scholarly journals Pralatrexate: Phase 1/2 Study in Japanese Patients with Relapsed or Refractory Peripheral T-Cell Lymphoma (PTCL)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4157-4157
Author(s):  
Yoshinobu Maeda ◽  
Kensei Tobinai ◽  
Hirokazu Nagai ◽  
Takahiko Nakane ◽  
Tatsu Shimoyama ◽  
...  
Keyword(s):  
T Cell ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Phase 1 ◽  
T Cell Lymphoma ◽  
Intermediate Risk ◽  
Phase 2 ◽  
Western Countries ◽  
Phase 2 Study ◽  
Previous Phase

Abstract Introduction:Pralatrexate (PDX) is a dihydrofolate reductase inhibitor with high affinity for reduced folate carrier 1 and folylpolyglutamate synthetase, resulting in extensive internalization and accumulation in tumor cells. In the previous phase 2 study for relapsed or refractory (R/R) PTCL in western countries, the overall response rate (ORR) was 29% (32 of 109 evaluable patients [pts]), as assessed by an independent central review (O'Connor et al. JCO 2011). We conducted this phase 1/2 study to evaluate the tolerability, safety, efficacy and pharmacokinetics of PDX in Japanese pts with R/R PTCL. Methods: Eligibility criteria included age ≥20, histologically confirmed PTCL according to the 2008 WHO classification, disease progression after ≥1 prior systemic therapy, ≥1 measurable disease and Eastern Cooperative Oncology Group performance status ≤2. PDX was administered intravenously weekly for 6 weeks in 7-week cycles with concurrent vitamin B12 and folic acid. There were 2 cohorts in phase 1: Cohort 1 was at 30 mg/m2 of the US-approved dose and Cohort 2 would start at 20 mg/m2 if 30 mg/m2 was not tolerated. The primary endpoint was ORR in phase 2 and secondary endpoints included duration of response (DoR), progression-free survival (PFS) and overall survival (OS). Response was evaluated by the independent central imaging review using the International Workshop Criteria (Cheson et al. JCO 1999). Cryotherapy and professional oral care (e.g. dental cleaning and oral hygiene instruction) by dentists before and during PDX treatment were recommended to reduce the severity of mucositis. An educational handbook was offered to all pts to learn symptoms, prevention and self-care of oral mucositis. Results:A total of 25 pts received ≥1 dose of PDX and were included in the safety analysis (median age 71 years; 68% male; median of 3 prior therapies; 32% refractory to the most recent therapy; 16% low risk, 48% low-intermediate risk, 24% high-intermediate risk and 12% high risk by International Prognostic Index). Of these, 3 pts were enrolled in phase 1 and 22 pts in phase 2. Two pts in phase 2 were excluded from the efficacy analysis due to lack of a confirmed diagnosis of PTCL by the central pathology review. In phase 1, no dose-limiting toxicity was observed in 3 pts for Cohort 1. In phase 2, using 30 mg/m2 as the recommended dose, the ORR was 45% (9 of 20 evaluable pts in phase 2; 90% CI, 26% to 65%) with 2 complete responses and 7 partial responses achieved in Cycle 1. At the time of data cut-off, median DoR of 9 responders was not reached (range, 1 to 358 days) and 4 responders were still on PDX treatment. The median PFS of all 20 evaluable pts was 150 days (95% CI, 43 to 183). Among 23 evaluable pts for efficacy in phase 1/2, 5 pts had died and median OS was not reached (range, 41 to 570 days) after a median follow-up of 183 days for censored cases. In contrast to the results from the previous phase 2 study in western countries showing the ORR of 8% (1 of 13) in pts with angioimmunoblastic T-cell lymphoma (AITL), the ORR in AITL pts was 44% (4 of 9), which was similar to the ORR in pts with PTCL not otherwise specified (50%; 6 of 12) or pts with anaplastic lymphoma kinase-negative anaplastic large cell lymphoma (50%; 1 of 2) in this study. The plasma PDX concentration peaked immediately after intravenous injection over 3 to 5 minutes and the elimination half-life was about 10 to 20 minutes. The most common grade (G) 3 or 4 adverse events were lymphopenia (52%; 13 pts), thrombocytopenia (40%; 10 pts), leukopenia (28%; 7 pts), neutropenia (24%; 6 pts), anemia (20%; 5 pts). Mucositis was observed in 21 pts (84%) including G1 (20%; 5 pts), G2 (44%; 11 pts) and G3 (20%; 5 pts). G4 mucositis did not occur in any pts. Median duration of G2 mucositis was 8 days (range, 3 to 15) and that of G3 was 12 days (range, 8 to 17). According to the criteria for dose modification, the dose of PDX was reduced to 20 mg/m2 due to mucositis in 6 pts. One pt discontinued the treatment due to G2 mucositis recurrence after dose reduction. All 25 treated pts received ≥1 time cryotherapy at PDX administration and 20 of them continued it throughout the study. Thirteen pts received ≥1 time dental scaling or dental cleaning. Conclusion: PDX at 30 mg/m2 weekly for 6 of 7 weeks was effective and well-tolerated in Japanese pts with R/R PTCL. Early oral or dental care potentially ameliorates mucositis and it may be useful for continuing PDX treatment more safely. This study was sponsored by Mundipharma KK. Disclosures Maeda: Mundipharma KK: Research Funding. Tobinai:Ono Pharmaceutical: Research Funding; Takeda: Honoraria, Research Funding; HUYA Bioscience: Honoraria; Daiichi Sankyo Co., Ltd.: Consultancy; Zenyaku Kogyo: Honoraria; SERVIER: Research Funding; GlaxoSmithKline: Research Funding; Kyowa Hakko Kirin: Research Funding; Janssen Pharmaceuticals: Honoraria, Research Funding; Chugai Pharma: Research Funding; Abbvie: Research Funding; Celgene: Research Funding; Eisai: Honoraria, Research Funding; Mundipharma KK: Honoraria, Research Funding. Nagai:Mundipharma KK: Research Funding; Takeda: Honoraria, Research Funding; Janssen: Research Funding. Nakane:Mundipharma KK: Research Funding. Shimoyama:Mundipharma KK: Research Funding. Nakazato:Mundipharma KK: Research Funding. Sakai:Mundipharma KK: Research Funding. Ishikawa:Mundipharma KK: Research Funding. Izutsu:Eisai: Honoraria; Chugai Pharmaceutical: Honoraria, Research Funding; Kyowa Hakko Kirin: Honoraria; Takeda Pharmaceutical: Honoraria; Janssen Pharmaceutical K.K.: Honoraria; Celgene: Research Funding; Gilead: Research Funding; Abbvie: Research Funding; Mundipharma KK: Research Funding. Ueda:Kyowa Hakko Kirin: Research Funding; Mundipharma KK: Consultancy.

