Romidepsin is a structurally unique, potent class 1 selective histone deacetylase inhibitor. The primary objective of this international, pivotal, single-arm, phase II trial was to confirm the ...efficacy of romidepsin in patients with relapsed or refractory peripheral T-cell lymphoma (PTCL).
Patients who were refractory to at least one prior systemic therapy or for whom at least one prior systemic therapy failed received romidepsin at 14 mg/m(2) as a 4-hour intravenous infusion on days 1, 8, and 15 every 28 days. The primary end point was the rate of complete response/unconfirmed complete response (CR/CRu) as assessed by an independent review committee.
Of the 131 patients enrolled, 130 had histologically confirmed PTCL by central review. The median number of prior systemic therapies was two (range, one to eight). The objective response rate was 25% (33 of 130), including 15% (19 of 130) with CR/CRu. Patient characteristics, prior stem-cell transplantation, number or type of prior therapies, or response to last prior therapy did not have an impact on response rate. The median duration of response was 17 months, with the longest response ongoing at 34+ months. Of the 19 patients who achieved CR/CRu, 17 (89%) had not experienced disease progression at a median follow-up of 13.4 months. The most common grade ≥ 3 adverse events were thrombocytopenia (24%), neutropenia (20%), and infections (all types, 19%).
Single-agent romidepsin induced complete and durable responses with manageable toxicity in patients with relapsed or refractory PTCL across all major PTCL subtypes, regardless of the number or type of prior therapies. Results led to US Food and Drug Administration approval of romidepsin in this indication.
Romidepsin is a histone deacetylase inhibitor approved by the FDA for the treatment of patients with cutaneous or peripheral T‐cell lymphoma who have received prior systemic therapy. The objective of ...this analysis was to evaluate the potential QTc effects of romidepsin. Patients with advanced malignancy received 4‐h infusions of 14 mg/m2 romidepsin on days 1, 8, and 15 of a 28‐day cycle. In cycle 2, a subset of patients received 1‐h infusions of 8–12 mg/m2 romidepsin. Patients were administered antiemetics before each romidepsin dose and electrolyte supplementation as needed. Electrocardiogram readings were performed prior to antiemetic administration, prior to romidepsin administration, and at specified time points over the subsequent 24 h. Romidepsin exposure and heart rate were also assessed. In the electrocardiogram‐evaluable population, 26 patients received romidepsin at 14 mg/m2 over 4 h. The maximum mean increases from the preantiemetic baseline for QTcF and heart rate were 10.1 msec (upper 90% CI, 14.5 msec) and 18.2 beats per minute, respectively. No patient in this study had an absolute QTcF value >450 msec and only one patient had an increase from the preantiemetic baseline of >60 msec. There was a mild reduction in the PR interval and no meaningful changes in the QRS interval. Despite the use of QT‐prolonging antiemetics, treatment with romidepsin did not markedly prolong the QTc interval through 24 h. Increases in calculated QTc may have been exaggerated as a consequence of transient increases in heart rate.
The available data support the absence of a major effect of romidepsin on the QTc interval. Administration of certain antiemetics and patient hypomagnesemia/hypokalemia can impact the QT interval, thus electrolyte levels should be kept in the normal range and consideration should be exercised when administering romidepsin with antiemetics and other drugs that prolong the QTc interval.
Romidepsin is a structurally unique, potent, bicyclic class 1 selective histone deacetylase inhibitor approved by the US Food and Drug Administration for the treatment of patients with cutaneous ...T-cell lymphoma who have received ≥ 1 prior systemic therapy and patients with peripheral T-cell lymphoma (PTCL) who have received ≥ 1 prior therapy. Approval for PTCL was based on results (n = 130; median follow-up, 13.4 months) from the pivotal study of romidepsin for the treatment of relapsed/refractory PTCL. The objective is to present updated data (median follow-up, 22.3 months) and to characterize patients who achieved long-term responses (≥ 12 months) to romidepsin.
Patients with PTCL who relapsed from or were refractory to ≥ 1 prior systemic therapy received romidepsin 14 mg/m2 as a 4-hour intravenous infusion on days 1, 8, and 15 every 28 days for up to 6 cycles; patients with response or stable disease could continue romidepsin beyond 6 cycles. The primary endpoint was rate of confirmed/unconfirmed complete response (CR/CRu) determined by an Independent Review Committee. Secondary endpoints included objective response rate (ORR) and duration of response (DOR). For patients who achieved CR/CRu, baseline characteristics by DOR (≥ 12 vs < 12 months) were examined.
