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.

Phase I Dose-Escalation Study of Cpi-613, in Combination with Bendamustine, in Relapsed or Refractory T-Cell Non-Hodgkin Lymphoma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4163-4163 ◽  
Author(s):  
Zanetta S. Lamar ◽  
Scott Isom ◽  
Rakhee Vaidya ◽  
Anne W Beaven ◽  
Zachariah A. McIver
Keyword(s):  
T Cell ◽  
Dose Escalation ◽  
Response Rate ◽  
Cell Lymphoma ◽  
Phase 1 ◽  
Single Agent ◽  
Hematologic Malignancies ◽  
T Cell Lymphoma ◽  
Non Hodgkin Lymphoma ◽  
Grade 3

Abstract Background:T cell lymphomas account for 10-15% of lymphoid malignancies and display significant heterogeneity. T cell lymphomas have a worse prognosis than most B cell lymphomas. For relapsed or refractory disease, there is not a standard treatment and median progression free and overall survival rates have been reported as 3.7 and 6.5 months, respectively. Therefore, optimal treatment for relapsed/refractory T cell Non-Hodgkin Lymphoma (NHL) is an unmet clinical need. CPI-613 is a lipoate derivative that has shown activity in hematologic malignancies. CPI-613 selectively targets the pyruvate dehydrogenase complex (PDC) and α-ketoglutarate dehydrogenase complex (KGDHC) in tumor cells. CPI-613 leads to the inhibition of the catalytic and regulatory functions of the PDC and the KGDHC causing alterations of mitochondrial enzyme complex activities and altering redox status, leading to apoptosis, necrosis and autophagy of tumor cells. The anti-tumor activity of CPI-613 is evident in various cancer cell lines, xenograft animal tumor models and clinical trials against a diverse group of cancers. Patients tolerate CPI-613 as a single agent at doses up to 3,000 mg/m2, according to Phase 1 trials in patients with solid tumors and hematologic malignancies. Bendamustine has shown single agent activity in the relapsed lymphoma setting with response rates of approximately 50% for T cell NHL. Here, we are conducting a Phase I study in which the primary objective was to evaluate the maximum tolerated dose (MTD) of CPI-613 while administered in combination with Bendamustine. The secondary objective was to determine response rate to treatment. Methods: This study is a phase 1, open label, modified 3+3 dose escalation clinical trial evaluating CPI-613 and Bendamustine combination therapy. CPI-613 was given at escalating doses starting at 2,000mg/m2 over 2 hrs on days 1-4, and on days 8, 11, 15 and 18. Bendamustine was infused at 90 mg/m2 on days 4 and 5 of each treatment cycle. Each treatment cycle was 4 weeks and repeated up to six cycles. Demographics, patient characteristics and dose levels are shown in the table below. There was no intra-patient dose escalation. Results: As of July 27, 2016, eight subjects have received at least one dose of study drug. Eight patients are evaluable for safety and five patients are evaluable for response. The most common grade 3 or higher toxicities were lymphopenia and neutropenia and occurred in 4 subjects. One patient dosed at 2750 mg/m2 had a dose limiting toxicity of grade 3 acute kidney injury and grade 4 lactic acidosis. The protocol was later amended to discontinue dose escalation at doses of 2750 mg/m2 or higher and to expand the 2500mg/m2 cohort. The overall response rate was 80%. Three patients with peripheral T cell lymphoma, NOS, obtained a complete response and 1 patient with mycosis fungoides had a partial response. One patient with T cell acute lymphomoblastic lymphoma had progressive disease. The median time to response is 1.8 months. Enrollment is ongoing and updated trial results will be presented. Conclusions: This first reported study of CPI-613 administration in combination with Bendamustine in subjects with relapsed or refractory T cell lymphoma showed a good safety profile and an excellent overall response rate of 80% with CRs in all three patients with peripheral T cell lymphoma, NOS. Although numbers are small, continued investigation is warranted as these response rates in a poor risk population of patients with relapsed/refractory T cell lymphoma are very exciting. Clinical trial: NCT02168907 Disclosures No relevant conflicts of interest to declare.

Identification of An Active, Well-Tolerated Dose of Pralatrexate In Patients with Relapsed or Refractory Cutaneous T-Cell Lymphoma (CTCL): Final Results of a Multicenter Dose-Finding Study.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2800-2800 ◽  
Author(s):  
Steven M Horwitz ◽  
Youn H. Kim ◽  
Francine M Foss ◽  
Jasmine M. Zain ◽  
Patricia Myskowski ◽  
...  
Keyword(s):  
T Cell ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Dose Intensity ◽  
Optimal Dose ◽  
T Cell Lymphoma ◽  
Dose Finding ◽  
Hematologic Toxicity ◽  
Cutaneous T Cell Lymphoma ◽  
Grade 3