scholarly journals Combined Hypomethylating Agents (HMA) and Histone Deacetylase Inhibitors (HDACi) Exhibit Compelling Activity in Patients with Peripheral T-Cell Lymphoma (PTCL) with High Complete Response Rates in Angioimmunoblastic T-Cell Lymphoma (AITL)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1002-1002 ◽  
Author(s):  
Lorenzo Falchi ◽  
Jennifer Kimberly Lue ◽  
Francesca Montanari ◽  
Enrica Marchi ◽  
Jennifer E Amengual ◽  
...  
Keyword(s):  
T Cell ◽  
Research Funding ◽  
Specific Activity ◽  
Cell Lymphoma ◽  
Phase 1 ◽  
Cell Lineage ◽  
B Cell Lymphoma ◽  
Complete Response ◽  
T Cell Lymphoma ◽  
Phase 2

Abstract Introduction: PTCL may represent the prototypical epigenetic malignant disorder. First, recurring mutations in important epigenetic regulators, such as TET2, IDH2, and DNMT3, have been described across several PTCL subtypes, though especially in AITL. Second, HDACi have only been approved as single agents in patients with relapsed/refractory (R/R) PTCL, and exhibit T-cell lineage-specific activity across disease subtypes. Thirdly, preclinical evidence from our group suggests marked class synergism between HDACi and HMA. In addition, across a panel of diverse T-cell lymphoma lines, the combination of HDACi and HMA induced the expression of many cancer testis antigens and genes involved in the interferon pathway/viral antigen response. Based on this collective experience, a phase 1/2 trial of romidepsin (ROMI) and oral 5-azacitidine (AZA) was launched to determine if this activity is reproduced in patients with R/R PTCL. Methods: Patients with R/R lymphoma were eligible for the phase 1, whereas the phase 2 only enrolled patients with PTCL, and included both R/R and treatment-naïve individuals. The dose-escalation portion of the study followed a 3+3 design with progressively increasing dose intensity across 7 cohorts. The phase 1 primary objectives were determination of the maximum tolerated dose and dose-limiting toxicity. Phase 2 primary objectives were overall response rate (ORR, i.e., complete response [CR] + partial response [PR]), progression free survival, and duration of response (DOR). Results: 36 patients have been enrolled to date, 26 in phase 1 and 10 in phase 2. In the intention-to-treat population the median age was 56 years [23-83] with 59% being males. Twelve patients had Hodgkin lymphoma, 8 had a B-cell lymphoma, and 16 had a T-cell lymphoma (6 enrolled in the phase 1 and 10 in phase 2). The median number of prior therapies was 6 [1-15] for the phase 1 population and 1 [0-6] for the phase 2. After a median of 2 cycles [0-16], all phase 1 patients have discontinued therapy, whereas 6 out of 10 patients in phase 2 are still on treatment after a median of 2.5 cycles [1-14]. No patient discontinued therapy due to adverse events (AE). The most frequent hematologic G3-4 AE included neutropenia (39%), lymphopenia (39%), and thrombocytopenia (28%). The most frequent non-hematologic G3-4 AE included febrile neutropenia (8%), hyponatremia (5%), and lung infection (5%). Other common G1-2 toxicities included hyperglycemia, hypoalbuminemia, nausea/vomiting, and fatigue. The recommended phase 2 dose for the combination was declared AZA 300 mg days 1-14 and ROMI 14 mg/m2 days 8, 15, and 22 on a 35-day cycle. Thirty-two patients are evaluable for response. Of these, 27 had measurable disease. The ORR and CR in the overall population are 41% and 22%, respectively. However, while only 2 (11%) patients with non-T-cell lymphoma responded, of which one was a CR, 11 of 14 (79%) patients with T-cell lymphoma responded, including 6 (43%) who attained CR (see waterfall plot in figure). Notably, all 6 evaluable patients with AITL responded, and 3 achieved a CR. Two of these 3 achieved PR before reaching CR. Responses have been durable and the median DOR has not been reached [0.2-13.1+ months]. The AUC for ROMI at 10 mg/m2 (N = 15) and 14 mg/m2 (N = 20) were 2021.5 +/- 1461.3 h*ng/mL and 1565.7 +/- 5656.2 h*ng/mL, respectively, with a median half-life of 4.8 and 4.9 hours respectively, which is comparable to single-agent values. Conclusions: The combination of AZA and ROMI is well tolerated, with cytopenias being the most common G3-4 AE. The combination appears to exhibit marked T-cell lineage-specific activity. The 100% ORR in AITL patients is unprecedented and warrants detailed follow-up. Ongoing sequencing analysis will evaluate the impact of recurring mutations on the clinical activity of the combination. The study is actively accruing (NCT01998035). Figure Figure. Disclosures O'Connor: ADC Therapeutics: Research Funding; Celgene: Research Funding; Seattle Genetics: Research Funding.

