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

NCT03141203 | Completed Phase 1 DMC FDA Drug

• 2 other identifiers: RG_13-1072013-001879-20
• Study Type: interventional
• Target: 50
• Locations: 1 country
• Sites: 13

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.

Conditions

Peripheral T Cell Lymphoma

Outcome Measures

Primary Outcomes (2)

• 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%

  Cycle 1 (each cycle is 28 days)

• Best overall response rate (PR + CR) at the MTD

  Assessed using the International response criteria

  Data will be collected over the first 8 cycles of therapy (each cycle is 28 days)

Secondary Outcomes (6)

• Toxicity of the combination of romidepsin and carfilzomib

  Adverse events information will be collected throughout the 36 month recruitment period of the trial and during the one year follow up period

• Best overall response at the MTD

  Information relating to this outcome will be collected up to and including the one year follow-up time point

• Maximum percentage change in the radiological sum of the product of the diameters from baseline, assessed using the Revised Response Criteria for Malignant Lymphoma

  Information relating to this outcome will be collected up to and including the one year follow-up time point

• Duration of response from time of first documented response until relapse or progression

  Information relating to this outcome will be collected up to and including the one year follow-up time point

• Progression free survival

  Information relating to this outcome will be collected up to and including the one year follow-up time point

Study Arms (6)

Dose Level 1

EXPERIMENTAL

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.

Drug: Romidepsin; Drug: Carfilzomib

Dose Level 2 (starting dose)

EXPERIMENTAL

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.

Drug: Romidepsin; Drug: Carfilzomib

Dose Level 3

EXPERIMENTAL

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.

Drug: Romidepsin; Drug: Carfilzomib

Dose Level 4

EXPERIMENTAL

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.

Drug: Romidepsin; Drug: Carfilzomib

Dose Level 5

EXPERIMENTAL

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.

Drug: Romidepsin; Drug: Carfilzomib

Dose Level 6

EXPERIMENTAL

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.

Drug: Romidepsin; Drug: Carfilzomib

Interventions

Romidepsin DRUG

10mg vial for Injection

Also known as: Istodax

Dose Level 1; Dose Level 2 (starting dose); Dose Level 3; Dose Level 4; Dose Level 5; Dose Level 6

Carfilzomib DRUG

60mg vial for injection

Also known as: Kyprolis

Dose Level 1; Dose Level 2 (starting dose); Dose Level 3; Dose Level 4; Dose Level 5; Dose Level 6

Eligibility Criteria

• Age: 16 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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)

Sponsors & Collaborators

• University of Birmingham: lead
• Bloodwise: collaborator
• Celgene: collaborator
• Amgen: collaborator

Study Sites (13)

Queen Elizabeth Hospital

Birmingham, United Kingdom

Location

St James's University Hospital

Leeds, United Kingdom

Location

Leicester Royal Infirmary

Leicester, United Kingdom

Location

Clatterbridge Cancer Centre

Liverpool, United Kingdom

Location

Guy's Hospital

London, United Kingdom

Location

St Bartholomew's Hospital

London, United Kingdom

Location

University College London Hospitals

London, United Kingdom

Location

Christie Hospital

Manchester, United Kingdom

Location

Nottingham University Hospitals

Nottingham, United Kingdom

Location

Churchill Hospital

Oxford, United Kingdom

Location

Derriford Hospital

Plymouth, United Kingdom

Location

Southampton General Hospital

Southampton, United Kingdom

Location

The Royal Marsden NHS Foundation Trust

Sutton, SM2 5PT, United Kingdom

Location

MeSH Terms

Conditions

Lymphoma, T-Cell, Peripheral

Interventions

romidepsin; carfilzomib

Condition Hierarchy (Ancestors)

Lymphoma, T-Cell; Lymphoma, Non-Hodgkin; Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Study Officials

• Graham Collins, MBBS DPhil

  Churchill Hospital, Oxford, UK

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 21, 2017
• First Posted: May 5, 2017
• Study Start: July 13, 2015
• Primary Completion: August 1, 2020
• Study Completion: September 23, 2021
• Last Updated: May 18, 2022

Record last verified: 2022-05

Data Sharing

• IPD Sharing: Will not share

Locations

GB (13)