scholarly journals Randomized Phase III Study of Alisertib or Investigator’s Choice (Selected Single Agent) in Patients With Relapsed or Refractory Peripheral T-Cell Lymphoma

2019 ◽  
Vol 37 (8) ◽  
pp. 613-623 ◽  
Author(s):  
Owen A. O’Connor ◽  
Muhit Özcan ◽  
Eric D. Jacobsen ◽  
Josep M. Roncero ◽  
Judith Trotman ◽  
...  
Keyword(s):  
T Cell ◽  
Overall Response Rate ◽  
Response Rate ◽  
Cell Lymphoma ◽  
Single Agent ◽  
T Cell Lymphoma ◽  
Phase Iii ◽  
Lower Percentage ◽  
Peripheral T Cell Lymphoma ◽  
Overall Response

PURPOSE The aim of this open-label, first-in-setting, randomized phase III trial was to evaluate the efficacy of alisertib, an investigational Aurora A kinase inhibitor, in patients with relapsed/refractory peripheral T-cell lymphoma (PTCL). PATIENTS AND METHODS Adult patients with relapsed/refractory PTCL—one or more prior therapy—were randomly assigned 1:1 to receive oral alisertib 50 mg two times per day (days 1 to 7; 21-day cycle) or investigator-selected single-agent comparator, including intravenous pralatrexate 30 mg/m2 (once per week for 6 weeks; 7-week cycle), or intravenous gemcitabine 1,000 mg/m2 or intravenous romidepsin 14 mg/m2 (days 1, 8, and 15; 28-day cycle). Tumor tissue (disease subtype) and imaging were assessed by independent central review. Primary outcomes were overall response rate and progression-free survival (PFS). Two interim analyses and one final analysis were planned. RESULTS Between May 2012 and October 2014, 271 patients were randomly assigned (alisertib, n = 138; comparator, n = 133). Enrollment was stopped early on the recommendation of the independent data monitoring committee as a result of the low probability of alisertib achieving PFS superiority with full enrollment. Centrally assessed overall response rate was 33% for alisertib and 45% for the comparator arm (odds ratio, 0.60; 95% CI, 0.33 to 1.08). Median PFS was 115 days for alisertib and 104 days for the comparator arm (hazard ratio, 0.87; 95% CI, 0.637 to 1.178). The most common adverse events were anemia (53% of alisertib-treated patients v 34% of comparator-treated patients) and neutropenia (47% v 31%, respectively). A lower percentage of patients who received alisertib (9%) compared with the comparator (14%) experienced events that led to study drug discontinuation. Of 26 on-study deaths, five were considered treatment related (alisertib, n = 3 of 11; comparator, n = 2 of 15). Two-year overall survival was 35% for each arm. CONCLUSION In patients with relapsed/refractory PTCL, alisertib was not statistically significantly superior to the comparator arm.

Low Absolute Lymphocyte Count Predicts Chemotherapy Response and Survival In Peripheral T-Cell Lymphoma, NOS

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3135-3135
Author(s):  
Yu Ri Kim ◽  
yun Deok Kim ◽  
Jin Seok Kim ◽  
June-Won Cheong ◽  
soo Jeong Kim ◽  
...  
Keyword(s):  
T Cell ◽  
Prognostic Factor ◽  
Overall Response Rate ◽  
Response Rate ◽  
Cell Lymphoma ◽  
Prognostic Index ◽  
Independent Prognostic Factor ◽  
T Cell Lymphoma ◽  
Peripheral T Cell Lymphoma ◽  
Overall Response