scholarly journals Phase 2 study of E7777 in Japanese patients with relapsed/refractory peripheral and cutaneous T‐cell lymphoma

2021 ◽  
Author(s):  
Hidetsugu Kawai ◽  
Kiyoshi Ando ◽  
Dai Maruyama ◽  
Kazuhito Yamamoto ◽  
Eiji Kiyohara ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Lymphoma ◽  
Japanese Patients ◽  
T Cell Lymphoma ◽  
Cutaneous T Cell Lymphoma ◽  
Phase 2 ◽  
Phase 2 Study

scholarly journals Daratumumab monotherapy for patients with relapsed or refractory natural killer/T-cell lymphoma, nasal type: an open-label, single-arm, multicenter, phase 2 study

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Huiqiang Huang ◽  
Jun Zhu ◽  
Ming Yao ◽  
Tae Min Kim ◽  
Dok Hyun Yoon ◽  
...  
Keyword(s):  
T Cell ◽  
Natural Killer ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Phase 2 ◽  
Nasal Type ◽  
Natural Killer T Cell ◽  
Phase 2 Study ◽  
Duration Of Response ◽  
Killer T Cell

Abstract Background Natural killer/T-cell lymphoma (NKTCL) is a disease with limited treatment options and poor outcomes. Daratumumab monotherapy demonstrated clinical activity in a single-patient case report. We present data from the primary analysis of a phase 2 study of daratumumab monotherapy in relapsed or refractory (R/R) NKTCL. Methods This phase 2 study with Simon’s two-stage design evaluated daratumumab in patients with histologically confirmed extranodal NKTCL, nasal type, per WHO classification that was refractory to or relapsed after ≥ 1 line of chemotherapy, who were not candidates for other treatment modalities. All patients received daratumumab 16 mg/kg intravenously once weekly for Cycles 1 and 2, every other week for Cycles 3 through 6, and every 4 weeks thereafter until progression or unacceptable toxicity; all cycles were 28 days. The primary end point was objective response rate (ORR) based on blinded independent central review per Revised Criteria for Response Assessment of Hodgkin and non-Hodgkin Lymphoma (Lugano classification). Results In total, 32 Asian patients received daratumumab. The ORR was 25.0% (95% confidence interval [CI] 11.5–43.4); all 8 responders had a partial response; and the median duration of response was 55.0 days (95% CI 29–339). At 10.2 months of median follow-up, median progression-free survival (PFS) was 53.0 days (95% CI 43–106); the 4-month PFS rate was 13.0%. Median overall survival (OS) was 141.0 days (95% CI 94–438); the 6-month OS rate was 42.9%. Nineteen (59.4%) patients had grade 3/4 treatment-emergent adverse events (TEAEs); the most common was thrombocytopenia (25.0%; n = 8). TEAEs leading to death occurred in 4 patients (death, respiratory failure, septic shock, and pneumonia); all were unrelated to daratumumab. Conclusions In patients with R/R NKTCL, daratumumab monotherapy was well tolerated with no new safety concerns and achieved an ORR of 25.0%. However, no patients achieved complete response, and duration of response was short. Trial registration ClinicalTrials.gov, NCT02927925. Registered 7 October 2016.