Abstract Abstract 2800 Background: Pralatrexate (FOLOTYN®) is an antifolate designed for preferential tumor uptake and accumulation. Pralatrexate was granted accelerated approval by the US Food and Drug Administration at a dose of 30 mg/m2 weekly for 6/7 weeks for relapsed or refractory peripheral T-cell lymphoma. Given that cutaneous T-cell lymphoma (CTCL) is often an indolent disease treated in a maintenance fashion, the goal of this trial was to identify a dose with clinical activity and minimal toxicity to allow continuous or maintenance treatment. In the present study, designated PDX-010, the initial dose of pralatrexate for relapsed or refractory CTCL was based on data showing that 30 mg/m2 demonstrated activity in patients with aggressive lymphoma. A dose de-escalation strategy was used in PDX-010 to identify an optimal dose for CTCL. Methods: Eligibility included CTCL histology of mycosis fungoides, Sézary syndrome, or primary cutaneous anaplastic large-cell lymphoma, with disease progression after at least 1 prior systemic therapy, and written informed consent. The starting dose and schedule was 30 mg/m2 of pralatrexate by intravenous (IV) push weekly for 3/4 weeks. If toxicity as defined per the protocol was observed, subsequent cohorts received reduced doses (20, 15, 10 mg/m2) and/or schedules (weekly for 3/4 or 2/3 weeks). All patients received supplementation with vitamin B12 1 mg intramuscularly every 8 to10 weeks, and folic acid 1 mg orally once daily (QD). Response was evaluated by the modified severity weighted adjustment tool (mSWAT) 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: Fifty-four patients were treated across 2 stages of this study. In the dose-finding phase, 31 patients were sequentially enrolled into 6 cohorts and treated at varying doses and schedules. The optimal dose and schedule, as defined in the protocol, was identified as 15 mg/m2 weekly for 3/4 weeks, based on the tolerability and efficacy (overall response rate [ORR] of 50%) observed in the initial 6 patients in that cohort. Among the 31 patients in the dose-finding stage, the ORR for patients treated at a dose intensity ≥15 mg/m2 weekly for 3/4 weeks was 61% (11/18), and the ORR for those patients treated in lower-dose cohorts was 8% (1/13). The second stage of the study included 23 additional patients treated at 15 mg/m2 weekly for 3/4 weeks, for a total of n = 29 patients treated at this optimal dose. Among these 29 patients, the median number of prior systemic therapies was 4.5 (range 1 to 11), and patients received pralatrexate for a median of 4 cycles (range 1 to 23). Patients enrolled in this cohort could be dose-escalated at investigator discretion if there was an absence of toxicity and a response < CR. At this time 53/54 patients treated in this study are evaluable for efficacy, including 28/29 patients treated at 15 mg/m2 for 3/4 weeks. At the optimal dose, the ORR was 43% (12/28) and 50% (20/40) in patients treated at a dose intensity ≥15 mg/m2 weekly for 3/4 weeks. At the optimal dose/schedule, grade 1–2 adverse events (AEs) occurring in >10% were fatigue (34%), mucositis (28%), nausea (24%), edema (24%), epistaxis (21%), pyrexia (17%), constipation (14%), and vomiting (14%). The only grade 3 AE in >10% was mucositis (17%). Hematologic toxicities were limited to grade 3 neutropenia (3%), grade 1–2 anemia (14%), grade 3 anemia (3%), grade 1–2 thrombocytopenia (7%), grade 3 thrombocytopenia (3%), grade 1–2 leukopenia (3%), and grade 4 leukopenia (3%). No grade 4 nonhematological toxicities were observed. Conclusions: Pralatrexate shows high activity with acceptable toxicity in patients with relapsed or refractory CTCL at the identified optimal dose and schedule of 15 mg/m2 weekly for 3/4 weeks. The lack of significant hematologic toxicity or cumulative toxicity seen in this study suggests that pralatrexate should be further evaluated as continuous or maintenance therapy for patients with CTCL. Final efficacy and tolerability data will be reported. Disclosures: Horwitz: Allos Therapeutics, Inc.: Consultancy, Research Funding. Foss:Allos Therapeutics, Inc.: Consultancy, Speaker. Zain:Allos Therapeutics, Inc. : Speakers Bureau. Lechowicz:Allos Therapeutics, Inc.: Consultancy; Celgene Corporation : Consultancy. Shustov:Allos Therapeutics, Inc.: Honoraria, Research Funding. Koutsoukos:Allos Therapeutics, Inc.: Employment. Fruchtman:Allos Therapeutics, Inc.: Employment. O'Connor:Allos Therapeutics, Inc.: Research Funding. Duvic:Allos Therapeutics, Inc.: Research Funding.

scholarly journals A Dose Escalation Study of RP6530, a Novel Dual PI3K δ/γ Inhibitor, in Patients with Relapsed/Refractory T-Cell Lymphoma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3004-3004 ◽  
Author(s):  
Yasuhiro Oki ◽  
Auris Huen ◽  
Prajak J Barde ◽  
Kumar Penmetsa ◽  
Alda Ashu ◽  
...  
Keyword(s):  
T Cell ◽  
Adverse Events ◽  
Dose Escalation ◽  
Cell Lymphoma ◽  
Phase 1 ◽  
Performance Status ◽  
T Cell Lymphoma ◽  
Clinical Activity ◽  
Dose Escalation Study ◽  
Grade 3

