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Evaluation of the Combination of Romidepsin and Carfilzomib in Relapsed/Refractory Peripheral T Cell Lymphoma Patients (RomiCar)

Primary Purpose

Peripheral T Cell Lymphoma

Status
Completed
Phase
Phase 1
Locations
United Kingdom
Study Type
Interventional
Intervention
Romidepsin
Carfilzomib
Sponsored by
University of Birmingham
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Peripheral T Cell Lymphoma

Eligibility Criteria

16 Years - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Age ≥ 16 years of age
  • Life expectancy > 12 weeks
  • ECOG performance status ≤ 2
  • Relapsed or refractory peripheral T-cell lymphoma including the following histologies: peripheral T-cell lymphoma not otherwise specified, angioimmunoblastic T-cell lymphoma, anaplastic large cell lymphoma, enteropathy associated T-cell lymphoma, extranodal NK/T-cell lymphoma, transformed mycosis fungoides, hepatosplenic T-cell lymphoma [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.]
  • Failed at least 1 prior therapy (but no upper limit of prior regimens)
  • Patients MAY have had a prior allogeneic stem cell transplant but must not require systemic immunosuppression for graft-versus-host disease (local treatments are permitted)
  • Adequate haematopoietic reserve (Hb ≥ 9g/dl, neutrophils ≥ 1.0x10^9/l and platelets ≥ 100x10^9/l or ≥ 75x10^9/l if marrow involvement documented)
  • Adequate liver function (bilirubin ≤ 1.5 x upper limit of normal (ULN) (unless due to Gilbert's syndrome), AST / ALT ≤ 2x ULN)
  • Adequate renal function (creatinine clearance ≥ 20ml/min as assessed by Cockcroft and Gault calculation)
  • Serum potassium ≥ 3.8 mmol/l, calcium ≥ 2.2 mmol/l and magnesium ≥ LLN prior to trial entry (supplements permitted)
  • CT measurable disease with at least 1 lesion having short axis > 1.5cm or splenomegaly > 14cm in cranio-caudal length attributable to relapsed lymphoma
  • Ability to give informed consent

Exclusion Criteria:

  • Persistent treatment related toxicities of CTCAE v4.0 grade ≥ 2
  • Previous treatment with histone deactylase inhibitor or proteasome inhibitor
  • Need for any other concurrent anti-cancer 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.
  • Concurrent medical illness deemed by the investigator as uncontrolled and/or clinically significant
  • 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
  • Co-existing active infection requiring parenteral antibiotics
  • Patients unable to swallow oral medication
  • Active infection with HIV, hepatitis B or hepatitis C
  • Radiotherapy* (except for palliative reasons), endocrine therapy, immunotherapy or use of other investigational agents 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
  • Major surgery within 4 weeks of trial entry
  • Patients with proven CNS involvement
  • QTc interval of >450ms or patients taking medications that significantly prolong the QT interval
  • Patients taking any inhibitors or strong inducers of CYP3A4, with the exception of dexamethasone.
  • Clinically significant cardiac disease ≥ NYHA Class III, symptomatic ischaemia, conduction abnormalities uncontrolled by conventional intervention or myocardial infarction within 6 months of trial entry
  • 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)
  • Patients and partners of childbearing potential not willing to use effective contraception during and for 3 months after therapy
  • Concurrent Pulmonary Hypertension
  • Left Ventricular Ejection Fraction (LVEF) of <40%

Sites / Locations

  • Queen Elizabeth Hospital
  • St James's University Hospital
  • Leicester Royal Infirmary
  • Clatterbridge Cancer Centre
  • Guy's Hospital
  • St Bartholomew's Hospital
  • University College London Hospitals
  • Christie Hospital
  • Nottingham University Hospitals
  • Churchill Hospital
  • Derriford Hospital
  • Southampton General Hospital
  • The Royal Marsden NHS Foundation Trust

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm Type

Experimental

Experimental

Experimental

Experimental

Experimental

Experimental

Arm Label

Dose Level 1

Dose Level 2 (starting dose)

Dose Level 3

Dose Level 4

Dose Level 5

Dose Level 6

Arm Description

8mg/m2 Romidepsin (administered on days 1, 8, 15) and 20/36mg/m2 Carfilzomib (administered days 1, 2, 8, 9, 15, 16) over 8 cycles of treatment. Carfilzomib dose will be 20mg/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.