Combination of sintilimab, anlotinib and pegaspargase "sandwich" with radiotherapy in localized natural killer/T cell lymphoma: A multicenter, phase 2 study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 7537-7537
Author(s):  
Zhiming Li ◽  
Peng Sun ◽  
Yu Wang ◽  
Hang Yang ◽  
Yajun Li ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Lymphoma ◽  
Risk Group ◽  
T Cell Lymphoma ◽  
Severe Toxicity ◽  
Phase 2 ◽  
Newly Diagnosed ◽  
Phase 2 Study ◽  
Tumor Types ◽  
Mild Toxicity

7537 Background: NK/T-cell lymphoma (NKTL) is a rare and distinct subtype NHL. Most newly diagnosed NKTL cases were localized-stage. For localized NKTL, RT alone is inadequate due to high systemic failure rate. Chemoradiation has been increasingly applied. However, current chemotherapy (CT) regimens have severe toxicity and infection, which reduce the completion of RT and patients’ medical compliance. Therefore, novel regimens with mild toxicity are needed. Sintilimab, a fully human anti-PD-1 monoclonal antibody, has showed encouraging antitumor efficacy in pts with r/r NKTL. Anlotinib, a multiple-targeted TKI that mainly blocks VEGF/VEGFR pathway, has been approved for several solid tumor types in china. Anti-angiogenesis therapy could improve efficacy of ICI in multiple tumor types. This multicenter, single-arm, phase 2 study aims to evaluate the efficacy and safety of sandwich chemoradiotion of sintilimab combined with anlotinib and pegaspargase (PEG-ASP) in newly diagnosed localized NKTL pts. Methods: Patients with pathologically confirmed previously untreated stage NKTL were enrolled. All enrolled patients received 3 cycles of sintilimab (200mg D1 ivdrip) combined with anlotinib (12mg po D1-14) and PEG-ASP (2500U/m2 D1) every 3 weeks followed by RT, then received additional 3 cycles of combination therapy as described above. The primary endpoint was overall response rate (ORR) by LUGANO 2014 criteria. Results: A total of 39 pts were enrolled, and 24 pts eligible for response evaluation (70.8% men; median age, 46 y [range 20-64]; 58.3% stage). According to PINK-E system, 8 pts (33.3%) were identified as intermediate risk group and 16 patients were low risk group. 23 of 24 patients completed protocol-specified therapeutic schemes, one patient discontinued the study after the second cycle due to disease progression. ORR was 95.8% (23/24, 95%CI: 76.9%-84.1%). Surprisingly, all the responded patients achieved CR, while 66.7% (16/24, 95%CI: 44.7%-83.6%) patients achieved CR after the second cycle. Median PFS and OS have not been reached. 1-year OS and PFS was 100% and 95.8%, respectively. All grade TRAEs occurred in 84.6% of all enrolled patients and 92.1% were grade 1-2. The most common TRAE was lymphocytopenia (9.9%). Of note, grade 3-4 hematological toxicity was reported in only one patient (4.2%). All AEs were resolved after symptomatic treatment, without systematic corticosteroid intervention. Conclusions: Sintilimab combined with anlotinib and PEG-ASP upfront and after radiotherapy was effective and could be well tolerated in localized NKTL, achieving promising CRR and rapid and long-term remission with mild toxicity. Further investigation of survival outcome is warranted. Clinical trial information: NCT03936452.

Brentuximab vedotin in The Treatment of Relapsed/Refractory CD30+ Peripheral T‐cell Lymphoma: a FIL Phase 2 Study

2022 ◽  
Author(s):  
Vittorio Stefoni ◽  
Cinzia Pellegrini ◽  
Lisa Argnani ◽  
Paolo Corradini ◽  
Anna Dodero ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Lymphoma ◽  
Brentuximab Vedotin ◽  
T Cell Lymphoma ◽  
Phase 2 ◽  
Peripheral T Cell Lymphoma ◽  
Phase 2 Study

scholarly journals Long‐term efficacy and safety of bexarotene for Japanese patients with cutaneous T‐cell lymphoma: The results of a phase 2 study (B‐1201)

2019 ◽  
Vol 46 (7) ◽  
pp. 557-563 ◽  
Author(s):  
Toshihisa Hamada ◽  
Yoshiki Tokura ◽  
Makoto Sugaya ◽  
Mikio Ohtsuka ◽  
Ryoji Tsuboi ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Lymphoma ◽  
Japanese Patients ◽  
T Cell Lymphoma ◽  
Cutaneous T Cell Lymphoma ◽  
Phase 2 ◽  
Efficacy And Safety ◽  
Term Efficacy ◽  
Phase 2 Study

Pralatrexate Is Active in Cutaneous T-Cell Lymphoma (CTCL): Results of a Multicenter, Dose-Finding Trial.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 919-919
Author(s):  
Steven M. Horwitz ◽  
Madeleine Duvic ◽  
Youn Kim ◽  
Jasmine M Zain ◽  
Mary Jo Lechowicz ◽  
...  
Keyword(s):  
T Cell ◽  
Adverse Events ◽  
Dose Reduction ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Phase 1 ◽  
Single Agent ◽  
Optimal Dose ◽  
T Cell Lymphoma ◽  
Grade 3

