| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| High grade serous ovarian cancer (includes histologically identical fallopian tube and primary peritoneal cancers and high grade G3 endometrioid histological subtypes) |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10066697 |
| E.1.2 | Term | Ovarian cancer recurrent |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To compare the length of remission from ovarian, primary peritoneal and fallopian tube cancer for patients taking rucaparib alone with patients on combinations of rucaparib with nivolumab or nivolumab and ipilimumab. This will be assessed using scan changes to show cancer shrinkage. Only patients with cancer that has come back and whose cancer is likely to respond to rucaparib (based on testing of their cancer tissue) will be recruited. |
|
| E.2.2 | Secondary objectives of the trial |
To assess the relative efficacy and safety of the addition of nivolumab +/- ipilimumab to rucaparib compared to rucaparib alone.
Overall Response (based on RECIST 1.1), RECIST and GCIG CA125 criteria and Ir-RECIST
Duration of RECIST Response
Overall Survival
Safety and Tolerability (toxicities will be coded using NCI-CTCAE Version 5)
Quality of Life (as measured by EQ-5D questionnaire)
Resource use for health economic assessment |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Age ≥16 yrs
- Written informed consent
- Histologically confirmed high-grade serous or Grade 3 endometrioid relapsed (as defined by RECIST v1.1) epithelial ovarian, fallopian tube, or primary peritoneal cancer:
If mixed histology >50% of the primary tumour must be confirmed to be high-grade serous or endometrioid upon review by local pathology with <50% being ‘other’, generally carcinosarcoma
Patients with high grade ovarian cancer histology of other than serous or endometrioid are also eligible if they are already known to harbour a deleterious germline or somatic BRCA1/2 mutation
NB patients who have an original diagnosis based on cytology only will not be eligible for trial entry unless a biopsy confirming criteria above is performed
- Received ≥1 prior platinum containing chemotherapy regimen(s).Patients can have had up to 3 prior lines (including primary therapy) of therapy for ovarian cancer. Agents administered in the maintenance setting will not be counted as a separate regimen but these must have been stopped at least 28 days prior to trial treatment. Hormonal agents (e.g. tamoxifen, letrozole, etc.), anti-angiogenic agents (e.g. bevacizumab, pazopanib, cediranib, etc.) and other non-chemotherapy agents will not be counted as a chemotherapy regimen but must have been stopped at least 28 days prior to trial treatment. No previous PARP inhibitor, anti-PD-1 or anti-PDL-1 or CTLA4 therapy.
- Had documented treatment-free interval of ≥3 - <12 months following the last chemotherapy regimen received. These time points are defined as time between Day 1 last cycle (this does not have to be a platinum but could be single agent liposomal doxorubicin or weekly taxol) and RECIST evaluable disease progression
-Has documented platinum free interval of ≥3 - <12 months from last platinum containing regimen. These time points are defined as time between Day 1 last cycle and first subsequent RECIST evaluable disease progression.
- RECIST evaluable disease (by RECIST criteria v1.1). Patients with CA125 progression in the absence of RECIST measurable disease will NOT be eligible
- Already known to have a deleterious germline or somatic BRCA1/2 mutation (central confirmation still required)OR be gBRCAwt LoHHIGH as confirmed by the central laboratory (Foundation Medicine)
NB: Tissue from BRCA mutant patients already identified locally will be required for confirmation. Sufficient archival formalin-fixed paraffin-embedded (FFPE) tumour tissue of adequate quality (see below) must be available for the central laboratory testing. Cytospin blocks from ascites are not acceptable. To be acceptable for Foundation Medicine testing, tumour tissue must be the most recently obtained specimen with at least 30% tumour content, and a minimum of 80% nucleated cellular content. In the event that archival tumour tissue is not available a screening biopsy sample must be collected and provided to the central laboratory
- Willingness to undergo mandatory biopsy pre cycle1 day1 (where technically feasible)(target lesions (RECIST criteria v1.1) should be avoided if possible).Patient who do not have disease amenable to biopsy are exempt from the biopsy provided all other inclusion criteria are met, they must have archival tumour tissue available for FM testing
- Adequate haematological and biochemical function as indicated below, performed within 14 days prior to randomization:
Absolute neutrophil count ≥1.5 x 109/L
Platelet count ≥100 x 109/L
Haemoglobin ≥90 g/L
Serum creatinine <1.5xULN or creatinine clearance ≥45 mL/min (measured or calculated by Cockcroft and Gault equation/Wright formula); confirmation of creatinine clearance is only required when serum creatinine is >1.5xULN
Total bilirubin <1.5xULN. In cases of Gilbert’s syndrome, bilirubin <2xULN is allowed
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) <3xULN if no demonstrable liver metastases or <5xULN in the presence of liver metastases
Alkaline phosphatase <5xULN
- Willingness to comply with scheduled visits, treatment plans and lab tests and other trial procedures.
