Peripheral T-cell lymphoma Cancer Peripheral T-cell lymphoma, not elsewhere classified
Conditions
Interventions
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
D
Sponsors
University of Birmingham (UK)
Eligibility
Sex/Gender
All
Inclusion criteria
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.
Exclusion criteria
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 involveme
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 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
| Measure | Time frame |
|---|---|
| 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 | — |
Countries
England, United Kingdom
Outcome results
None listed