Abstract Abstract 3135 Peripheral T cell lymphoma, not otherwise specified (PTCL, NOS) is heterogenous groups of aggressive T-cell lymphoma and treatment outcome is dismal. Lymphopenia is an independent prognostic factor for survival for B-cell lymphoma. The ALC at diagnosis on survival in T-cell lymphoma has not been studied. Thus, we studied the role of ALC at diagnosis on clinical outcome in patients with PTCL, NOS. Between 2001 and 2009, 32 patients with PTCL, NOS reviewed for the study. Median patient age was 57 (range 34–78) years. Median ALC at the time of diagnosis was 1.54 (range 0.41–12.64×109/L). Patients were divided two groups according to ALC count 1.0 ×109/L. Ten patients (31%) had lower ALC at diagnosis. Median follow up duration was 299 days (range 11–2164 days). Overall response rate was 61.5% (16 of 26 patients) and complete response (CR) rate was 42% (11 of 26 patients). Only two patients reached CR in low ALC group.There was no significant difference in overall response rate because of small number of patients. Superior overall survival was observed with an ALC 1.0 × 109/L (N = 22) versus an ALC < 1.0 × 109/L (N=10) (median OS: not reached vs 242 days, OS rates at 5 years, 57% vs 0%, p =0.016, respectively). Multivariate analysis demonstrated ALC to be an independent prognostic indicator for OS (Hazard Ratio 3.5, 95% confidence intervals 1.2–10.2; p<0.019) when compared to the International prognostic index (IPI) and Prognostic Index for PTCLU (PIT). This study suggested that low ALC is an independent prognostic factor for survival in patients with PTCL, NOS. Disclosures: No relevant conflicts of interest to declare.

Update of the NCI multiinstitutional phase II trial of romidepsin, FK228, for patients with cutaneous or peripheral T-cell lymphoma

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 8027-8027 ◽  
Author(s):  
R. Piekarz ◽  
R. Frye ◽  
J. Wright ◽  
W. Figg ◽  
S. Allen ◽  
...  
Keyword(s):  
T Cell ◽  
Histone Deacetylase Inhibitors ◽  
Overall Response Rate ◽  
Response Rate ◽  
Cell Lymphoma ◽  
Single Agent ◽  
T Cell Lymphoma ◽  
Cell Transplant ◽  
Overall Response ◽  
Prior Therapy

8027 Background: The histone deacetylase inhibitors (HDIs) are a class of differentiating agents undergoing clinical testing. Like other HDIs, romidepsin (FK228) modulates expression of genes involved in cell cycle regulation and markers of differentiation in cancer cell lines, leading to induction of differentiation or apoptosis. Romidepsin has demonstrated clinical activity in patients with T-cell lymphoma. Methods: Patients with CTCL (42) or PTCL (36) were enrolled in the NCI multi-institutional trial and assigned to cohorts based on extent of prior therapy and pathology. Romidepsin is administered on days 1, 8, and 15 of a 28 d cycle with a starting dose of 14mg/m2. Responses for patients with PTCL are measured using Cheson criteria, and CTCL using RECIST criteria. Results: Cohort one, composed of 27 patients who had previously received no more than 2 prior cytotoxic regimens of chemotherapy, has completed enrollment. Responses observed include 3 patients with CR and 7 patients with partial responses, yielding an overall response rate of 37%. Of note, responses were observed independent of stage of disease. Among 18 patients with stage IV disease, 6 patients had a complete or partial response, including 3 patients with Sézary syndrome. When including patients with greater than 2 prior cytotoxic regimens, the overall response rate was 31%. A replicate arm has been opened with the goal of confirming the response rate observed in the first cohort. Response data have not been evaluated from this arm at this time. Responses observed in 36 patients with refractory or relapsed PTCL includes 3 patients with CR and 8 patients with partial responses, comprising an overall response rate of 30%. Responses were observed independent of prior therapy, with some patients having undergone prior stem-cell transplant. Molecular endpoint analysis was performed on peripheral mononuclear cells (PBMNCs) and tumor biopsies from treated patients evaluating histone acetylation and changes in gene expression. Conclusions: Romidepsin as a single agent appears to have significant single agent activity in patients with CTCL and PTCL. Combination therapy with romidepsin may increase efficacy and should be pursued. This protocol remains open to accrual. No significant financial relationships to disclose.

scholarly journals Belinostat Induces High Overall Response Rate (ORR) in Patients with Relapsed or Refractory Angioimmunoblastic T-Cell Lymphoma (AITL)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4050-4050
Author(s):  
Ahmed Sawas ◽  
Helen Ma ◽  
Andrei Shustov ◽  
Pamela Hsu ◽  
Gajanan Bhat ◽  
...  
Keyword(s):  
T Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Overall Response Rate ◽  
Response Rate ◽  
Cell Lymphoma ◽  
Single Agent ◽  
T Cell Lymphoma ◽  
Advisory Committees ◽  
Overall Response

