scholarly journals Frontline Brentuximab Vedotin Plus Cyclophosphamide, Doxorubicin and Prednisone in Patients with Peripheral T-Cell Lymphoma with Less Than 10% CD30 Expression (SGN35-032, Trial in Progress)

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1401-1401
Author(s):  
Deepa Jagadeesh ◽  
Scott Knowles ◽  
Steven M. Horwitz
Keyword(s):  
T Cell ◽  
Research Funding ◽  
Response Rate ◽  
Cell Lymphoma ◽  
Brentuximab Vedotin ◽  
T Cell Lymphoma ◽  
Efficacy And Safety ◽  
Time To Event ◽  
Peripheral T Cell Lymphoma ◽  
Secondary Endpoints

Abstract Background Brentuximab vedotin (BV) was the first antibody-drug conjugate to be approved in multiple cancer types (Gauzy-Lazo 2020). The combination of a CD30-directed monoclonal antibody, a protease-cleavable linker, and the microtubule-disrupting agent monomethyl auristatin E drives the anticancer activity of BV by inducing CD30-targeted cell cycle arrest and apoptosis as well as the bystander effect on adjacent cells (Sutherland 2006, Hansen 2016, Schönberger 2018). In the ECHELON-2 phase 3 clinical trial, BV, cyclophosphamide, doxorubicin, and prednisone (A+CHP) showed efficacy in patients with peripheral T-cell lymphoma (PTCL) across a range of CD30 expression levels, including the lowest eligible level of 10% by immunohistochemistry when compared with patients treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) (Advani 2019). It is hypothesized that A+CHP will demonstrate efficacy in PTCL with <10% CD30 expression because i) clinical responses to BV have occurred in patients with PTCL, cutaneous T-cell lymphoma, or B-cell lymphoma with low (<10%) and undetectable CD30 expression (Jagadeesh 2019) and ii) CD30 expression levels were not predictive of A+CHP responses in non-systemic anaplastic large cell lymphoma (sALCL) (Advani 2019). Study Design and Methods SGN35-032 is a dual-cohort, open-label, multicenter, phase 2 clinical trial (NCT04569032) designed to evaluate the efficacy and safety of A+CHP in patients with non-sALCL PTCL and CD30 expression of <10% on tumor cells. Up to approximately 40 patients will be enrolled in each of the CD30-negative (expression <1%) and the CD30-low (expression ≥1% to <10%) cohorts. Patients will be enrolled based on local results but only patients with CD30 expression <10% per central confirmation will be analyzed for the primary and secondary endpoints. Patients will receive 21-day cycles of A+CHP for 6-8 cycles. Key inclusion criteria include adults with newly diagnosed PTCL, excluding sALCL, per the World Health Organization 2016 classification; CD30 expression <10% by local assessment; and fluorodeoxyglucose-avid disease by positron emission tomography (PET) and measurable disease of at least 1.5 cm by computed tomography (CT), as assessed by the site radiologist. Patients with previous exposure to BV or doxorubicin will not be eligible. The primary endpoint of this trial is objective response rate (ORR) per blinded independent central review (BICR) using the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Secondary endpoints include ORR by BICR using the modified Lugano criteria (Cheson 2014), complete response rate, progression-free survival (PFS), and duration of response per BICR using the Revised Response Criteria for Malignant Lymphoma (Cheson 2007), overall survival, and safety and tolerability. A PET scan is required at baseline, after Cycle 4, and after the completion of study treatment. Follow-up restaging CT scans will be performed over the next 2 years. In both the CD30-negative and the CD30-low cohorts, efficacy and safety endpoints will be summarized using descriptive statistics to describe continuous variables by cohort. Time-to-event endpoints, such as PFS, will be estimated using Kaplan-Meier (KM) methodology and KM plots will be presented. Medians for time-to-event analyses (e.g., median PFS) will be presented and two-sided 95% confidence intervals will be calculated using the log-log transformation method. Enrollment is planned for 15 US sites and 32 sites across the Czech Republic, France, Italy, and the UK. Disclosures Knowles: Seagen Inc.: Current Employment. Horwitz: ADC Therapeutics, Affimed, Aileron, Celgene, Daiichi Sankyo, Forty Seven, Inc., Kyowa Hakko Kirin, Millennium /Takeda, Seattle Genetics, Trillium Therapeutics, and Verastem/SecuraBio.: Consultancy, Research Funding; Affimed: Research Funding; Aileron: Research Funding; Acrotech Biopharma, Affimed, ADC Therapeutics, Astex, Merck, Portola Pharma, C4 Therapeutics, Celgene, Janssen, Kura Oncology, Kyowa Hakko Kirin, Myeloid Therapeutics, ONO Pharmaceuticals, Seattle Genetics, Shoreline Biosciences, Inc, Takeda, Trillium Th: Consultancy; Celgene: Research Funding; C4 Therapeutics: Consultancy; Crispr Therapeutics: Research Funding; Daiichi Sankyo: Research Funding; Forty Seven, Inc.: Research Funding; Kura Oncology: Consultancy; Kyowa Hakko Kirin: Consultancy, Research Funding; Millennium/Takeda: Research Funding; Myeloid Therapeutics: Consultancy; ONO Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Research Funding; Secura Bio: Consultancy; Shoreline Biosciences, Inc.: Consultancy; Takeda: Consultancy; Trillium Therapeutics: Consultancy, Research Funding; Tubulis: Consultancy; Verastem/Securabio: Research Funding.