- Evidence of non-childbearing status. For women of childbearing potential: negative serum pregnancy test within 7 days of randomisation and 1 day of trial treatment
- Patients with synchronous tumours
-Life expectancy of >12 wks
-ECOG 0 or 1 |
|
| E.4 | Principal exclusion criteria |
- Prior chemotherapy, biological therapy, radiation therapy, hormonal anti-cancer therapy, immunotherapy, other anticancer agents within 28 days of starting trial treatment (does not include palliative radiotherapy at focal sites which cannot be used as measurable RECIST target sites). Treatment with any other investigational agent within the preceding 4 weeks or within 5 half-lives of the investigational agent, whichever is longer.
- Any prior PARP inhibitor, anti PD-1 or anti PD-L1, anti-PD-L2, anti-CD137, or cytotoxic T lymphocyte-associated antigen 4 (CTLA4) antibody (including ipilimumab, tremelimumab or any other antibody or drug specifically targeting T-cell co-stimulation or immune checkpoint pathways.
- Pregnant or lactating
- Women of childbearing age and reproductive potential who are not willing, or their male partners are not willing, to use two highly effective forms of contraception.
- With the exception of alopecia and stable peripheral neuropathy from previous taxanes, any unresolved toxicities from prior chemotherapy should be no greater than CTCAE G1 at time of starting trial treatment
- Major surgery within 3weeks or minor surgery within 5days of trial entry (excluding placement of vascular access devices)
- Spinal cord compression, known leptomeningeal involvement or brain metastases, unless treated and stable off steroids for at least 4 weeks prior to randomization
- Warfarin is not permitted.Anticoagulation with low molecular weight heparin and anti Factor X is allowed. Patients who have a new diagnosis of deep vein thrombosis or pulmonary embolism within 2 weeks of randomisation are permitted if clinically stable on a therapeutic dose of LMWH or anti-Factor X.
- Any haemopoietic growth factors (e.g G-CSF, GM-CSF, erythropoeitin) and blood/platelet transfusions within 2weeks prior to randomization or patients requiring regular blood transfusions (e.g 2 or more times in the 4weeks prior to first dose of trial drug),granulocyte colony-stimulating factor,or platelet transfusions.
- Hospitalization for bowel obstruction within 3months prior to randomization
- Any gastrointestinal disorder or defect that would, in the opinion of the Investigator, interfere with absorption of rucaparib
- Has a known diagnosis of immunodeficiency, active infection including hepatitis B, hepatitis C, and human immunodeficiency virus (screening for these is not required). Receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7days prior to first dose of trial treatment. Includes prior organ transplantation including allogenic stem-cell transplant. The following are exceptions to this exclusion criterion:
a.Intranasal, inhaled, topical steroids, or local steroid injections (e.g intra-articular injection)
b.Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or equivalent
c.Steroids as premedication for hypersensitivity reactions (e.g CT scan premedication)
- Has a known history of active TB (Bacillus Tuberculosis)
- Previous additional malignancy that is processing or has required active treatment in the last 2years. Exceptions include:
o Non-melanomatous skin cancer (if adequately treated)
o previous DCIS or breast cancer > 5 years as long as adequately treated or
o in situ or early (up to stage 1B1) cervical cancer (if adequately treated)
o VIN or vulval cancer (if adequately treated)
o prior or synchronous endometrial cancer (if adequately treated), provided all of the following criteria are met: G1 or G2, no LVSI and FIGO (2010) stage IA only
- Has active autoimmune disease that has required systemic treatment in the past 2years (i.e with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g levothyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. Patients with diabetes typeI, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible.
- Has received a live vaccine within 30 days of planned start trial therapy.
- Any evidence of severe or uncontrolled systemic disease
- Hypersensitivity to trial IMPs and their excipients |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression free survival (PFS) based on RECIST v1.1. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Patients will have scans performed every 8 weeks during the first year, thereafter 16 weekly until RECIST disease progression. |
|
| E.5.2 | Secondary end point(s) |
To assess the relative efficacy and safety of the addition of nivolumab +/- ipilimumab to rucaparib compared to rucaparib alone.
•Overall Response (based on RECIST v1.1, RECIST and GCIG CA125 criteria and Ir-RECIST)
•Duration of RECIST Response
•Overall Survival
•Safety and Tolerability (toxicities will be coded using NCI CTCAE Version 5)
•QoL as measured by EQ-5D
•Resource use for health economic assessment
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Scans will be performed every 8 weeks during the first year, thereafter 16 weekly until RECIST disease progression.
Toxicities will be assessed at every clinic visit, at the end of treatment visit, and for up to 100 days post last dose of trial treatment.
Questionnaires will be completed at the start of each treatment cycle, at the end of treatment visit, and at each follow-up visit until patient has progressed.
Resource use will be assessed at each visit, at the end of treatment visit, and at each follow-up visit until patient has progressed. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 29 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| For the purpose of complying with UK Clinical Trial Regulations, the trial will be considered ‘closed’ when the follow-up point for the primary analysis of the final experimental arm has been reached. However, the intention is that further observational follow-up of all patients enrolled in the trial may continue until all randomised patients have died. This will initially be via the trial sites, but in longer term may use national registers. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 31 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 31 |
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