The evidence supporting this protocol is provided by two phase II trials, one published in 2011 by Piekarz et. alr and the other in 2012 by Coiffier et. al.r
The Piekarz study is a phase II, single arm trial treating relapse refractory PTCL patients. Forty seven patients with PTCL of various subtypes (including PTCL NOS, angioimmunoblastic, ALK-negative anaplastic large cell lymphoma, and enteropathy-associated T-cell lymphoma) were enrolled in the study. Two patients were excluded from the response assessment, one with AITL deemed ineligible after the first dose and another patient was reclassified as DLBCL. Both patients were evaluated for toxicity. All patients had received prior treatment with a median of 3 prior therapies,including 18 patients who also had a SCT. Exclusion criteria included CNS involvement, pregnancy, cardiac factors (unstable angina, myocardial infarction within 12 months, LVEF below normal or corrected QT interval > 480 ms) , HIV infection, or prior therapy with an HDAC inhibitor.r
Romidepsin was administered at a dose of 14mg/m2 on days 1, 8 and 15 of a 28 day cycle. The first two patients were initially commenced on 18mg/m2 on days 1 and 5 of a 21 day cycle but this was changed for tolerability. Patients received a median of 3 (range:1-57) cycles and 9 (range:1-169) doses. Primary end point was response rate and toxicity profile.r
The study by Coiffier et alr is a prospective, single-arm, phase II trial conducted at multiple centres internationally in patients with relapsed or refractory disease. Of 131 patients enrolled, 130 were deemed eligible with histologically confirmed PTCL by central review. One patient with a diagnosis of DLBCL was excluded from the efficacy assessments. The majority of patients had stage III or IV disease and 36 patients had bone marrow involvement. All but one patient had previously been treated with chemotherapy, most commonly CHOP either alone or in combination with other agents or monoclonal antibodies. Twenty patients had received prior monoclonal antibody therapy, 14 had received other types of immunotherapy and 21 had undergone prior ASCT.
Patients received the same dose and schedule as the Piekarz trial of romidepsin 14mg/m2 as a 4 hour infusion on days 1, 8, 15 at 28 day cycles for up to six cycles. Patients with SD, PR or CR/CRu (unconfirmed) could extend therapy until progression of disease or another withdrawal criterion was met. The primary end point was CR/CRu as determined by the independent review committee. Secondary end points included ORR (CR/CRu + PR), duration of response, time to objective disease progression and change in ECOG PS. PFS was also assessed.r
| Source |
Study & Year Published |
Supports Use |
Is the dose and regimen consistent with the protocol? |
Comments |
| Phase II trials |
Piekarz et al 2011r |
Yes |
Yes |
|
| Phase II trials |
Coiffier et al 2012r |
Yes |
Yes |
|
| Guidelines |
Date published/revised |
Supports Use |
Is the dose and regimen consistent with the protocol? |
Comments |
| NCCN |
V.5 2018 |
Yes |
- |
|
| BCCA |
August 2017 |
Yes |
Yes |
|
| CCO |
November 2017 |
Yes |
Yes |
|
Efficacy
In the Piekarz trial, of the 45 patients that were assessed for response, ORR was 38%, CR of 18% and PR of 20%. 11% of patients had stable disease (SD). Median duration of response was 8.9 months. The duration of response was 29.7 months in patients with CR, 5.2 months in patients with PR and 6 months for patients with SD. Of the 18 patients who had undergone previous SCT, 6 had a response to treatment with romidepsin: 3 CR and 3 PR.r
© Blood 2011
The Coiffier study reported a median duration of follow up of 13.4 months at time of data cut-off. As per the independent review committee assessment, ORR was 25% (33 of 130), including 15% with CR/CRu (table 2). However, responses were seen in more common PTCL subtypes: 7 of PTCL NOS, AITL and ALK-1-negative ALCL and not in the six rarer subtypes; however only 13 patients across these rarer subtypes were treated (table 3). Thirty-three patients (25%) had SD, of which 23 patients were free from progression at ≥ 90 days.r
© ASCO 2012
© ASCO 2012
The Coiffier study had a median time to objective response of 1.8 months and median time to CR/CRu of 3.7 months. Mean and median duration of treatment were 4.2 and 1.4 months, respectively. Fifty patients were treated for at least 4 cycles, 36 patients were treated for more than six cycles and longer follow-up showed that 18 patients were treated for ≥ 12 cycles.rr
Overall median PFS was 4 months. Median was 18 months for patients with CR/CRu, 7 months for patients with PR and 6 months for patients with SD. Of the 82 patients who had a baseline ECOG PS score > 0 and available post-baseline data, 34 (41%) had a documented improvement in ECOG PS.r
Subsequent data published in 2016 of the Coiffier trial demonstrated a median follow-up of 22.3 months, a median duration of response of 22.3 months and longest response ongoing at 56 months.r
Toxicity
Most adverse events reported in the Coiffier trial were mild to moderate in severity and the most common grade 3-4 AEs were thrombocytopenia, neutropenia and infection. Nausea and vomiting (primarily grade 1-2) were the most frequent drug-related AEs but did not result in discontinuation.r
© ASCO 2012
The majority of patients tolerated the full dose of romidepsin; 61 patients had dose interruptions and 14 patients required a dose reduction to 10mg/m2. Dose interruptions were most commonly attributed to thrombocytopenia (18%), infection (12%) and neutropenia (11%). Thrombocytopenia was the most common cause for dose reduction in patients.r
Twenty-five patients discontinued therapy due to AE. Major causes for drug discontinuation was thrombocytopenia, pneumonia, fatigue, dyspnoea and sepsis (2% each). Eight patients died within 30 days of the last dose of romidepsin. Three patients died from PD and the remaining 5 an infection or event that occurred during infection was reported as the cause of death. One death was assessed to be possibly treatment related: the patient received two doses of romidepsin before withdrawing consent and died 3 weeks after the last dose from multi-organ failure in the setting of sepsis and PD.r
In the Piekarz trial, only first cycle toxicity was reported (see table below). Haematologic abnormalities were common and included leucopenia (47%),thrombocytopenia (47%), granulocytopenia (45%), anaemia (40%) and lymphopenia (17%). Dose reductions were mandated in 20 patients: 16 for thrombocytopenia, 6 for neutropenia and 3 for both. In 6 of these 20 patients, additional dose reductions occurred for ongoing AEs such as fatigue, elevated LFTs, anorexia, diarrhoea, infection, or fever.r
© Blood 2011
Piekarz reported 2 deaths in patients with PTCL while on study and 5 deaths in patients within 30 days of the study. The deaths on study included 1 patient with rapid PD further complicated by a pericardial effusion and a second patient with a cardiac history of significant atherosclerotic disease. Of the 5 patients who died within 30 days of the study; 4 died of disease progression. One patient achieved CR but later died with high-grade fevers, thrombocytopenia, and elevated LFTs after receiving the first dose of his 15th cycle. r