A study to determine the maximum tolerated dose and activity of the combination of romidepsin and carfilzomib in relapsed or refractory peripheral T-cell lymphoma
| ISRCTN | ISRCTN42054893 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN42054893 |
| EudraCT/CTIS number | 2013-001879-20 |
| ClinicalTrials.gov number | NCT03141203 |
| Secondary identifying numbers | 15553 |
- Submission date
- 11/12/2013
- Registration date
- 11/12/2013
- Last edited
- 04/12/2024
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Cancer
Prospectively registered
Protocol
Statistical analysis plan
Results
Individual participant data
Plain English summary of protocol
Contact information
Ms Eszter Nagy
Scientific
Scientific
Cancer Research UK Clinical Trials Unit
The University of Birmingham
Edgbaston
Birmingham
B15 2TT
United Kingdom
| Phone | +44 (0)121 371 7862 |
|---|---|
| romicar@trials.bham.ac.uk |
Study information
| Study design | Non-randomized interventional treatment trial |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Non randomised study |
| Study setting(s) | Hospital |
| Study type | Treatment |
| Participant information sheet | Not available in web format, please use contact details to request a participant information sheet |
| Scientific 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 |
| Study acronym | RomiCar |
| Study objectives | RomiCar is a prospective, single arm, multicentre phase I/II clinical trial for patients with relapsed or refractory peripheral T-cell lymphoma. The following designs will be used in each phase: Phase I: Continual Reassessment Method (CRM) to determine the Maximum Tolerated Dose (MTD) of the combination of romidepsin and carfilzomib. Phase II: A'Hern's single stage design to assess the activity (best overall response rate (PR + CR)) of the combination of romidepsin and carfilzomib over 8 cycles of treatment. |
| Ethics approval(s) | NRES Committee East Midlands - Northampton, 30/12/2013, ref:13/EM/0462 |
| Health condition(s) or problem(s) studied | Peripheral T-cell lymphoma |
| Intervention | Carfilzomib, Proteasome inhibitor Romidepsin, Histone deacetylase (HDAC) inhibitor Romidepsin dose (days 1, 8, 15) Dose level 1: 8 mg/m2 Dose level 2 (starting dose):10 mg/m2 Dose level 3: 10 mg/m2 Dose level 4: 12 mg/m2 Dose level 5: 12 mg/m2 Dose level 6: 14 mg/m2 Carfilzomib dose* (days 1, 2, 8, 9, 15, 16) Dose level 1: 20/36 mg/m2 Dose level 2 (starting dose): 20/36 mg/m2 Dose level 3: 20/45 mg/m2 Dose level 4: 20/45 mg/m2 Dose level 5: 20/56 mg/m2 Dose level 6: 20/56 mg/m2 * For all dose levels, the carfilzomib dose will be 20 mg/m2 for the first 2 doses (i.e. day 1 and 2 of cycle 1), rising to the target dose for subsequent doses and cycles. Patients in the phase II will receive the Maximum Tolerated Dose determined by phase I results. Treatment is intravenous and given in cycles (each lasting 28 days). Treatment is given on the days stated in the table above. Patients will receive treatment for 8 cycles and further cycles may be given at the investigator's discretion if the patient has not progressed. Follow-up is a minimum of 1 year. Follow Up Length: 12 month(s) Study Entry: Registration only |
| Intervention type | Drug |
| Pharmaceutical study type(s) | |
| Phase | Phase I/II |
| Drug / device / biological / vaccine name(s) | Romidepsin, carfilzomib |
| Primary outcome measure | Current primary outcome measures as of 11/06/2018: 1. Maximum Tolerated Dose (MTD) of the combination of romidepsin and carfilzomib (Phase I); Timepoint(s): Within 4 weeks of treatment with the combination 2. Best Overall Response Rate (Phase II); Timepoint(s): During 8 cycles of treatment with the combination Previous primary outcome measures: Maximum Tolerated Dose (MTD) of the combination of romidepsin and carfilzomib (Phase I); Timepoint(s): Within 4 weeks of treatment with the combination |
| Secondary outcome measures | Current secondary outcome measures as of 11/06/2018: 1. Best Overall Response Rate (Phase II); Timepoint(s): During treatment and until the end of the trial 2. Duration of response from time of first documented response until relapse or progression; Timepoint(s): From first response through to end of follow-up 3. Maximum % change in the radiological sum of the products of the diameters from baseline; Timepoint(s): During 8 cycles of combination treatment 4. Overall Survival; Timepoint(s): From baseline until the end of the trial 5. Progression Free Survival (Phase II); Timepoint(s): From baseline until the end of the trial 6. Toxicity of the combination of romidepsin and