E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Peripheral T-cell Lymphoma |
|
E.1.1.1 | Medical condition in easily understood language |
Peripheral T-cell lymphoma (PTCL) consists of a group of rare and usually aggressive (fast-growing) Non-Hodgkins Lymphomas that develop from mature T-cells |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10034626 |
E.1.2 | Term | Peripheral T-cell lymphoma unspecified refractory |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10034625 |
E.1.2 | Term | Peripheral T-cell lymphoma unspecified recurrent |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
• Determine the MTD of the combination of romidepsin and carfilzomib based on a CRM with target Dose Limiting Toxicity (DLT) set at 25% • Assess the activity of the combination at the MTD in terms of overall response
|
|
E.2.2 | Secondary objectives of the trial |
Phase I • Toxicity of the combination of romidepsin and carfilzomib using CTCAE v4 • Best overall response during the first 8 cycles of treatment at the MTD • Maximum % change in the radiological sum of the product of the diameters from baseline • Duration of response from time of first documented response until relapse or progression
Phase II • Best overall response rate post 8 cycles of treatment until the end of the trial, assessed using International response criteria • Toxicity of the combination of romidepsin and carfilzomib using CTCAE v4 • Maximum % change in the radiological sum of the product of the diameters from baseline • Duration of response from time of first documented response until relapse or progression • Progression free survival • Overall survival
An exploratory objective is to determine whether the expression of the protein HR23B can be used as a predictive biomarker of response to this combination |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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 • Failed at least 1 prior therapy (but no upper limit of prior regimens) • Adequate haematopoietic reserve (Hb ≥ 9g/dl, neutrophils ≥ 1.0x109/l and platelets ≥ 100x109/l or ≥ 75x109/l if marrow involvement documented) • Adequate liver function (bilirubin ≤ 1.5 x ULN, AST / ALT ≤ 2x ULN) • Adequate renal function (creatinine clearance ≥ 20ml/min as assessed by Cockcroft and Gault calculation) • Serum potassium ≥ 4.0 mmol/l, calcium ≥ 2.2 mmol/l and magnesium ≥ 0.85 mmol/l prior to trial entry • 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 * 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. |
|
E.4 | Principal 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 • 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 ≥ 480ms or patients taking medications that significantly prolong the QT interval (Appendix 7) • 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
|
|
E.5 End points |
E.5.1 | Primary end point(s) |
Phase I Maximum Tolerated Dose (MTD) of the combination of romidepsin and carfilzomib as determined by the Continual Reassessment Method with a predefined target Dose Limiting Toxicity (DLT) probability of 25%. Phase II Best overall response rate (Partial Response + Complete Response) during the first 8 cycles of treatment at the MTD using International response criteria |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
MTD will be determined over 1 cycle of treatment (4 weeks) Best overall response will be determined over 8 cycles of treatment (32 weeks). |
|
E.5.2 | Secondary end point(s) |
Phase I • Toxicity of the combination of romidepsin and carfilzomib using CTCAE v4 • Best overall response during the first 8 cycles of treatment at the MTD • Maximum % change in the radiological sum of the product of the diameters from baseline • Duration of response from time of first documented response until relapse or progression
Phase II • Best overall response rate post 8 cycles of treatment until the end of the trial, assessed using International response criteria • Toxicity of the combination of romidepsin and carfilzomib using CTCAE v4 • Maximum % change in the radiological sum of the product of the diameters from baseline • Duration of response from time of first documented response until relapse or progression • Progression free survival • Overall survival |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Toxicity, best overall response and maximum change in % SPD will be assessed over the first 8 cycles (32 weeks). Duration of response is from time of first documented response until relapse or progression PFS and OS will be estimated at 6, 12, 24 and 36 months |
|
E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 13 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
LVLS plus 6 months for final data cleaning |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 2 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 2 |