Abstract Abstract 919 Background: Pralatrexate enters cancer cells via the reduced folate carrier-1 (RFC-1) and is efficiently polyglutamated by folylpolyglutamyl synthetase (FPGS), leading to high intracellular retention. In a Phase 1/2 study of patients with hematologic malignancies, pralatrexate demonstrated activity in aggressive T-cell lymphoma with a maximum tolerated dose (MTD) of 30 mg/m2 once weekly for 6 of 7 weeks. The generally indolent course of CTCL may be better treated at lower doses in a maintenance fashion if a lower incidence and severity of adverse events can be achieved while preserving activity. PDX-010 is an open-label, single-agent, multicenter, Phase 1 dose-reduction trial in patients with relapsed or refractory CTCL. The primary objective is to identify an optimal dose and schedule of pralatrexate for these patients. Methods: Eligibility included mycosis fungoides (MF), Sézary syndrome (SS), and primary cutaneous anaplastic large cell lymphoma (ALCL); with disease progression after at least 1 prior systemic therapy. The pralatrexate dose and schedule started at 30 mg/m2 by IV push on 3 of 4 weeks and subsequent cohorts received reduced doses (20, 15, 10 mg/m2) and/or schedules (3/4 or 2/3 weeks) of pralatrexate based on tolerability. All patients received supplementation with vitamin B12 1 mg intramuscularly every 8-10 weeks and folic acid 1 mg orally once daily. As we sought a well tolerated regimen the definition of DLTs to trigger dose reduction included toxicities such as grade ≥ 3 neutropenia, grade ≥ 2 thrombocytopenia, febrile neutropenia, grade ≥ 2 mucositis/stomatitis, and any toxicity leading to dose omission or reduction in cycle 1. If DLT occurred and a response was seen, the following cohort was opened at the next lower dose or next less frequent schedule. Response was evaluated by modified severity-weighted adjustment tool (SWAT) every 2 cycles for 6 months and then every 4 cycles. For patients with lymph node involvement, scans were completed at baseline and upon clinical response or end of treatment, whichever occurred first. Results: Thirty-one patients received pralatrexate, with 18 (58%) men and median age of 57 yrs (range, 30-81). Patients had received a median of 6 prior therapies (range, 1-25). Cohorts at the following doses/schedules were enrolled: 30 mg/m2 x 3/4 weeks (n=2), 20 mg/m2 x 3/4 weeks (n=3), 20 mg/m2 x 2/3 weeks (n=7), 15 mg/m2 x 3/4 weeks (n=6), 15 mg/m2 x 2/3 weeks (n=3), and 10 mg/m2 x 3/4 weeks (n=10). Patients received pralatrexate for a median of 72 days (range, 7-491+); 4 patients received >10 cycles of treatment. The most common treatment-related adverse events (all grades) were mucositis (18 patients [58%]), nausea (14 patients [45%]), fatigue (14 patients [45%]), pyrexia (7 patients [23%]), vomiting (6 patients [19%]), anemia (6 patients [19%]), and edema (5 patients [16%]). Grade 3-4 treatment-related toxicities in >1 patient each were mucositis (4 patients [13%]) and anemia (2 patients [6%]). Mucositis was dose limiting (≥ grade 2) in 8 patients (26%). A total of 11 responses were observed, including 2 complete responses and 9 partial responses. In the 18 patients who received pralatrexate at a dose intensity of 15 mg/m2 x 3/4 weeks or greater, the objective response rate was 56% (10/18 patients). This appeared to be the threshold dose for substantial activity in CTCL, below which the incidence of responses decreased in this dose de-escalation trial. Conclusion: Pralatrexate shows impressive activity in the treatment of relapsed CTCL. The optimal dose and schedule that provided activity with tolerability for CTCL was determined to be pralatrexate 15 mg/m2 weekly on 3 of 4 weeks. This cohort is being expanded to better assess efficacy and durability. Disclosures: Horwitz: Allos Therapeutics, Inc: Consultancy, Research Funding. Duvic:Allos Therapeutics, Inc.: Research Funding. Lechowicz:Allos Therapeutics, Inc.: Consultancy. Fruchtman:Allos Therapeutics, Inc.: Employment.

Final Results From a Pivotal, Multicenter, International, Open-Label, Phase 2 Study of Romidepsin In Progressive or Relapsed Peripheral T-Cell Lymphoma (PTCL) Following Prior Systemic Therapy

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 114-114 ◽  
Author(s):  
Bertrand Coiffier ◽  
Barbara Pro ◽  
H. Miles Prince ◽  
Francine M Foss ◽  
Lubomir Sokol ◽  
...  
Keyword(s):  
T Cell ◽  
Board Of Directors ◽  
Systemic Therapy ◽  
Research Funding ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Phase 2 ◽  
Open Label ◽  
Advisory Committees ◽  
Prior Systemic Therapy