10mg/m2 Romidepsin (administered on days 1, 8, 15) and 20/36mg/m2 Carfilzomib (administered days 1, 2, 8, 9, 15, 16) over 8 cycles of treatment. Carfilzomib dose will be 20mg/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.

10mg/m2 Romidepsin (administered on days 1, 8, 15) and 20/45mg/m2 Carfilzomib (administered days 1, 2, 8, 9, 15, 16) over 8 cycles of treatment. Carfilzomib dose will be 20mg/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.

12mg/m2 Romidepsin (administered on days 1, 8, 15) and 20/45mg/m2 Carfilzomib (administered days 1, 2, 8, 9, 15, 16) over 8 cycles of treatment. Carfilzomib dose will be 20mg/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.

12mg/m2 Romidepsin (administered on days 1, 8, 15) and 20/56mg/m2 Carfilzomib (administered days 1, 2, 8, 9, 15, 16) over 8 cycles of treatment. Carfilzomib dose will be 20mg/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.

14mg/m2 Romidepsin (administered on days 1, 8, 15) and 20/56mg/m2 Carfilzomib (administered days 1, 2, 8, 9, 15, 16) over 8 cycles of treatment. Carfilzomib dose will be 20mg/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.

Outcomes

Primary Outcome Measures

Maximum Tolerated Dose of the combination of romidepsin and carfilzomib
MTD as determined by the continual reassessment model (CRM) with a predefined target Dose Limiting Toxicity (DLT) probability of 25%
Best overall response rate (PR + CR) at the MTD
Assessed using the International response criteria

Secondary Outcome Measures

Toxicity of the combination of romidepsin and carfilzomib
Assessed using CTCAE v4
Best overall response at the MTD
Assessed using International response criteria
Maximum percentage change in the radiological sum of the product of the diameters from baseline, assessed using the Revised Response Criteria for Malignant Lymphoma
Assessed on suitable target and non-target lesions
Duration of response from time of first documented response until relapse or progression
Progression free survival
Overall survival

Full Information

First Posted
February 21, 2017
Last Updated
May 17, 2022
Sponsor
University of Birmingham
Collaborators
Bloodwise, Celgene, Amgen
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1. Study Identification

Unique Protocol Identification Number
NCT03141203
Brief Title
Evaluation of the Combination of Romidepsin and Carfilzomib in Relapsed/Refractory Peripheral T Cell Lymphoma Patients
Acronym
RomiCar
Official 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 Type
Interventional

2. Study Status

Record Verification Date
May 2022
Overall Recruitment Status
Completed
Study Start Date
July 13, 2015 (Actual)
Primary Completion Date
August 2020 (Actual)
Study Completion Date
September 23, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Birmingham
Collaborators
Bloodwise, Celgene, Amgen