Trial-in-Progress: Frontline Brentuximab Vedotin and CHP (A+CHP) in Patients with Peripheral T-Cell Lymphoma with Less Than 10% CD30 Expression

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 30-30
Author(s):  
Deepa Jagadeesh ◽  
Robert B. Sims ◽  
Steven M. Horwitz
Keyword(s):  
T Cell ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Large Cell ◽  
Brentuximab Vedotin ◽  
T Cell Lymphoma ◽  
Peripheral T Cell Lymphoma ◽  
Advisory Committees ◽  
Kaplan Meier ◽  
Secondary Endpoints

Background In the ECHELON-2 phase 3 clinical trial, brentuximab vedotin, cyclophosphamide, doxorubicin, and prednisone (A+CHP) showed clinically meaningful and statistically significant efficacy in patients with peripheral T-cell lymphoma (PTCL) across a range of CD30 expression levels, including the lowest eligible level of 10% by IHC. In addition to the ECHELON-2 study, response data are available from an additional 344 subjects with CD30-expressing PTCL and other large-cell lymphomas (including angioimmunoblastic T-cell lymphoma and peripheral T-cell lymphoma-NOS) who had been treated in studies with brentuximab vedotin as a single agent or in combination with chemotherapy, in both frontline and relapsed/refractory settings. Among these 344 subjects, 184 had tumors with CD30 expression <10% by local assessment, including 83/184 with undetectable CD30 by immunohistochemistry (CD30=0). Responses to brentuximab vedotin have been observed at all levels of CD30 expression, including in tumors with undetectable CD30 levels (Advani 2019; Horwitz 2019). It is hypothesized that A+CHP will demonstrate efficacy in subjects with PTCL and CD30 expression <10% because: i) brentuximab vedotin has shown activity in lymphomas with low CD30 expression; and ii) the activity of CHP chemotherapy in PTCL is unrelated to CD30 expression. This study will include subjects with PTCL subtypes other than systemic anaplastic large cell lymphoma (sALCL). Study Design and Methods This is a dual-cohort, open-label, multicenter, phase 2 clinical trial designed to evaluate the efficacy and safety of A+CHP in subjects with non-sALCL PTCL and CD30 expression <10% on tumor cells. Enrollment will be based on CD30 expression per local lab assessment. Subjects will be assigned to 1 of 2 cohorts based on CD30 expression; up to approximately 40 subjects will be enrolled in the CD30 negative (expression <1%) cohort and approximately 40 subjects will be enrolled in the CD30 positive (expression ≥1% to <10%) cohort. An archived tumor biopsy specimen will be submitted to a central pathology lab for confirmation of CD30 expression. Only subjects with CD30 expression <10% per central confirmation will be analyzed for the primary and secondary endpoints. Subjects will receive 21-day cycles of A+CHP for a target of 6-8 cycles. The primary endpoint of this trial is objective response rate (ORR) per blinded independent central review (BICR). Key secondary endpoints include CR and PFS per BICR and overall survival. Key inclusion criteria include the following: subjects aged 18 years and older with newly diagnosed PTCL, excluding sALCL, per the WHO 2016 classification; CD30 expression <10% by local assessment; and fluorodeoxyglucose-avid disease by PET and measurable disease of at least 1.5 cm by CT, as assessed by the site radiologist. Lymphoma response and progression will be assessed by BICR using Revised Response Criteria for Malignant Lymphoma and modified Lugano criteria. A CT scan will be performed at the time of suspected clinical progression. Subsequent restage assessments (CT scans only) will be performed according to the calendar, relative to the first dose of study treatment, to ensure that tumor progression is uniformly assessed between the treatment arms. Efficacy and safety endpoints will be summarized with descriptive statistics by cohort, with the CD30 negative cohort and the CD30 positive cohort. The summary of overall (CD30 negative and positive cohort combined) may be presented as appropriate. Descriptive statistics (mean, median, standard deviation, minimum, and maximum) will be used to describe continuous variables. Time-to-event endpoints, such as PFS, will be estimated using Kaplan-Meier methodology and Kaplan-Meier plots will be presented. Medians for time-to-event analyses (eg, median PFS), will be presented and two-sided 95% confidence intervals will be calculated using the log-log transformation method. The trial will have sites open in the US and multiple countries in Europe, with enrollment planning to begin in September 2020. Disclosures Jagadeesh: Verastem: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; MEI Pharma: Research Funding; Debiopharm Group: Research Funding; Regeneron: Research Funding. Sims:Seattle Genetics, Inc.: Current Employment, Current equity holder in publicly-traded company, Other: Travel expenses. Horwitz:ASTEX: Consultancy; Millenium/Takeda: Consultancy, Research Funding; Corvus: Consultancy; Innate Pharma: Consultancy; Mundipharma: Consultancy; Seattle Genetics: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; Forty Seven: Consultancy, Research Funding; Infinity/Verastem: Research Funding; Celgene: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Aileron: Consultancy, Research Funding; ADCT Therapeutics: Consultancy, Research Funding; Janssen: Consultancy; Myeloid Therapeutics: Consultancy; Verastem: Consultancy, Research Funding; Vividion Therapeutics: Consultancy; Affirmed: Consultancy; Kura Oncology: Consultancy; Miragen: Consultancy; Kyowa Hakka Kirin: Consultancy, Research Funding; Beigene: Consultancy; C4 Therapeutics: Consultancy; Daiichi Sankyo: Research Funding; Portola: Consultancy, Research Funding.

