A Phase 2, randomized, double-blind, placebo-controlled trial of clinical activity and safety of subcutaneous A6 in women with asymptomatic CA125 progression after first-line chemotherapy of epithelial ovarian cancer

Results Data are available for 24 women (placebo, n = 12; low-dose, n = 8; high-dose n = 4). Å6 therapy was associated with a statistically significant delay in time to clinical progression (log-rank p -value 0.01) with a median of 100 days (95% CI: 64,168) for women who received Å6 compared with 49 days (95% CI: 29,67) for women who received placebo. The treatments appeared to be well tolerated. Treatment was not associated with CA125 response ( p = 0.44). On-treatment values for plasma urokinase plasminogen activator receptor were statistically significantly lower in the Å6 groups compared with placebo ( p = 0.02). Conclusions Å6 therapy increases time to clinical disease progression and appears to be well tolerated in this patient population. Keywords Asymptomatic CA 125 progression Epithelial A6 therapy Introduction Both absolute values of CA125 and trends in CA125 values over time have been shown to have important prognostic significance for women with ovarian carcinoma at the time of diagnosis, after first-line surgery and chemotherapy, and in the monitoring of the response to chemotherapy and recurrence of disease [1–4] . In most women with ovarian cancer in clinical remission, an increase in serum CA125 concentrations above normal levels predates clinical relapse by approximately 2 to 3 months [2,4–6] . This finding may have important implications for the therapy and prognosis by allowing earlier diagnosis and intervention than might otherwise be possible [2,5,7] . The urokinase plasminogen activator system plays an important role in the growth and spread of most solid tumors [8,9] . Binding of single-chain urokinase plasminogen activator (uPA) to its cell surface receptor, urokinase plasminogen activator receptor (uPAR), unleashes a cascade of events leading to extracellular proteolysis, cell migration, cell invasion, angiogenesis, and metastasis. Serum and urine concentrations of uPA and uPAR correlate with tumor extent and clinical outcome in several malignancies, including breast [10–13] ; cervical [14] ; ovarian [14–16] ; endometrial [14,17–19] ; colorectal [20] ; and prostate cancers [21,22] , which provides the rationale for the development of inhibitors of this pathway. Å6 is an 8 amino-acid peptide derived from single-chain urokinase plasminogen activator (scuPA). In vitro, Å6 interferes with the uPA/uPAR cascade in a novel uPAR-independent manner and abrogates downstream effects. Nonclinical studies have shown that Å6 has anti-angiogenic, anti-migratory, and anti-invasive properties, but is not antiproliferative [23,24] . Results from anti-tumor studies in tumor-bearing mice show that in addition to inhibiting major vessel formation, Å6 also inhibits branching morphogenesis. In vivo nonclinical studies have also shown that Å6 has anti-neoplastic activity in models of prostate cancer [25] , glioblastoma multiforme [26] , and breast cancer [24] . The increased tumor necrosis seen after Å6 treatment in nonclinical models is believed to be due to decreased vascularization resulting in increased apoptosis [24] . In vitro data [16] indicate that in ovarian carcinoma cells, scuPA not only enhances tissue invasion through matrix proteolysis, but also may act, in autocrine fashion, to stimulate cancer cell proliferation. Additionally 2 groups of investigators have produced evidence that in patients with ovarian carcinoma, increases of circulating soluble uPAR concentrations are frequent, and may be indicative of poor prognosis [ 13 , 15 ]. Results from earlier phase 1 trials suggest that single doses of Å6 as high as 300 mg subcutaneously and repeated doses as high as 150 mg subcutaneously every 12 hours for 6 days were well tolerated in a population of healthy volunteers [27] . In another phase 1 study, Å6 showed promising preliminary anti-neoplastic activity in women with advanced gynecologic malignancies, using daily dosing regimens of 150 and 300 mg/day; 4 of 8 patients with ovarian cancer treated with daily Å6 achieved stable disease for at least 4 months, with 1 maintaining disease stability for 12 months [28] . Thus, the anti-angiogenic, anti-migratory, and anti-invasive properties coupled with an excellent safety profile to date makes Å6 an attractive agent for the early treatment of patients with ovarian cancer and asymptomatic