Abstract Introduction: The δ isoform of PI3K is highly expressed in cells of hematopoietic origin. The γ isoform is associated with T-lymphocytes and neutrophils and plays a distinct role in T-cell function. Since δ/γ isoforms are synergistic in the growth and survival of certain T-cell malignancies, dual targeting of PI3K δ/γ is an attractive intervention strategy in patients with T-cell lymphoma. RP6530 is a novel, highly specific dual PI3K δ/γ inhibitor with nanomolar inhibitory potency for both isotypes. It has shown acceptable safety profile and efficacy in patients (pts) with advanced hematologic malignancies in a Phase 1 study (ASH 2015). Herein, we present the preliminary results from an ongoing Phase 1/1b, dose escalation study of RP6530 in 11 pts with mature T-cell neoplasms (NCT02567656). Methods: The study consists of dose escalation cohorts to determine the MTD of RP6530 using a standard 3+3 design, followed by two expansion cohorts enrolling 20 pts with peripheral T-cell lymphoma (PTCL) and 20 pts with cutaneous T-cell lymphoma (CTCL). Pts with a diagnosis of PTCL or CTCL who have received at least one prior systemic therapy, ECOG performance status ≤ 2 and measurable/evaluable disease are eligible. This study evaluated the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and clinical activity of RP6530 administered twice daily (BID) in 28-day cycles. Responses were evaluated for PTCL and CTCL based on IWG criteria (Cheson 2014) and the modified Severity Weighted Assessment Tool (mSWAT) respectively. Dose limiting toxicity (DLT) was defined by a toxicity of grade 3/4 that is considered related to treatment during the first cycle of treatment. Results: To date eleven pts (6 PTCL and 5 CTCL) (5 males and six females) have been enrolled at three dose levels: 200 mg BID, 400 mg BID and 800 mg BID. ECOG performance status score was 0/1/2 in 10/1/0 pts, respectively, with a mean age of 68 yrs (range 52-76). Pts had a median of 3 (range: 3-6) prior treatment regimens, and 5 pts had refractory disease and 6 relapsed on prior treatments. RP6530 was well tolerated without any DLT or related serious adverse event reported to date. A total of 52 non-serious adverse events were reported: 41 Grade 1/2 and 11 Grade 3/4. The most common adverse events included mild vomiting (18%), diarrhoea (18%), fatigue (18%), and rash (18%). No Grade 3/4 adverse events were deemed related to RP6530 except for ALT/AST elevation in one pt. No pt discontinued treatment due to a safety issue. Dose-proportional increases in plasma concentrations were observed in PKs. Dose escalation is currently ongoing at 800 mg BID. Five pts were evaluated for responses at Cycle 3, Day1. Two pts (1 PTCL and 1 CTCL) experienced PR (40%) that are ongoing >5 months, and three pts experienced stable disease lasting for >3 months (60%). Three pts experienced rapid disease progression during first cycle, and discontinued treatment prematurely. Conclusion: This ongoing study of RP6530 demonstrated an acceptable safety profile at doses evaluated, with a promising clinical activity. The results support further evaluation of RP6530 in pts with mature T-cell neoplasms. Disclosures Oki: Novartis: Research Funding. Barde:Rhizen Pharmaceuticals SA: Employment. Penmetsa:Rhizen Pharmaceuticals SA: Employment. Viswanadha:Incozen Therapeutics: Employment.

A Phase I/II Study (JACKPOT8) of DZD4205, a Selective JAK1 Inhibitor, in Refractory or Relapsed Peripheral T- Cell Lymphoma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 19-20
Author(s):  
Won-Seog Kim ◽  
Dok-Hyun Yoon ◽  
Hyeon-Seok Eom ◽  
Youngil Koh ◽  
Jae-Yong Kwak ◽  
...  
Keyword(s):  
T Cell ◽  
Adverse Events ◽  
Phase I ◽  
Research Funding ◽  
Tumor Response ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Peripheral T Cell Lymphoma ◽  
Once Daily ◽  
Grade 3

