J.A. Villella

Ovarian cancer clinical trial endpoints: Society of Gynecologic Oncology white paper

OBJECTIVE To explore the value of multiple clinical endpoints in the unique setting of ovarian cancer. METHODS A clinical trial workgroup was established by the Society of Gynecologic Oncology to develop a consensus statement via multiple conference calls, meetings and white paper drafts. RESULTS Clinical trial endpoints have profound effects on late phase clinical trial design, result interpretation, drug development, and regulatory approval of therapeutics. Selection of the optimal clinical trial endpoint is particularly provocative in ovarian cancer where long overall survival (OS) is observed. The lack of new regulatory approvals and the lack of harmony between regulatory bodies globally for ovarian cancer therapeutics are of concern. The advantages and disadvantages of the numerous endpoints available are herein discussed within the unique context of ovarian cancer where both crossover and post-progression therapies potentially uncouple surrogacy between progression-free survival (PFS) and OS, the two most widely supported and utilized endpoints. The roles of patient reported outcomes (PRO) and health related quality of life (HRQoL) are discussed, but even these widely supported parameters are affected by the unique characteristics of ovarian cancer where a significant percentage of patients may be asymptomatic. Original data regarding the endpoint preferences of ovarian cancer advocates is presented. CONCLUSIONS Endpoint selection in ovarian cancer clinical trials should reflect the impact on disease burden and unique characteristics of the treatment cohort while reflecting true patient benefit. Both OS and PFS have led to regulatory approvals and are clinically important. OS remains the most objective and accepted endpoint because it is least vulnerable to bias; however, the feasibility of OS in ovarian cancer is compromised by the requirement for large trial size, prolonged time-line for final analysis, and potential for unintended loss of treatment effect from active post-progression therapies. A large magnitude of effect in PFS improvement should establish benefit, and further communication with regulatory authorities to clarify acceptable endpoints should be undertaken.

Survivin-targeted immunotherapy drives robust polyfunctional T cell generation and differentiation in advanced ovarian cancer patients

DepoVax™ is an innovative and strongly immunogenic vaccine platform. Survivin is highly expressed in many tumor types and has reported prognostic value. To generate tumor-specific immune response, a novel cancer vaccine was formulated in DepoVax platform (DPX-Survivac) using survivin HLA class I peptides. Safety and immune potency of DPX-Survivac was tested in combination with immune-modulator metronomic cyclophosphamide in ovarian cancer patients. All the patients receiving the therapy produced antigen-specific immune responses; higher dose vaccine and cyclophosphamide treatment generating significantly higher magnitude responses. Strong T cell responses were associated with differentiation of naïve T cells into central/effector memory (CM/EM) and late differentiated (LD) polyfunctional antigen-specific CD4+ and CD8+ T cells. This approach enabled rapid de novo activation/expansion of vaccine antigen-specific CD8+ T cells and provided a strong rationale for further testing to determine clinical benefits associated with this immune activation. These data represent vaccine-induced T cell activation in a clinical setting to a self-tumor antigen previously described only in animal models.

Outcomes of endometrial cancer patients undergoing surgery with gynecologic oncology involvement

OBJECTIVE This study was undertaken to compare the outcomes of patients with endometrial cancer who had primary surgery with gynecologic oncology involvement at university or community hospitals. METHODS The study population consisted of all patients who had primary surgery for endometrial cancer with involvement of the attending physicians of the Division of Gynecologic Oncology. The patients were divided into two groups based on whether their surgery was performed at a university or community hospital. Demographic and clinical data were abstracted from the medical records. RESULTS There were no significant differences between the two groups with regard to Quetelet index (kg/m2); intervals between biopsy and consultation, consultation and surgery, and biopsy and surgery; estimated blood loss; incidence of operative or hospital complications; frequency of appropriate surgical staging; stage distribution; histology or grade; and hospital stay. Patients at a university hospital were significantly older, had a higher severity index, were more likely to have had a vaginal hysterectomy, and participate in a research protocol. Both the Quetelet index and the severity index were significantly higher for patients who had vaginal hysterectomy than for those who had either laparoscopically assisted vaginal hysterectomy or total abdominal hysterectomy. When analyzed by surgical approach, the frequencies of pelvic and paraaortic lymph node sampling were comparable between the groups. Both the Quetelet and severity indices were significantly higher for patients who did not have lymph node sampling. CONCLUSION Involvement of a gynecologic oncologist at the time of primary surgery for endometrial cancer was associated with comparable outcomes in both the university and community hospital setting.