The ORR to romidepsin was 25%, including 15% with CR/CRu. The median DOR for all responders was 28 months (range, < 1-48+) and was not reached for those who achieved CR/CRu. Patients with lack of response or transient response to prior therapy achieved durable responses with romidepsin. Of the 19 patients who achieved CR/CRu, 10 had long-term (≥ 12 months) responses; none of the baseline characteristics examined-including heavy pretreatment, response to prior therapy, or advanced disease-precluded long-term responses to romidepsin. With a median progression-free survival of 29 months, patients who achieved CR/CRu for ≥ 12 months had significantly longer survival vs those with CR/CRu for < 12 months or < CR/CRu. Extended treatment and longer follow-up did not affect the reported safety profile of romidepsin.
Treatment with romidepsin leads to highly durable responses in a subset of patients with relapsed/refractory PTCL, with responses ongoing as long as 48 months.
We report results from a study exploring the combination of romidepsin, bortezomib, and dexamethasone for the treatment of patients with multiple myeloma (MM) previously treated with > 1 prior ...therapy. The primary objective was to determine the maximum tolerated dose (MTD) of the combination using a novel accelerated dose-escalation schedule in patients with relapsed or refractory MM. The secondary objective was to determine overall response (OR), time to progression (TTP), and overall survival (OS). The MTD identified was bortezomib 1.3 mg/m2 (days 1, 4, 8, and 11), dexamethasone 20 mg (days 1, 2, 4, 5, 8, 9, 11, and 12), and romidepsin 10 mg/m2 (days 1, 8, and 15) every 28 days. Thrombocytopenia (64%) was the most common ≥ grade 3 hematologic toxicity. Peripheral neuropathy occurred in 76% of patients (n = 19) (≥ grade 3, 8%; 95% confidence interval CI 1%-26%). Maintenance romidepsin 10 mg/m2 (on days 1 and 8 of a 28-day cycle) proved feasible, with 12 patients receiving a median of 7.5 cycles (range: 1-29). An OR (M-protein) of > minor response (MR) was seen in 18 of 25 patients (72%); 2 (8%) had complete remissions (CRs) and 13 (52%) had partial responses (PRs), including 7 (28%) with very good PRs (VGPRs). The median TTP was 7.2 (95% CI: 5.5-19.6) months, and the median OS was > 36 months. This regimen shows activity with manageable toxicity and warrants further evaluation. This trial was registered at www.clinicaltrials.gov as NCT00431990.
Summary
Romidepsin is an epigenetic agent approved for the treatment of patients with cutaneous or peripheral T‐cell lymphoma (CTCL and PTCL). Here we report data in all patients treated on the ...National Cancer Institute 1312 trial, demonstrating long‐term disease control and the ability to retreat patients relapsing off‐therapy. In all, 84 patients with CTCL and 47 with PTCL were enrolled. Responses occurred early, were clinically meaningful and of very long duration in some cases. Notably, patients with PTCL receiving romidepsin as third‐line therapy or later had a comparable response rate (32%) of similar duration as the total population (38%). Eight patients had treatment breaks of 3·5 months to 10 years; in four of six patients, re‐initiation of treatment led to clear benefit. Safety data show slightly greater haematological and constitutional toxicity in PTCL. cDNA microarray studies show unique individual gene expression profiles, minimal overlap between patients, and both induction and repression of gene expression that reversed within 24 h. These data argue against cell death occurring as a result of an epigenetics‐mediated gene induction programme. Together this work supports the safety and activity of romidepsin in T‐cell lymphoma, but suggests a complex mechanism of action.
The objective of this phase III study was to determine the efficacy, safety, and pharmacokinetics of denileukin diftitox (DAB389IL-2, Ontak Ligand Pharmaceuticals Inc, San Diego, CA) in patients with ...stage Ib to IVa cutaneous T-cell lymphoma (CTCL) who have previously received other therapeutic interventions.
Patients with biopsy-proven CTCL that expressed CD25 on > or = 20% of lymphocytes were assigned to one of two dose levels (9 or 18 microg/kg/d) of denileukin diftitox administered 5 consecutive days every 3 weeks for up to 8 cycles. Patients were monitored for toxicity and clinical efficacy, the latter assessed by changes in disease burden and quality of life measurements. Antibody levels of antidenileukin diftitox and anti-interleukin-2 and serum concentrations of denileukin diftitox were also measured.
