Final Results of a Phase 2 NCI Multicenter Study of Romidepsin in Patients with Relapsed Peripheral T-Cell Lymphoma (PTCL).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1657-1657 ◽  
Author(s):  
Richard Piekarz ◽  
John Wright ◽  
Robin Frye ◽  
Steven L Allen ◽  
David Joske ◽  
...  
Keyword(s):  
T Cell ◽  
Median Duration ◽  
Multicenter Study ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Hdac Inhibitors ◽  
T Cell Lymphoma ◽  
Phase 2 ◽  
Duration Of Response ◽  
Grade 3

Abstract Abstract 1657 Poster Board I-683 Background The histone deacetylase (HDAC) inhibitors are a class of epigenetic agents undergoing clinical testing. HDAC inhibitors modulate expression of genes involved in cell cycle regulation, leading to induction of differentiation or apoptosis. Romidepsin, a novel pan-HDAC inhibitor, has previously demonstrated activity as a single agent in patients (pts) with cutaneous T-cell lymphoma (CTCL) in two phase 2 studies. Aims To evaluate the efficacy and tolerability of romidepsin in the treatment of advanced PTCL and as an exploratory endpoint, to examine the molecular effects of romidepsin in both PTCL and CTCL. Methods This Phase 2, open-label, multi-arm, multicenter study enrolled 46 PTCL pts from the NCI and 9 extramural sites. CTCL pts were also enrolled in this study. This study is now closed to accrual. Pts with relapsed or refractory PTCL who had received at least one prior standard chemotherapy regimen were eligible. Pts received romidepsin 14 mg/m2 as a 4-hr infusion on days 1, 8 and 15 every 28 days. Responses were assessed using elements of the IWG criteria and RECIST, as appropriate, for pts with lymph node involvement and extranodal disease. Results 46 pts (24 [52%] men and 22 [48%] women) with a mean age of 59 (range: 28 to 84) years were treated with romidepsin. 32 pts received ≥ 2 cycles of therapy. Mean number of prior therapies was 4.8 (range 1 to 14). Objective disease response rates (ORR) are summarized in the table. The mean number of cycles of treatment was 6.8 (range 1-47) and the overall median duration of response was 9.0 months (range 1.8 months to 5.8 yrs) for all pts. The median duration of response for the 5 pts who achieved CR was 6.0 months (range 2.8 months to 5.8 yrs).The most frequent drug-related AEs (all grades, all cycles) were generally mild and included: nausea (74%; 9% ≥grade 3), fatigue (72%; 20% ≥grade 3), decreased platelets (72%; 35% ≥grade 3), cardiovascular/general-other (72%; 0% ≥grade 3) and decreased AGC (65%; 43% ≥grade 3). One death, in a pt with significant cardiovascular disease who had achieved a CR, was considered possibly related to treatment. Conclusions This study demonstrates tolerability and durable clinical benefit (ORR of 33% and median duration of response of 9.0 months) of romidepsin in pts with recurrent or refractory PTCL. Based on these promising results, a Phase 2B protocol investigating romidepsin in pts with relapsed or refractory PTCL is ongoing at multiple international centers. Disclosures Kirschbaum: Gloucester Pharmaceuticals: Consultancy.

Results of a Phase 2 NCI Multicenter Study of Romidepsin in Patients with Relapsed Peripheral T-Cell Lymphoma (PTCL).

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1567-1567 ◽  
Author(s):  
Richard Piekarz ◽  
John Wright ◽  
Robin Frye ◽  
Steven L. Allen ◽  
Michael Craig ◽  
...  
Keyword(s):  
T Cell ◽  
Median Duration ◽  
Multicenter Study ◽  
Cell Lymphoma ◽  
Hdac Inhibitors ◽  
Clinical Results ◽  
T Cell Lymphoma ◽  
Phase 2 ◽  
Duration Of Response ◽  
Grade 3

