Symptoms and General Pathology

All Conditions

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Urinary Tract, Sexual Organs, and Pregnancy Conditions

Gland and Hormone Related Diseases

Rare Diseases

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Ovarian Neoplasms

Carcinoma, Ovarian Epithelial

Carcinoma

Endocrine Gland Neoplasms

Ovarian Diseases

Adnexal Diseases

Genital Diseases, Female

Genital Diseases

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Female Urogenital Diseases

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Female Urogenital Diseases and Pregnancy Complications

Genital Neoplasms, Female

Urogenital Neoplasms

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Gonadal Disorders

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Ovarian Cancer

Ovarian Epithelial Cancer

Antineoplastic Agents

All Drugs and Chemicals

Niraparib

Poly(ADP-ribose) Polymerase Inhibitors

Enzyme Inhibitors

SBRT treatment will commence within 7 days post randomisation and will be administered as detailed in the SOPRANO Radiotherapy Planning and Delivery Guidelines document. Doses will vary between 3 fractions over 5 days to 8 fractions over 19 days depending on the location of the lesions being treated.

Niraparib treatment will start 4 weeks post completion of SBRT treatment and will continue daily until disease progression or other discontinuation criteria are met. Niraparib comes in oral tablet form and the starting dose will be 200mg per day (once a day) or 300mg per day (once a day) calculated by participant's weight and platelet count.

SBRT treatment will commence within 7 days post randomisation and will be administered as detailed in the SOPRANO Radiotherapy Planning and Delivery Guidelines document. Doses will vary between 3 fractions over 5 days to 8 fractions over 19 days depending on the location of the lesions being treated.

Niraparib used following SBRT treatment until disease progression

Niraparib oral capsule

SBRT may be delivered using a specialist SBRT platform, such as CyberKnife or with a linear accelerator with SBRT capabilities.

SBRT

Lorna Smith

Laura Moretti

Susana Banerjee

SOPRANO is a multi-centre, randomised phase II trial which aims to assess the impact of Stereotactic radiotherapy (SBRT) and continuing treatment with a PARP inhibitor (PARPi) for patients with oligometastatic or oligoprogressive ovarian, fallopian tube and primary peritoneal carcinoma. SOPRANO will also establish the feasibility and acceptability of delivering SBRT in this setting.

Oligometastases or oligoprogression of ovarian cancer while on a PARPi may occur due to a secondary sub-clonal mutation causing acquired resistance in a small volume of tumour rather than having global tumour resistance. Eradication of the resistant disease with stereotactic radiotherapy (SBRT) would enable continuation of the PARPi to maintain control of disease that has retained drug sensitivity and this has the potential to impact disease outcomes.

For the purposes of this ovarian cancer trial, oligoprogression refers to the situation whereby 3 or less lesions of disease show evidence of progression. If there were previously other sites of disease, these remain in response or stable. Oligometastatic disease refers to the situation whereby complete response to treatment has been obtained and the disease relapse occurs that is limited in number and distribution (≤3 metastatic/recurrent lesions).

SOPRANO will explore whether there is activity of SBRT and SBRT followed by niraparib in the case of oligometastatic or oligoprogression disease post prior PARPi in recurrent ovarian cancer.

The trial will recruit patients with oligometastic or oligoprogressive ovarian cancer (≤3 sites/lesions) who have progressed on or following at least 6 months of treatment with PARP Inhibitor (PARPi). Patients will be randomised to one of two parallel non-comparative treatment cohorts:

* Cohort 1: SBRT followed by niraparib
* Cohort 2: SBRT alone

In both cohorts, therapy will continue until disease progression deemed by the investigator to warrant a change in treatment, unacceptable toxicity, withdrawal of consent or if the investigator decides it is not in the best interest of the patient to continue.

Adverse events, including toxicity from trial treatment will be collected and graded according to The National Cancer Institute (NCI) Common Terminology Criteria (CTC) Version 5.0 (http://ctep.cancer.gov/reporting/ctc.html).

Participants will be asked to consent for future linkage with routinely collected health data via national registries to trace their eventual vital status and assess subsequent unexpected comorbidities.

