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ORIGINAL RESEARCH |
From the Department of Obstetrics and Gynecology, University of Arizona, Health Sciences Center, Tucson, Arizona; Department of Gynecology, Oststadtkranken-haus Hannover, Hannover, Germany; Women and Children’s Hospital, Los Angeles, California; Department of Obstetrics and Gynecology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma; Louisiana State University Health Center, New Orleans, Louisiana; Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts; and ZYCOS Inc, Lexington, Massachusetts.
Address reprint requests to: Francisco Garcia, MD, MPH, Department of Obstetrics and Gynecology, University of Arizona, Health Sciences Center, 1501 North Campbell Avenue, Tucson, AZ 85724; e-mail: fcisco{at}email.arizona.edu.
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ABSTRACT |
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 ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONAPPENDIXREFERENCES |
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METHODS: A multicenter, double-blind, randomized, placebo-controlled trial was conducted in a group of women with biopsy-confirmed CIN 2/3. Subjects were randomized to 3 intramuscular doses of either placebo or ZYC101a (100 or 200 µg). Six months after the first injection, subjects underwent cervical conization. The primary endpoint for this study was histologically confirmed resolution of CIN 2/3. A total of 161 subjects were randomized, dosed, and evaluated for safety. After central pathology review, 127 subjects were evaluable for efficacy.
RESULTS: The most common adverse events were related to the injection site, were mild to moderate, and did not worsen at later treatments. The proportion of subjects who resolved was higher in the ZYC101a groups compared to placebo (43% versus 27%), but the difference was not statistically significant (P = .12). In a prospectively defined population of women younger than 25 years (n = 43), resolution was significantly higher in the combined ZYC101a groups compared to placebo (70% versus 23%; P = .007). ZYC101a activity was not restricted to HPV-16–or HPV-18–positive lesions.
CONCLUSIONS: ZYC101a was shown to be well tolerated in all patients and to promote the resolution of CIN 2/3 in women younger than 25 years.
LEVEL OF EVIDENCE: I
Given the slow progression rates of CIN 2/3, an agent that promotes disease resolution in an acceptable time-frame may provide an alternative to ablative or surgical procedures. In the event that histologic resolution is not achieved during the treatment window, women may be treated with the standard approach. Such an alternative is especially important given the changing demography of the disease and the increasingly young patient population in whom the effects of treatment (and possibly repeat treatment) are not well understood and the probability of cervical cancer is very low.
For these reasons, medical alternatives, including the agent reported in this study, are being developed as "front-line treatment" modalities. An ideal therapeutic approach would result in the clearance of CIN 2/3 without destroying cervical tissue. A National Cancer Institute consensus panel suggested that a medical therapeutic agent would be valuable for this disease,13 and an American Association of Cancer Research Task Force on the Treatment and Prevention of Intraepithelial Neoplasia suggested that a 50% objective regression rate would be clinically meaningful in the setting of high-grade cervical intraepithelial lesions.14 The purpose of this study was to evaluate the safety and efficacy of such a medical therapeutic, ZYC101a, in the front-line treatment of high-grade cervical dysplasia.
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MATERIALS AND METHODS |
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ABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONAPPENDIXREFERENCES |
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This phase 2 trial was multicenter, double blind, randomized, and placebo controlled. The last patient completed follow-up in May 2002. Assuming resolution rates of 33% and 80% for placebo and treated groups, respectively, a sample size of 30 patients in each group yields a power greater than 90%. The assumption for spontaneous resolution was based on phase 1 results, whereas the assumption of 80% efficacy was taken from efficacy rates of invasive procedures, which range from 60–90%. Subjects were enrolled and randomized equally to placebo, 100 µg DNA, or 200 µg DNA. The sample size calculation was performed as a 2:1 ratio for placebo versus combined treatment because there were no data to suggest that the 2 doses of ZYC101a differed in efficacy. Subjects were randomized within each study center in blocks of 6; no other stratification variables were used. The randomization was generated and validated by an independent contract research organization using SAS 6.12 for Windows (SAS Institute, Cary, NC). Numbered containers were provided to each site by an independent packaging company and kept in the study site pharmacy. Subjects were then assigned a randomization number in sequential order. After randomization, subjects were injected intramuscularly (lateral quadriceps), once every 3 weeks (weeks 0, 3, and 6), for a total of 3 doses. Approximately 6 months after study entry, all subjects underwent a surgical excisional conization, most often using a loop electrical surgical excision procedure (LEEP).
