CeNturIOn
Research type
Research Study
Full title
An open-label, randomised, phase 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.
IRAS ID
233151
Contact name
Marcia Hall
Contact email
Sponsor organisation
NHS Greater Glasgow & Clyde
Eudract number
2017-004780-13
ISRCTN Number
ISRCTN10490346
Duration of Study in the UK
5 years, 0 months, 31 days
Research summary
Research Summary
CeNturIOn is a trial for patients with ovarian cancer whose cancer has come back (relapsed) within a year of completing their last treatment. Patients in this position generally die of their cancer in the next 1-2 years. For some, especially those carrying changes in their BRCA genes (BRCA 1/2), treatment with PARP inhibitors like rucaparib, prolongs survival by approximately 12 months. Many patients who do NOT carry BRCA genetic changes also respond to PARP inhibitors but generally only for 6 months. This trial examines whether better remissions from PARP inhibitors can be obtained, by augmenting patient’s immune systems. There is evidence that combining immune stimulation with other treatment strategies in many cancers is more effective.
This trial is comparing treatment with rucaparib alone with a combination of rucaparib plus nivolumab, +/- ipilimumab. Nivolumab and ipilimumab enhance the body’s immune response to cancer cells by acting on receptors on the T-cell surface (PD-1/CTLA4)). This trial is randomised – neither treating teams nor patients can decide which group they will be in for treatment, this is determined by computer. There are three groups. The first will get only rucaparib tablets, taken twice a day, continuously. The second group will be treated with rucaparib tablets twice daily and nivolumab as a drip over 30mins every 2 weeks. The third group will receive rucaparib tablets, nivolumab (as previously described) and ipilimumab drips, also given as 30mins drip (30mins after the nivolumab) but every 6 weeks.We will not be recruiting patients whose cancers are not likely to respond to PARP inhibition at all by testing the cancer tissue (biopsied or removed at diagnosis) of all potential patients prior to trial entry. We will be examining how long patients remain in remission whilst on trial treatment and comparing the outcomes of each group against each other.
Summary of Results
Thank you to study participants
• Study title
CeNturIOn: An open-label, randomised, phase 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• Who carried out the research? (including details of sponsor, funding and any competing
interests)
The research was carried out by Chief Investigator Professor Marcia Hall and was co-ordinated by the Glasgow Oncology Clinical Trials Unit (formerly known as Cancer Research UK Glasgow Clinical Trials Unit). The trial was co-sponsored by NHS Greater Glasgow & Clyde and the University of Glasgow. The trial was funded by Bristol-Myers Squibb, Clovis Oncology and Cancer Research UK.• What public involvement there was in the study (how many people, what their relevant
lived experience was, and what they did) There were 5 PPI (Patient and Public Involvement) representatives involved in the trial overall. All of them were patients with ovarian cancer. PPI1 was instrumental in the set-up period of the safety run-in phase, reviewing the trial design and the patient information sheet and informed consent form. PPI2 supported the Trial Management Group (TMG) to process an amendment to the randomised phase of the trial. Due to the risk that the individuals with advanced ovarian cancer may not be able to help throughout the time period of the trial, due to their own personal circumstances, we had named representatives who would stand in if needed (PPI3 and PPI4). PPI5 joined the TMG when the trial was in the close down process to help advise on the dissemination of results to patients.• Where and when the study took place
The trial opened to recruitment at the Chief Investigator’s site, Mount Vernon Cancer Centre, on 24th May 2019 and then opened at the Western General Hospital, Edinburgh on 7th August 2019. Only two sites were required for the safety run-in phase, which recruited until August 2021. Unfortunately, the trial did not proceed to Phase II therefore further sites were not activated.• Why was the research needed?