Abstract Background: The histone deacetylase (HDAC) inhibitors are a class of epigenetic agents undergoing clinical testing. HDAC inhibitors modulate expression of genes involved in cell cycle regulation, leading to induction of differentiation or apoptosis. Romidepsin, a novel, HDAC inhibitor, has previously demonstrated activity as a single agent in patients (pts) with T-cell lymphoma in a phase 1 NCI study. Aims: To evaluate the efficacy and tolerability of romidepsin in the treatment of advanced PTCL and as an exploratory endpoint, to examine the molecular effects of romidepsin in both PTCL and cutaneous T-cell lymphoma (CTCL). Methods: This Phase 2, open-label, multi-arm, multicenter study enrolled 43 PTCL pts from the NCI and 9 extramural sites. CTCL pts were also enrolled in this study. The clinical results for pts with PTCL are presented here; the clinical results for the pts with CTCL and the biomarker analyses for both PTCL and CTCL are presented elsewhere. This study is now closed to accrual. Pts with relapsed or refractory PTCL or primary cutaneous anaplastic large cell lymphoma were eligible. Pts received romidepsin 14 mg/m2 as a 4-hr infusion on days 1, 8 and 15 every 28 days. Responses were assessed using elements of the IWG criteria and RECIST, as appropriate, for pts with lymph node involvement and extranodal disease. Results: 43 pts (23[53%] men and 20 [47%] women) with a mean age of 58.1 (range: 27 to 84) years were treated with romidepsin. 31 pts received ≥ 2 cycles of therapy. Mean number of prior therapies was 3.9 (range 1 to 12). Objective disease response rates (ORR) are summarized in the table. The mean number of cycles of treatment was 6.8 (range 1–37) and the overall median duration of response was 8.3 months (range 1.6 months to 4.8+ yrs) for all pts. The median duration of response for the 7 pts who achieved CR was 8.5 months (range 4.6 months to 4.8+yrs). The most frequent drug-related AEs (all grades, all cycles) were generally mild and included: nausea (86%; 0% ≥grade 3), fatigue (79%; 0% ≥grade 3), decreased platelets (70%; 7% ≥grade 3), and decreased AGC (63%; 5% ≥grade 3). One death, in a pt with significant cardiovascular disease who had achieved a CR, was considered possibly related to treatment. Conclusions: This study demonstrates tolerability and durable clinical benefit (ORR of 39% and median duration of response of 8.3 months) of romidepsin in pts with recurrent or refractory PTCL. Based on these promising results, a Phase 2B protocol investigating romidepsin in pts with progressive or relapsed PTCL is ongoing at multiple international centers. All Pts N=43 Pts ≥ 2 cycles N=31 ORR (CR+PR), n (%) 17 (39%) 17 (55%) PR, n (%) 10 (23%) 10 (32%) CR, n (%) 7 (16%) 7 (23%)

Final Results of a Phase II Trial of Belinostat (PXD101) in Patients with Recurrent or Refractory Peripheral or Cutaneous T-Cell Lymphoma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 920-920 ◽  
Author(s):  
Brad Pohlman ◽  
Ranjana Advani ◽  
Madeleine Duvic ◽  
Kenneth B. Hymes ◽  
Tanin Intragumtornchai ◽  
...  
Keyword(s):  
T Cell ◽  
Median Duration ◽  
Cell Lymphoma ◽  
Stage Iv ◽  
T Cell Lymphoma ◽  
Cutaneous Lesions ◽  
Stage Iv Disease ◽  
Duration Of Response ◽  
Post Infusion ◽  
Grade 3