Background: Peripheral T-Cell Lymphoma (PTCL) is an aggressive malignancy which lacks effective treatment. Emerging data suggests that the JAK-STAT pathway may play an important role in mediating pathogenesis of PTCL. DZD4205 (AZD4205) is an orally available, potent and highly selective JAK1 inhibitor. In T-cell lymphoma cell lines, DZD4205 modulates pSTAT3 pathway and suppresses cell proliferation, and in tumor xenograft models, DZD4205 exhibits dose-dependent anti-tumor activities, with good correlation with drug exposure and modulations of pSTAT3 in tumor tissues. A phase I/II study (JACKPOT8) was initiated to assess the safety, tolerability, pharmacokinetics and anti-tumor efficacy of DZD4205 in patients with refractory/relapsed (r/r) PTCL. Methods: The JACKPOT8 study (ClinicalTrials.gov Identifier: NCT04105010) included two parts: Part A, dose escalation and Part B, dose expansion. In Part A, patients with r/r PTCL who have progressed on or were refractory to systemic therapy will be enrolled and treated with DZD4205 at two different dose levels, 150 mg or 250 mg once daily. In Part B, patients will receive DZD4205 treatment at a defined dose. The primary objective is to assess the safety and tolerability of DZD4205, and the secondary objectives include anti-tumor efficacy and pharmacokinetics. Evaluation of safety/tolerability and tumor response will be based on the CTCAE version 5.0 and 2014 Lugano classification, respectively. Patients will be treated until disease progression, intolerance to adverse events, or withdrawal of consent. Results: As of June 30, 2020, a total of 23 patients with r/r PTCL were enrolled and received DZD4205 at 150 mg (n = 19) or 250 mg (n = 4) once daily. Patient characteristics: median age (range): 65.0 years (34-79); median prior systemic therapies (range): 2 lines (1-8). Four patients had undergone prior hematopoietic stem cell transplantation (HSCT). Six patients had bone marrow involvement at the study entry. Histological subtypes included peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) (n = 10, 43.5%), angioimmunoblastic T-cell lymphoma (AITL) (n = 10, 43.5%), ALK-negative anaplastic large cell lymphoma (ALCL ALK-) (n = 2, 8.7%) and extra-nodal nasal NK/T-cell lymphoma (NKTCL) (n = 1, 4.3%) . Preliminary data showed that 20 patients experienced treatment emergent adverse events (TEAEs), among whom 13 (56.5%) had ≥ grade 3 TEAEs. Based on local investigators' assessment, eight patients (34.8%) had ≥ grade 3 TEAEs which were considered to be related to DZD4205. The most common (&gt; 5% incidence) DZD4205-related TEAEs (any grade) included thrombocytopenia (n = 6, 26.1%), neutropenia (n = 4, 17.3%), decreased appetite (n = 3, 13.0%), nausea (n = 2, 8.7%), interstitial lung disease (n = 2, 8.7%) and pneumonia (n = 2, 8.7%). Most TEAEs were manageable with dose interruption and reduction. Preliminary PK data is available in 20 patients (n = 19 at 150 mg, n = 1 at 250 mg). Exposure at 250 mg is higher than 150 mg following a single and multiple dose. As expected from long t1/2 of DZD4205, accumulation of about 3 folds in AUC was observed. DZD4205 had flat PK profile with small difference between Css,max and Css,min after 22 days of once daily dosing, which is an optimal PK profile to maintain DZD4205 concentrations above effective levels throughout the dosing interval. As of June 30, 2020, 22 patients (n = 19 at 150 mg, n = 3 at 250 mg) had at least one post-treatment Lugano assessment. In 150 mg cohort, 8 out of 19 patients showed tumor response, with objective response rate (ORR) of 42%, among whom 4 (21%) had complete response (CR) and another 4 (21%) partial response (PR). In 250 mg cohort, 1 out of 3 patients showed tumor response, with ORR of 33%. Tumor response was observed in subtypes including AITL, PTCL-NOS, ALCL (ALK-) and NKTCL. At the data cut-off date, the longest duration on treatment was &gt; 8 months. Patient enrolment is ongoing. Updated clinical data will be shared at the meeting. Conclusion: DZD4205 shows good tolerability, pharmacokinetic profiles and promising anti-tumor efficacy in patients with r/r PTCL, indicating its potential as a therapeutic option for this unmet medical need. Disclosures Kim: Donga: Research Funding; Kyowa-Kirin: Research Funding; Roche: Research Funding; Johnson&Johnson: Research Funding; Celltrion: Research Funding; Mundipharma: Research Funding. Yoon:Celltrion: Honoraria; Samyang: Research Funding; Amgen, Chongkundang, Celgene, Astrazeneca: Consultancy. Wang:Dizal Pharmaceuticals: Current Employment. Li:Dizal Pharmaceuticals: Current Employment. Huang:Dizal Pharmaceuticals: Current Employment. Deng:Dizal Pharmaceuticals: Current Employment. Chen:Dizal Pharmaceuticals: Current Employment. Yang:Dizal Pharmaceuticals: Current Employment.

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.

scholarly journals Phase 1 Study of Subcutaneous Recombinant Human (rh) Interleukin-15 and Intravenous Alemtuzumab in Patients with Rrelapsed/Refractory T-Cell Lymphoma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 23-24
Author(s):  
Milos D. Miljkovic ◽  
Kevin C Conlon ◽  
Jennifer Albert ◽  
Deborah Allen ◽  
Thomas A. Waldmann
Keyword(s):  
T Cells ◽  
T Cell ◽  
Adverse Events ◽  
Nk Cells ◽  
Cd8 T Cells ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Interleukin 15 ◽  
Grade 3 ◽  
Dose Levels