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
Yes
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This is a multicentre phase I/II trial looking at the combination of romidepsin and carfilzomib. The aim of the phase I part is to determine the maximum tolerated dose (MTD) of the combination. This part will recruit up to 27 patients, plus possibly an additional 3 patients at the MTD. The aim of the phase II part is to assess the activity of the combination at the maximum tolerated dose in 28 patients (including at least 6 patients treated at the MTD from phase I). Patients will receive 8 cycles of romidepsin with carfilzomib and response will be assessed every second cycle. Patients will be followed up for progression and survival until the end of the trial.
Detailed Description
This is a prospective, single arm, phase I/II, multicentre, dose finding study of romidepsin in combination with carfilzomib. The aim of the phase I is to establish the MTD of the combination using a restricted two-stage CRM. The MTD is defined as the dose level that is closest to the level at which 25% of patients experience a DLT over the first cycle of treatment. The intention in phase I is to evaluate the DLT-inducing effects of doses in cohorts of patients. Patients will be treated in cohorts at a dose level and each patient will be evaluated for presence or absence of DLT. In stage I, the first cohort of 3 patients will be enrolled at the starting dose, i.e. dose level 2. If none experiences a DLT, the next cohort of 3 patients will be recruited at the next higher level, i.e. dose level 3. This escalation routine will continue until the first DLT is observed or the maximum recruitment for stage I is reached. As soon as the first DLT is observed, dose escalation and de-escalation will be guided by the CRM design that will recommend the dose believed to have associated DLT-rate closest to 25%. If the trial escalates, each dose below the newly tested dose is regarded as being tolerable. In stage II, we will consider variable cohort sizes of up to eight patients. Patients are screened for eligibility before they are formally registered. During screening, we expect it to transpire that some patients will be ineligible. To maximise recruitment and reduce trial suspension period between cohorts in this rare disease, we will allow for the flexibility of variable cohort sizes by screening cohorts of up to eight patients. We will allocate screening slots so that the sum of: a) the number of patients already receiving treatment in the current cohort; and (b) the number of patients in screening; does not exceed eight. If a patient is screened and proves to be eligible, they will be recruited to the trial. The first three patients in a cohort will receive the dose-level allocated to the cohort. Patients who are inevaluable, as described immediately above, can be replaced. If the fourth to eighth patients are recruited to a cohort and the dose allocated to the cohort is not yet regarded as tolerable, the fourth to eighth patients will receive the next dose-level below. Otherwise, they will receive the same dose level as the previous patients in the cohort. The aim of the described strategy is to maximise recruitment but not expose more than three patients to a dose that has not yet been demonstrated tolerable. The model will be updated regularly and subsequent recommended doses will be assigned to patients iteratively until the maximum sample size is reached, or the trial is stopped early because there is a high chance that the lowest dose is too toxic. It is expected that the CRM will likely allocate patients to the eventual MTD at the later stage of the trial as more data accumulate. Recruitment will be permitted to continue seamlessly to the Phase II component at the latest recommended MTD dose, in consultation with the Trial Safety Committee, unless it is considered necessary to halt recruitment The initial guess of MTD is at dose combination level 4, however to exercise caution, dose level 2 is defined as the starting dose level. Dose Levels 8mg/m2 Romidepsin (days 1, 8, 15), 20/36mg/m2 Carfilzomib (days 1, 2, 8, 9, 15, 16) (Starting dose) 10mg/m2 Romidepsin (days 1, 8, 15), 20/36mg/m2 Carfilzomib (days 1, 2, 8, 9, 15, 16) 10mg/m2 Romidepsin (days 1, 8, 15), 20/45mg/m2 Carfilzomib (days 1, 2, 8, 9, 15, 16) 12mg/m2 Romidepsin (days 1, 8, 15), 20/45mg/m2 Carfilzomib (days 1, 2, 8, 9, 15, 16) 12mg/m2 Romidepsin (days 1, 8, 15), 20/56mg/m2 Carfilzomib (days 1, 2, 8, 9, 15, 16) 14mg/m2 Romidepsin (days 1, 8, 15), 20/56mg/m2 Carfilzomib (days 1, 2, 8, 9, 15, 16) For all dose levels, the carfilzomib dose will be 20mg/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. Once the MTD is defined, patients recruited at a lower dose may receive the MTD for any subsequent cycles of treatment at the discretion of the treating Investigator and the Chief Investigator. The phase II component will aim to provide a preliminary estimate of activity in 28 patients at the MTD combination established in phase I. The phase II component is based on A'Hern's single arm, single stage design and would utilise patients allocated to the MTD in phase I. Patients will be recruited over a 36-month period and will receive a minimum of 8 cycles of treatment. Patients will continue to be followed up for progression and survival until the end of the trial.