Abstract Abstract 920 Background: Belinostat is a pan-HDAC inhibitor of the hydroxamate chemical class that is well-tolerated and has shown clinical activity. Methods: Open label, multicenter trial enrolling patients (pts) with peripheral T-cell lymphoma (PTCL) or cutaneous T-cell lymphoma (CTCL) who failed ≥ 1 prior systemic therapy. Pts received 1000 mg/m2 IV belinostat over 30 min on days 1 to 5 of a 3-wk cycle. Primary endpoint was objective response (OR) assessed by IWG criteria for PTCL and by SWAT (cutaneous lesions) and IWG criteria (non-cutaneous lesions) for CTCL. Pruritus in pts with CTCL was assessed using a 10-point scale; relief defined as reduction of pruritus score of ≥ 3 points in pts with baseline score ≥ 3. ECGs were monitored and reviewed centrally (pre-/ post-infusion ECGs on all treatment days in cycle 1, and pre-/ post-infusion ECGs on day 1 of subsequent cycles) to evaluate potential cardiac toxicity. Results: The study enrolled a total of 53 treated pts, including 20 and 29 evaluable pts with a diagnosis of PTCL and CTCL, respectively. The 20 pts with PTCL [10 PTCL-unspecified (PTCL-U), 3 anaplastic large cell lymphoma (ALCL), 3 angioimmunoblastic TCL (AITL), 3 NK/T-cell lymphoma, and 1 subcutaneous panniculitis-like TCL (SPTCL)] had received a median of 3 prior systemic therapies (range 1 – 10), and 40 % of them had stage IV disease. 5/20 (25%) PTCL pts responded with 2 CR (both in patients with PTCL-U) and 3 PR (PTCL-U, AITL, ALCL). The 5 responding pts had a median duration of response of 159+ days (range 1 – 504+). Additionally, SD was observed in 5 pts (2 PTCL-U, 2 NK/T-cell, and 1 ALCL) with median duration of SD of 109+ days (range 80 -185+). The 29 pts with CTCL [15 mycosis fungoides (MF), 7 Sezary syndrome (SS), 5 non MF/SS, 2 unclassified] had received a median of 1 prior skin directed therapies (range 0 – 4) and 3 prior systemic therapies (range 1 – 9), and 55 % of them had stage IV disease. 4/29 (14%) CTCL pts responded with 2 CR (ALCL, MF) and 2 PR (MF, SS). The 4 responding pts had a median duration of response of 273 days (range 48 - 469+). Importantly, time to response was short with a median of 16 days (range 14-35). In addition, SD was observed in 17 pts (10 MF, 3 SS, 2 non MF/SS, 2 unclassified) with current duration of up to 127 days. Pruritus relief (score reduction ≥ 3) was seen in 7 of 14 pts with significant baseline pruritis. Median time to pruritus relief was also short, 16 days (range 7-45). Hematological toxicity was minimal without any grade 4 events (shift from baseline) and only one pt each experiencing grade 3 neutropenia and grade 3 thrombocytopenia, respectively. No grade 3 QTcF prolongation was detected in more than 700 ECGs. Four grade 3/4 drug-related AEs were reported: pruritis, rash/erythema, edema, and adynamic ileus. Conclusions: Belinostat monotherapy is safe, well tolerated, and efficacious in pts with recurrent/refractory T-cell lymphoma with durable remissions in both CTCL and PTCL. These results are the basis for a pivotal study with belinostat monotherapy in pts with PTCL. Disclosures: Advani: Seattle Genetics, Inc.: Research Funding. Duvic:Topotarget: research support for conduct of clinical trial. Fagerberg:TopoTarget A/S: Employment, Equity Ownership. Foss:Eisai : Speakers Bureau.

Final Clinical Results of a Phase 2 NCI Multicenter Study of Romidepsin in Recurrent Cutaneous T-Cell Lymphoma (Molecular Analyses Included).

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1568-1568 ◽  
Author(s):  
Susan Bates ◽  
Richard Piekarz ◽  
John Wright ◽  
Robin Frye ◽  
William Douglas Figg ◽  
...  
Keyword(s):  
T Cell ◽  
Multicenter Study ◽  
Drug Exposure ◽  
Cell Lymphoma ◽  
Clinical Results ◽  
T Cell Lymphoma ◽  
Cutaneous T Cell Lymphoma ◽  
Phase 2 ◽  
Molecular Analyses ◽  
Grade 3

