RomiCar
Research type
Research Study
Full title
Phase I/II study to determine the maximum tolerated dose and activity of the combination of romidepsin and carfilzomib in relapsed or refractory peripheral T-cell lymphoma
IRAS ID
136755
Contact name
Graham Collins
Contact email
Sponsor organisation
University of Birmingham
Eudract number
2013-001879-20
ISRCTN Number
N/A
Clinicaltrials.gov Identifier
N/A
Research summary
Summary of Research
RomiCar is a phase I/II study of the combination of romidepsin and carfilzomib in patients with relapsed or refractory peripheral T-cell lymphoma (PTCL). The phase I component aims to find the Maximum Tolerated Dose (MTD) of the combination and the phase II aims to assess the Best Overall Response Rate of the combination at the MTD.
Romidepsin is a histone deacetylase (HDAC) inhibitor which has been shown in phase II studies to achieve response rates of 25-38% when used alone. Studies in cell lines and animal models have shown that HDAC inhibitors and proteasome inhibitors (carfilzomib) work in synergy in several cancers.
As these drugs have not been used together before, it is not known what the safe dose of each drug is when combined. The trial will recruit between 31-57 patients from 13 Trials Acceleration Programme (TAP) centres over 3 years. The research is funded by Leukaemia and Lymphoma Research with additional educational grants from Celgene and Onyx for sample collection and biomarker analysis.
The MTD will be established during the phase I using a Continual Reassessment Model. Once the MTD has been found, 28 patients will be recruited to the phase II component to assess activity.
Treatment will be delivered in cycles (each cycle lasts 4 weeks) and patients will need to attend clinic on days 1, 2, 8, 9, 15 and 16 of each cycle. Patients will receive blood tests at each visit and a physical exam at the start of each cycle. Patients will also receive a CT scan every 2 cycles for the first 8 cycles.
Patients will receive 8 cycles of treatment and then have the option to continue with the combination or romidepsin alone until their disease progresses. All patients will be followed up for a minimum of 1 year and until the study closes.Summary of Results
Name of Chief Investigator: Dr Graham Collins Chief Investigator ORCID ID:
IRAS ID:
Name of the Research Ethics Committee that issued a Favourable Opinion for the study: NRES Committee East Midlands – NorthamptonSponsor Organisation Name: University of Birmingham Study start date: 13th Jul 2015 Study end date: 23rd Sep 2021 Funder's reference number: 13018 TAP trial Name of Registry: EudraCT Study Registration Number/Identifier: 2013-001879-20 Is the study protocol publicly available? Yes, ISRCTN42054893 Trial name Phase I/II study to determine the maximum tolerated dose and activity of the combination of romidepsin and carfilzomib in relapsed or refractory peripheral T-cell lymphoma
Protocol number: RG_13-107
Acknowledgment
The research team would like to thank the participating patients and families, whose support and time is gratefully acknowledged.Abstract
Purpose of the study: To see if a drug called romidepsin in combination with another drug called carfilzomib is safe and if it benefits patients with relapsed or refractory peripheral T cell lymphoma (rrPTCL).
What was tested: In this phase I/II dose finding trial, the initial stage of the trial (phase I) looked at what dose of romidepsin in combination with carfilzomib was tolerated best by patients (the maximum tolerated dose or MTD), and in the second stage of the trial (phase II) all patients were treated with the dose found to be safest in phase I to see how well the treatment works.People taking part: 50 patients took part in this trial, recruited between August 2015 and November 2019. This included 34 patients for the phase I and an additional 16 patients for the phase II.
Results: Overall the results of the study found the safe dose level for the combination of romidepsin with carfilzomib to be dose level 3, but the combination was found to be not clinically effective for most patients and will not be recommended for further investigation in this patient population.
Safety: In this study, researchers found that there were no safety concerns over the use of romidepsin in combination with carfilzomib.Who sponsored this study?
