshein NB, et al: Taxol: A unique antineoplastic agent with significant activity in advanced ovarian epithelial neoplasms. Ann Intern Med 111:273-279, 1989 21. Makar AP, Kristensen GB, Bormer OP, et al: Serum CA125 level allows early identification of nonresponders during induction chemotherapy. Gynecol Oncol 49:73-79, 1993[CrossRef][Medline]
22. Ozols RF, Bundy BN, Greer BE, et al: Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: A Gynecologic Oncology Group study. J Clin Oncol 21:3194-3200, 2003 23. Ehlen T, Gordon AN, Fingert H, et al: Adjuvant treatment with monoclonal antibody, OvaRex MAb-B43.13 (OV) targeting CA125, induces robust immune responses associated with prolonged time to relapse (TTR) in a randomized, placebo-controlled study in patients (pts) with advanced epithelial ovarian cancer (EOC). Proc Am Soc Clin Oncol 21:9a, 2002 (abstr 31)
24. Markman M, Liu PY, Wilczynski S, et al: Phase III randomized trial of 12 versus 3 months of maintenance paclitaxel in patients with advanced ovarian cancer after complete response to platinum and paclitaxel-based chemotherapy: A Southwest Oncology Group and Gynecologic Oncology Group trial. J Clin Oncol 21:2460-2465, 2003
25. McGuire WP, Hoskins WJ, Brady MF, et al: Cyclophosphamide and cisplatin compared with paclitaxel and cisplatin in patients with stage III and IV ovarian cancer. N Engl J Med 334:1-6, 1996
26. Bristow RE, Tomacruz RS, Armstrong DK, et al: Survival effect of maximal cytoreductive surgery for advanced ovarian carcinoma during the platinum era: A meta-analysis. J Clin Oncol 20:1248-1259, 2002 27. Schultes BC, Whiteside TL: Monitoring of immune responses to CA125 with an IFN-gamma ELISPOT assay. J Immunol Methods 279:1-15, 2003[CrossRef][Medline]
28. Ozols RF: Recurrent ovarian cancer: Evidence based treatment. J Clin Oncol 20:1161-1163, 2002 Submitted September 3, 2003; accepted June 1, 2004. This article has been cited by other articles:
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ABSTRACT
INTRODUCTION
receptors CD64 and CD32, the complement receptor CD35, and the mannose receptor CD206. The microsomal compartmentalization of the complex and subsequent presentation of immunogenic peptides on the major histocompatibility complex molecules is altered. The components of the complex are cross-presented in the context of both class II and, importantly, class I major histocompatibility complex. This permits induction of both CD4 and CD8 T-cell responses specific for B43.13 and CA-125. A recently completed clinical study established that cellular immunity can also be induced to autologous tumor in a treatment-emergent fashion after administration of intravenous (IV) oregovomab, that induction of the cellular immune response is associated with a survival benefit.
