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

Official title

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

Overview

SOPRANO is a multi-centre phase II trial designed to assess the impact of SBRT with or without 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.

Detailed description

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). Participants may enter 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.

Interventions

• Drug Niraparib oral capsule
  Niraparib used following SBRT treatment until disease progression
• Radiation SBRT
  SBRT may be delivered using a specialist SBRT platform, such as CyberKnife or with a linear accelerator with SBRT capabilities.

Primary outcome measures

• Progression free survival [Time frame: The primary timepoint of most interest for PFS is at six months after trial entry]

Secondary outcome measures (10)

• Time to first subsequent systemic therapy [Time frame: Time to first subsequent systemic therapy assessed up to 2 years after trial entry.]
• Time to first subsequent anti-cancer therapy [Time frame: Time to first subsequent anti-cancer therapy assessed up to 2 years after trial entry.]
• Overall survival [Time frame: The primary timepoint of interest for OS is at two years after trial entry.]
• Local control at site of SBRT [Time frame: Local control at site of SBRT assessed up to 2 years after trial entry.]
• Time to 'Out of SBRT field' progression [Time frame: Time to 'Out of SBRT field' progression assessed up to 2 years after trial entry.]
• Clinician reported acute and late toxicity [Time frame: Acute events are defined as those occurring up to 3 months follow up; late events are reported from 6 months post trial entry.]
• Quality of Life Assessments - FACT-O [Time frame: 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 trial entry and at disease progression.]
• Quality of Life Assessments - EQ5D [Time frame: 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 trial entry and at disease progression.]
• Feasibility of recruitment rate for the trial [Time frame: Recruitment is expected to be over 2.5 years]
• Proportion of patients receiving SBRT in the absence of new developing widespread disease [Time frame: Proportion of patients receiving SBRT in the absence of new developing widespread disease assessed up to 2 years after trial entry.]

Eligibility criteria

Inclusion criteria

• Patients ≥ 18 years of age.
• Histologically confirmed epithelial ovarian, fallopian tube or primary peritoneal cancer. (if cytology report includes immunohistochemistry confirming ovarian cancer, patient should not be excluded).
• Radiological disease progression whilst on, or following, any prior PARP inhibitor therapy. The PARP inhibitor is required to have been the patient's last systemic therapy.
• Minimum duration of 6 months PARP inhibitor therapy as first line therapy or treatment for recurrent disease.
• ≤3 lesions of progressive disease.
• Each lesion to undergo SBRT <4 cm axial diameter, and feasible for SBRT as discussed in the SOPRANO virtual MDT (vMDT) meeting.
• Measurable disease by RECIST criteria v1.1, which can be accurately assessed at baseline by CT or MRI. Patients with CA125 progression in the absence of measurable disease will NOT be eligible. The following is an exception to this criterion: Lymph nodes with a short-axis diameter ≥10 mm may be included when there is clear evidence of malignancy (e.g., PET-positive nodes and radiologically progressive disease), acknowledging that clinically significant nodal disease may occur below the standard RECIST threshold.
• No contra-indication to restarting a PARP inhibitor.
• Patients for whom surgery for recurrent disease is not planned.
• Adequate baseline organ function to allow SBRT to all relevant targets as deemed by the investigator.
• ECOG performance status of 0 or 1.
• Predicted life expectancy ≥ 6 months.
• Women of child-bearing potential who are confirmed NOT to be pregnant. This should be evidenced by a negative urine or serum pregnancy test within 72 hours prior to start of trial treatment. Patients will be considered to be not of child-bearing potential if they are:

• Post-menopausal -- defined as aged more than 50 years and amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments, OR women under 50 years old who have been amenorrhoeic for at least 12 months following cessation of all exogenous hormonal treatments and have serum follicle- stimulating hormone (FSH), luteinizing hormone (LH) and plasma oestradiol levels in the post-menopausal range for the institution.
• Able to provide documentation of irreversible surgical sterilisation by hysterectomy, bilateral ovarian failure or bilateral salpingectomy but not tubal ligation.
• Radiation or chemotherapy-induced oophorectomy or menopause with > 1 year since last menses.
• Willingness to commit to scheduled visits, treatments plans, laboratory tests and trial procedures.
• Histological tissue specimen (tissue block or 8-10 unstained slides) must be available prior to commencing SBRT (specimen can be the sample at diagnosis or taken at relapse or progression). Otherwise, a biopsy must be carried out to obtain sufficient tissue for translational analyses.
• Able to swallow, absorb and retain oral medication.
• Able to provide written, informed consent.

Exclusion criteria

• Co-morbidities which would preclude the safe use of SBRT.
• Progressing or newly diagnosed brain metastases identified at the time of trial entry, not amenable to radical surgery or stereotactic radiosurgery. Previously treated brain metastases (i.e. palliative radiotherapy or systemic therapy) which have remained clinically and radiologically stable for ≥ 6 months are permissible.
• Prior radiotherapy near the oligometastatic / oligoprogressive lesion precluding ablative SBRT. Suitability of lesions for ablative SBRT as part of the trial defined in Section 6.1 of this document and will be determined by the SOPRANO virtual MDT.
• Treatment with any other investigational medicinal product (IMP) within the 4 weeks prior to trial entry.
• Pregnant or lactating women.
• Women of childbearing age and potential who are not willing to use a highly effective contraceptive measure.
• Any unresolved toxicities from prior therapy should be no greater than CTCAE Grade 1 with the exception of Grade 2 alopecia or chemo-induced neuropathy at trial entry.
• Clinical/radiological evidence of bowel obstruction (e.g. hospitalisation) or symptoms of sub-acute bowel obstruction within 6 weeks prior to trial entry.
• Any other malignancy which has been active or treated within the past 3 years, with the exception of non-melanoma skin cancer. If prior treatment for another malignancy has taken place, then confirmation of ovarian/fallopian tube/peritoneal cancer progression is required e.g. biopsy, and discussion with the trial Chief Investigator and SBRT Lead
• Judgment by the Investigator that the patient is unsuitable to participate in the trial and/or the patient is unlikely to comply with trial procedures, restrictions and requirements.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

United Kingdom · 7 centers

• St James's University Hospital — Leeds
• Leicester Royal Infirmary — Leicester
• The Christie NHS Foundation Trust — Manchester
• Western General Hospital — Edinburgh
• The Royal Marsden NHS Foundation Trust — Sutton
• University College London Hospitals — London
• The Royal Marsden NHS Foundation Trust — London

Identifiers

NCT: NCT05990192 · ICR-CTSU/2022/10082 · 2022-003175-42 · CCR5726 · 23/LO/0719

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