This study was sponsored by the University of Birmingham. The Romicar trials office can be contacted via ROMICAR@trials.bham.ac.ukGeneral Information about the trial
The study took place in the United Kingdom only. Recruitment began in August 2015 and ended in November 2019. The trial closed in September 2021 when all patients had stopped trial treatment and all data had been collected.The main objective of the phase I part of the study was to determine the maximum dose of romidepsin in combination with carfilzomib that could be tolerated by patients with rrPTCL. In phase II, the trial determined how well patients responded to this drug combination dose over 8 cycles of treatment and if it was safe. This involved looking at the toxicity of the drug combination for patients as well as its effectiveness against rrPTCL in terms of survival and disease improvement.
The trial used a Continuous Reassessment Model (CRM) design which gives flexibility in recruiting patients to the various dose levels which enhances the ability of the trial to recruit in a timely way despite the rare and aggressive nature of the disease.
What patients were included in this study?
This trial included only patients with PTCL that had relapsed (their cancer had returned) or was refractory (their previous treatment did not work). Although the trial was open to all adults, the median age of the patients entering the trial was 63 years. More men than women took part (70% compared to 30%).Patients needed to have adequate liver and kidney function to participate and be fit and able to attend hospital to receive treatment.
Patients were not able to participate in the trial if they had brain or spine involvement, evidence of HIV, Hepatitis B or Hepatitis C infection, or certain heart conditions. Patients, both male and female, needed to agree to use effective contraception during the trial and female patients could not be pregnant or lactating at trial entry.
What medicines were studied?
Patients received romidepsin in combination with carfilzomib. Romidepsin is a drug called a histone deacetylase inhibitor (HDAC). HDACs are enzymes that control histones, a group of proteins that are important for the formulation of DNA. Romidepsin works by blocking these enzymes, stopping them from functioning normally, this stops the cancer cells growing and dividing. Carfilzomib is a proteasome inhibitor- it works by interfering with the breakdown of proteins in cancer cells so that they build up in these cells, and the cells stop working properly and die.
Romidepsin has been shown to have some beneficial effect, with acceptable side effects, in other phase II studies in rrPTCL. Some pre-clinical studies have suggested that a combination of romidepsin and carfilzomib may more beneficial than romidepsin alone, and it was thought that this combination would also show favourable results for patients with rrPTCL.
What were the side effects?
Serious Adverse Events (SAEs) were reported whilst patients were on trial treatment and for 4 weeks after they finished treatment. SAEs include untoward medical occurrences that result in patients being admitted to hospital, are life threatening, result in death, cause long term or significant disability or incapacity or cause birth defects.
Hospitalisations for supportive treatment due to the patient’s cancer getting worse or death from their PTCL were not reported as SAEs. Unfortunately, this was expected for this patient group and would not be considered related to trial treatment.
56 SAEs were experienced by 31 patients, of which 34 events were judged to be related to romidepsin, and 33 events related to carfilzomib. There were 35 treatment-related serious adverse reactions (SARs) of which there were 11 fevers, 1 infusion-related reaction, 1 haemolytic anaemia, 2 vomiting, 3 hypotension, 2 abdominal pain, 4 lung infections, 3 sepsis, and 1 each of dehydration, shortness of breath, pulmonary embolism, irregular fast heartbeat, bronchial infection, pneumonia, fatigue and febrile neutropenia. There were also 2 SUSARs (suspected unexpected serious adverse reaction- a serious adverse event that is not listed on the study drug product information, so is unexpected, and is at least possibly related to the drug), one was influenza A and one was cardiac-related.
The trial also collected Adverse Events (AEs) where they were Grade 2 or above, unless they were haematological (related to the blood or bone marrow), and all Grade 3 or above events were reported. AEs are medical occurrences that are considered severe or medically significant but not immediately life threatening. Grade 2 AEs are moderate events, where minimal, local or non-invasive intervention is required, and Grade 3 AEs are severe or medically significant events that are not immediately life-threatening. Grade 4 AEs are life-threatening needing urgent intervention and Grade 5 resulted in death. These AEs include events both related and unrelated to trial treatment.