scholarly journals CEOP/IVE/GDP Alternating Regimen Compared with CEOP As the First-Line Therapy for Newly Diagnosed Patients with Peripheral T-Cell Lymphoma: Results from a Phase 2, Multi-Center, Randomized, Controlled Clinical Trial

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1556-1556 ◽  
Author(s):  
Mingci Cai ◽  
Shu Cheng ◽  
Wang Xin ◽  
Jianda Hu ◽  
Yongping Song ◽  
...  
Keyword(s):  
T Cell ◽  
Response Rate ◽  
Cell Lymphoma ◽  
Study Groups ◽  
T Cell Lymphoma ◽  
Phase 2 ◽  
Newly Diagnosed ◽  
Efficacy And Safety ◽  
Peripheral T Cell Lymphoma ◽  
Randomized Controlled

Background Cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) or CHOP-like chemotherapy is widely used for treatment of peripheral T-cell lymphoma (PTCL). Given the poor response to CHOP-based regimens and the potential anti-lymphoma activity by alternating chemotherapy in PTCL, we conducted a phase 2, multi-center, randomized, controlled trial, comparing the efficacy and safety of CEOP/IVE/GDP alternating regimen with CEOP in a Chinese cohort of newly diagnosed patients with PTCL. Methods The primary endpoint of the study was the complete response rate (CRR). Patients with newly diagnosed PTCL, except for anaplastic large cell lymphoma (ALCL)- anaplastic lymphoma kinase (ALK) positive, were 1:1 randomly assigned. Patients in the CEOP/IVE/GDP group received intravenous cyclophosphamide 750 mg/m², epirubicin 70 mg/m², and vincristine 1.4 mg/m² (up to a maximum of 2 mg) on day 1, and oral prednisone 60 mg/m2 (up to a maximum of 100 mg) on day 1-5 every 21 days, at the 1st and 4th cycle with CEOP. Intravenous ifosfamide 2000 mg/m2 on day 1-3, epirubicin 70 mg/m2 on day 1, and etoposide 100 mg/m2 on day 1-4 every 21 days, at the 2nd and 5th cycle with IVE. Intravenous gemcitabine 1000 mg/m² on day 1, and 8, cisplatin 25 mg/m² on day 1-3, and dexamethasone 40mg on day 1-4 every 21 days, at the 3rd and 6th cycle with GDP, for a total of 6 cycles. Patients in the CEOP group received standard CEOP regimen every 21 days for 6 cycles. Analysis of efficacy and safety was of the intent-to-treat population. The study was registered with ClinicalTrials.gov, number NCT02533700. Findings Between Sep 22, 2015 and Sep 23, 2018, 102 patients were randomly assigned to two treatment groups: 51 each to the CEOP/IVE/GDP and the CEOP group. One patient was excluded because of the change of diagnosis and 3 patients withdrew informed consent before treatment in both study groups. 