Background: Angioimmunoblastic T-cell lymphoma (AITL) is a relatively common subtype of peripheral T-cell lymphoma (PTCL) that typically presents with lymphadenopathy, extranodal disease, including rash, and is associated with frequent infections due to immune dysregulation. Patients with AITL generally have a poor prognosis, even with aggressive chemotherapy as responses to standard chemotherapy are often suboptimal. Recent advances in cancer biology suggest that AITL is derived from T-follicular helper cells and is often characterized by gross epigenetic dysregulation. Histone deacetylase (HDAC) inhibitors have demonstrated significant activity in T-cell neoplasms. The BELIEF trial established an overall response rate of 25% in patients with relapsed/refractory PTCL who were treated with belinostat, with a duration of response of about 1 year, leading to accelerated approval. Herein, we present a subset analysis of the data for patients with AITL. Methods: Patients with histologically confirmed PTCL (N = 129) who experienced failure with or refractory to ≥ 1 prior systemic therapy received belinostat 1,000 mg/m(2) as daily 30-minute infusions on days 1 to 5 every 21 days. Central assessment of response used International Working Group criteria. Primary endpoint was overall response rate (ORR). Secondary endpoints included duration of response (DoR) and progression-free and overall survival (PFS). Results: Of 129 patients, 22 patients had AITL; most had advanced disease (91% stage III/IV; 36% with bone marrow involvement). The median number of prior therapies was 2 (range, 1-5), and 3 (14%) patients were refractory to their last line of therapy. The ORR for patients with AITL was 46% (10/22; 95%CI: 24 - 68%), with a complete response (CR) in 4 of 22 patients (18%). Of the ten responders, the median time to response of 11.3 weeks (range, 4.7 - 24.4 weeks) in the AITL subgroup. After a median follow up of 21.5 months, the median PFS was 4.2 months (95%CI: 1.5 -13.9) and the median DOR was 13.6 months (95%CI: 1.4 - 29.4) as shown in Figure 1. For all patients with AITL treated with belinostat, the median OS was 9.2 months (95%CI: 6.8 - 21.5). The most common grade 3 to 4 adverse events were asthenia (n=2), fatigue (n=2), anemia (n=2), thrombocytopenia (n=2), neutropenia (n=2), and septic shock (n=2). Conclusions: Single-agent belinostat induced rapid and durable responses in patients with relapsed/refractory AITL. At the end of the study, there were 37% patients with ongoing responses at 2 years. Patients with clinical benefit from belinostat continued treatment until progression of disease. These results support the use of belinostat in relapsed/refractory AITL as a single agent and provide rationale for combination therapies in clinical trials. Disclosures Sawas: Seattle Genetics, Gilead, Daiichi Sanko: Consultancy; Affimed: Research Funding. Shustov:Spectrum Pharmaceuticals: Consultancy, Research Funding. Hsu:Spectrum Pharmaceuticals: Employment. Bhat:Spectrum Pharmaceuticals: Employment. Acosta:Acrotech Biopharma: Employment. Horwitz:Astex: Consultancy; Kyowa Hakko Kirin: Consultancy; Infinity/Verastem: Consultancy, Research Funding; Innate Pharma: Consultancy; Kyowa Hakko Kirin: Consultancy; Trillium: Research Funding; Affimed: Consultancy; ADCT Therapeutics: Research Funding; Kura: Consultancy; ADCT Therapeutics: Research Funding; Aileron: Research Funding; Seattle Genetics: Consultancy, Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trillium: Research Funding; Aileron: Research Funding; Trillium: Research Funding; Miragen: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding; Kura: Consultancy; Forty-Seven: Research Funding; Millennium/Takeda: Consultancy, Research Funding; ADCT Therapeutics: Research Funding; Mundipharma: Consultancy; Kura: Consultancy; Miragen: Consultancy; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Consultancy; Astex: Consultancy; Seattle Genetics: Consultancy, Research Funding; Astex: Consultancy; Portola: Consultancy; Celgene: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding; Aileron: Research Funding; Trillium: Research Funding; Forty-Seven: Research Funding; Infinity/Verastem: Consultancy, Research Funding; Innate Pharma: Consultancy; Miragen: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Mundipharma: Consultancy; Portola: Consultancy; Mundipharma: Consultancy; Portola: Consultancy; Aileron: Research Funding; Forty-Seven: Research Funding; Kura: Consultancy; Kyowa Hakko Kirin: Consultancy; Seattle Genetics: Consultancy, Research Funding; Portola: Consultancy; ADCT Therapeutics: Research Funding; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astex: Consultancy; Innate Pharma: Consultancy; Kyowa Hakko Kirin: Consultancy; Miragen: Consultancy; Affimed: Consultancy; Affimed: Consultancy; Corvus Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Innate Pharma: Consultancy; Seattle Genetics: Consultancy, Research Funding; Forty-Seven: Research Funding; Affimed: Consultancy; Millennium/Takeda: Consultancy, Research Funding. O'Connor:Mundipharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADCT Therapeutics, Affimed, Agensys, Merck, Seattle Genetics, Spectrum, Trillium, and Verastem Oncology.: Research Funding; TG Therapeutics: Other: Travel Support, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Results From a Pivotal, Open-Label, Phase II Study of Romidepsin in Relapsed or Refractory Peripheral T-Cell Lymphoma After Prior Systemic Therapy