In total 938 AEs were reported among 49 patients.
The most common Grade 3 and 4 AEs were thrombocytopenia (decreased platelets in the blood, that can result in bruising and bleeding) and neutropenia (decreased neutrophils, a type of white blood cell), experienced by 37% and 33% of patients respectively. 20% of patients experienced anaemia (not enough red blood cells to carry oxygen to your body’s organs). These haematological toxicities relate to fewer functioning blood cells being produced by the bone marrow, which is both a side effect of chemotherapy treatments and something that is commonly observed in patients with lymphoma.
The most common non-blood related AEs were hyponatremia, fatigue, fever, hypotension and sepsis, which were all experienced by less than 10% of patients.
During the trial there were 39 deaths reported, 35 were disease-related, 3 were of unknown cause, and 1 was related to treatment received after stopping trial treatment.
What were the overall results of the study?
Overall, this study found that romidepsin in combination with carfilzomib was safe but was not effective in treating patients with rrPTCL.
In total, 50 patients were registered to the Romicar trial. 34 patients were recruited to phase I of the study, and all started treatment. 7 of these patients were later replaced due to early treatment discontinuation. 16 additional patients were recruited to phase II, one of which did not start treatment as they were found to be ineligible post registration (they had a re-biopsy which showed they had a type of lymphoma which is excluded from the study). Combining the newly recruited patients with those treated at the maximum tolerated dose from Phase I, a total of 34 patients were included the phase II analysis.
The aim of Phase I of the study was to determine the maximum dose of the combination of romidepsin and carfilzomib which was tolerable for patients with rrPTCL.
Dose limiting toxicities (DLTs) are side effects of a drug that are deemed unacceptable compared to the likelihood of potential patient benefit. 7 DLTs were observed in 6 patients with the 3 different dose levels tested in Phase I of the trial, (1 in dose level 2, and 3 in dose levels 3 and 4).
It was decided from looking at the phase I results that dose level 3 was the recommended dose of romdepsin and carfilzomib combination to use in the Phase II part of the study. Dose level 3 was 10mg/ml romidepsin and 20mg/m2 carfilzomib for the first 2 doses (45 mg/m2 for further doses).
The research team looked at how many patients PTCL improved with treatment. In this trial, a response was recorded if the patient had a Complete Response (CR) or a Partial Response (PR) to treatment. The patients’ responses were determined by using published criteria (called Cheson criteria) to assess any change in the total size of their tumours by comparing their CT scans after every 2 cycles of treatment with the scan they had at the start of the study.
In the phase II stage, the best response to treatment during 8 cycles of treatment showed 11 out of 34 (32%) patients had responded to treatment [5 patients (22%) with a complete response, 6 patients (26%) with a partial response]. Six patients (26%) showed stable disease and 6 patients (26%) relapsed/progressed. However 11 patients relapsed/progressed before reaching the cycle 2 assessment time point.
The research team also looked at the duration of response of patients. Looking at overall survival of the 50 patients, 62% of patients survived for 6 months and 41% survived for 12 months. Looking at how long all the patients lived without disease progression, 29% had a six-month progression-free survival, 17% had 12-month progression-free survival. Looking at how long the 17 patients that responded or had stable disease lived without disease progression, 71% had a six-month progression free survival.How has this study helped patients and researchers? The study successfully used a CRM model to determine the MTD for the combination of romidepsin and carfilzomib, but the combination was not a clinically effective treatment for most patients with rrPTCL.
Where can I find more information about this study?
To learn about this study, you can find more detailed information on the website ISRCTN registry A summary is also provided on the Cancer Research UK website.
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East Midlands - Leicester South Research Ethics Committee
REC reference
13/EM/0462
Date of REC Opinion
30 Dec 2013
REC opinion
Favourable Opinion