carfilzomib; Timepoint(s): During combination treatment Previous secondary outcome measures: 1. Best Overall Response Rate (Phase II); Timepoint(s): During 8 cycles of treatment with the combination 2. Duration of response from time of first documented response until relapse or progression; Timepoint(s): From first response through to end of follow-up 3. Maximum % change in the radiological sum of the products of the diameters from baseline; Timepoint(s): During 8 cycles of combination treatment 4. Overall Survival; Timepoint(s): From baseline to 6, 12, 24 and 36 months 5. Progression Free Survival (Phase II); Timepoint(s): From baseline to 6, 12, 24 and 36 months 6. Toxicity of the combination of romidepsin and carfilzomib; Timepoint(s): During combination treatment |
| Overall study start date | 13/07/2015 |
| Completion date | 23/09/2021 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 16 Years |
| Sex | Both |
| Target number of participants | Planned Sample Size: 58; UK Sample Size: 58 |
| Total final enrolment | 50 |
| Key inclusion criteria | Current inclusion criteria as of 11/06/2018: 1. Aged ≥16 years 2. Life expectancy > 12 weeks 3. ECOG performance status ≤2 4. Relapsed or refractory* peripheral Tcell lymphoma including the following histologies: peripheral Tcelllymphoma not otherwise specified, angioimmunoblastic Tcell lymphoma, anaplastic large cell lymphoma, enteropathy associated Tcell lymphoma, extranodal NK/Tcell lymphoma, transformed mycosis fungoides, hepatosplenic Tcell lymphoma 5. Failed at least 1 prior therapy (but no upper limit of prior regimens) 6. Adequate haematopoietic reserve (Hb ≥ 9 g/dl, neutrophils ≥1.0x10(9)/l and platelets ≥100x10(9)/l or ≥75x10(9)/l if marrow involvement documented) 7. Adequate liver function (bilirubin ≤1.5 x upper limit of normal (ULN) (unless due to Gilbert’s syndrome), AST / ALT ≤2x ULN) 8. Adequate renal function (creatinine clearance ≥ 20ml/min as assessed by Cockcroft and Gault calculation) 9. Serum potassium ≥ 3.8 mmol/l, calcium ≥ 2.2 mmol/l and magnesium ≥ LLN prior to trial entry (supplements permitted) 10. CT measurable disease with at least 1 lesion having short axis >1.5 cm or splenomegaly >14 cm in craniocaudal length attributable to relapsed lymphoma 11. Ability to give informed consent *For all relapsed patients, relapse must be confirmed by tissue biopsy (or bone marrow trephine if no other tissue available). For refractory patients, a biopsy must have been obtained within the last 6 months and preferably to confirm refractory disease. In rare cases (such as when re-biopsy is not possible), the initial diagnostic biopsy may be accepted, provided that the patient has been reviewed at the local MDT who agreed that the presentation is consistent with relapsed/refractory T cell lymphoma, and this has been documented. Previous inclusion criteria: 1. Age ≥ 16 years of age 2. Life expectancy > 12 weeks 3. ECOG performance status ≤ 2 4. Relapsed or refractory* peripheral Tcell lymphoma including the following histologies: peripheral Tcelllymphoma not otherwise specified, angioimmunoblastic Tcell lymphoma, anaplastic large cell lymphoma, enteropathy associated Tcell lymphoma, extranodal NK/Tcell lymphoma, transformed mycosis fungoides, hepatosplenic Tcell lymphoma 5. Failed at least 1 prior therapy (but no upper limit of prior regimens) 6. Adequate haematopoietic reserve (Hb ≥ 9g/dl, neutrophils ≥ 1.0x109/l and platelets ≥ 100x109/l or ≥ 75x109/l if marrow involvement documented) 7. Adequate liver function (bilirubin ≤ 1.5 x ULN, AST / ALT ≤ 2x ULN) 8. Adequate renal function (creatinine clearance ≥ 20ml/min as assessed by Cockcroft and Gault calculation) 9. Serum potassium ≥ 4.0 mmol/l, calcium ≥ 2.2 mmol/l and magnesium ≥ 0.85 mmol/l prior to trial entry 10. CT measurable disease with at least 1 lesion having short axis > 1.5cm or splenomegaly > 14cm in craniocaudal length attributable to relapsed lymphoma 11. Ability to give informed consent * For all relapsed patients, relapse must be confirmed by tissue biopsy (or bone marrow trephine if no other tissue available). For refractory patients, a biopsy must have been obtained within the last 6 months and preferably to confirm refractory disease. |
