Signal TrAnsduction Pathway Activity Analysis in OVarian cancER

Rationale: Ovarian cancer is one of the most lethal cancers in the world. Standard therapy consists of debulking surgery and chemotherapy. However, despite this aggressive treatment, recurrent disease almost invariably occurs resulting in a five-year survival rate of approximately 30%. Tumour growth is driven by several signal transduction pathways (STPs), and twelve major STPs have been identified as important for carcinogenesis. Currently, several targeted therapy drugs are available and new targeted drugs are being developed. With a newly developed technique, Signal Transduction Activation (STA) analysis, it is possible to assess which pathway is predominant in a specific (ovarian) cancer sample. Therefore, we hypothesize that specifically targeting the predominant STP might impair tumour growth and improve survival.

Objective: This study aims to investigate the progression-free survival (PFS) according to RECIST 1.1 criteria on matched targeted therapy by STA-analysis (PFS2) in comparison to the PFS recorded on the therapy administered immediately prior to enrolment (PFS1) in women with recurrent ovarian cancer.

Study design: A multi-centre prospective, parallel-group, cohort study. Study population: Recurrent ovarian cancer patients with platinum-resistant disease, patients who refrain from standard therapy and patients who are not yet eligible for standard palliative chemotherapy, including all histological subtypes.

Intervention: STA-analysis will be performed on a biopsy taken from the recurrent tumour. Patients will be included if a predominant pathway is identified for which a matched targeted drug is available and deemed adequate by the multidisciplinary tumour board. We will start with targeted therapy in patients with oestrogen receptor, androgen receptor, phosphoinositide 3-kinase and Hedgehog pathway active tumours, since targeted therapy interceding these pathways are easily available with tolerable side effects.

Main study parameters/endpoints: The primary outcome is therapy response defined as PFS2/PFS1 ratio according to RECIST 1.1 criteria. Secondary outcomes include the proportion of patients with an actionable active pathway and the proportion of patients receiving matched targeted therapy, best overall response (according to RECIST 1.1 criteria), one-year survival, overall survival, predictive value of STA-analysis results, side effects, quality of life, cost-effectiveness and change in STP activity score comparing the score before treatment and after disease progression.

• Proportion of patients with an actionable active pathway for which targeted therapy is recommended in relation to the number of patients who underwent a biopsy. [Срок оценки: From date of biopsy until the date of the result from Multi-disciplinary Tumor Board Meeting, up 14 days after biopsy date.]
• Proportion of patients who receive matched targeted therapy in relation to the number of patients included in each study arm. [Срок оценки: From start date matched targeted therapy until the end of the study enrollment, up to 36 months.]
• Best overall response defined by RECIST 1.1 criteria based on radiological imaging. [Срок оценки: From baseline, radiological evaluation every 12 weeks after the start of targeted therapy until the date of documented disease progression or death, whichever comes first, assessed up to 12 months.]
• One-year survival [Срок оценки: From start date of targeted therapy until date of death or one year follow-up, whichever comes first.]
• Overall survival [Срок оценки: From start date of targeted therapy until the date of death, assessed up to 36 months.]
• Predictive value of STA-analysis results on matched targeted therapy response. [Срок оценки: From start date targeted therapy until response evaluation at 12 weeks after start of targeted therapy.]
• Side effects [Срок оценки: From start date of targeted therapy after two weeks, every 12 weeks from targeted therapy start date, until 12 weeks after end of treatment.]
• Health Related Quality of Life [Срок оценки: From baseline, every 12 weeks after start date of treatment until 12 weeks after end of treatment.]
• Cost-effectiveness [Срок оценки: From baseline, every 12 weeks after start date of targeted therapy until 12 weeks after end of treatment.]
• Change in pathway activity score after disease progression compared to pathway activity score before start of matched therapy. [Срок оценки: From date of biopsy until 4 weeks after date of documented progression of disease.]