Overall, 30% of the 71 patients with CTCL treated with denileukin diftitox had an objective response (20% partial response; 10% complete response). The response rate and duration of response based on the time of the first dose of study drug for all responders (median of 6.9 months with a range of 2.7 to more than 46.1 months) were not statistically different between the two doses. Adverse events consisted of flu-like symptoms (fever/chills, nausea/vomiting, and myalgias/arthralgias), acute infusion-related events (hypotension, dyspnea, chest pain, and back pain), and a vascular leak syndrome (hypotension, hypoalbuminemia, edema). In addition, 61% of the patients experienced transient elevations of hepatic transaminase levels with 17% grade 3 or 4. Hypoalbuminemia occurred in 79%, including 15% with grade 3 or 4 changes. Tolerability at 9 and 18 microg/kg/d was similar, and there was no evidence of cumulative toxicity.
Denileukin diftitox has been shown to be a useful and important agent in the treatment of patients whose CTCL is persistent or recurrent despite other therapeutic interventions.
Abstract
Patients with cutaneous T-cell lymphoma (CTCL) frequently experience severe pruritus that can significantly impact their quality of life. Romidepsin is approved by the US Food and Drug ...Administration (FDA) for the treatment of patients with CTCL who have received at least one prior systemic therapy, with a reported objective response rate of 34%. In a phase 2 study of romidepsin in patients with CTCL (GPI-04-0001), clinically meaningful reduction in pruritus (CMRP) was evaluated as an indicator of clinical benefit by using a patient-assessed visual analog scale. To determine the effect of romidepsin alone, confounding pruritus treatments including steroids and antihistamines were prohibited. At baseline, 76% of patients reported moderate-to-severe pruritus; 43% of these patients experienced CMRP, including 11 who did not achieve an objective response. Median time to CMRP was 1.8 months, and median duration of CMRP was 5.6 months. Study results suggest that the clinical benefit of romidepsin may extend beyond objective responses.
Abstract 2680
Romidepsin is a class 1 selective histone deacetylase (HDAC) inhibitor approved in the United States for patients with relapsed/refractory cutaneous and peripheral T-cell lymphomas. ...Potential cardiac class effects of HDAC inhibitors have been variably reported. We have previously reported that detailed electrocardiogram (ECG) analyses from 110 patients across 3 clinical studies showed clinically insignificant, transient ECG changes that were not associated with functional cardiovascular changes. The primary objective of the study described herein was to further evaluate the potential of romidepsin to prolong QT and assess any possible relationship between romidepsin plasma concentration and heart rate-corrected QT interval duration (QTc).
Patients from GPI-06–0005, an exploratory phase 1 study of adult patients with advanced malignancies treated with 1-hour or 4-hour intravenous (IV) romidepsin infusion, received ECG assessments on Day 1 of cycles 1 and 2: baseline (both pre- and post-antiemetic premedication) and at each pharmacokinetic (PK) sampling time (0.25, 0.5, 1, 2, 3, 4, 6, 8, and 24 hours after initiation of romidepsin dosing). Patients either received a 4-hour IV infusion at 14 mg/m2 on Days 1, 8, and 15 of each 28-day cycle for 6 cycles or for 1 cycle followed by 8–12 mg/m2 infused over 1 hour for 5 cycles. Post-antiemetic baseline was included to isolate the effects of romidepsin as antiemetics alone may increase the QTc interval. All ECGs were read by a central ECG laboratory and overread by a cardiologist for verification of interval measurements. Standard analyses as defined in the International Conference on Harmonization E14 Guidance, Clinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for Non-Antiarrhythmic Drugs were used. Nonlinear mixed effect modeling was used to analyze the exposure-response relationship of romidepsin and QTc.