| Key exclusion criteria | Current exclusion criteria as of 11/06/2018: 1. Persistent treatment related toxicities of CTCAE v4.0 grade ≥ 2 2. Previous treatment with histone deactylase inhibitor or proteasome inhibitor 3. Need for any other concurrent anticancer drug (apart from corticosteroids at a dose equivalent to prednisolone ≤7.5mg daily). A steroid prephase may be used but should be stopped by the first day of cycle 1. 4. Concurrent medical illness deemed by the investigator as uncontrolled and/or clinically significant 5. Coexisting active infection requiring parenteral antibiotics 6. Patients unable to swallow oral medication 7. Active infection with HIV, hepatitis B or hepatitis C 8. Radiotherapy* (except for palliative reasons), endocrine therapy, immunotherapy or use of other investigationalagents within 28 days prior to trial entry (or a longer period depending on the defined characteristics of the agents used, please contact the trials office for confirmation). *Limited field radiotherapy to an isolated lesion in bone or soft tissue must be completed 2 weeks prior to trial entry 9. Major surgery within 4 weeks of trial entry 10. Patients with proven CNS involvement 11. QTc interval of >450ms or patients taking medications that significantly prolong the QT interval 12. Clinically significant cardiac disease ≥ NYHA Class III, symptomatic ischaemia, conduction abnormalities uncontrolled by conventional intervention or myocardial infarction within 6 months of trial entry 13. Pregnant and lactating patients (patients of childbearing potential must have a negative pregnancy test prior to study entry and within 7 days prior to the start of treatment. Postmenopausal females (> 45 years old and without menstruation for > 1 year) and surgically sterilised females are exempt from a pregnancy test) 14. Patients and partners of childbearing potential not willing to use effective contraception during and for 3 months after therapy 15. Concurrent Pulmonary Hypertension 16. Left Ventricular Ejection Fraction (LVEF) of<40% 17. Patients taking any inhibitors or strong inducers of CYP3A4, with the exception of dexamethasone. 18. Previous systemic malignancy within the last 3 years unless treated with curative intent with no sign of recurrence. Other exceptions include non-melanotic skin cancer or carcinoma in-situ of the uterine cervix Previous exclusion criteria: 1. Persistent treatment related toxicities of CTCAE v4.0 grade ≥ 2 2. Previous treatment with histone deactylase inhibitor or proteasome inhibitor 3. Need for any other concurrent anticancer drug (apart from corticosteroids at a dose equivalent to prednisolone ≤7.5mg daily). A steroid prephase may be used but should be stopped by the first day of cycle 1. 4. Concurrent medical illness deemed by the investigator as uncontrolled and/or clinically significant 5. Coexisting active infection requiring parenteral antibiotics 6. Patients unable to swallow oral medication 7. Active infection with HIV, hepatitis B or hepatitis C 8. Radiotherapy* (except for palliative reasons), endocrine therapy, immunotherapy or use of other investigationalagents within 28 days prior to trial entry (or a longer period depending on the defined characteristics of the agents used, please contact the trials office for confirmation). *Limited field radiotherapy to an isolated lesion in bone or soft tissue must be completed 2 weeks prior to trial entry 9. Major surgery within 4 weeks of trial entry 10. Patients with proven CNS involvement 11. QTc interval of ≥ 480ms or patients taking medications that significantly prolong the QT interval (Appendix 7) 12. Clinically significant cardiac disease ≥ NYHA Class III, symptomatic ischaemia, conduction abnormalities uncontrolled by conventional intervention or myocardial infarction within 6 months of trial entry 13. Pregnant and lactating patients (patients of childbearing potential must have a negative pregnancy test prior to study entry and within 7 days prior to the start of treatment. Postmenopausal females (> 45 years old and without menstruation for > 1 year) and surgically sterilised females are exempt from a pregnancy test) 14. Patients and partners of childbearing potential not willing to use effective contraception during and for 3 months after therapy |
| Date of first enrolment | 13/07/2015 |
| Date of final enrolment | 31/08/2019 |
Locations
Countries of recruitment
- England
- United Kingdom
Study participating centres
Christie Hospital
Manchester
M20 4BX
United Kingdom
M20 4BX
United Kingdom
Churchill Hospital
Oxford
OX3 7LE
United Kingdom
OX3 7LE
United Kingdom
Derriford Hospital
Plymouth
PL6 8DH
United Kingdom
PL6 8DH
United Kingdom
Clatterbridge Cancer Centre
Liverpool
L7 8XP
United Kingdom
L7 8XP
United Kingdom
Leicester Royal Infirmary
Leicester
LE1 5WW
United Kingdom
LE1 5WW
United Kingdom
Nottingham City Hospital
Nottingham
NG5 1PB
United Kingdom
NG5 1PB
United Kingdom
The Royal Marsden Hospital