Assessment of disease by RECIST will be required 8 weekly following completion of SBRT for the first year and 12 weekly thereafter until disease progression meeting the primary endpoint.

SBRT Alone or Followed by Niraparib for Oligometastases or Oligoprogression in Ovarian Cancer Following PARPi Therapy

SOPRANO: Stereotactic Radiotherapy Alone or Followed by Niraparib for Oligometastases or Oligoprogression in Ovarian Cancer Following PARP Inhibitor Therapy

Time to widespread metastatic disease will be measured from the time of randomisation until radiological evidence of widespread metastatic disease, defined as greater than or equal to 4 metastatic sites, regional or distant, or a combination thereof.

Time to second subsequent therapy is defined as time from initiation of first subsequent therapy to commencing second line of therapy (local or systemic) or death (if this occurs before commencement of second subsequent treatment).

Measurement of potential mechanisms of PARP inhibitor resistance, immune-mediated effects, radiosensitivity and toxicities. Measured between baseline and 4 weeks post-SBRT, 16, 24 and 48 weeks post randomisation, and disease progression.

Progression free survival is defined as time from randomisation to evidence of progression of cancer at any site or death from any cause. Progression events should be imaging defined in all tumour types according to RECIST v1.1 criteria. Where SBRT specific consensus response assessment criteria exist for specific sites (e.g. spine), progression of SBRT treated lesions will be defined according to these guidelines.

Time to first subsequent systemic therapy is defined as time from randomisation to commencing next systemic line of therapy or death from any cause (if this occurs before commencement of first subsequent treatment).

Time to first subsequent anti-cancer therapy is defined as time from randomisation to commencing next line of therapy (local or systemic) or death from any cause (if this occurs before commencement of first subsequent treatment).

Overall survival (OS) defined as time from randomisation to death from any cause.

Local control at site of SBRT is defined as time from randomisation until radiological evidence of progression at the treated site and be measured on a lesion based analysis using RECIST v1.1 criteria

Time to 'Out of SBRT field' progression is defined as time from randomisation until radiological evidence of progression outside of treated area(s) for SBRT treatment using RECIST v1.1.

Clinician reported acute and late toxicity will be graded using NCI CTCAE v5.0. Adverse events will be collected from start of treatment to disease progression (and 30 days post last dose of Niraparib for patients in cohort 1.

Functional Assessment of Cancer Therapy - Ovarian (FACT-O): FACT-O is a self-report measure that assesses physical well-being, social/family well-being, emotional well-being, functional well-being and ovarian cancer-specific subscale. The higher the score, the better the QOL.

Quality of Life will be collected at baseline prior to start of SBRT treatment, 4 weeks post SBRT treatment, 16, 24 and 48 weeks post randomisation and at disease progression. Changes from baseline at each time point will be compared within groups as well as between treatment cohorts.

EQ-5D-5L: The EQ-5D-5L is a self-assessed, health related, quality of life questionnaire. The scale measures quality of life on a 5-component scale including mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. The higher the score, the better the QOL.

Quality of Life will be collected at baseline prior to start of SBRT treatment, 4 weeks post SBRT treatment, 16, 24 and 48 weeks post randomisation and at disease progression. Changes from baseline at each time point will be compared within groups as well as between treatment cohorts.

Feasibility of recruitment is defined as the recruitment rate for the trial

Proportion of patients receiving SBRT in the absence of new developing widespread disease, defined as greater than or equal to 4 metastatic sites, regional or distant, or a combination thereof.

Royal Marsden NHS Foundation Trust

Institute of Cancer Research, United Kingdom

Adenocarcinoma

Uterine Neoplasms

Cystadenocarcinoma, Serous

Endometrial Neoplasms

Cystadenocarcinoma

Uterine Diseases

Neoplasms, Cystic, Mucinous, and Serous

Adenocarcinoma of the Appendix

Single arm. Following the initial assessment and endometrial biopsy the participants will receive niraparib for 28 days. After the treatment period the patients will be surgically staged. All participants will receive the standard of care.