ZYC101a (ZYCOS Inc, Lexington, MA) is an investigational agent and was formulated based on its precursor, ZYC101, which showed promise in phase 1 trials.15,16 Both drugs are composed of plasmid DNA encapsulated in biodegradable poly (D,L-lactide-co-glycolide) microparticles.17 The ZYC101a product includes the complete HPV-encoding sequences contained within ZYC101 (HPV-16 E7, human lymphocyte antigen A2 restricted), in addition to regions encoding segments of HPV-16 and HPV-18 E6 and E7 viral proteins. Although built upon these 2 HPV oncogenic types, the drug construct was designed to elicit broad-spectrum anti-HPV activity by using sequences that contain cross-reactive T cell epitopes. ZYC101a supplied as lyophilized powder was reconstituted with United States Pharmacopeia sterile saline for a final volume of 1 mL. The placebo was sterile United States Pharmacopeia saline. Because the placebo did not match the study drug in appearance, a research pharmacist, or designee, reconstituted and prepared the solution for injection. The syringe was then given to a nurse not associated with subject contact and evaluation, who administered the injection under conditions that masked the identity of study drug from the subject and all other study staff.
At enrollment (up to 12 weeks before the first dose was administered), all eligible subjects underwent a medical history and physical examination. Subjects were monitored by colposcopic evaluation, cytology, and HPV testing at weeks 6, 10, 18, and 26. Additional visits included colposcopic evaluations at weeks 0, 3, 14, and 22.
Entry into the study was based on a community-obtained histopathologic diagnosis. Entry cervical diagnostic punch biopsy and exit cone biopsy were independently reviewed by 2 study pathologists and classified according to published criteria.18,19 Nonconcordant diagnoses were adjudicated by independent review of the slides by a third pathologist and consensus achieved in a conference of all 3 study pathologists who remained blinded to treatment assignment.
Pap samples were collected in liquid-based medium (ThinPrep; Cytyc Corporation, Boxborough, MA) at study sites, coded, and submitted to a central laboratory for processing and cytologic evaluation. After evaluation, all the samples were transported to the HPV testing laboratory for polymerase chain reaction and DNA hybrid capture analysis.
For the polymerase chain reaction analysis, 1 mL of liquid sample (PreservCyt; Cytyc Corporation) was processed,20 and an aliquot was analyzed by polymerase chain reaction using MY09/MY11 primers designed to amplify a product from the L1 open-reading frame of a wide spectrum of HPV types.21 The HPV types were assigned by comparison of restriction-fragment–length polymorphisms with published sequence data.22 Each experiment included a set of positive and negative control samples. Hybrid Capture II analysis (Digene Corporation) was performed on 4 mL of the residual PreservCyt sample.23
General immune status as well as the level of HPV-directed immune reactivity was evaluated at each visit using 
interferon enzyme-linked immunospot with phytohemagglutinin or sets of pooled peptides derived from the ZYC101a coding region. The limit of detection and the fold change required for scoring as a positive response was calculated by analyzing the intraassay and interassay variability.