CeNturIOn was a trial for patients with ovarian cancer whose cancer had come back (relapsed) within a year of completing their last treatment. Patients in this position generally die of their cancer in the next 1-2 years if no further treatment is given. For some, especially those carrying changes in their BRCA genes (BRCA 1/2), treatment with tablets known as PARP inhibitors (like rucaparib), prolonged survival by approximately 12 months. Many patients who do NOT carry BRCA genetic changes also respond to PARP inhibitors but generally only for 6 months and without increasing how long they live. The CeNturIOn trial was to examine whether better remissions and survival from PARP inhibitors could be obtained, by combining treatment with treatments that enhance the patients’ immune system. There was evidence, through other clinical trials, that combining treatments that stimulate the immune system (immune therapies) with other types of treatment in many cancers was more effective.• What were the main questions studied?
The main question for the trial was to investigate whether the addition of nivolumab (an immunotherapy drug), or nivolumab and ipilimumab (another type of immunotherapy drug), to rucaparib was more effective, compared with rucaparib alone, in patients with relapsed ovarian cancer. The safety run-in phase was to check that giving the three drugs together (nivolumab, ipilimumab and rucaparib) was safe and tolerable before proceeding to Phase II of the trial.• Who participated in the study?
15 patients were recruited to 2 safety run-in cohorts (7 patients to cohort 1 and 8 patients to cohort 2).• What treatments or interventions did the participants take/receive?
During Safety Cohort 1 and 2 (first 4 patients), patients received all three drugs below (triplet therapy) at the following doses (this was repeated every 6 weeks):
• Rucaparib (R) 600mg orally twice daily every day (continuously) • Nivolumab (N) 240mg intravenously (IV) on days 1, 15 and 29 (administered prior to ipilimumab) • Ipilimumab (I) 1mg/kg IV on day 1During Safety Cohort 2 (remaining patients), patients received all three drugs as detailed above but the rucaparib dose was reduced to 400mg twice a day.
• What medical problems (adverse reactions) did the participants have?
Patients had a number of adverse reactions that were potentially expected for these medications, including haematological (abnormal blood count) and non-haematological. The majority of side effects were mild, e.g. tiredness and sickness. Some participants also experienced more serious side effects although these were seen less frequently. These included low blood counts (e.g. low red blood cell counts, low white cell counts, and low platelets), changes to kidney function, mood, breathing, infections, blood pressure, and bowel habit. There were other side effects such as inflammation of the heart and the bowel. There was 1 death on study that was due to an E. Coli bowel infection, although this was not felt to be definitely caused by any of the 3 drugs.• What happened during the study?
Following an initial recommendation by the Safety Review Committee (SRC), the Independent Data Monitoring Committee (IDMC) and the Umbrella Trials Steering Committee (UTSC) reviewed the side effects after the first 6 patients had received the combination of three drugs. As most of the patients had only managed half or less of the planned rucaparib during the first cycle of their treatment, it was not possible to draw conclusions about the safety of the three drugs together. So, a second safety run-in cohort was performed. In this cohort, the number of prior lines of treatment was limited to a maximum of three, as extensive prior treatments may limit how well patients can tolerate treatments. Provided patients managed to receive at least 60% of the planned rucaparib in the first 6 weeks, they could be included in the safety analysis. If they experienced severe side effects known as dose limiting side effects related to one of the trial treatments, that meant they could not tolerate 60%, this would indicate the combination was not tolerable. Provided this triplet combination was found to be safe and any toxicities (side effects) acceptable, the randomised Phase II part of the trial was expected to open.In pre-planned rules, if 2 or more patients experienced severe side effects (dose limiting toxicity), the combination would have been regarded as not tolerable.
After recruitment of four patients, three of whom were evaluable to the second safety run-in cohort, the SRC reviewed all data, and recommended that the dose of rucaparib be reduced from 600mg twice a day to 400mg twice a day. A further three evaluable patients were to be recruited at this level. If the safety cohorts found that the triplet combination was tolerable, then Phase II of the trial could be started. This part of the trial was to be randomised and aimed to recruit 234 patients with relapsed high grade serous ovarian carcinoma. Patients would receive either rucaparib alone or rucaparib and nivolumab or rucaparib and nivolumab and ipilimumab.
Unfortunately, the trial did not progress to Phase II due to termination of the contract with one of the pharmaceutical companies.
• What were the results of the study?