Sutton
SM2 5PT
United Kingdom
SM2 5PT
United Kingdom
Southampton General Hospital
Southampton
SO16 6YD
United Kingdom
SO16 6YD
United Kingdom
St Bartholomew's Hospital
London
EC1A 7BE
United Kingdom
EC1A 7BE
United Kingdom
St James's University Hospital
Leeds
LS9 7TF
United Kingdom
LS9 7TF
United Kingdom
The Queen Elizabeth Hospital
Birmingham
B15 2TH
United Kingdom
B15 2TH
United Kingdom
University College London Hospital
London
NW1 2BU
United Kingdom
NW1 2BU
United Kingdom
Sponsor information
University of Birmingham (UK)
University/education
University/education
Cancer Research UK Clinical Trials Unit
Institute for Cancer Studies
Edgbaston
Birmingham
B15 2TT
England
United Kingdom
| RomiCar@trials.bham.ac.uk | |
"ROR" |
https://ror.org/03angcq70 |
Funders
Funder type
Industry
Celgene Europe Ltd
No information available
Bloodwise
Private sector organisation / Other non-profit organizations
Private sector organisation / Other non-profit organizations
- Location
- United Kingdom
Amgen
Government organisation / For-profit companies (industry)
Government organisation / For-profit companies (industry)
- Alternative name(s)
- Amgen Inc., Applied Molecular Genetics Inc.
- Location
- United States of America
Results and Publications
| Intention to publish date | 31/07/2023 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Available on request |
| Publication and dissemination plan | To be confirmed at a later date |
| IPD sharing plan | The datasets generated during the current study will be available upon request from the CRCTU’s Director’s Committee (CRCTU-General@adf.bham.ac.uk) within 6 months after the publication of the outcome measures, unless the trial results are to be used as part of a regulatory submission where release of the data may be delayed or be subject to the approval of a third party. In addition, for trials with long-term follow-up primary outcome data (e.g. response) may be available before secondary outcome data (e.g. survival). Only scientifically sound proposals from appropriately qualified research groups will be considered for data and/or sample sharing. A data sharing agreement will cover the terms and conditions of the release of trial data and will include publication requirements, authorship and acknowledgements and obligations for the responsible use of data. An anonymised encrypted dataset will be transferred directly using a secure method and in accordance with the University of Birmingham’s IT guidance on encryption of datasets. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Basic results | 15/02/2023 | 16/02/2023 | No | No | |
| HRA research summary | 28/06/2023 | No | No | ||
| Plain English results | 04/12/2024 | No | Yes |
Additional files
Editorial Notes
04/12/2024: Cancer Research UK plain English results and total final enrolment added.
20/02/2023: The intention to publish date has been changed from 01/08/2022 to 31/07/2023.
16/02/2023: An updated basic results summary has been uploaded.
14/02/2023: The basic results summary has been removed pending addition of an updated version.
30/09/2022: A basic results summary has been uploaded.
11/02/2022: The intention to publish date has been changed from 01/02/2022 to 01/08/2022.
27/10/2021: The overall trial end date has been changed from 01/02/2021 to 23/09/2021.
03/04/2019: The condition has been changed from "Topic: National Cancer Research Network; Subtopic: Lymphoma; Disease: Lymphoma (non-Hodgkin's)" to "Peripheral T-cell lymphoma" following a request from the NIHR.
18/07/2018: IPD sharing statement added.
11/06/2018: The following changes were made to the trial record:
1. The primary and secondary outcome measures and inclusion and exclusion criteria were updated.
2. The overall trial end date was changed from 13/07/2020 to 01/02/2021.
3. The target number of participants was changed from 57 to 58.
4. The recruitment end date was changed from 13/07/2018 31/08/2019.
5. Guy's Hospital and Royal Liverpool University Hospital were removed and Clatterbridge Cancer Centre and The Royal Marsden Hospital were added to the trial participating centres.
6. Leukaemia and Lymphoma Research and Onyx Therapeutics, Inc. were removed as funders and Bloodwise and Amgen Ltd. were added.
04/08/2016: The following changes were made to the trial record:
1. The overall trial start date was changed from 01/02/2014 to 13/07/2015.
2. The overall trial end date was changed from 01/02/2016 to 13/07/2020.
3. The recruitment start date was changed from 01/02/2014 to 13/07/2015.
4. The recruitment end date was changed from 01/02/2016 to 13/07/2018.