The primary efficacy variable was based on the histologic diagnosis of conization-derived cervical tissue (presence or absence of CIN 2/3). Inclusion in this endpoint analysis required confirmation of the initial diagnosis of CIN 2/3 by the independent panel of pathologists, each of whom was blinded to patient treatment. Histologic resolution was defined as an outcome of either "normal" or "CIN 1," which included the category of "atypical squamous epithelium suggestive of HPV" at time of exit. Lack of histologic resolution was defined as residual CIN 2/3 or invasive carcinoma at study exit. In general, continuous variables were summarized by descriptive statistics, including number, mean, median, standard deviation, minimum, and maximum. Categorical variables were presented with the number and percentage in each category. All percentages were calculated using nonmissing data as the denominator. All statistical tests were 2-sided with an 
= .05 level of significance. The demographic and baseline diagnostic data between placebo and the combined active groups were calculated. The P values were based on Cochran-Mantel-Haenszel tests for colposcopy, and on Fisher exact test for the other data. For colposcopy, the Cochran-Mantel-Haenszel test, stratified by pooled center, was performed. For other efficacy variables, the Fisher exact test was performed because the data came from a central laboratory or reader. The center-to-center variation was taken into account only for the colposcopy, which was performed at the individual centers. Because histology was based on an independent reader, there was no center variation to control for. For all efficacy analyses, unless explicitly stated otherwise, placebo was compared against the 2 active groups combined, and only if the P value was lower than .05 was placebo compared against each of the active treatment groups separately. The populations analyzed included the safety population (all patients receiving at least 1 dose) and the modified intent-to-treat population (patients who had confirmed CIN 2/3 at baseline and who had cone biopsy data with a confirmed exit diagnoses). Analyses were also performed on a prospectively defined subpopulation of the modified intent-to-treat population of subjects who were younger than 25 years. This was supported by the findings of the phase 1 study showing that 100% of the patients (n = 4) younger than 25 years experienced resolution of CIN 2/3 after treatment with ZYC101. All statistical analyses were performed using PC SAS 6.12 (SAS Institute, Cary, NC).
An additional substudy, using a single set of 20 LEEP slides that was not associated with the trial, was performed to explore the level of interreader variability. The slide set was sent consecutively to each of the 3 study pathologists. A 
statistic was computed between each pair of readers.
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RESULTS |
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). This group was evaluated for drug safety and tolerability. Of the original group of 161 subjects, 27 were found to have enrollment biopsy findings that were not confirmed by the independent panel of pathologists as CIN 2/3. This finding suggests that a significant number of biopsies were overread by the local pathology laboratories. Another 7 subjects did not have exit histopathology results for review at the conclusion of the study (4 subjects were pregnant, 1 was lost to follow-up, 1 underwent conization at a clinic not associated with the trial, and 1 exit slide was not available for adjudication). Therefore, 127 subjects were eligible for analysis of drug-efficacy endpoints (modified intent-to-treat population). The randomization of patients into the different groups is detailed in Table 1 and illustrates balance across the 3 study arms with regard to age, race/ethnicity, human lymphocyte antigen type, hormonal birth control use, tobacco use, and the presence of HPV-16 or HPV-18 (Table 2). Twenty-four distinct HPV types were identified at baseline, including types 16, novel, 31, 58, 52, 56, 66, 18, and 53 (listed in order of prevalence). Novel viruses were those for which restriction-fragment–length polymorphism patterns could not be assigned to a known virus type.
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. The study drug was well tolerated at both the 100-µg and 200-µg dose levels, with no major systemic side effects reported. Local injection site reactions, including mild-to-moderate pain, erythema, and induration, were more frequently reported by women receiving ZYC101a, regardless of dose, compared with placebo (P < .05). In each case, these symptoms resolved spontaneously or with the use of nonprescription analgesics. Compared to placebo, more subjects in the combined ZYC101a group (albeit not a statistically significant number) reported other events, including unspecified injection-site reactions, sore throat not otherwise specified, and back pain; however, there was no dose-effect trend for these events. Two subjects reported serious adverse events; 1 in the placebo group (ovarian dermoid complicated by subsequent postoperative ileus) and 1 in the ZYC101a group (breast cancer diagnosed 1 week after the first injection); however, the investigators concluded that neither was causally related to study drug. A total of 6 pregnancies occurred as a consequence of contraceptive failures during the course of the study; 4 of these occurred in the ZYC101a study arms. Overall, 4 pregnancies resulted in live births. One pregnancy was electively terminated, and 1 pregnant subject was lost to follow-up. One subject, a 33-year-old randomized to the 200-µg dose, had stage III invasive squamous cell carcinoma upon review of the LEEP conization specimen. Neither serial cytology nor colposcopy had detected disease progression in this subject before LEEP, and a review of the biopsy and endocervical curettage specimens at entry did not indicate carcinoma.