BACKGROUND: Interleukin-15 (IL-15) is a member of the 4-α helix bundle family of cytokines. Administration of single-agent IL-15 to patients with cancer produced substantial increases and activation of natural killer (NK) cells and CD8+ T cells, but no clinical responses. Subsequent studies showed that IL-15 enhances the efficacy of anti-tumor monoclonal antibodies that work through antibody-dependent cell cytotoxicity, a process mediated by NK cells. In the MET-1 xenograft mouse model, the combination of IL-15 and the anti-CD52 antibody alemtuzumab led to significantly more durable responses than each agent by itself. Here we report the final results of the phase I trial of IL-15 and alemtuzumab in patients with relapsed and refractory T-cell lymphoma (NCT02689453). METHODS: In this phase I single-center trial IL-15 was given subcutaneously 5 days per week for 2 weeks in a standard 3+3 dose escalation scheme (DL1: 0.5μg/kg, DL2: 1μg/kg, DL3: 2μg/kg), followed by alemtuzumab 30mg intravenously three times weekly for 4 weeks. Primary endpoints were type and frequency of adverse events and the maximum tolerated dose of IL-15. RESULTS: A total of eleven patients (pts) were treated at DL1 (3), DL2 (4) and DL3 (4). Seven pts had acute adult T-cell leukemia (ATL), two had chronic ATL, and two had peripheral T-cell lymphoma not otherwise specified (PTCL-NOS). There were no dose-limiting toxicities through the maximum planned dose of 2μg/kg/day. Two pts both with acute subtype ATL were unable to complete treatment due to rapidly progressive disease early in their treatment course, but there was no evidence tumor simulation or expansion of circulating ATL cell numbers during the period of IL-15 administration Hematologic AEs included lymphopenia (all 11 pts, 7 with grade 3/4), neutropenia (8 pts, 2 with grade 3), anemia (10 pts, 1 with grade 3), and thrombocytopenia (4 pts, 1 with grade 3). The most common non-hematologic AEs were infusion-related reactions experienced by 10 of the 11 pts during alemtuzumab infusion, and urticaria (4, pts, 2 with grade 3, both of whom at MTD). Two pts had incidental findings of a catheter-associated thrombus and pulmonary emboli, necessitating institution of prophylactic anticoagulation for subsequent pts after which no additional thromboembolic events were seen. Infectious adverse events included one case each of CMV reactivation without end-org involvement, HSV reactivation, Zoster, bacterial sinusitis, and cellulitis (in a patient with ATL and skin involvement), all grade 2. There was no evidence of graft versus host disease in two pts with previous allogeneic stem cell transplantation, and there were no serious adverse events attributable to IL-15. Administration of IL-15 resulted in a median 2.1-fold increase (range 1.2-3.4) in absolute lymphocyte count, 2.5-fold (1-5.9) increase in the number of circulating CD8+ T cells, and 7.2-fold (1.1-17.1) increase in NK cells across all dose levels (Figure 1A). At the MTD, the median ALC, CD8+ T cell, and NK cell increases were 2, 2.1, and 15.3-fold respectively. The overall response rate was 45% with 2/11 complete responses (CR) and 3/11 partial responses (PR) (Figure 1B). Notably, all pts with leukemic disease attained CR in the blood (Figure 1C), with varying response in other compartments. A patient with acute ATL had a CR at first restaging but developed central nervous system relapse after four weeks; this remained the only site of disease until the patient's death 8 months later. A patient with PTCL-NOS had a delayed response, with a PR at 3 and CR at 5 months which was ongoing at 12-month follow-up. Two pts with chronic ATL had PRs which lasted 10 and 4 months, and a patient with acute ATL had a PR at first restaging which was ongoing at the end of treatment. In all pts, response was correlated with normalization of serum LDH and soluble CD25. Analysis of peripheral blood mononuclear cells from responders and non-responders using single-cell RNA-seq is under way and will be presented. CONCLUSION: Combination of IL-15 and alemtuzumab was safe at all dose levels administered with no evidence of treatment related disease stimulation. The contribution of IL-15 to the known clinical efficacy of alemtuzumab in relapsed/refractory T-cell malignancies needs to be assessed in a randomized trial. Further evaluation of IL-15 in the post-allogeneic transplant setting, particularly prior to donor lymphocyte infusion, is also planned. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: alemtuzumab for T-cell lymphoma

scholarly journals Final Results of Phase 1/1b Study of Tenalisib, Dual PI3K δ/γ Inhibitor in Patients with Relapsed/Refractory T-Cell Lymphoma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2831-2831 ◽  
Author(s):  
Swaminathan P. Iyer ◽  
Brad M. Haverkos ◽  
Jasmine Zain ◽  
Radhakrishnan Ramchandren ◽  
Mary Jo Lechowicz ◽  
...  
Keyword(s):  
T Cell ◽  
Adverse Events ◽  
Board Of Directors ◽  
Dose Escalation ◽  
Safety Profile ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Phase 1 ◽  
Clinical Activity ◽  
Advisory Committees

Introduction: Tenalisib (RP6530) is a novel, highly specific, dual PI3K δ/γ inhibitor with nano-molar inhibitory potency at the enzyme and cellular level. PI3K plays a critical role in T-cell development and activation and several studies have validated the PI3K-AKT pathway as a potential therapeutic target in T cell lymphomas. Preliminary results of the ongoing Phase 1/1b T-cell lymphoma (TCL) study demonstrated an acceptable safety profile with encouraging clinical activity in relapsed/refractory TCL (Oki, ASCO 2018 and Iyer, ASH 2018). We now present the final results of the study (NCT02567656). Methods: This study comprised of four-dose escalation cohorts, followed by two dose expansion cohorts at MTD enrolling 20 patients each in PTCL and CTCL cohorts. Patients had histologically confirmed TCL, ECOG PS ≤2, and had received ≥1 prior therapy. Patients received Tenalisib [200 mg BID-800 mg BID (fasting), 800 mg (fed only)] orally until progression or unacceptable toxicity. The primary objectives were to determine the MTD and pharmacokinetic profile. The secondary objective was to evaluate overall response rate (ORR) and duration of response. Responses were evaluated for PTCL and CTCL based on IWG criteria (Cheson 2007) and mSWAT respectively. Adverse events were graded according to CTCAE v4.03. Results: Fifty-eight patients were enrolled in study, 19 in dose escalation and 39 in dose expansion (28 PTCL and 30 CTCL). Median number of prior therapies was 4 (range, 1-15). Safety assessment of 58 patients receiving at least one dose of Tenalisib demonstrated an acceptable safety profile. Treatment related Grade≥3 AEs were elevated ALT/AST (21%), rash (5%), and hypophosphatemia (3%). These events were reversible and managed by withholding study drug. Additionally, in few patients (N=9), steroids were used to manage elevated ALT/AST. There were six treatment related serious adverse events, none of these led to fatal outcome. At end of the study, four (3 CTCL; 1 PTCL) patients who completed minimum 8 cycles of therapy were rolled over to a compassionate use study (NCT03711604) and were followed up. Efficacy assessments demonstrated an ORR of 46% (3 CR and 13 PR) and clinical benefit rate (CR+PR+SD) of 77%. Subset efficacy analysis showed an ORR in PTCL of 47% (3 CR; 4 PR) and in CTCL of 45% (9 PR). The median time to initial response was 1.8 months and was similar in both sub-types. The overall median DOR was 4.91 months (range 0.9-26.6); in PTCL patients the DOR was 6.53 months, (range: 0.97-21.0) and 3.8 months (range: 1.67-25.67) in CTCL patients. In 3 PTCL patients who achieved CR, the median DOR was 19.5 months (range 7.5-21). Conclusion: Tenalisib demonstrated promising clinical activity and an improved safety profile in patients with relapsed/ refractory TCL. Currently, a phase I/II combination study to further evaluate safety and efficacy with romidepsin is ongoing in this target population. Disclosures Iyer: Arog: Research Funding; Bristol-Myers Squibb: Research Funding; Novartis: Research Funding; Seattle Genetics, Inc.: Research Funding; Genentech/Roche: Research Funding; Incyte: Research Funding. Zain:Spectrum: Consultancy; Seattle Genetics: Consultancy. Korman:Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Glaxo: Honoraria, Membership on an entity's Board of Directors or advisory committees; Immune Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Kyowa: Research Funding; Leo: Research Funding; Menlo: Research Funding; Merck: Research Funding; Novartis: Consultancy, Honoraria, Speakers Bureau; Pfizer: Research Funding; Principia: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Research Funding; Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Rhizen: Research Funding; Sun: Honoraria, Membership on an entity's Board of Directors or advisory committees; Syntimmune: Research Funding; UCB: Research Funding; Valeant: Honoraria, Membership on an entity's Board of Directors or advisory committees; Eli Lilly: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Dermira: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Routhu:Rhizen Pharmaceuticals S.A.: Employment. Barde:Rhizen Pharmaceuticals S.A.: Employment. Nair:Rhizen Pharmaceuticals S.A.: Employment. Huen:Galderma Inc: Research Funding; Glaxo Smith Kline Inc: Research Funding; Rhizen Pharmaceuticals: Research Funding; Innate Pharmaceuticals: Research Funding.