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Peripheral T Cell Lymphoma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
50 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Dose Level 1
Arm Type
Experimental
Arm Description
8mg/m2 Romidepsin (administered on days 1, 8, 15) and 20/36mg/m2 Carfilzomib (administered days 1, 2, 8, 9, 15, 16) over 8 cycles of treatment. Carfilzomib dose will be 20mg/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.
Arm Title
Dose Level 2 (starting dose)
Arm Type
Experimental
Arm Description
10mg/m2 Romidepsin (administered on days 1, 8, 15) and 20/36mg/m2 Carfilzomib (administered days 1, 2, 8, 9, 15, 16) over 8 cycles of treatment. Carfilzomib dose will be 20mg/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.
Arm Title
Dose Level 3
Arm Type
Experimental
Arm Description
10mg/m2 Romidepsin (administered on days 1, 8, 15) and 20/45mg/m2 Carfilzomib (administered days 1, 2, 8, 9, 15, 16) over 8 cycles of treatment. Carfilzomib dose will be 20mg/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.
Arm Title
Dose Level 4
Arm Type
Experimental
Arm Description
12mg/m2 Romidepsin (administered on days 1, 8, 15) and 20/45mg/m2 Carfilzomib (administered days 1, 2, 8, 9, 15, 16) over 8 cycles of treatment. Carfilzomib dose will be 20mg/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.
Arm Title
Dose Level 5
Arm Type
Experimental
Arm Description
12mg/m2 Romidepsin (administered on days 1, 8, 15) and 20/56mg/m2 Carfilzomib (administered days 1, 2, 8, 9, 15, 16) over 8 cycles of treatment. Carfilzomib dose will be 20mg/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.
Arm Title
Dose Level 6
Arm Type
Experimental
Arm Description
14mg/m2 Romidepsin (administered on days 1, 8, 15) and 20/56mg/m2 Carfilzomib (administered days 1, 2, 8, 9, 15, 16) over 8 cycles of treatment. Carfilzomib dose will be 20mg/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.
Intervention Type
Drug
Intervention Name(s)
Romidepsin
Other Intervention Name(s)
Istodax
Intervention Description
10mg vial for Injection
Intervention Type
Drug
Intervention Name(s)
Carfilzomib
Other Intervention Name(s)
Kyprolis
Intervention Description
60mg vial for injection
Primary Outcome Measure Information:
Title
Maximum Tolerated Dose of the combination of romidepsin and carfilzomib
Description
MTD as determined by the continual reassessment model (CRM) with a predefined target Dose Limiting Toxicity (DLT) probability of 25%
Time Frame
Cycle 1 (each cycle is 28 days)
Title
Best overall response rate (PR + CR) at the MTD
Description
Assessed using the International response criteria
Time Frame
Data will be collected over the first 8 cycles of therapy (each cycle is 28 days)
Secondary Outcome Measure Information:
Title
Toxicity of the combination of romidepsin and carfilzomib
Description
Assessed using CTCAE v4
Time Frame
Adverse events information will be collected throughout the 36 month recruitment period of the trial and during the one year follow up period
Title
Best overall response at the MTD
Description
Assessed using International response criteria
Time Frame
Information relating to this outcome will be collected up to and including the one year follow-up time point
Title
Maximum percentage change in the radiological sum of the product of the diameters from baseline, assessed using the Revised Response Criteria for Malignant Lymphoma
Description
Assessed on suitable target and non-target lesions
Time Frame
Information relating to this outcome will be collected up to and including the one year follow-up time point
Title
Duration of response from time of first documented response until relapse or progression
Time Frame
Information relating to this outcome will be collected up to and including the one year follow-up time point
Title
Progression free survival
Time Frame
Information relating to this outcome will be collected up to and including the one year follow-up time point
Title
Overall survival
Time Frame
Information relating to this outcome will be collected up to and including the one year follow-up time point