CA125 progression. Currently, there is no data that shows a survival benefit with early therapeutic intervention in patients with asymptomatic biochemical recurrent ovarian cancer compared to treatment when clinical recurrence is detected. The current study was designed to assess clinical activity of 2 dose levels of Å6 as measured by time to clinical progression and safety of Å6, and to determine effects of Å6 on CA125 concentrations and on biomarkers of the urokinase system. On the basis of these results, we investigated the ability of Å6 to increase the time to clinical progression in women with epithelial ovarian cancer who had increasing CA125 serum values without clinical signs of disease progression. Patients and methods Patients The study protocol was approved by Institutional Review Boards at all participating institutions and all patients had provided written informed consent forms before any study-related procedures were done. Patients were prospectively enrolled in this study from 11 institutions in the United States of America. Women were eligible for study inclusion if they were aged 18 years or more and had a history of histologically or cytologically documented primary epithelial ovarian carcinoma, fallopian tube cancer, or primary peritoneal carcinoma, and had obtained a clinical remission with normal CA125 values after first-line chemotherapy. All patients were required to have increasing CA125 values greater than 2 times the upper limit of normal (ULN) and a documented doubling to more than 2 times the institution's ULN, persisting at least 28 days. Patients were to have no clinically evident disease progression and had to have a life expectancy of greater than 12 weeks and an Eastern Collaborative Oncology Group (ECOG) Performance Status of 1 or less. All patients were required to have adequate hematologic, hepatic, renal, and cardiac function. Patients were excluded from study enrollment if they were pregnant or lactating or had active, clinically significant infection; ascites; gastrointestinal bleeding within 3 months of study entry; chronic anticoagulation; history of venous thrombotic disorders within 12 months of study entry; history of stroke; history of myocardial infarction within 3 months of study entry; or history of sensitivity to peptide products. Study drugs Å6 injection for subcutaneous administration (Paralit™, Ångstrom Pharmaceuticals, Solana Beach, California, USA) was provided in prefilled syringes, each syringe containing 1.5 mL at a concentration of 100 mg/mL as peptide, equivalent to 150 mg of active drug. The matching placebo preparation consisted of sterile aqueous phosphate buffer. The study drugs were self-administered as daily subcutaneous injections. The placebo group received 2 concurrent injections of the control agent; the low-dose group received 1 injection of Å6 concurrent with 1 injection of the control agent; and the high-dose group received 2 concurrent injections of Å6. Study design This study was a phase 2, multicenter, double-blind, placebo-controlled study that evaluated the use of Å6 in women with epithelial ovarian cancer to delay the time to disease progression. Eligible patients were to be randomly assigned to treatment in a 1:1:1 ratio to the placebo, low-dose (150 mg) Å6, and high-dose (300 mg) Å6. Treatment was administered as daily subcutaneous injections over a 28-day cycle. Patients were to undergo a first cycle of treatment, followed by 7 days off drug. Patients who tolerated the treatment were eligible to continue receiving Å6 without interruption for up to 11 additional cycles or until further disease progression was documented. Patients were monitored from the time of first dose administration for any evidence of clinical or chemical response. The determination of measurable disease was defined by standard RECIST criteria [29] . Disease progression was defined by at least one of these criteria: measurable disease by physical examination, computed tomography (CT) scan, or magnetic resonance imaging; or newly documented ascites or pleural effusions on CT scan; or global deterioration in health status without clinical evidence of increasing disease which, in the opinion of the investigator, was attributable to the cancer and required a change in therapy; or doubling of the amount of CA125 compared with baseline values. Safety was assessed by reports of adverse events and changes in clinical laboratory values, including hematology, clinical chemistry, and urinalysis. Patients were