Clinical Safety and Activity in a Phase 1 Trial of IPI-145, a Potent Inhibitor of Phosphoinositide-3-Kinase-δ,γ, in Patients with Advanced Hematologic Malignancies

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3663-3663 ◽  
Author(s):  
Ian W. Flinn ◽  
Steven M. Horwitz ◽  
Manish Patel ◽  
Anas Younes ◽  
James R. Porter ◽  
...  
Keyword(s):  
T Cell ◽  
Dose Escalation ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Phase 1 ◽  
Hematologic Malignancies ◽  
Lymphocytic Leukemia ◽  
Grade 3 ◽  
Expansion Cohort ◽  
Dose Levels

Abstract Abstract 3663 Introduction: Phosphoinositide-3-kinases (PI3Ks) play pivotal roles in cell signaling and regulate a variety of cellular functions relevant to oncogenesis. Impaired development and function of B and T lymphocytes has been demonstrated in PI3K-δ and PI3K-γ isoform knockout mice, supporting the development of PI3K-δ,γ specific inhibitors for B- and T-cell lymphoid malignancies. IPI-145 is a potent PI3K-δ,γ inhibitor in clinical development for patients (pts) with hematologic malignancies. The activity of IPI-145 via PI3K-δ and PI3K-γ isoform inhibition has been characterized in biochemical and cellular assays and demonstrated in preclinical models of B- and T-cell mediated disease. Early results of the Phase 1 study in pts with advanced hematologic malignancies are reported here. Methods and Patients: This Phase 1 dose-escalation study is designed to evaluate the safety, pharmacokinetics (PK) and activity of orally administered IPI-145 in pts with advanced hematologic malignancies, including T-cell lymphomas/leukemias. Sequential cohorts of pts are enrolled at progressively higher dose levels with expansion cohorts of pts with select hematologic malignancies. IPI-145 is administered orally 2 times per day (BID) continuously in 28-day cycles. Tumor response is evaluated based on disease-specific standard criteria. Results: As of 16 July 2012, the study had enrolled 20 pts; 5 pts with chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia (SLL), 4 with indolent non-Hodgkin's lymphoma (iNHL), 3 with aggressive B-cell NHL [including diffuse large B-cell lymphoma (DLBCL) n=2 and Richter's transformation n=1], 3 with multiple myeloma (MM), 2 with Hodgkin's lymphoma (HL), 2 with T-cell lymphoma [anaplastic large-cell lymphoma (ALCL) n=2] and 1 with mantle cell lymphoma (MCL). Of these pts, 11 are male and 9 female, with a median [range] age of 63 years [30–81], with 36% <6 month from most recent prior systemic therapy. The median [range] number of prior therapies was 3 [1–8]. IPI-145 doses administered include 8 mg BID (n=1), 15 mg BID (n=6), 25 mg BID (n=7), 35 mg BID (n=3), and 50 mg BID (n=3). The median [range] number of treatment cycles was 2 [1–8], with 12 (60%) pts continuing on treatment. Adverse events (AEs) have occurred in 13 (65%) pts, including 7 (35%) pts with AEs Grade ≥3. Treatment-related AEs occurred in 11 pts (55%) with Grade ≥3 occurring in 5 pts (25%). Grade 4 neutropenia was the one dose limiting toxicity observed to date (15 mg dose cohort). New Grade ≥3 hematological laboratory abnormalities included neutropenia [n= 6 (30%)] and thrombocytopenia [n= 1 (5%)]. Grade 3 ALT/AST elevations occurred in 1 (5%) MM pt with onset 6 weeks after IPI-145 initiation. Preliminary PK show dose-proportional increases in plasma Cmax and AUC over the dose range studied. Further, the PK and initial pharmacodynamic (PD) data from the first 3 cohorts (8–25 mg BID) predict continuous suppression of the PI3K-δ pathway with increasing inhibition of the PI3K-γ pathway with a 25 mg BID dose or greater. In the evaluable pts (n=11), responses were observed at the 8, 15, and 25 mg BID dose levels including 2/3 CLL/SLL pts (0 CR/2 PR/1 SD), 1/2 iNHL pts (1 CR/0 PR/1 SD), and 1/1 in MCL (1 PR). No responses have been observed to date in evaluable pts with MM (0/3) or aggressive NHL (0/2). All pts with at least SD after 2 cycles (n=6) remain on treatment including the first pt dosed. Based on the PK/PD and the preliminary activity observed in pts with CLL, iNHL and MCL, an expansion cohort is enrolling pts in these select hematologic diseases dosed at 25 mg BID to further evaluate the safety and preliminary activity of IPI-145. Dose escalation continues with a focus on pts with T-cell malignancies and DLBCL where increasing suppression of the PI3K-γ isoform may improve the efficacy profile. Additional expansion cohorts in T-cell lymphoma, DLBCL, myeloproliferative neoplasms and the acute leukemias will better define disease specific activity. Conclusions: IPI-145, an oral, potent PI3K-δ,γ inhibitor, appears to be well tolerated and has shown initial clinical activity in pts with iNHL, MCL, and CLL. A dose of 25 mg BID effectively inhibits PI3K-δ, providing a rationale for expansion in CLL/iNHL/MCL. Additional safety and efficacy data from the ongoing dose escalation evaluation in T-cell/aggressive NHL and the CLL/iNHL/MCL expansion cohort will be presented. Disclosures: Flinn: Infinity Pharmaceuticals, Inc.: Research Funding. Horwitz:Seattle Genetics: Consultancy, Research Funding; Allos: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy; Genzyme: Consultancy; Kyowa Hakko Kirin Pharma: Consultancy; Johnson & Johnson: Consultancy; Infinity Pharmaceuticals, Inc. : Research Funding. Patel:Infinity Pharmaceuticals, Inc. : Research Funding. Younes:Novartis: Honoraria, Research Funding; Celgene: Honoraria; Seattle Genetics: Honoraria, Research Funding; Sanofi-Aventis: Honoraria, Research Funding; MIllenium: Honoraria; Incyte: Honoraria; Genentech: Research Funding; Infinity Pharmaceuticals, Inc. : Research Funding; Gilead: Research Funding. Porter:Infinity Pharmaceuticals, Inc. : Employment. Sweeney:Infinity Pharmaceuticals, Inc. : Employment. Allen:Infinity Pharmaceuticals, Inc. : Employment. Kelly:Infinity Pharmaceuticals, Inc. : Employment. Kahl:Infinity Pharmaceuticals, Inc. : Research Funding.