2012 ◽  
Vol 30 (6) ◽  
pp. 631-636 ◽  
Author(s):  
Bertrand Coiffier ◽  
Barbara Pro ◽  
H. Miles Prince ◽  
Francine Foss ◽  
Lubomir Sokol ◽  
...  
Keyword(s):  
T Cell ◽  
Phase Ii ◽  
Systemic Therapy ◽  
Response Rate ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Complete Response ◽  
T Cell Lymphoma ◽  
Peripheral T Cell Lymphoma ◽  
Prior Systemic Therapy

Purpose 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 and Methods 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/m2 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. Results 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%). Conclusion 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.

scholarly journals The mTORC1 inhibitor everolimus has antitumor activity in vitro and produces tumor responses in patients with relapsed T-cell lymphoma

Blood ◽  
2015 ◽  
Vol 126 (3) ◽  
pp. 328-335 ◽  
Author(s):  
Thomas E. Witzig ◽  
Craig Reeder ◽  
Jing Jing Han ◽  
Betsy LaPlant ◽  
Mary Stenson ◽  
...  
Keyword(s):  
T Cell ◽  
Antitumor Activity ◽  
Overall Response Rate ◽  
Response Rate ◽  
Cell Lymphoma ◽  
Mtor Pathway ◽  
T Cell Lymphoma ◽  
Overall Response ◽  
Key Points

Key Points The mTOR pathway is constitutively activated in the TCL cells and is responsible for TCL proliferation. This is first trial to demonstrate that mTORC1 inhibitors (everolimus) have substantial antitumor activity (44% overall response rate) in patients with relapsed TCL.

scholarly journals Efficacy and Survival in Newly Diagnosed Advanced Extranodal Natural Killer/T-Cell Lymphoma: A Randomized, Controlled, Multicenter and Open-Labled Study with Ddgp Regimen Versus SMILE Regimen

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 463-463 ◽  
Author(s):  
Xinhua Wang ◽  
Lei Zhang ◽  
Xiangli Liu ◽  
Xin Li ◽  
Ling Li ◽  
...  
Keyword(s):  
Overall Survival ◽  
T Cell ◽  
Overall Response Rate ◽  
Randomized Clinical Trials ◽  
Response Rate ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Stage Iii ◽  
Newly Diagnosed ◽  
Overall Response