Abstract Background: Responses to the novel HDAC inhibitor romidepsin were observed in patients (pts) with T-cell lymphoma in a phase 1 NCI trial. Aims: To evaluate the efficacy and tolerability of romidepsin in the treatment of advanced cutaneous T-cell lymphoma (CTCL). As an exploratory endpoint, to examine the molecular effects of romidepsin in both CTCL and peripheral T-cell lymphoma (PTCL). Methods: This Phase 2, open-label, multi-arm, multicenter study enrolled 71 CTCL pts from the NCI and 9 extramural sites. PTCL pts were also enrolled. Clinical results for pts with CTCL and biomarker analyses for both PTCL and CTCL are presented here; clinical results for the PTCL pts are presented elsewhere. This study is now closed to accrual. Pts with recurrent CTCL (Stages IA-IVB) received romidepsin at 14 mg/m2 as a 4-hr infusion on days 1, 8 and 15 q 28 days. Responses were assessed using a composite endpoint that evaluated overall changes in skin (modified Physicians Global Assessment), lymph nodes, extranodal visceral lesions and abnormal circulating T-cells. Molecular endpoints evaluated in NCI pts were: histone acetylation in peripheral blood mononuclear cells (PBMCs); MDR-1 gene expression in PBMCs and in biopsy samples; and blood fetal hemoglobin levels. Results: 71 pts (48 men and 23 women) with a mean age of 56 yrs (range 28–84) were enrolled and received romidepsin; 63 pts received ≥2 cycles of therapy. Mean number of prior therapies was 3.4 (range 1–10). Objective disease response rates (ORR) are presented in the table. Overall disease control (CR+PR+SD90) was 62% in all pts and 70% in pts who received ≥2 cycles. Target skin lesions were followed and changes were generally similar to overall skin changes. Median duration of response (DOR) was 11 months (mo) and the maximum DOR as of data cut-off was 5.5+ yrs. The most frequent drug-related AEs (all grades, all cycles) were generally mild, including nausea (82%; 4% ≥grade 3), fatigue (73%; 14% ≥ grade 3), electrocardiogram T-wave amplitude decreased (69%, 0% ≥grade 3); hemoglobin decreased (59%, 9% ≥grade 3), and platelet count decreased (59%; 13% ≥grade 3). Six pts died within 30 days of study drug administration: 2 after salvage chemotherapy, 1 with ARDS due to PD, 2 with infection, and 1 of unknown cause; 2 of these deaths were considered possibly related to treatment. An increase in all biomarkers measured was observed, although not in all pts. Correlation between global histone H3 acetylation (AcH3) at the 24-hr time point and Cmax, AUC, and clearance was observed (r = 0.37, 0.36, and −0.44, respectively, p = 0.03). Pts with major responses were more likely to have higher levels of AcH3 at 24 hr. Conclusions: This study demonstrates tolerability and durable clinical benefit (ORR of 35% and median DOR of 11 mo in all pts) of romidepsin in pts with recurrent CTCL. Significant responses were observed at all stages of disease, including an ORR of 32% in all pts with stage ≥IIB and 20% in all pts with stage IV. Time to response was rapid, within 2 mo in most pts, and responses were durable, >6 mo in most pts. Molecular analyses confirmed that romidepsin inhibits its target deacetylases in pts. Increases were not observed in all pts, perhaps reflecting, in part, variable drug exposure or variable response to HDAC inhibition. Correlation of global acetylation with PK parameters suggests that increased drug exposure results in increased global acetylation. All Pts N=71 Pts ≥ 2 cycles N=63 ORR (CR+PR), n (%) 25 (35%) 25 (40%) PR, n (%) 21 (30%) 21 (33%) CR, n (%) 4 (6%) 4 (6%) SD90, n(%) 19 (27%) 19 (30%) Overall disease control (CR+PR+ SD90) 44 (62%) 44 (70%) DOR 11 (1+ mo, 5.5+ yrs) 11 (1+ mo, 5.5+ yrs) OR for pts with stage ≥ IIB, n (%) 20/62 (32%) 20/55 (36%) SD90= stable disease for ≥90 days

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 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.

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 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 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.

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.

Phase II Trial of Proteasome Inhibitor Bortezomib in Patients With Relapsed or Refractory Cutaneous T-Cell Lymphoma

2007 ◽  
Vol 25 (27) ◽  
pp. 4293-4297 ◽  
Author(s):  
Pier Luigi Zinzani ◽  
Gerardo Musuraca ◽  
Monica Tani ◽  
Vittorio Stefoni ◽  
Enrica Marchi ◽  
...  
Keyword(s):  
T Cell ◽  
Proteasome Inhibitor ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Sensory Neuropathy ◽  
T Cell Lymphoma ◽  
Cutaneous T Cell Lymphoma ◽  
Skin Involvement ◽  
Common Grade ◽  
Grade 3

Purpose To determine the antitumor activity of the proteasome inhibitor bortezomib in patients with cutaneous T-cell lymphoma (CTCL) or peripheral T-cell lymphoma unspecified (PTCLU) with isolated skin involvement. Patients and Methods From May 2005 to June 2006 at our institute, we treated patients with previously pretreated CTCL or PTCLU using bortezomib as a single agent, at a dose of 1.3 mg/m2 intravenously on days 1, 4, 8, and 11, every 21 days for a total of six cycles. Results Fifteen patients were registered, of whom 12 (10 CTCL, all mycosis fungoides, and two PTCLU with isolated skin involvement) were assessable. The overall response rate was 67%, with two (17%) complete remissions and six (50%) partial remissions. The remaining four patients had disease progression. Histologically, the responder patients were seven with CTCL and one with PTCLU with isolated skin involvement. All responses were durable, lasting from 7 to 14 or more months. Overall, the drug was well tolerated, with no grade 4 toxicity. The most common grade 3 toxicities were neutropenia (n = 2), thrombocytopenia (n = 2), and sensory neuropathy (n = 2). Conclusion This study suggests that bortezomib was well tolerated and has significant single-agent activity in patients with cutaneous T-cell lymphoma.

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