A phase II randomized trial of Observation versus stereotactic ablative RadiatIon for OLigometastatic prostate CancEr (ORIOLE)

Abstract

Background: We describe a randomized, non-blinded Phase II interventional study to assess the safety and efficacy of stereotactic ablative radiotherapy (SABR) for hormone-sensitive oligometastatic prostate adenocarcinoma, and to describe the biology of the oligometastatic state using immunologic, cellular, molecular, and functional imaging correlates. 54 men with oligometastatic prostate adenocarcinoma will be accrued. The primary clinical endpoint will be progression at 6 months from randomization with the hypothesis that SABR to all metastases will forestall progression by disrupting the metastatic process. Secondary clinical endpoints will include local control at 6 months post-SABR, toxicity and quality of life, and androgen deprivation therapy (ADT)-free survival (ADT-FS). Further fundamental analysis of the oligometastatic state with be achieved through correlation with investigational 18F-DCFPyL PET/CT imaging and measurement of circulating tumor cells, circulating tumor DNA, and circulating T-cell receptor repertoires, facilitating an unprecedented opportunity to characterize, in isolation, the effects of SABR on the dynamics of and immunologic response to oligometastatic disease.

Methods/design: Patients will be randomized 2:1 to SABR or observation with minimization to balance assignment by primary intervention, prior hormonal therapy, and PSA doubling time. Progression after 6 months will be compared using Fisher's exact test. Hazard ratios and Kaplan-Meier estimates of progression free survival (PFS), ADT free survival (ADT-FS), time to locoregional progression (TTLP) and time to distant progression (TTDP) will be calculated based on an intention-to-treat. Local control will be assessed using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. Withdrawal from the study prior to 6 months will be counted as progression. Adverse events will be summarized by type and grade. Quality of life pre- and post- SABR will be measured by Brief Pain Inventory.

Discussion: The ORIOLE trial is the first randomized, non-blinded Phase II interventional study in the North America evaluating the safety and efficacy of SABR in oligometastatic hormone-sensitive prostate cancer. Leading-edge laboratory and imaging correlates will provide unique insight into the effects of SABR on the oligometastatic state.

Trial registrations: ClinicalTrials.gov Identifier: NCT02680587. URL of Registry: https://ichgcp.net/clinical-trials-registry/NCT02680587 Date of Registration: 02/08/2016. Date of First Participant Enrollment: 05/23/2016.

Keywords: Oligometastasis; Prostate cancer; Stereotactic ablative radiotherapy; Stereotactic body radiation therapy.

Conflict of interest statement

Ethics approval and consent to participate

This study will be carried out in compliance with the protocol and Good Clinical Practice, as described in: ICH Harmonized Tripartite Guidelines for Good Clinical Practice 1996; US 21 Code of Federal Regulations dealing with clinical studies (including parts 50 and 56 concerning informed consent and IRB regulations); and the Declaration of Helsinki, concerning medical research in humans (Recommendations Guiding Physicians in Biomedical Research Involving Human Subjects, Helsinki 1964, amended Tokyo 1975, Venice 1983, Hong Kong 1989, Somerset West 1996). The investigator agrees to adhere to the instructions and procedures described in it and thereby to adhere to the principles of Good Clinical Practice. Written informed consent are obtained from each patient before any study-specific procedure takes place. Participation in the study and date of informed consent patient are being documented appropriately in each patient’s files. A Data Monitoring Committee is in place to monitor the trial. Data and safety monitoring oversight is conducted by the SKCCC at Johns Hopkins Safety Monitoring Committee. Per the SKCCC at Johns Hopkins Safety Monitoring plan, the CRO AQ will forward summaries of all monitoring reports to the Safety Monitoring Committee for review.

Consent for publication

Not applicable.

Competing interests

MGP is a co-inventor on a US Patent covering 18F–DCFPyL and as such is entitled to a portion of any licensing fees and royalties generated by this technology. This arrangement has been reviewed and approved by the Johns Hopkins University in accordance with its conflict of interest policies. MAG has served as a consultant to Progenics Pharmaceuticals, the licensee of 18F–DCFPyL. The remaining authors declare no conflict of interest.

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Figures

Fig. 1

ORIOLE Study Schema. Subjects who meet eligibility criteria and qualify for enrollment will be stratified and randomized as demonstrated