Condition category
Cancer
Date applied
02/02/2018
Date assigned
14/02/2018
Last edited
14/05/2018
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
Not yet recruiting

Plain English Summary

Lay summary under review with external organisation.

Trial website

Contact information

Type

Public

Primary contact

Mrs Karen Allan

ORCID ID

Contact details

Cancer Research UK Clinical Trials Unit - partner in CaCTUS (Cancer Clinical Trials Unit Scotland)
Level 0
Beatson West of Scotland Cancer Centre
Gartnavel General Hospital
Glasgow
G12 0YN
United Kingdom
+44 141 301 7959
karen.allan.3@glasgow.ac.uk

Additional identifiers

EudraCT number

2017-004780-13

ClinicalTrials.gov number

Protocol/serial number

CeNturIOn-2016

Study information

Scientific title

An open-label, randomised, phase I/II trial of ruCaparib combined with Nivolumab +/- Ipilimumab to augment response in homologous repair deficient patients with relapsed Ovarian, primary peritoneal and fallopian tube cancer

Acronym

CeNturIOn

Study hypothesis

The addition of nivolumab with or without ipilimumab will improve clinical efficacy as compared to rucaparib monotherapy in patients with homologous recombination deficient relapsed high grade serous ovarian (fallopian tube, primary peritoneal) carcinoma.

Ethics approval

Not provided at time of registration.

Study design

Phase I/II open-label randomised multicentre trial

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Not available in web format, please use contact details to request a participant information sheet.

Condition

Relapsed high grade serous ovarian (fallopian tube, primary peritoneal) carcinoma

Intervention

After an initial safety run-in phase, part randomised (to the phase II part of the trial) to one of the three trial treatment arms by a computer which decides randomly which treatment the patient will receive, like tossing a coin or rolling a die.

Treatment Arm 1: Rucaparib alone (R) participants begin by taking oral rucaparib tablets twice a day (approximately 12 hours apart) continuously for each 42-day cycle. This dose may be reduced if the participant has side effects.

Treatment Arm 2: Rucaparib with Nivolumab (RN) participants begin by taking oral rucaparib tablets twice a day (approximately 12 hours apart) continuously for each 42-day cycle. Participants also have a drip of nivolumab (taking approximately 60 minutes) every 2 weeks. The dose of rucaparib may be reduced if the patient has side effects relating to this drug.

Treatment Arm 3: Rucaparib with Nivolumab and Ipilimumab (RNI) participants begin by taking rucaparib tablets twice a day (approximately 12 hours apart) continuously for each 42-day cycle. Participants also have a drip of nivolumab (taking approximately 60-minutes) every 2 weeks and a 30-minute drip of ipilimumab every 6 weeks. The dose of rucaparib may be reduced if the patient has side effects relating to this drug.

Intervention type

Drug

Phase

Phase I/II

Drug names

Rucaparib, Nivolumab and Ipilimumab

Primary outcome measures

Progression-Free Survival (PFS) is measured using the RECIST v 1.1. with CT scans performed every 8 weeks for the first year and then every 16 weeks until disease progression. PFS is defined as the time from randomisation to confirmed progression or death form any cause (whichever occurs first).

Secondary outcome measures

1. Overall response is measured using RECIST 1.1 and separately on combined RECIST / GCIG CA125 criteria using CT scans performed every 8 weeks for the first year and then every 16 weeks until disease progression
2. Duration of response
3. Overall survival measured using date of death. Overall survival is defined as the time from the date of randomisation until death from any cause.
4. Safety and tolerability is assessed using the based on toxicities coded using NCI-CTCAE v4.03.Toxicities are reviewed before treatment, Days 1/15/28/42 for all cycles, and at the end of treatment
5. Quality of life is assessed using the EQ-5D-5L questionnaire at baseline, before each cycle of treatment and at the end of treatment
6. resource use for health economic assessment prior to each cycle of treatment and at the end of treatment