Phase I trial of subcutaneous (SQ) alemtuzumab (A) and CHOP in T-cell lymphoma: Preliminary results

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 7594-7594 ◽  
Author(s):  
P. Porcu ◽  
R. A. Baiocchi ◽  
J. Lee ◽  
T. S. Lin ◽  
K. Blum ◽  
...  
Keyword(s):  
T Cell ◽  
Phase I ◽  
Cell Lymphoma ◽  
Single Agent ◽  
T Cell Lymphoma ◽  
Mutational Status ◽  
Oral Valganciclovir ◽  
Grade 3 ◽  
Dose Levels ◽  
Cmv Reactivation

7594 Background: T-cell lymphomas are highly chemoresistant. Cure rates with combination chemotherapy do not exceed 25–30%. We showed that A, a humanized IgG1 targeting the CD52 antigen expressed on most human leukocytes, is cytotoxic for malignant T-cells in vitro and in vivo, regardless of p53 mutational status (Blood 106, 3380, 2005). Thus, we initiated a Phase I study with A and CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) in T-cell lymphoma. Methods: Accrual goal: 15–18 patients (pts) with untreated (u) or relapsed (r) peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma (CTCL), excluding ALK-1-positive anaplastic large cell lymphoma. Primary objective: maximal tolerated dose (MTD). All pts receive single agent SQ A loading (3, 10, 30 mg) over 5 days, followed by one SQ A dose with each CHOP every 21 days for a total of 8 cycles. A dose levels: 3, 10, 20 and 30 mg. All pts receive valacyclovir and trimethoprim-sulfamethoxasole, plus G-CSF and erythropoietin according to guidelines. Results: Eight of the nine enrolled pts on cohort 1 (A=3 mg) and cohort 2 (A=10 mg) are evaluable for toxicity (uPTCL= 4, rPTCL=1, rCTCL=3). All pts completed single agent A loading on time and tolerated well further SQ A. No cycle was delayed due to myelosuppression. There were no opportunistic infections or neutropenic fevers. Four pts completed all planned therapy. Three pts did not complete therapy due to progression (2) or toxicity (1). One pt remains on study after 4 cycles. There were no Grade 4 adverse events (AEs). Grade 3 AEs included fatigue (1), anemia (1), dyspnea (1) and emesis (1). Cohort 1 was expanded due asymptomatic cytomegalovirus [CMV] reactivation requiring hospitalization for thrice daily foscarnet, thus resulting in Grade 3 AE. Protocol was amended and subsequent asymptomatic CMV reactivations (2) were treated with oral valganciclovir. No symptomatic CMV reactivation occurred. Conclusions: At current dose levels, SQ A can be easily and safely administered with CHOP chemotherapy and growth factor support, without excessive myelosuppression or infectious AEs. Asymptomatic CMV reactivation can be managed with oral valganciclovir. Further A dose escalation is in progress. [Table: see text]

scholarly journals XPO1 Inhibitor (ATG-010) Plus Chemotherapy per Investigator's Choice for Heavily Pretreated Patients with Relapsed or Refractory (R/R) Peripheral T-Cell Lymphoma (PTCL) and Extranodal NK/T-Cell Lymphoma (ENKTL)：Preliminary Results from a Multicenter, Single-Arm, Phase Ib Study (TOUCH Trial)