Abstract Abstract 114 Background: Romidepsin is a potent HDAC inhibitor approved by the FDA for patients (pts) with cutaneous T-cell lymphoma who have received at least 1 prior systemic therapy. Durable clinical benefit and tolerability of romidepsin in pts with recurrent or refractory PTCL have been previously observed in a phase 2 trial conducted by the National Cancer Institute. The aim of this phase 2, single-arm, open-label registration study was to evaluate the activity of romidepsin in a larger number of pts with progressive or relapsed PTCL. Methods: Pts with histologically confirmed PTCL (PTCL NOS, angioimmunoblastic T-cell lymphoma, ALCL [ALK-1 negative], other subtypes) who failed or were refractory to ≥ 1 prior systemic therapy, and had measurable disease and ECOG performance status 0–2 were eligible. Exclusions included inadequate bone marrow or other organ function and significant cardiovascular abnormalities. Pts received romidepsin 14 mg/m2 as a 4-h IV infusion on days 1, 8, and 15 every 28 days for up to 6 cycles; treatment could be extended for stable disease (SD) or response. The primary endpoint was rate of complete response (CR + CRu) as evaluated by a central Independent Review Committee (IRC) using International Working Criteria for non-Hodgkin's lymphoma. IRC assessment consisted of a 2-step process, with initial radiographic review of images (CT, MRI) followed by an overall clinical assessment based on the radiology evaluations, photographs, and relevant clinical parameters. Secondary endpoints included objective response rate (ORR): CR + CRu + partial response (PR), investigator-assessed responses, duration of response, time to response, and safety. Results: 131 pts from 48 US, European, and Australian sites were enrolled and received at least 1 dose of romidepsin (as-treated population); 130 patients had histologically confirmed PTCL by central review. Mean age of all pts was 59.4 y (range, 20–83) and median time since diagnosis was 1.25 y (range, 0–17). Median number of prior systemic therapies was 2 (range, 1–8). 21 pts (16%) had failed a prior stem cell transplant. Responses assessed by the IRC are noted in the table below. Longest duration of response is 26+ mo and 16 (94%) of the 17 pts with a CR had not progressed as of the data cutoff (March 31, 2010). Investigator-assessed responses included 21 pts (16%) with CR + CRu, 18 pts (14%) with PR for an ORR of 30%. Currently, 13 pts continue to receive treatment (range, 10–36 cycles). Adverse events (AEs) were reported in 126 of 131 pts (96%). AEs reported in ≥ 20% of pts were nausea (59%), fatigue (41%), vomiting (38%), thrombocytopenia (38%), diarrhea (35%), pyrexia (34%), neutropenia (30%), anorexia (28%), constipation (28%), anemia (23%), and dysgeusia (21%). AEs ≥ grade 3 were reported for 86 pts (66%), with the most common (≥ 5%) being pneumonia (5%), pyrexia (5%), sepsis (5%), and vomiting (5%). 60 pts (46%) had at least 1 serious AE: the most frequently reported (≥ 5%) were pyrexia (7%), pneumonia (5%), vomiting (5%), and sepsis (5%). 22 pts (17%) withdrew due to AEs. 8 pts (6%) died within 30 days of the last dose of romidepsin; 1 death, due to sepsis, was assessed as possibly related to treatment. Conclusions: Complete and durable responses were observed with single agent romidepsin in pts with relapsed PTCL. These data support the therapeutic potential for romidepsin in relapsed PTCL and suggest that romidepsin is a strong candidate for inclusion in future novel regimens for these diseases. As of the data cutoff (March 31, 2010), the median duration of follow-up for CR is 8.2 mo. Disclosures: Coiffier: Gloucester: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau. Off Label Use: Romidepsin is indicated for the treatment of cutaneous T-cell lymphoma (CTCL) in patients who have received at least one prior systemic therapy. Romidepsin is not currently approved for the treatment of peripheral T-cell lymphoma (PTCL). Pro:Celgene: Research Funding. Prince:Celgene: Consultancy, Honoraria, Research Funding. Foss:Celgene: Consultancy; Eisai: Consultancy, Speakers Bureau; Merck: Speakers Bureau; Allos: Consultancy, Speakers Bureau; Cephalon: Speakers Bureau. Sokol:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Caballero:Celgene: Membership on an entity's Board of Directors or advisory committees. Morschhauser:Roche: Consultancy, Honoraria; Bayer: Honoraria. Padmanabhan:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Shustov:Celgene: Research Funding. Nichols:Celgene: Employment. Carroll:Celgene: Employment. Balser:Gloucester Pharmaceutical: Consultancy. Horwitz:Celgene: Consultancy, Honoraria.

scholarly journals Nanatinostat (Nstat) and Valganciclovir (VGCV) in Relapsed/Refractory (R/R) Epstein-Barr Virus-Positive (EBV +) Lymphomas: Final Results from the Phase 1b/2 VT3996-201 Study

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 623-623
Author(s):  
Bradley M. Haverkos ◽  
Onder Alpdogan ◽  
Robert Baiocchi ◽  
Jonathan E Brammer ◽  
Tatyana A. Feldman ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Phase 2 ◽  
Advisory Committees ◽  
Phase 1B