assessed for serum CA125 concentrations every 4 weeks until the end of study. Chemical response was determined as complete response (CA125 returned to normal range); partial response (CA125 decreased by at least 50%); progressive disease (CA125 increased by at least 100%); or stable disease (neither responsive nor progressive disease). Serum samples were collected at scheduled visits to assess biomarkers of urokinase plasminogen activator system. uPA and plasminogen activator-1 (PAI-1) concentrations were determined in EDTA plasma using the uPA assay (IMUBIND uPA ELISA) and the plasminogen activator-1 (PAI-1) assay (IMUBIND PAI-1 ELISA from American Diagnostica Inc (Stamford, CT, USA). Assays were performed according to the instructions provided with the assays. Soluble uPAR concentration was analyzed in EDTA plasma using the assay (uPAR Quantikine ELISA) from R&D Systems (Minneapolis, MN, USA) according to the assay instructions. End points The primary measure of efficacy was delay in time to clinical progression. Secondary efficacy endpoints were changes in CA125 concentrations and biomarkers of the urokinase system (uPA, uPAR, PAI-1). Safety was measured by reports of adverse events and changes in laboratory values. Statistical analysis The statistical analysis was prospectively defined. All patients who were randomly assigned to treatment and either completed at least the first cycle of treatment or failed to complete 1 cycle of treatment due to adverse experiences were evaluated for efficacy. Comparisons of clinical response rates between placebo and treatment groups were made with Fisher's exact test. Time to progression estimates and survival curves were generated using the Kaplan–Meier method and comparison between treatment groups were made with the log-rank test. Time to clinical progression was calculated from the first dose of study agent to the first evidence of progressive disease. Patients who completed the study or who discontinued early from the study without an event were censored as of the date that their study participation ended. Patients who died or had an unknown outcome were to be considered as failures for analysis. Summary statistics were calculated for chemical response rate with CA125 tumor-marker assessments and percent changes from baseline at each scheduled assessment. Linear mixed models were used to compare changes in CA125 concentrations and to test for associations between each of the 3 biomarkers (uPA, uPAR, and PAI-1) and the treatment group across visits, adjusting for patients who had no evidence of disease progression for at least 1 cycle. Results Patients The study started in April 2004 and ended in March 2006. A total of 48 women were planned for this study, but the study was ended early after only 24 women were randomly assigned, treated, and followed to the end of their study participation. Errors in patient assignment were noted after unblinding, and randomization was not 1:1:1 as planned, but 3:2:1 (placebo:150 mg Å6:300 mg Å6); because of the small sample size and imbalance in randomization, the data are presented as placebo and combined Å6 (150 and 300 mg) groups. No significant differences in baseline characteristics were seen among the treatment groups ( Table 1 ). All the trial patients had prior platinum and taxane based combination chemotherapy and aggressive debulking surgery leading to clinical remission before study enrollment. Additionally, 1 (4%) woman had received hormonal therapy and 1 (4%) woman had had thoracentesis before surgery and chemotherapy. The serum CA125 concentrations at screening for both the placebo and combined Å6 treatment groups were increased, with a median value of 119.1 U/mL (range: 52.2–1242) and 107.5 U/mL (range: 51–764), respectively. All patients received at least 1 dose of study medication and all but 2 (8%) patients (both in the placebo group) completed at least 1 cycle of study medication. No patients completed the study medication through the end of the study (through cycle 12). One (4%) woman in the low-dose Å6 group discontinued treatment after 1 cycle due to withdrawal of consent, and the remaining 23 patients were terminated early from the study due to disease progression after treatment with 1 to 8 cycles. Study endpoints Clinical activity of Å6 as measured by time to clinical progression Despite the randomization imbalance, the early termination, and the small sample size of the trial, treatment with Å6 was associated with improved time to clinical progression