Background Extranodal NK/T cell lymphoma (ENKTL) is rare in western countries but rather common in Asia and South America, characterized with Epstein-Barr virus (EBV) infection. Patients with advanced stage (III/IV) ENKTL has a poor survival and low response to conventional CHOP-like chemotherapy, with a 5-year overall survival rate of only 30%. Retrospective study showed that SMILE regimen had a certain effect on ENKTL, but the toxicity limited its further clinical application. More effective treatment regimens are required to be explored for systematic, prospective, controlled, randomized clinical trials. Recently, studies revealed that asparaginase-based combination chemotherapy such as P-Gmox(Pegaspargase, Gemcitabine, Oxaliplatin)is effective in patients of ENKTL. However standard treatment for newly untreated advanced ENKTL is still controversial. We developed a refined chemotherapeutic DDGP (dexamethasone, cisplatin, gemcitabline, and peg-asparaginase) regimen and proceeded a prospective randomized, multicenter and open-label clinical trial to evaluate and compare the efficacy and safety of DDGP with SMILE regimen in patients with newly diagnosed stage III/IV ENKTL in January 2011. Based on the encouraging interim results in 2016(Li, L et al.Clin Cancer Res, 2016), we presented the final results of this clinical investigation (ClinicalTrials.gov, No. NCT01501149). Patients and methods: The study was initiated at 9 centers in China in January 2011. Patients aged 14-70 with newly diagnosed ENKTL in stages III/IV, and ECOG performance score of 0-2 were enrolled. According to a computer-generated randomization schedule, eligible patients were assigned either DDGP regimen (cisplatin 20 mg/m² on day 1-4; dexamethasone 15mg/m2 on d1-5; gemcitabine 800mg/m2 on d1,8; pegaspargase 2500 IU/m2 on d1; 21 days per cycle)or SMILE regimen (methotrexate 2g/m2 on d1; dexamethasone 40mg/m2 on d2-4; ifosfamide 1500mg/m2 on d2-4; L-asparaginase 6000 U/m2 on d3-9; etoposide 100 mg/m2 on d2-4; 21 days per cycle) for up to 6 cycles unless disease progression, unacceptable toxicity or patient rejection. Efficacy was evaluated every two cycles. The primary endpoint was progression-free survival (PFS), and secondary endpoints included overall response rate (ORR) and overall survival (OS). In addition we compared the safety and tolerability between DDGP and SMILE regimens. The Kaplan-Merier method was used to evaluate for survival of freedom from events, and the log-rank test was used to evaluate differences among two groups. Results: A total of 87 eligible newly diagnosed advanced ENKTL patients were randomly assigned for the study and 80 patients were included into intention-to-treat population (40 patients in DDGP group and 40 patients in SMILE group). Data were collected from January 2011 to February 2019. Baseline characteristics of the two group patients were well balanced. At median follow-up of 41.5 months, the median PFS and OS in the SMILE group were 6.83 months and 75.2 months, respectively, while the median PFS and OS in the DDGP group have not been reached (Fig 1). The 3-year PFS rate and 5-year OS rate in DDGP group were higher than in SMILE group (56.6% vs. 41.8% for 3-year PFS, P=0.004; 74.3% vs. 51.7% for 5-year OS, P=0.02). No difference of the complete remission (CR) rate was observed between two groups, while overall response rate (ORR) in DDGP group was higher than in SMILE group (90.0% vs. 60.0%, p=0.002) (Table 1). More frequently 3/4 grade hematologic toxicities such as leucopenia and netropenia were observed in SMILE group than in DDGP group (p=0.022, p=0.015). Non-hematologic toxicities included elevated transaminase, mucositis and allergy were higher in SMILE group than in DDGP group(p=0.027, p&lt;0.001, p=0.024). Pancreatitis occurred in 2 patients in SMILE group, but not in DDGP group (Table 2). In addition, treatment-related deaths rate was up to 17.5% in SMILE regimen which was mainly caused by infection and hemorrhage due to bone marrow suppression. Such event was only 10% in DDGP regimen. Conclusion: DDGP regimen produced prolonged survival, better tolerability and safety than SMILE regimen in newly diagnosed advanced ENKTL. Disclosures No relevant conflicts of interest to declare.

scholarly journals Belinostat in combination with standard cyclophosphamide, doxorubicin, vincristine and prednisone as first-line treatment for patients with newly diagnosed peripheral T-cell lymphoma

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Patrick B. Johnston ◽  
Amanda F. Cashen ◽  
Petros G. Nikolinakos ◽  
Anne W. Beaven ◽  
Stefan Klaus Barta ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Dose Intensity ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
T Cell Lymphoma ◽  
Hematologic Toxicity ◽  
Peripheral T Cell Lymphoma ◽  
Grade 3