15 patients were recruited to 2 safety run-in cohorts between May-Oct 2019 (7 patients) and Aug 2020-Jun 2021 (8 patients). Only 1 patient from the first safety run-in cohort met the evaluation criteria that was later changed in the protocol in February 2020. The remaining 6 patients in this cohort received less than 43% of rucaparib dosing in the first 6 weeks. This was considered too small to accurately assess tolerability of the triplet combination.Following the introduction of an additional evaluability criteria (more than 60% of starting dose of rucaparib should be taken in the 6-week DLT period), a further 4 patients were recruited to start at 600mg twice a day of rucaparib. Of these, the first patient achieved 60.3% of rucaparib doses in the DLT period (the first 6 weeks of treatment) and the second patient, only 33%. A further patient had a DLT when admitted to hospital on day 18 of the first cycle with acute renal failure. This was thought to be an immune-related nephritis (inflammation of the kidney) related to the immunotherapy drugs and the patient was taken off trial. For this reason, the SRC suggested reducing the starting dose of rucaparib to 400mg twice a day and limited the number of ipilimumab cycles to four in total.
7 of the 15 patients were evaluable for assessment. Of these, 4 patients started on rucaparib 600mg twice a day, receiving >60% in first 6 weeks; 3 received rucaparib 400mg twice a day throughout (median dose intensity 82.5%). 1 patient died of E Coli sepsis related to colitis which was thought to be probably related to ipilimumab and rucaparib and possibly related to nivolumab.
The median overall progression free survival (PFS) (the average length of time after the start of treatment in which a patient is alive, and their cancer does not grow or spread) was 3.4 months, and the median PFS for the evaluable cohort was 4.3 months. The median overall survival (OS) (the average length of time a patient is alive since treatment) was 11.1 months, and the median OS for the evaluable cohort was 9.5 months.
It was concluded that the triplet treatment was safe for further evaluation (with rucaparib 400mgBD starting dose).
• How has this study helped patients and researchers?
The study showed it was possible to combine 2 different immunotherapy drugs, ipilimumab and nivolumab, targeting CTLA4 and PD-1 axis respectively along with rucaparib, a PARP inhibitor, in high grade serous ovarian cancer patients that had previously been treated with a PARP inhibitor and whose cancer had returned. This regimen was tolerable and warranted further investigation. Although it was terminated early, the study showed that this could have been a potential strategy to overcome PARP inhibitor resistance but needed a larger phase II study to explore this fully.• Details of any further research planned
There is no further clinical research planned with this study due to a change in strategy with the pharmaceutical industry. It has become clear since the study was initially designed, that immunotherapy is not as effective in treating ovarian cancer patients, compared to other tumour sites. The focus on novel therapeutic strategies in ovarian cancer is therefore taking a different direction, e.g. focusing on antibody drug conjugates.Translational research proposals have been proposed by the scientific team based at Brunel University on the patient samples that were collected. These will be reviewed by an ethical research panel to ensure that they are appropriate.
• Where can I learn more about this study?
A summary will be published on the CancerHelp website (https://gbr01.safelinks.protection.outlook.com/?url=http%3A%2F%2Fcancerhelp.cancerresearchuk.org%2F&data=05%7C02%7Charrow.rec%40hra.nhs.uk%7C96f37b2cb5e041af4d9c08dd1f63648e%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C638701233925354732%7CUnknown%7CTWFpbGZsb3d8eyJFbXB0eU1hcGkiOnRydWUsIlYiOiIwLjAuMDAwMCIsIlAiOiJXaW4zMiIsIkFOIjoiTWFpbCIsIldUIjoyfQ%3D%3D%7C0%7C%7C%7C&sdata=CGGDIKKSelrOgXtxxkYCzMB%2FavfgVEPyCm5D9pgjr9E%3D&reserved=0).
An academic paper will be published in keeping with good practice in a peer reviewed journal so that the wider community can read about the study. We will share this with ovarian cancer charities to help disseminate information.REC name
London - Harrow Research Ethics Committee
REC reference
18/LO/1022
Date of REC Opinion
22 Aug 2018
REC opinion
Further Information Favourable Opinion