Abstract Introduction: EBV can be associated with several types of lymphomas, with reported frequencies of up to 8-10% in diffuse large B cell lymphoma (DLBCL), 30-100% in peripheral T cell lymphoma (PTCL) subtypes, 80% in post-transplant lymphoproliferative disease (PTLD), and 15-30% in classical Hodgkin lymphoma (HL), with adverse impact on outcomes. Nanatinostat (Nstat) is a Class-I selective oral HDAC inhibitor that induces the expression of the lytic BGLF4 EBV protein kinase in EBV + tumor cells, activating ganciclovir (GCV) via phosphorylation. This results in GCV-induced inhibition of viral and cellular DNA synthesis and apoptosis. Herein we report the final results from this exploratory study for patients with R/R EBV + lymphomas (NCT03397706). Methods: Patients aged ≥18 with histologically confirmed EBV + lymphomas (defined as any degree of EBER-ISH positivity), R/R to ≥1 prior systemic therapies with an absolute neutrophil count ≥1.0×10 9/L, platelet count ≥50×10 9/L, and no curative treatment options per investigator were enrolled into 5 dose escalation cohorts to determine the recommended phase 2 doses (RP2D) of Nstat + VGCV for phase 2 expansion. Phase 2 patients received the RP2D (Nstat 20 mg daily, 4 days per week + VGCV 900 mg orally daily) in 28-day cycles until disease progression or withdrawal. Primary endpoints were safety/RP2D (phase 1b) and overall response rate (ORR) (phase 2); secondary endpoints were pharmacokinetics, duration of response (DoR), time to response, progression free survival and overall survival. Responses were assessed using Lugano 2014 response criteria beginning at week 8. Results: As of 18 June 2021, 55 patients were enrolled (phase 1b: 25; phase 2: 30). Lymphoma subtypes were DLBCL (n=7), extranodal NK/T-cell (ENKTL) (n=9), PTCL, not otherwise specified (PTCL-NOS) (n=5), angioimmunoblastic T cell lymphoma (n=6), cutaneous T cell (n=1), HL (n=11), other B cell (n=3), and immunodeficiency-associated lymphoproliferative disorders (IA-LPD) (n=13), including PTLD (n=4), HIV-associated (n=5), and other [n=4: systemic lupus erythematosus (SLE) (n=2), common variable/primary immunodeficiency (n=2)]. Median age was 60 years (range 19-84), M/F 35/20, median number of prior therapies was 2 (range 1-11), 76% had ≥2 prior therapies, 78% were refractory to their most recent prior therapy, and 84% had exhausted standard therapies. EBER positivity ranged from <1 to 90% in 42 tumor biopsies with central lab review. The most common treatment-emergent adverse events (TEAEs) of all grades were nausea (38%), neutropenia (34%), thrombocytopenia (34%), and constipation (31%). Grade 3/4 TEAEs in >10% of patients included neutropenia (27%), thrombocytopenia (20%), anemia (20%), and lymphopenia (14%). Dose reductions and interruptions due to treatment-related AEs were reported in 14 (25%) and 16 (29%) patients, respectively. Only 1 patient had to discontinue therapy. There were no cases of CMV reactivation. For 43 evaluable patients (EBER-ISH + with ≥ 1 post-treatment response assessment) across all histologies, the investigator-assessed ORR and complete response (CR) rates were 40% (17/43) and 19% (8/43) respectively. Patients with T/NK-NHL (n=15; all refractory to their last therapy) had an ORR of 60% (n=9) with 27% (n=4) CRs. Two patients (ENKTL and PTCL-NOS) in PR and CR respectively were withdrawn at 6.7 and 6.6 months (m) respectively for autologous stem cell transplantation. For DLBCL (n=6), ORR/CR was 67%/33% (both CRs were in patients refractory to first-line R-CHOP). For IA-LPD (n=13), ORR/CR was 30%/20% (PTLD: 1 CR, other: 1 CR, 1 PR). For HL (n=10), there was 1 PR (4 SD). The median DoR for all responders was 10.4 m, with a median follow-up from response of 5.7 m (range 1.9-34.1 m). For the 17 responders, 8 lasted ≥ 6 months. Conclusions: The combination of Nstat and VGCV was well-tolerated with a manageable toxicity profile and shows promising efficacy in patients with R/R EBV + lymphomas, particularly in refractory T/NK-NHL, a heterogeneous group of aggressive lymphomas with dismal outcomes, with multiple durable responses. Further evaluation of this novel combination therapy for the treatment of recurrent EBV + lymphomas is ongoing in the phase 2 VT3996-202 trial. Disclosures Haverkos: Viracta Therapeutics, Inc.: Honoraria, Research Funding. Baiocchi: Prelude Therapeutics: Consultancy; viracta: Consultancy, Current holder of stock options in a privately-held company; Codiak Biosciences: Research Funding; Atara Biotherapeutics: Consultancy. Brammer: Seattle Genetics: Speakers Bureau; Celgene: Research Funding; Kymera Therapeutics: Consultancy. Feldman: Alexion, AstraZeneca Rare Disease: Honoraria, Other: Study investigator. Brem: Karyopharm: Membership on an entity's Board of Directors or advisory committees; SeaGen: Speakers Bureau; BeiGene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees; KiTE Pharma: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics/Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Morphosys/Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Scheinberg: Roche: Consultancy; Abbvie: Consultancy; BioCryst Pharmaceuticals: Consultancy; Alexion pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau. Joffe: AstraZeneca: Consultancy; Epizyme: Consultancy. Katkov: Viracta Therapeutics, Inc.: Current Employment. McRae: Viracta Therapeutics, Inc.: Current Employment. Royston: Viracta Therapeutics, Inc.: Current Employment. Rojkjaer: Viracta Therapeutics, Inc.: Current Employment. Porcu: Viracta: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Innate Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Daiichi: Honoraria, Research Funding; Kiowa: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Spectrum: Consultancy; DrenBio: Consultancy.