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). In the moderate intent-to-treat population, there was no statistical difference (P = .12) in clearance of disease at the time of conization among subjects receiving ZYC101a (43%) compared with those receiving placebo (27%). In the prospectively defined subgroup of women younger than 25 years, there was a statistically higher disease resolution rate for subjects treated with ZYC101a compared with placebo (70% versus 23%, P = .007). Given the intent and design of the ZYC101a formulation, broad antiviral activity was anticipated and the results from this study confirm that resolution induced by ZYC101a was not limited to specific HPV types. Subjects younger than 25 years with HPV-16 or HPV-18 at study entry, as well as subjects with other HPV subtypes at entry, experienced higher rates of resolution than did the corresponding subjects who received placebo (64% versus 22% and 73% versus 25%, respectively).
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The proportion of subjects within each treatment group without colposcopically visible lesions increased slowly but consistently, from 0% at baseline to between 35–40% at the time of LEEP. Although the patients younger than 25 years tended to have smaller lesions, the size of lesion at entry was not a predictor of clinical outcome when the entire study population was considered.
Further analyses using descriptive statistics were performed on the 2 age groups (younger than 25 years versus 25 years or older) to explore which factors might influence the resolution rates on ZYC101a (Table 5). Almost twice as many subjects younger than 25 years as compared to those 25 years or older had more than 1 HPV type at baseline or experienced new distinct HPV exposures while participating in the study. These data may explain why 30% more subjects younger than 25 years had elevated immune responses to HPV at baseline. These age groups were comparable in the general immune status at baseline (as determined by mitogenic stimulations). Although immune responses to HPV did increase in many subjects (Table 5), there was no correlation between an elevated HPV-specific immune responses and clinical response. Fifty percent of the younger women had a history of at least 1 live birth at study entry; this rate was increased to 75% in the older women. Compared with subjects 25 years or older, fewer subjects younger than 25 years used oral contraceptives (49% versus 60%), but this difference was not statistically significant. Each of the prospectively determined covariates was independently evaluated in logistic regression analyses. The single factor that significantly influenced clinical outcome was age, but only if the subjects were treated with ZYC101a.