compared with placebo (log-rank p -value = 0.01). Median time to progression for women treated with Å6 (100 days, 95% CI = 64,168) was statistically significantly greater than median time to progression for women who received placebo (49 days, 95% CI = 29,67) ( Fig. 1 ). Four of 11 women (36%) who were treated with Å6 remained on treatment with stable disease at the start of cycle 6 by both CA 125 and RECIST criteria A 75-year-old woman with primary peritoneal cancer remained on the trial for 10 cycles with no progression of disease on CT scans, although disease progression was documented by a doubling in CA125 concentrations. Safety of Å6 Reported adverse events were similar between the placebo and treatment groups. Most (83%) patients experienced at least 1 adverse event: 10/12 (83%) in the placebo group, 8/8 (100%) in the low-dose group, and 2/4 (50%) in the high-dose group. None of the patients died or discontinued treatment due to adverse events. The most common body systems affected by adverse events were general disorders (and administration site conditions) and gastrointestinal disorders with 14 (58%) and 12 (50%) patients, respectively. The most common complaints were fatigue (placebo, n = 2; Å6 groups, n = 2); injection site bruising (placebo, n = 2; Å6 groups, n = 2); nausea (placebo, n = 1, Å6 groups, n = 3); injection site erythema (placebo, n = 1; Å6 groups, n = 2); stomatitis (placebo, n = 3); vomiting (placebo, n = 1; Å6 groups, n = 2); and abdominal distension (Å6 groups, n = 3). All adverse events were grade 1 or grade 2. Three women experienced serious adverse events, 1 in each of the treatment groups, but only 1 was determined to be possibly related to study drug by the investigator. A 74-year-old woman with no history of cardiac abnormalities was hospitalized with a week-long history of nausea without vomiting, heartburn, and indigestion; and acute symptoms of diaphoresis, chest pressure, shortness of breath, anxiety, hyperventilation and numbness after receiving Å6 300 mg for approximately 1 month. Serious cardiorespiratory illness was ruled out, and her symptoms resolved completely without sequelae; study medication was discontinued. No clinically significant differences or changes from baseline were seen in laboratory values for any patient. Effects of Å6 on CA125 concentrations Because disease progression had already been documented through other means, only 9/22 (41%) women were evaluated for chemical response at cycle 3/day 1 (the first scheduled assessment). Eight patients (placebo, n = 1; Å6 groups, n = 7) had stable disease and 1 patient (placebo group) had progressive disease. Treatment was not associated with chemical response (Fisher's exact test p -value = 0.44). Treatment was not associated with either a change in CA125 concentration ( p -value = 0.71) or percent change from baseline ( p -value = 0.21). Effects of Å6 on biomarkers of the urokinase system Assay data were available for 18/24 patients in the study. Data through cycle 4/day 1 were used, because only 5 patients had any data after that time point. No significant differences (analysis of variance p -value < 0.05) were seen at baseline (cycle 1/day 1) between the placebo and treatment groups for any of the biomarkers. For soluble uPAR, a statistically significant difference (linear mixed model p -value, 0.02, unadjusted for multiple comparisons) was seen on therapy between placebo and treatment groups. No other statistically significant differences between placebo and treatment groups, with on-treatment values for PAI-1 receptor lower in Å6-treated patients. No other statistically significant differences between placebo and treatment groups, or between patients who achieved stable disease and those who did not, were observed for any of the 3 biomarkers ( Table 2 ). Discussion Despite improvement in survival for women with advanced ovarian cancer over the past 4 decades using aggressive cytoreductive surgery followed by platinum- and taxane-base chemotherapy, many women who achieve remission will subsequently experience recurrent disease. Increasing CA125 concentrations usually precede and predict recurrence, which causes anxiety for the patients and a clinical dilemma for the physician. Previous studies have addressed the lead time of an increasing CA125 concentration above normal levels to clinical appearance of disease in 2 to 4.5 months [2,6] . In a cohort of 31 women with normal CA125 concentrations after the completion of combination chemotherapy for ovarian