TIER
Research type
Research Study
Full title
A Phase I/II Study of Thiotepa, Ifosphamide, Etoposide and Rituximab for the treatment of relapsed or refractory primary central nervous system lymphoma
IRAS ID
148036
Contact name
Kathryn Paterson
Contact email
Eudract number
2014-000227-24
Clinicaltrials.gov Identifier
CAS number, HM1023
Research summary
Research Summary
TIER is a phase I/II study of the combination of thiotepa, ifosphamide, etoposide and rituximab in patients with relapsed or refractory primary central nervous system lymphoma (PCNSL). The phase I component aims to find the Maximum Tolerated Dose (MTD) of thiotepa when combined with the 3 other drugs. The phase II aims to assess the Overall Response Rate of the combination at the MTD.
The combination of Rituximab, Ifosphamide and Etoposide (R-IE) has shown some encouraging results in PCNSL. However, many chemotherapy agents are not able to cross the blood brain barrier (BBB) and have an effect on tumours in the brain and spine. Thiotepa is an alkylating agent capable of crossing the BBB and therefore has the potential to improve the activity of R-IE. As thiotepa has not been added to the R-IE regimen before in PCNSL, it is not known what the safe dose of thiotepa is when combined.
TIER will recruit up to 40 patients from 20 specialist centres over 3 years and is funded by Leukaemia and Lymphoma Research with free thiotepa provided by Adienne. The MTD will be established during the phase I using a 3+3 cohort design. 28 patients will be recruited to the phase II to assess activity.
Treatment will be delivered over 2 cycles (each cycle lasts 21 days) and patients will either be treated as inpatients or attend clinic on days 1-5 and then twice a week until stable. Patients will receive blood tests at each visit. At the start of each cycle, patients will also have a neurological exam and assessments. MRI scans will be conducted for disease assessment and research.
Following 2 cycles of treatment, patients may continue with TIE (no rituximab) for a further 2 cycles. All patients will be followed up every 3 months for a minimum of 2 years.
Summary of Results
What were the overall results of the study?
It was concluded that thiotepa can be safely incorporated into this multidrug regimen, and produce a meaningful response rate worthy of further clinical development.
No DLTs were observed with any of the 3 different dose levels tested in Phase I of the trial, therefore the recommended dose of thiotepa to use in the Phase II part of the study (in combination with ifosfamide, etoposide and rituximab), was established as 50mg/m2.
The researchers looked at how well this combination of 4 drugs was tolerated by patients on the trial. Of 36 patients, 32 completed 1 cycle of TIER and 26 patients completed 2 cycles of TIER. For the patients able to go on to receive cycle 2 of TIER, 11 patients had a delay in starting the cycle (mainly due to administrative/organizational delays in their treatment). Two patients needed to wait until their blood counts had recovered before starting cycle 2. The average delay in starting the second cycle of TIER was 2 days. Only 4 patients (11%) needed a reduction in the dose of any of the 4 TIER drugs.
Next, the research team looked at how many patient’s PCNSL improved with treatment. After 2 cycles of TIER (using the dose of 50mg/m2 thiotepa established in Phase I), 14 out of 27 patients (52%) had responded to treatment. 4 patients didn’t respond to treatment and their disease progressed, and 9 patients did not have an MRI scan after 2 cycles of TIER so could not be evaluated.
In this trial, a response was recorded if the patient had a Complete Response (CR), an unconfirmed Complete Response (CRu) or a Partial Response (PR) to treatment. The patients’ responses were determined by comparing their MRI scan after 2 cycles of treatment with the scan they had at the start of the study, and used published criteria (called IPCG criteria) to assess any tumors in their brain and spinal cord as well as any abnormalities in their eyes and lymphoma cells in their CSF.
The reasons that 9 patients did not have an MRI scan after 2 cycles of TIER, were because their disease had progressed (1 patient), they had died due to their disease (4 patients) or because they had discontinued on the trial (4 patients). Of the 14 patients who did respond to 2 cycles of TIER, 10 subsequently developed progressive disease.
The research team also looked at how long people lived for after treatment with TIER. They found that on average patients survived for 5 months after the start of treatment, and their disease progressed at around 3 months. Patients who achieved a CR or CRu after 2 cycles of TIER had a longer average survival time of around 11 months, and on average their disease progressed later, at around 6 months after the start of treatment.
After 2 cycles of TIER, the patient’s doctor could choose the best treatment option for their patient. Of 17 patients who went on to receive further treatment after TIER, 6 patients had an ASCT, 2 patients had whole-brain radiotherapy, and 9 patients received thiotepa with iphosphamide and etoposide (TIE) only.
Overall survival was longest in the 6 patients who underwent ASCT. After an average follow-up of 50 months, 2 patients had relapsed and died 14 and 27 months after trial entry. The 4 surviving patients were in sustained remission 24, 36, 50 and 52 months after starting the trial.
Of the patients that received whole-brain radiotherapy, one relapsed and died after 10 months, and the other patient was still in remission at 37 months. For the patients receiving TIE only, 5 patients died, one withdrew from the trial (at around 5 months), 2 were lost to follow up (at 4 and 12 months), and one patient was still alive at 25 months.
The study also collected information about the patient’s previous treatment for PCNSL, before they started on the TIER trial. This information was used to see if patients responded differently to TIER depending on the previous treatments they had received. The researchers found that patients who had not previously received thiotepa had longer overall survival times (around 5 months) compared to patients who had received a combination of drugs that included thiotepa (around 3 months). However, it is important to note here that the number of patients included each of these groups is small.
Lastly, the researchers looked at whether responses and survival after TIER were affected by the responses patients had shown to their previous treatment. They found that patients who had not relapsed until at least 12 months from their previous treatment survived a little longer (around 9 months), compared to patient that had relapsed within 12 months (around 3 months survival). Ten out of 15 patients with a relapse time of greater than 12 months since their previous treatment responded to TIER, whereas only 4 out of 12 patients with a relapse time of less than 12 months since their previous treatment had a response to TIER treatment. Again, the numbers of patients involved in this analysis is very small and so the significance of these results is not clear.How has this study helped patients and researchers?
The TIER trial was the first trial to look at what dose of thiotepa can be given within a combination of drugs for the treatment of PCNSL. It is also one of the few dose-finding trials of any drug in patients with rrPCNSL.Damage to a patient’s cognition and brain function (such as concentration, memory and speech problems) are a common feature of PCNSL, and these can limit a patient’s ability to consent to join a trial of a new therapy. Using a clearly defined consent process within a legal framework, these patients were able to be included in TIER, if this was deemed to be in their best interest and presumed will according to their legal representative. 17% of the patients on the trial were not able to give their own consent, but were able to be included in the trial by this process. This is important for other researchers and for patients and their families, because it shows a clear way to include patients lacking capacity to consent for themselves into clinical trials of new therapies.
The TIER trial has shown that thiotepa can be safely incorporated into a multidrug regimen for patients with PCNSL, and opens up the possibility of combining thiotepa with other agents to try to increase the time in remission for these patients.
The final analysis for this study was completed in April 2022.
REC name
London - Chelsea Research Ethics Committee
REC reference
14/LO/1568
Date of REC Opinion
8 Oct 2014
REC opinion
Further Information Favourable Opinion