10. Eligibility

Sex
All
Minimum Age & Unit of Time
16 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Age ≥ 16 years of age Life expectancy > 12 weeks ECOG performance status ≤ 2 Relapsed or refractory peripheral T-cell lymphoma including the following histologies: peripheral T-cell lymphoma not otherwise specified, angioimmunoblastic T-cell lymphoma, anaplastic large cell lymphoma, enteropathy associated T-cell lymphoma, extranodal NK/T-cell lymphoma, transformed mycosis fungoides, hepatosplenic T-cell lymphoma [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.] Failed at least 1 prior therapy (but no upper limit of prior regimens) Patients MAY have had a prior allogeneic stem cell transplant but must not require systemic immunosuppression for graft-versus-host disease (local treatments are permitted) Adequate haematopoietic reserve (Hb ≥ 9g/dl, neutrophils ≥ 1.0x10^9/l and platelets ≥ 100x10^9/l or ≥ 75x10^9/l if marrow involvement documented) Adequate liver function (bilirubin ≤ 1.5 x upper limit of normal (ULN) (unless due to Gilbert's syndrome), AST / ALT ≤ 2x ULN) Adequate renal function (creatinine clearance ≥ 20ml/min as assessed by Cockcroft and Gault calculation) Serum potassium ≥ 3.8 mmol/l, calcium ≥ 2.2 mmol/l and magnesium ≥ LLN prior to trial entry (supplements permitted) CT measurable disease with at least 1 lesion having short axis > 1.5cm or splenomegaly > 14cm in cranio-caudal length attributable to relapsed lymphoma Ability to give informed consent Exclusion Criteria: Persistent treatment related toxicities of CTCAE v4.0 grade ≥ 2 Previous treatment with histone deactylase inhibitor or proteasome inhibitor Need for any other concurrent anti-cancer 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. Concurrent medical illness deemed by the investigator as uncontrolled and/or clinically significant 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 Co-existing active infection requiring parenteral antibiotics Patients unable to swallow oral medication Active infection with HIV, hepatitis B or hepatitis C Radiotherapy* (except for palliative reasons), endocrine therapy, immunotherapy or use of other investigational agents 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 Major surgery within 4 weeks of trial entry Patients with proven CNS involvement QTc interval of >450ms or patients taking medications that significantly prolong the QT interval Patients taking any inhibitors or strong inducers of CYP3A4, with the exception of dexamethasone. Clinically significant cardiac disease ≥ NYHA Class III, symptomatic ischaemia, conduction abnormalities uncontrolled by conventional intervention or myocardial infarction within 6 months of trial entry 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) Patients and partners of childbearing potential not willing to use effective contraception during and for 3 months after therapy Concurrent Pulmonary Hypertension Left Ventricular Ejection Fraction (LVEF) of <40%
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Graham Collins, MBBS DPhil
Organizational Affiliation
Churchill Hospital, Oxford, UK
Official's Role
Principal Investigator
Facility Information:
Facility Name
Queen Elizabeth Hospital
City
Birmingham
Country
United Kingdom
Facility Name
St James's University Hospital
City
Leeds
Country
United Kingdom
Facility Name
Leicester Royal Infirmary
City
Leicester
Country
United Kingdom
Facility Name
Clatterbridge Cancer Centre
City
Liverpool
Country
United Kingdom
Facility Name
Guy's Hospital
City
London
Country
United Kingdom
Facility Name
St Bartholomew's Hospital
City
London
Country
United Kingdom
Facility Name
University College London Hospitals
City
London
Country
United Kingdom
Facility Name
Christie Hospital
City
Manchester
Country
United Kingdom
Facility Name
Nottingham University Hospitals
City
Nottingham
Country
United Kingdom
Facility Name
Churchill Hospital
City
Oxford
Country
United Kingdom
Facility Name
Derriford Hospital
City
Plymouth
Country
United Kingdom
Facility Name
Southampton General Hospital
City
Southampton
Country
United Kingdom
Facility Name
The Royal Marsden NHS Foundation Trust
City
Sutton
ZIP/Postal Code
SM2 5PT
Country
United Kingdom

12. IPD Sharing Statement

Plan to Share IPD
No

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Evaluation of the Combination of Romidepsin and Carfilzomib in Relapsed/Refractory Peripheral T Cell Lymphoma Patients

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