cancer, increased CA125 concentrations were defined as a single laboratory value > 35 U/mL [6] . The lead time in this retrospective study of increasing CA125 concentrations to the clinical appearance of disease was a median of 4.5 months (range: 0.5–29.5). This study was reported in 1990, when clinical progression was detected by CA125 concentrations and a physical examination in 92% of all women. Computed tomography scans and second-look surgery detected clinical disease in the remaining 8% of the patients. In a subset analysis of a prospective trial completed in 1996, comparing 5 and 8 cycles of platinum-based therapy for the treatment of women with ovarian cancer, 124 women (62% of study population) who had increased CA125 concentrations that had normalized to < 40 U/mL were studied [2] . In women with a single increase of CA125 concentrations to a value > 60 U/mL, the median lead time to clinical progression was 63 days. In women with a single increase of CA125 concentrations to a value > 100 U/mL, the median lead time to clinical progression was 31.5 days. The frequency of CT scans in women with increasing CA125 concentrations was not reported. There is also evidence in smaller studies that rising CA 125 levels within the “normal range” also predict recurrence of ovarian cancer [30,31] . In a small study, 11 patients with 3 consecutive rises of CA 125 levels within the normal range were identified and all developed recurrent disease within 12–33 months (median 22 months). The mean lead time from the third early rising CA 125 value to documentation of recurrence was 189 days (range 84–518) [30] . A second study looked at the ability of rising CA 125 levels below 35 U/ml, in patients with ovarian cancer in remission to predict recurrence. Twenty two patients recurred at a median interval of 11 months and a relative increase in CA 125 of 100% or absolute increases of 5 U/ml or 10 U/ml above baseline nadir were predictive of recurrence with a sensitivity of 100% or specificity of 94% [31] . In the United States, most physicians tend to quickly order an imaging study, usually a CT scan, for women with increasing CA125 values. Imaging technology of spiral CT scans, thinner slices, 3-dimensional reconstructions, and positron emission tomography scans has led to earlier detection of more subtle lesions. In our study, the median pretreatment CA125 concentrations in the placebo and treatment groups were 119.1 and 107.5 U/mL, respectively, and the median lead time to clinical progression was 49 days in untreated women; this is comparable to previously reported data [2] . In this context, a statistically significant doubling of progression-free survival with Å6 therapy to a median of 100 days is important. One of the women in the high-dose Å6 treatment group was 75 years old and had been diagnosed with primary peritoneal cancer. This patient remained on study for 10 cycles of treatment with no progression of disease noted on CT scans. In a population of women with CA125-documented progression of ovarian cancer, Å6 treatment was associated with improvement in time to disease progression compared with placebo (long-rank p -value = 0.01). Patients treated with Å6 had a statistically significantly longer time to progression (100 days; 95% CI = 64,168) than did patients who received placebo (49 days; 95% CI = 29,67). Å6 was well tolerated with mild side effects and no treatment interruptions. Apart from our study, Å6 has been associated with disease stabilization in women with advanced ovarian cancer in the previous phase 1 trial in gynecological malignancies [28] . Although designed primarily to test the safety of Å6 in women with gynecologic malignancies, trial participants were followed closely to document any observed anti-tumor activity by both Gynecologic Cancer Intergroup (GCIG) [32] and RECIST criteria. No patient achieved a partial or complete tumor responses on a CT scan, but 4/8 (50%) women with advanced ovarian epithelial cancer in the cohorts that received 150 mg and 300 mg of Å6 injections daily experienced periods of stable disease for at least 4 cycles. These patients were all heavily pretreated with a median of 5 previous therapies. This is the first report of a successful therapeutic intervention in patients with asymptomatic biochemical recurrence. The ability of a biological agent to prolong the appearance of disease and to delay chemotherapy with its associated side effects is significant. 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