Abstract Background Belinostat is a histone deacetylase inhibitor approved for relapsed refractory peripheral T-cell lymphoma (PTCL). The primary objective of this study was to determine the maximum tolerated dose (MTD) of belinostat combined with CHOP (Bel-CHOP). Secondary objectives included safety/tolerability, overall response rate (ORR), and belinostat pharmacokinetics (PK). Methods Patients were ≥ 18 years with histologically confirmed, previously untreated PTCL. Patients received belinostat (1000 mg/m2 once daily) + standard CHOP for 6 cycles with varying schedules using a 3 + 3 design in Part A. Part B enrolled patients at MTD dose. Results Twenty-three patients were treated. One patient experienced DLT (Grade 3 non-hematologic toxicity) on Day 1–3 schedule, resulting in escalation to Day 1–5 schedule (n = 3). No DLTs were observed and Day 1–5 schedule with 1000 mg/m2 was declared as MTD. Twelve additional patients were enrolled in Part B using MTD. Median relative dose intensity was 98%. All patients experienced adverse events (AEs), including nausea (78%), fatigue (61%), and vomiting (57%). Serious AEs occurred in 43%, with febrile neutropenia (17%) and pyrexia (13%). Overall ORR was 86% with 71% reported CR at MTD. Belinostat PK parameters were similar to single-agent. Conclusions Bel-CHOP was well tolerated and MTD in CHOP combination was the same dose and schedule as single agent dosing. Trial Registration: ClinicalTrials.gov Identifier: NCT01839097.

Results From a Prospective, Open-Label, Phase II Trial of Bendamustine in Refractory or Relapsed T-Cell Lymphomas: The BENTLY Trial

2013 ◽  
Vol 31 (1) ◽  
pp. 104-110 ◽  
Author(s):  
Gandhi Damaj ◽  
Rémy Gressin ◽  
Krimo Bouabdallah ◽  
Guillaume Cartron ◽  
Bachra Choufi ◽  
...  
Keyword(s):  
T Cell ◽  
Response Rate ◽  
Cell Lymphoma ◽  
Single Agent ◽  
T Cell Lymphoma ◽  
Open Label ◽  
Previous Response ◽  
Angioimmunoblastic Lymphadenopathy ◽  
Prior Chemotherapy ◽  
T Cell Lymphomas

Purpose To determine the efficacy and safety of bendamustine as a single agent in refractory or relapsed T-cell lymphomas. Patients and Methods Patients with histologically confirmed peripheral T-cell lymphoma (PTCL) or cutaneous T-cell lymphoma who progressed after one or more lines of prior chemotherapy received bendamustine at 120 mg/m2 per day on days 1 through 2 every 3 weeks for six cycles. The primary end point was overall response rate (ORR). Secondary end points were duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Results Of the 60 patients included, 27 (45%) were refractory to their last prior chemotherapy, and the median duration of the best previous response was 6.6 months. Histology was predominantly angioimmunoblastic lymphadenopathy and PTCL not otherwise specified. The disease was disseminated in the majority of patients (87%). The median number of previous lines of chemotherapy was one (range, one to three). Twenty patients (33%) received fewer than three cycles of bendamustine, mostly because of disease progression. In the intent-to-treat population, the ORR was 50%, including complete response in 17 patients (28%) and partial response in 13 patients (22%). Bendamustine showed consistent efficacy independent of major disease characteristics. The median values for DoR, PFS, and OS were 3.5, 3.6, and 6.2 months, respectively. The most frequent grade 3 to 4 adverse events were neutropenia (30%), thrombocytopenia (24%), and infections (20%). Conclusion Bendamustine showed an encouraging high response rate across the two major PTCL subtypes, independent of age and prior treatment, with acceptable toxicity in refractory or relapsed T-cell lymphoma.

Safe and Effective Treatment of Patients with Peripheral T-Cell Lymphoma (PTCL) with the Novel HDAC Inhibitor, Belinostat, in Combination with CHOP: Results of the Bel-CHOP Phase 1 Trial

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 253-253 ◽  
Author(s):  
Patrick B. Johnston ◽  
Amanda F. Cashen ◽  
Petros G. Nikolinakos ◽  
Anne W Beaven ◽  
Stefan Klaus Barta ◽  
...  
Keyword(s):  
T Cell ◽  
Response Rate ◽  
Cell Lymphoma ◽  
Large Cell ◽  
T Cell Lymphoma ◽  
Peripheral T Cell Lymphoma ◽  
Anaplastic Lymphoma ◽  
Not Otherwise Specified ◽  
Baseline Characteristics ◽  
Grade 3