Overall trial start date

01/10/2016

Overall trial end date

30/04/2024

Reason abandoned

Eligibility

Participant inclusion criteria

1. Age ≥ 16 years
2. Written informed consent prior to participating in the trial and any trial related procedures being performed
3. Histologically confirmed high-grade serous or Grade 3 endometrioid epithelial ovarian, fallopian tube, or primary peritoneal cancer
3.1. 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’, e.g. carcinosarcoma – please contact CTU for advice if uncertain. The high-grade serous / endometrioid sections should be used for FM and translational blocks.
3.2. 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 entry into the trial unless a biopsy confirming criteria above is performed.
4. 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.
5. Has 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.
6. 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 RECIST evaluable disease progression.
7. RECIST evaluable disease (by RECIST criteria v1.1). Patients with CA125 progression in the absence of RECIST evaluable disease will NOT be eligible.
8. Already known to have a deleterious germline or somatic BRCA1/2 mutation (proof required from local testing) OR be gBRCAwt LoHHIGH or BRCA 1/2 mutant as confirmed by the central laboratory (Foundation Medicine).
Note: 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. If it is a mixed tumour, the majority of the specimen sent for central testing and translational work should be the high-grade component, e.g. not the carcinosarcoma / clear cell features. In the event that archival tumour tissue is not available a screening biopsy sample must be collected and provided to the central laboratory.
9. Willingness to undergo mandatory biopsy pre cycle 1 day 1, where safe and technically feasible. RECIST target lesions should be avoided if possible. A further biopsy is optional at the end of trial treatment. Patients who do not have disease amenable to biopsy are exempt from the biopsy, provided all other inclusion criteria are met, however they must have archival tumour tissue available for central laboratory (Foundation Medicine) testing.
10. Adequate haematological and biochemical function as indicated below, performed within 14 days prior to randomisation:
10.1. Absolute neutrophil count >1.5 x 109/L
10.2. Platelet count >100 x 109/L
10.3. Haemoglobin >90 g/L (blood / platelet transfusions within 2 weeks prior to randomisation or patients requiring regular haematopoetic support factors or blood transfusions, e.g. 2 or more times in the 4 weeks prior to first dose of trial drug, are not eligible).
10.4. Serum creatinine <1.5 times ULN 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 >1.5 times the ULN
10.5. Total bilirubin <1.5 times ULN. In cases of Gilbert’s syndrome, bilirubin < 2 x ULN is allowed
10.6. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) <3 times ULN if no demonstrable liver metastases or <5 times ULN in the presence of liver metastases
10.7. Alkaline phosphatase <5 x ULN
10.8. Albumin > 25 g/L
11. Willingness to comply with scheduled visits, treatment plans and laboratory tests and other trial procedures.
12. Evidence of non-childbearing status. For women of childbearing potential:
12.1. negative serum pregnancy test within 7 days of trial treatment
12.2. (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) and luteinizing hormone (LH) levels in the post-menopausal range for the institution
OR
12.3. Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation.
13. Patients with synchronous tumours e.g. ovarian and endometrial or history of prior malignancy are eligible provided that there is biopsy evidence that the disease measurable (by RECIST version 1.1, on CT / MRI is ovarian in origin and of appropriate histological types (see above).
14. Ability to swallow oral medication
15. Life expectancy of at least 12 weeks
16. ECOG Performance Status of 0,1

Participant type

Patient

Age group

Adult

Gender

Female

Target number of participants

234

Participant exclusion criteria

1. Prior chemotherapy, biological therapy, radiation therapy, hormonal anti-cancer therapy, immunotherapy, other anticancer agents within 28 days of starting trial treatment (not including palliative radiotherapy at focal, non-RECIST target sites). Treatment with any investigational agent within the preceding 4 weeks or within 5 half-lives of the investigational agent, whichever is longer.
2. 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)
3. Pregnant or lactating women
4. 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. In addition, patients will be excluded if they are not willing to use contraception for the duration of the trial and for 6 months following the last dose of trial treatment.
5. With the exception of alopecia and stable peripheral neuropathy from previous taxanes, any unresolved toxicities from prior chemotherapy should be no greater than CTCAE (Version 4.03) Grade 1 at the time of starting trial treatment
6. Major surgery within 3 weeks or minor surgery within 5 days of trial entry (excluding placement of vascular access devices)
7. Spinal cord compression, known leptomeningeal involvement or brain metastases, unless treated and stable either on physiological doses of steroids (eg <10mg prednisolone) or off steroids altogether for at least 4 weeks prior to randomisation
8. Oral anticoagulants such as warfarin are 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.
9. Any haemopoietic growth factors (e.g., G-CSF, GM-CSF) and blood / platelet transfusions within 2 weeks prior to randomization or patients requiring regular blood transfusions (e.g. 2 or more times in the 4 weeks prior to first dose of trial drug), granulocyte colony-stimulating factor, or platelet transfusions
10. Hospitalization for bowel obstruction within 3 months prior to randomization
11. Any gastrointestinal disorder or defect that would, in the opinion of the Investigator, interfere with absorption of rucaparib
12. 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 7 days prior to the first dose of trial treatment. Includes prior organ transplantation including allogenic stem-cell transplant. The following are exceptions to this exclusion criterion:
12.1. Intranasal, inhaled, topical steroids, or local steroid injections (e.g. intra-articular injection)
12.2. Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or equivalent
12.3. Steroids as premedication for hypersensitivity reactions (e.g. CT scan premedication)
13. Has a known history of active TB (Bacillus Tuberculosis)
14. Previous additional malignancy that is progressing or has required active treatment in the last 2 years. Please discuss with the CTU if further clarification is required. Exceptions include:

14.1. Non-melanomatous skin cancer (if adequately treated or not requiring treatment)

14.2. Previous DCIS or breast cancer > 5 years as long as adequately treated

14.3. In situ or early (up to stage 1B1) cervical cancer (if adequately treated)

14.4 VIN or vulval cancer (if adequately treated)

14.5. 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 

15. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency etc.) is not considered a form of systemic treatment. Patients with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible. 

16. Has received a live vaccine within 30 days of planned start of trial therapy. Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g. Flu-Mist®) are live attenuated vaccines, and are not allowed. 