ECG data were available for 26 patients who received romidepsin at 14 mg/m2 over a 4-hour IV infusion (approved dosing regimen). Fourteen of these patients also received 8–12 mg/m2 romidepsin over a 1-hour IV infusion; 3 patients received 8 mg/m2, 6 received 10 mg/m2, and 5 received 12 mg/m2. The majority of the 26 patients were female (62%) and White (89%); median age was 61.7 years (range, 44–82 years). Patients who received romidepsin at 12 mg/m2 as a 1-hour infusion had a median plasma Cmax up to 2.5-fold higher than that observed with the approved dosing regimen. The time courses of mean QTcF (Fridericia correction), QTcI (individual correction) and ΔQTcF, as well as median romidepsin plasma concentration were examined. No marked trend was evident, except for some evidence of a modest change in QTcF that was temporally dissociated from the pharmacokinetic profile. However, no consistent pattern of pharmacodynamic counterclockwise hysteresis was noted across or within patients. Exposure-response modeling demonstrated no statistically significant effect of romidepsin concentration on QTc. As shown in the Figure comparing change in QTcF relative to baseline pre-antiemetic administration or post-antiemetic administration, there was a slight mean decrease from post-antiemetic baseline in QTcF at each time point following romidepsin administration, and a mean increase relative to pre-antiemetic baseline. Mean changes in QTcF from the post-antiemetic, pre-romidepsin baseline for the 14 mg/m2 4-hour infusion were negative for all assessments. The maximum upper bound of the 90% confidence interval (CI) for the change from post-antiemetic, pre-romidepsin baseline was 5.59 ms noted at the 6-hour time point; mean change in QTcF at this time was –0.11 ms. No patients in this study developed a QTcF > 450 ms in the 24-hour period following the start of infusion. No trends were observed across lower dose levels (8-, 10-, and 12-mg/m2) for the 1-hour romidepsin infusions.
No concentration-dependent effects of romidepsin on the duration of QTc interval were identified, including at romidepsin exposures up to more than 2.5-fold higher than the approved and clinically used dosing of 14 mg/m2 as a 4-hour IV infusion. Display omitted
Godfrey:Geron Corporation: Consultancy; Neurocrine Biosciences: Consultancy; Agios: Consultancy; Adnexus: Consultancy; Lundbeck, Inc.: Consultancy; Vertex Pharmaceuticals: Equity Ownership; Anoixis Corporation: Employment; Celgene: Consultancy. Off Label Use: Dosing in studies is off label. Cabell:Celgene: Consultancy. Balser:Celgene: Contracted Consultancy. Wolfson:Celgene: Contracted Consultancy. Nichols:Celgene: Employment, Equity Ownership.
Histone deacetylase inhibitor romidepsin has demonstrated durable clinical responses and tolerability in patients with relapsed/refractory peripheral and cutaneous T-cell lymphoma (PTCL, CTCL). ...Selection of novel drug therapies for patients with relapsed/refractory aggressive lymphoma requires not only considerations regarding efficacy but also careful evaluation of toxicities as well as overall clinical benefit. The purpose of this analysis was to examine common adverse events (AEs) reported in pivotal trials of romidepsin in relapsed/refractory PTCL or CTCL and to more clearly define the overall AE profile in these populations.
Patients with relapsed/refractory PTCL or CTCL were treated with romidepsin at 14 mg/m(2) as a 4-hour intravenous infusion on days 1, 8, and 15 of 28-day cycles for up to 6 cycles; patients with at least stable disease could extend therapy until progressive disease or another withdrawal criterion was met. All enrolled patients who received ≥ 1 dose of romidepsin were included in the AE analyses.
Overall, safety profiles of common AEs were similar, although patients with relapsed/refractory PTCL had more frequent hematologic toxicities and grade ≥ 3 infections. In both patient populations, the greatest incidence of grade ≥ 3 AEs and the majority of discontinuations due to AEs occurred during cycles 1-2. Early discontinuations were primarily related to infection, thrombocytopenia, or electrocardiogram abnormalities, confirming the need to closely monitor patients with poor bone marrow reserve or other comorbidities. Despite this, 28% of patients with relapsed/refractory PTCL and 36% of patients with relapsed/refractory CTCL continued on romidepsin treatment for ≥ 6 cycles.
This study demonstrates that patients with relapsed/refractory PTCL or CTCL have similar AE profiles with romidepsin treatment, although patients with PTCL experienced more frequent and more severe hematologic toxicities and more frequent grade ≥ 3 infections. The greatest incidence of grade ≥ 3 AEs and the majority of discontinuations due to AEs occurred during treatment cycles 1-2. Extended dosing of romidepsin can be tolerated in responding patients.
NCT00426764,NCT00106431.