scholarly journals Brentuximab Vedotin As Single Agent in the Treatment of Relapsed/Refractory CD30 Positive Peripheral T-Cell Lymphoma Patients: A Phase 2 Study of the Fondazione Italiana Linfomi

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 21-21
Author(s):  
Vittorio Stefoni ◽  
Paolo Corradini ◽  
Lorella Orsucci ◽  
Stefano Volpetti ◽  
Lisa Argnani ◽  
...  
Keyword(s):  
T Cell ◽  
Board Of Directors ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Progression Free Survival ◽  
T Cell Lymphoma ◽  
Phase 2 ◽  
Advisory Committees ◽  
Not Otherwise Specified ◽  
Phase 2 Study

Options are limited for patients with relapsed or refractory (R/R) peripheral T-cell lymphoma (PTCL) for whom the median overall survival (OS) and progression free survival (PFS) are less than 6 months. Patients who are candidates for allogeneic stem cell transplantation can be cured should they achieve adequate response to salvage therapy prior to transplant. Patients who relapse after transplant or who are not transplant candidates are often treated with sequential single-agent therapies with non-curative intent. Only four agents are FDA-approved for the treatment of R/R PTCL including pralatrexate, romidepsin and belinostat. The objective response rate to each of these agents is only 25-30% and duration of response (DOR) is limited. For a specific subtype of PTCL, namely systemic anaplastic large-cell lymphoma, single-agent brentuximab vedotin (BV) treatment resulted in an 86% overall response rate (ORR) and a 57% complete response (CR) rate in R/R disease. A phase 2 study evaluated the efficacy and safety of BV in angioimmunoblastic T-cell lymphoma (AITL) and PTCL not otherwise specified reporting an ORR of 41% (Horwitz et al, Blood. 2014). We conducted a phase 2 study to determine the antitumor efficacy of single-agent BV (1.8 mg/kg administered intravenously every 3 weeks for a maximum of 16 cycles) as measured by the ORR in R/R CD30+ PTCL patients (PTCL not otherwise specified, AITL and transformed mycosis fungoides). Secondary objectives were to assess duration of tumor control, including duration of response and progression-free survival, overall survival and the safety and tolerability of BV in this setting. ClinicalTrials.gov Identifier: NCT02497131. From September 2015 and September 2019, 25 patients were enrolled and 23 (population for the final analysis) received at least one BV infusion (median 5, range 2-16). There were 10 females, 18 patients were in stage IV and 16 subjects were refractory to the last therapy. Median number of therapies received prior to BV was 2 (range 1-6). Final ORR was 30.4%, with 4 CR. CR patients were 3 PTCL not otherwise specified and 1 AITL with response duration of 2.8, 3.3, 4.5 and 10.7 months, respectively. Best response was achieved at the III cycle. PFS was 4.3% at 12 months (median reached at 4.4 months), OS at 12 months was 49.8% (median reached at 11.4 months) and median DOR was 3.4 months. No correlation between CD30 expression per central review and response was observed. Twenty-one hematological toxicities occurred, 14 of them were grade ≥3 (10 thrombocytopenia and 4 neutropenia, all resolved or improved during BV therapy). Among extra-hematological toxicities (n=26, 3.5% grade ≥3), 7 were serious adverse events. To note, 6 of them (23.1%) were lung infection/pneumonia. Only one peripheral neuropathy (grade 1) occurred. In terms of response, the ORR and PFS in this trial are comparable to those in similar populations studied with both other recently approved agents, such as pralatrexate and romidepsin, and with the other phase 2 study on BV. The ORR of 30% and the OS of in the present study places BV among the active agents for PTCL. Safety concerns emerged about infections, claiming for a strict monitoring for these toxicities. Disclosures Corradini: Gilead: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Kite: Consultancy, Honoraria; KiowaKirin: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Incyte: Consultancy; Servier: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other; BMS: Other; Daiichi Sankyo: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Other: Travel and accommodations paid by for; F. Hoffman-La Roche Ltd: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: Travel and accommodations paid by for; AbbVie: Consultancy, Honoraria, Other: Travel and accommodations paid by for; Amgen: Consultancy, Honoraria, Other: Travel and accommodations paid by for. Zinzani:Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Eusapharma: Consultancy, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; EUSA Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kirin Kyowa: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics, Inc.: Honoraria, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Consultancy, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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