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2452-2452
Author(s):  
Huiqiang Huang ◽  
Yan Gao ◽  
Huilai Zhang ◽  
Keshu Zhou ◽  
Jianqiu Wu ◽  
...  
Keyword(s):  
T Cell ◽  
Adverse Events ◽  
Disease Progression ◽  
Nuclear Export ◽  
Cell Lymphoma ◽  
Fatal Outcome ◽  
T Cell Lymphoma ◽  
Clinical Activity ◽  
Heavily Pretreated ◽  
Grade 3

Abstract Background The prognosis of R/R PTCL and ENKTL remains poor. Current therapeutic options are limited, highlighting the need for novel approaches. ATG-010 (selinexor) is a novel, oral selective inhibitor of nuclear export, which blocks exportin 1. It has demonstrated clinical activity in different hematological malignancies. Preclinical synergistic anti-tumor effects are confirmed when combined with gemcitabine, cisplatin, or etoposide. Method The aim of this study was to evaluate safety and efficacy of ATG-010 plus GemOx or ICE regimen followed by ATG-010 maintenance in patients (pts) with R/R PTCL or ENKTL in China. The study planned to enroll 30 pts with PTCL-NOS, AITL, ALCL, PTCL-TFH, FTL and ENKTL. Pts must have had prior exposure to an anthracycline-based regimen for PTCL or an asparaginase-based regimen for ENKTL, and were relapsed or refractory from the last therapy. ATG-010 was administered orally (60 mg day 1, 8) plus standard-dose of either ICE or GemOx regimen every 3 weeks as per investigator's choice. If response was achieved after initial 2-6 cycles, pts continued to receive ATG-010 maintenance at the dose of 60 mg weekly until disease progression, intolerability or withdrawal of consent. Primary endpoints included safety according to the NCI CTCAE 5.0 and overall response rate (ORR) evaluated by investigators according to the Lugano criteria (2014). Secondary endpoints included duration of response (DOR), progression-free survival (PFS) and overall survival (OS). This trial was registered at ClinicalTrials.gov (NCT04425070). Results From Aug 18, 2020 to June 25, 2021, 24 pts (20 in GemOx cohort, 4 in ICE cohort) were enrolled and received at least one cycle of treatment. In this abstract, we report results of the GemOx cohort with 9 (45%) PTCL-NOS, 6 (30%) ENKTL, 4 (20%) AITL, and 1 (5%) ALCL ALK-. At study entry, median age was 55 years (range 35-69); 17 (85%) had stage III/IV disease. Five (36%) pts with PTCL had IPI score ≥3, and 5 (83%) ENKTL pts with had PINK-E score ≥2. Median number of prior regimens was 3.5 (range 1-7) with 5.5 for ENKTL and 2 for PTCL. All pts were refractory from last therapy; 11 (55%) pts had received gemcitabine-based regimens. Median time from last-line therapy to this trial was 1.5 months (range 1.0-16.7). The most common treatment-emergent adverse events (TEAEs) were hematological toxicities. All grade hematological TEAEs were neutropenia (90%), thrombocytopenia (90%) and anemia (85%). Grade≥3 hematological TEAEs included neutropenia (85%), thrombocytopenia (80%) and anemia (40.0%). The most common (&gt;30%) non-hematological TEAEs were nausea (70%), diarrhea (65%), decreased appetite (65%), asthenia/fatigue (60%), vomiting (50%), pyrexia (40%), and hyponatremia (35%). Grade≥3 non-hematological TEAEs (≥10%) were diarrhea (15%) and pyrexia (10%). Serious TEAEs occurred in 7 (35%) pts with the most common being thrombocytopenia (20%). Three (15%) pts discontinued treatment due to TEAEs. TEAEs with a fatal outcome occurred in 1(5%) patient, who experienced rapid disease progression before death. The majority of adverse events were manageable by dose modification and supportive care. Of 17 efficacy evaluable pts, ORR was 52.9% (9/17), and CR rate was 35.3% (6/17). ORR of PTCL-NOS, ENKTL, AITL, ALCL were 62.5% (5/8), 60% (3/5), 0 (0/3), 100% (1/1); CR rate were 37.5%, 40%, 0, 100%, respectively. At a median follow-up of 6.1months, median PFS, DOR and OS of the whole cohort was 2.9, 3.1 months, and not reached (6-month OS rate 68.9%), respectively. Patients with ENKTL enjoyed a relatively longer median PFS (4.7 months). Conclusions ATG-010 plus GemOx regimen showed a manageable safety profile, and favorable activity with impressive CR rate in refractory pts, potentially offering a new therapeutic option for heavily pretreated pts with refractory PTCL or ENKTL. Disclosures Lou: Antengene Therapeutics Ltd.: Current Employment. Fei: Antengene Therapeutics Ltd.: Current Employment. Wang: Antengene Therapeutics Ltd.: Current Employment. Lynch: Antengene Therapeutics Ltd.: Current Employment.

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