Abstract 3641
Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of lymphoproliferative disorders, and most subtypes have a poor prognosis even with aggressive chemotherapy. Romidepsin is a ...potent class 1 histone deacetylase inhibitor approved by the US Food and Drug Administration for treatment of patients with PTCL who have received at least 1 prior therapy and patients with cutaneous T-cell lymphoma who have received at least 1 prior systemic therapy. A phase 2, single-arm, open-label registration study (GPI-06–0002) demonstrated the clinical benefit and tolerability of romidepsin in patients with relapsed or refractory PTCL (data cutoff: Oct 2010). Here, we present an update of the efficacy of GPI-06–0002 and characterize patients who achieved long-term responses (≥ 12 months) as of Dec 2011 (median follow-up: 22.3 months).
Patients with histologically confirmed PTCL (N = 130) who failed or were refractory to ≥ 1 prior systemic therapy received romidepsin 14 mg/m2 as a 4-hour intravenous infusion on days 1, 8, and 15 every 28 days for up to 6 cycles; treatment could be extended for responding patients. The primary endpoint was confirmed/unconfirmed complete response (CR/CRu) determined by an independent review committee (IRC) based on the International Workshop Response Criteria. Secondary endpoints included objective response rate (ORR: CR/CRu + partial response), duration of response (DOR), and time to progression. Disease response was assessed every 2 treatment cycles. Baseline patient characteristics by DOR (≥ 12 months vs < 12 months) were examined.
The majority of the 130 patients had stage III or IV disease (70%); 28% had bone marrow involvement. PTCL not otherwise specified (53%) and angioimmunoblastic T-cell lymphoma (21%) were the most common subtypes. Patients received a median of 2 prior systemic therapies (range, 1–8); 38% of patients were refractory to their last line of therapy. The ORR was 25% (33 of 130 patients), including CR/CRu in 15% (19 of 130) of patients. The median duration of objective response was 28 months, with the longest response ongoing at 48 months (Figure). Of the 19 patients who achieved CR/CRu, 13 (68%) had not experienced disease progression per the IRC at a median follow-up of 25.8 months. The median duration of CR had not yet been reached (range, 1–48+ months; Figure). Of the 19 patients who achieved CR/CRu, 10 were long-term responders (responses ≥ 12 months). Interestingly, heavy pretreatment (≥ 4 prior systemic therapies) did not preclude patients from achieving long-term CR/CRu: 5 of 10 patients (50%) who maintained CR/CRu for ≥ 12 months were heavily pretreated vs 1 of 9 (11%) patients with CR/CRu maintained for < 12 months. Long-term CR/CRu was achieved regardless of response to last prior therapy; only 2 of 10 (20%) long-term responders had an objective response on their last treatment. In contrast, 6 of 9 (67%) patients with CR/CRu for < 12 months responded to their last prior therapy. Furthermore, advanced disease did not preclude long-term response to romidepsin: all 10 patients (100%) who maintained CR/CRu for ≥ 12 months had stage III/IV disease vs 55.5% of those who maintained CR/CRu for < 12 months. Other characteristics, such as Eastern Cooperative Oncology Group performance status, International Prognostic Index score, age, sex, and race, were similar among patients achieving CR/CRu for ≥ 12 months or < 12 months.
Single-agent romidepsin induced durable responses in patients with relapsed/refractory PTCL, with responses ongoing at 48 months. None of the examined patient and disease characteristics predicted failure to achieve long-term remissions. These results support the use of romidepsin in relapsed/refractory PTCL. Display omitted
Coiffier:Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Pro:Allos: Honoraria; Spectrum : Honoraria; Seattle Genetics : Research Funding; Celgene: Honoraria, Research Funding. Prince:Celgene : Consultancy, Honoraria, Research Funding. Foss:Celgene : Consultancy. Sokol:Celgene : Honoraria, Speakers Bureau. Morschhauser:Celgene : Consultancy, Honoraria. Pinter-Brown:Celgene : Consultancy; Allos : Consultancy. Shustov:Celgene : Honoraria, Research Funding, Speakers Bureau. Nielsen:Celgene: Employment, Equity Ownership. Nichols:Celgene: Consultancy, Employment, Equity Ownership. Horwitz:Celgene: Consultancy, Research Funding; Kyowa Hakko Kirin Pharma: Consultancy; Bristol-Myers Squibb: Consultancy; Allos: Consultancy, Research Funding; Genzyme: Consultancy; Johnson & Johnson: Consultancy; Infinity Pharmaceuticals: Research Funding; Seattle Genetics: Consultancy, Research Funding.
PDF