Abstract Background: Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of non-Hodgkin lymphomas associated with poor prognosis and repeated recurrence for most subtypes. Currently, anthracycline-based therapies such as cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) or CHOP-like therapies are recommended as the first-line treatment for PTCL, but the prognosis remains poor with most patients relapsing within 5 years. Thus, improved treatment strategies are still needed. Belinostat is a potent, pan-histone deacetylase inhibitor that was recently approved in the United States for the treatment of patients with relapsed or refractory PTCL (R/R PTCL). Approval was based on results from the pivotal Phase 2 BELIEF study (O'Connor et al, JCO, 2015) of belinostat in R/R PTCL, which demonstrated durable clinical benefit (objective response rate [ORR] 25.8%) and tolerability. Since belinostat (Bel) and each of the components of the CHOP regimen target different aspects of the cell cycle with different mechanisms of action, there is potential for a synergistic effect of a Bel-CHOP combination treatment regimen for patients with PTCL. Methods: Patients with PTCL received CHOP in association with 1000 mg/m2 of belinostat on various schedules, repeated every 21-days for up to 6 cycles. The cohort schema followed a traditional "3+3" dose escalation design. The objective of Part A of the study was to determine the Maximum Tolerated Dose (MTD) of the Bel-CHOP combination. Once the MTD was determined, at least 10 more patients were to be treated in the Expansion Phase (Part B). Belinostat was to be administered as a 1000 mg/m2 IV infusion once daily for up to 5 days, depending on the assigned cohort (Fig 1). The starting cohort was Cohort 3 (CHOP + 1000 mg/m2 of daily belinostat on Days 1-3). Patients received primary prophylaxis with growth factor (G-CSF) support. Dose-limiting toxicities (DLT) were considered during the 1st cycle and included: non-hematological toxicity Grades 3-4, platelet count &lt; 25 X 109/L at any time or ANC &lt; 0.5 X 109/L lasting more than 7 days despite G-CSF administration. The primary endpoint of the study was the determination of the MTD of the Bel-CHOP combination. Secondary endpoints included safety, tolerability and ORR (complete response [CR] + partial response [PR]) and pharmacokinetics. Results: A total of 23 patients were enrolled in the study, 11 of which were treated in Part A. One patient in Part A was deemed inevaluable because the patient died due to disease progression before completing Cycle 1. The MTD was determined to be 1000 mg/m2 on Days 1-5 (Cohort 5); 12 more patients were then treated at this dose level (Part B). The only DLT experienced in the study was in Cohort 3 (Grade 3 Nausea and Vomiting). At the time of this abstract, 18/23 patients (78%) have completed all 6 cycles of Bel-CHOP, with 87% completing at least 4 cycles. Ten patients (43%) had at least one serious adverse event (SAE) and 18 (78%) had at least one Grade 3 or 4 adverse event (AE). The most frequent Grade 3/4 AEs were hematological in nature: neutrophil count decreased (26%), anemia (22%), neutropenia (17%) and white blood cell count decreased (17%). The ORR for the18 patients that have completed an End of Study Visit is 89% (16/18), with the vast majority achieving a CR [72% (n=13)], and 17% (n=3) a PR. Progressive disease was reported in 2 patients. Conclusions: These results demonstrate that the combination of belinostat with CHOP (Bel-CHOP) is well tolerated, with all components of CHOP and belinostat being given at their standard therapeutic doses. The rates of AEs were consistent with those typically reported with CHOP alone, and clinical activity was demonstrated with a response rate of 89% based on 18 evaluable patients. Thus, Bel-CHOP is a promising new regimen in PTCL that will be further tested in a Phase 3 randomized trial. Table. Table. Figure 1. Summary of Demographic and Baseline Characteristics AITL= angioimmunoblastic T-cell lymphoma; ALCL =anaplastic large-cell lymphoma; ALK = anaplastic lymphoma kinase; NOS = not otherwise specified Figure 1. Summary of Demographic and Baseline Characteristics. / AITL= angioimmunoblastic T-cell lymphoma; ALCL =anaplastic large-cell lymphoma; ALK = anaplastic lymphoma kinase; NOS = not otherwise specified Disclosures Barta: Seattle Genetics: Research Funding. Bhat:Spectrum Pharmaceuticals, Inc: Employment. Song:Spectrum Pharmaceutical, Inc: Employment. Choi:Apectrum Pharmaceuticals, Inc: Employment. Allen:Spectrum Pharmaceuticals, Inc: Employment. Foss:Spectrum Pharmaceuticals; Celgene: Seattle Genetics: Infinity; Millenium: Consultancy, Honoraria, Research Funding, Speakers Bureau.

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