Low dose oral niraparib capsules (2 x 100 mg) once a day for 28 days

Shannon Salvador, MD MSc

David Knigin, MD PhD

Walter Gotlieb, MD PhD

The study will investigate the effect of niraparib on tumor tissue in chemotherapy naïve, newly diagnosed, high-grade endometrial cancer patients. Biomarkers of cognate molecular pathways as well as investigational assays will be used to study the antineoplastic effect of the drug.

Niraparib is a FDA approved Poly(ADP-ribose) polymerase inhibitor (PARPi) for the treatment of platinum-sensitive ovarian serous carcinoma. The safety profile of niraparib was established in phase III clinical trials. The therapeutic effect of niraparib on serous endometrial carcinoma is now being investigated in several clinical trials. However, the antineoplastic effect and the safety profile of niraparib in chemotherapy naïve high-grade endometrial cancer patients is unknown. By employing a phase 0 exploratory trial design, the investigators will study the niraparib's effect on endometrial cancer in chemotherapy naïve patients using molecular biomarkers as sentinels for the antineoplastic effect. Women diagnosed by endometrial biopsy with high-grade endometrial cancer will receive niraparib for 28 days. Staging surgery will be performed 4-6 weeks after the diagnosis (standard of care). The investigators will use the pre-operative biopsy and the surgical specimen to perform comparative multidimensional analysis of endometrial tumors before and after exposure to niraparib.

Niraparib in High-grade Endometrial Cancer Trial

The Molecular and the Clinical Effects of Preoperative Niraparib in Patients With High-grade Endometrial Cancer: Phase 0 Exploratory Trial

Gene expression profile by RNA sequencing extracted from snap-frozen tumor tissue. Unsupervised hierarchical clustering of 2-fold changed genes will be used to detect the pathways affected by niraparib treatment.

Mutational signature and the altered genes of the DNA repair pathway will be identified by DNA next generation sequencing. Genomic findings will be correlated with molecular analysis for discovery of biomarkers for niraparib sensitivity in chemotherapy-naïve endometrial cells.

Cancer cell proliferation will be quantitatively assessed using immunohistochemical staining for cell-cycle proteins.

Ki-67 (MIB) stains nuclei of cells in G1-S-G2 phases of the cell-cycle. The proliferation index will be calculated as percent of tumor positive cells. The primary outcome fold change in proliferation index after exposure to niraparib. The quantification will be done by image analysis software with pathologist supervision.

The levels of different cell-cycle related proteins increase and decrease throughout the cell cycle, each having its own expression pattern.

Tumor specimens will be stained for Cyclin D1, Geminin and p21 proteins. The proportion of positive nuclei of each marker after exposure to niraparib will be estimated. The results will be integrated to study the effect of niraparib on endometrial cancer cells proliferation.

Cleaved caspase-3 (cCas-3) marks cells that activated the programmed cell-death process. cCas-3 positive tumor cells will be compared before and after the exposure to niraparib.

Comparison of the thickness of endometrial lining before and after treatment

Investigation of the effect of preoperative niraparib on CA125 levels in patients with high grade endometrial carcinoma

Assessment of adverse effects of niraparib in chemotherapy naïve patients according to CTCAE 5.0

Patients' well being will be assessed by a validated questionnaire: Functional Assessment of Cancer Therapy - General (FACT-G). https://www.facit.org

Patients' well being will be assessed by a validated questionnaire: Functional Assessment of Cancer Therapy - Endometrial (FACT-en). https://www.facit.org

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
SBRT Alone or Followed by Niraparib for Oligometastases or Oligoprogression in Ovarian Cancer Following PARPi Therapy	NCT05990192	Ovarian Cancer ...	Niraparib oral ... SBRT	18 Years -	Institute of Cancer Research, United Kingdom
SBRT Alone or Followed by Niraparib for Oligometastases or Oligoprogression in Ovarian Cancer Following PARPi Therapy	NCT05990192	Ovarian Cancer ...	Niraparib oral ... SBRT	18 Years -	Institute of Cancer Research, United Kingdom
Niraparib in High-grade Endometrial Cancer Trial	NCT05289648	Endometrial Can... Serous Adenocar... Uterine Neoplas...	Niraparib oral ...	18 Years -	Sir Mortimer B. Davis - Jewish General Hospital

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