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DISCUSSION |
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The independent panel of pathologists determined that a significant number of patient biopsy results were not indicative of CIN 2/3. As a result, many patients were not available for the primary efficacy endpoint analysis. To prevent this in future studies, a centralized pathology laboratory will be used and biopsy samples will be confirmed for CIN 2/3 before randomization. The high interobserver concordance rates ( between 0.6 and 0.8) among study pathologists confirmed the objectivity and utility of this histologic endpoint.24
All subjects with confirmed CIN 2/3 at entry and with evaluable LEEP specimens were included in the analysis of the primary endpoint. In this population, there was no statistically significant difference in histologic resolution in the combined ZYC101a treatment group compared to placebo. However, analyses of the prospectively defined population of subjects younger than 25 years suggested a clinically and statistically significant increase in resolution for those patients treated with ZYC101a versus placebo. The analysis of this population was suggested by findings of the phase 1 study.15 In that study, CIN 2/3 resolved in 6 subjects (5 with normal histology and 1 with CIN 1), including 100% of subjects younger than 25 years (4 subjects). The remaining 2 patients with resolution were 28 and 30 years old. Age has been identified as an important covariate in the natural regression rate or persistence of CIN 2/3.25 The finding that a significantly higher proportion of patients younger than 25 years treated with ZYC101a experienced resolution of CIN 2/3 than their older counterparts is clinically important, and is interesting from a biologic perspective. It is unlikely that differences in demography and baseline diagnostic characteristics can explain this observation given that these appear to be balanced between treatment groups in the younger-than-25-years and 25-years-and-older populations. One notable difference between these populations was the higher gravidity and parity rates of those 25 years or older. In addition, the younger-than-25-years group had increased exposure to new viral infections during the study and had higher baseline HPV-directed immune responses. Continuous priming of the immune system by HPV exposures may contribute to the increased baseline responses in these subjects. Older women presenting with CIN 2/3 may have had the disease for quite some time, and a more robust immune response might be required for their elimination. Women younger than 25 years are more likely to have been exposed to virus for a shorter period; thus, their transformed cells are likely to have undergone fewer virus-induced changes. In addition, disease in the older subjects more likely represents an HPV infection that has persisted for longer and has disturbed the local cytokine environment of the cervix. Persistence is associated with an immunosuppressive cytokine profile that could control the activity of effector immune cells.26
ZYC101a was safe and well tolerated. Adverse events were primarily limited to the injection site, which included pain, erythema, induration, and nonspecific reactions, did not intensify after subsequent injection or necessitate medical intervention. In the current study, between 7% (placebo) and 12% (ZYC101a treated) of subjects progressed to early LEEP based on clinical criteria (ie, apparent increase in lesion size or severity of colposcopic appearance); however, none of these patients had histologic evidence of progression beyond CIN 2/3. One subject was determined to have invasive carcinoma at study conclusion, a rate (0.6%) that was expected based on historical data. For women younger than 25 years, this rate would likely be even lower. Collectively, the safety data sets provided by this study as well as by others25,27–29 confirm the safety of a 6-month treatment interval between treatment with a medical therapeutic and reassessment of histology. For ethical reasons, all patients in this study had to undergo definitive treatment at the end of the 6-month period. In future studies, lesion resolution may be measured by a combination of colposcopy and biopsy thereby enabling the durability of the response to be studied. In this regard, study designs such as those proposed by the American Association for Cancer Research Task Force on the Treatment and Prevention of Intraepithelial Neoplasia can be considered.14
Sexual activity in adolescents and young women puts them at significant risk for exposure to high-risk, oncogenic strains of HPV. This has subsequently resulted in a significant increase in the incidence of CIN 2/3 in woman younger than 30 years.19,30 Over the course of a young woman’s life, the current standard of care may result in multiple surgical treatments for CIN 2/3, particularly in women with a history of early sexual activity. Resolution of CIN 2/3 lesions by medical therapeutics such as ZYC101a may eliminate the need for invasive procedures in young women.
The data collected in this study are supportive of the continued clinical development of ZYC101a for the treatment of CIN 2/3 in women younger than 25 years. If the efficacy and safety of ZYC101a are confirmed, a new treatment paradigm might involve administering ZYC101a to the young woman with a diagnosis of CIN 2/3, and after a 6-month period, performing a diagnostic colposcopy and biopsy. A persistent finding of CIN 2/3 would result in the use of invasive procedures, whereas a diagnosis of either CIN 1 or normal histology would lead to continued monitoring consistent with current management guidelines.
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APPENDIX |
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Footnotes |
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Financial Disclosure
This study was fully supported by ZYCOS Inc. Drs. Hedley and Urban are employees of ZYCOS and, as such, have stock options. Drs. Beach and Silverman are consultants for the company and have stock options.
doi: 10.1097/01.AOG.0000110246.93627.17
Received July 3, 2003. Received in revised form October 7, 2003. Accepted October 17, 2003.
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30. Moscicki AB. Human papillomavirus infection in adolescents. Adolesc Gynecol 1999;46:783–807.
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