17. As judged by the Investigator, any evidence of severe or uncontrolled systemic diseases (e.g. severe hepatic impairment, interstitial lung disease [bilateral, diffuse, parenchymal lung disease], uncontrolled chronic renal diseases [glomerulonephritis, nephritic syndrome or renal tubular acidosis], current unstable or uncompensated respiratory or cardiac conditions, uncontrolled hypertension, active bleeding diatheses or active infection, Torsades de Pointes within 12 months of trial entry, known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial[includes patients with known alcohol or drug abuse])
18. Unsuitable to participate in the trial because the patient is unlikely to comply with trial procedures, restrictions and requirements
19. Hypersensitivity to rucaparib, nivolumab or ipilimumab or any of the excipients

Recruitment start date

01/12/2018

Recruitment end date

01/06/2022

Locations

Countries of recruitment

United Kingdom

Trial participating centre

Mount Vernon Cancer Centre
Rickmansworth Road
Northwood
HA6 2RN
United Kingdom

Trial participating centre

The Beatson West of Scotland Cancer Centre
1053 Great Western Road
Glasgow
G12 0YN
United Kingdom

Trial participating centre

Royal Surrey County Hospital
Egerton Road
Guildford
GU2 7XX
United Kingdom

Trial participating centre

Western General Hospital, Edinburgh
Crewe Rd S
Edinburgh
EH4 2XU
United Kingdom

Trial participating centre

Churchill Hospital
Old Road Headington
Oxford
OX3 7LE
United Kingdom

Trial participating centre

Clatterbridge Centre for Oncology
Clatterbridge Road
Birkenhead
CH63 4JY
United Kingdom

Trial participating centre

The Christie
Wilmslow Road
Manchester
M20 4BX
United Kingdom

Trial participating centre

The Royal Marsden
The Royal Marsden Hospital 203 Fulham Road Chelsea
London
SW3 6JJ
United Kingdom

Trial participating centre

St Bartholomew's Hospital
W Smithfield
London
EC1A 7BE
United Kingdom

Trial participating centre

Worthing Hospital
Lyndhurst Road
Worthing
BN11 2DH
United Kingdom

Trial participating centre

Royal Berkshire Hospital
Craven Road
Reading
RG1 5AN
United Kingdom

Trial participating centre

St James' University Hospital
Beckett Street
Leeds
LS9 7TF
United Kingdom

Trial participating centre

Southampton General Hospital
Tremona Road
Southampton
SO16 6YD
United Kingdom

Trial participating centre

Kent and Canterbury Hospital
Ethelbert Road
Canterbury
CT1 3NG
United Kingdom

Trial participating centre

Leicester General Hospital
Gwendolen Road
Leicester
LE5 4PW
United Kingdom

Trial participating centre

Royal United Hospital
Combe Park
Bath
BA1 3NG
United Kingdom

Trial participating centre

Queen Elizabeth Hospital
Mindelsohn Way
Birmingham
B15 2WB
United Kingdom

Trial participating centre

Velindre Cancer Centre
Velindre Road
Cardiff
CF14 2TL
United Kingdom

Trial participating centre

Addenbrookes Hospital
Hills Road
Cambridge
CB2 0QQ
United Kingdom

Trial participating centre

Guys and St Thomas Hospitals
London
SE1 9RT
United Kingdom

Trial participating centre

Warwick Hospital
Lakin Road
Warwick
CV34 5BW
United Kingdom

Trial participating centre

Norfolk and Norwich University Hospital
Colney Lane
Norwich
NR4 7UY
United Kingdom

Trial participating centre

Gloucestershire Royal Hospital
Great Western Road
Gloucester
GL1 3NN
United Kingdom

Trial participating centre

Broomfield Hospital
Court Road Broomfield
Chelmsford
CM1 7ET
United Kingdom

Trial participating centre

Royal Derby Hospital
Derby
DE22 3NE
United Kingdom

Trial participating centre

Belfast City Hospital
Belfast
BT9 7AB
United Kingdom

Sponsor information

Organisation

NHS Greater Glasgow & Clyde

Sponsor details

Greater Glasgow Health Board
J B Russell House
Gartnavel Royal Hospital
1055 Great Western Road
Glasgow
G12 0XH
United Kingdom

Sponsor type

Other

Website

Organisation

University of Glasgow

Sponsor details

The University Court of the University of Glasgow
University Avenue
Glasgow
G128QQ
United Kingdom

Sponsor type

Other

Website

Funders

Funder type

Industry

Funder name

Bristol-Myers Squibb

Alternative name(s)

Bristol-Myers Squibb Company, BMS

Funding Body Type

private sector organisation

Funding Body Subtype

corporate

Location

United States of America

Funder name

Clovis Oncology

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Results and Publications

Publication and dissemination plan

Planned publication in a high-impact peer reviewed journal.

IPD sharing statement:
The datasets generated during and/or analysed during the current study will be stored in a non-publically available repository.

Intention to publish date

01/04/2025

Participant level data

Stored in repository

Results - basic reporting

Publication summary

Publication citations

Additional files

Editorial Notes

14/05/2018: Internal review.