49 patients in the CEOP/IVE/GDP group and 49 patients in the CEOP group were included into efficacy and safety analysis as intent-to-treatment population. CRR at the end of treatment (EOT) in the CEOP/IVE/GDP group was similar as the CEOP group (36.7% vs. 32.7%, OR 0.84, 95% CI 0.36-1.88; p=0.835), while overall response rate (ORR) at EOT was higher in the CEOP/IVE/GDP group (73.5% vs. 51.0%, OR 0.38, 95% CI 0.17-0.86; p=0.037). There was no difference in median progression-free survival (15.4 months [95% CI 9.8-21.1] vs 10.7 months [4.5-16.8]; HR 0.73, 95% CI 0.45-1.18; p=0.20) or overall survival (24.3 months [95% CI 17.0-31.6] vs 21.9 months [7.5-36.2]; HR 0.69, 95% CI 0.41-1.17; p=0.17) between the CEOP/IVE/GDP and the CEOP group. Grade 3-4 hematological and non-hematological adverse events were similar between two study groups. Interpretation CEOP/IVE/GDP regimen showed similar CRR at EOT as CEOP regimen in PTCL. Nevertheless, CEOP/IVE/GDP increased ORR at EOT and could potentially bridge more patients to hematopoietic stem cell transplantation. Disclosures No relevant conflicts of interest to declare.

scholarly journals Salvage Therapy with Brentuximab-Vedotin and Bendamustine for Patients with Relapsed/Refractory T Cell Lymphoma. a Multicenter and Retrospective Study

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 620-620
Author(s):  
Krimo Bouabdallah ◽  
Raphaëlle Aubrais ◽  
Loïc Chartier ◽  
Charles Herbaux ◽  
Anne Banos ◽  
...  
Keyword(s):  
Retrospective Study ◽  
T Cell ◽  
Salvage Therapy ◽  
Research Funding ◽  
Response Rate ◽  
Cell Lymphoma ◽  
Multivariable Analysis ◽  
Brentuximab Vedotin ◽  
T Cell Lymphoma ◽  
Hematologic Toxicity

Abstract Methods : This multicentric retrospective study aimed to evaluate the efficacy and the safety of the combination of BBV in patients with non-cutaneous R/R PTCL among 21 LYSA centers in France and Belgium. The primary objective was to evaluate the best overall response rate (ORR) (complete response (CR) and partial response (PR)). Secondary objectives were progression free survival (PFS), overall survival (OS), duration of response (DoR), impact of transplantation on outcome, and safety. Patients treated between January 2013 and October 2020 were reviewed and all the data were collected through an electronic questionnaire sent to all the physicians. Results : Eighty two patients with R/R PTCL (40 angioimmunoblastic lymphoma (AITL), 2 T-cell lymphoma with TFH phenotype ,13 PTCL not otherwise specified (PTCL NOS), 5 Alk+ anaplastic large cell lymphoma (ALCL), 17 Alk- ALCL, , 1 Extranodal NK-/T-cell lymphoma, 3 Enteropathy-associated T-cell lymphoma (EATL), 1 subcutaneous panniculitis) were included. Median age at beginning of BBV was 60 years, most of patients were male (61%), had advanced stage (88%) and an IPI ≥ 2 (79%). Half of patients were refractory to their last treatment. Median number of prior regimens was 1 (range 1 to 6). The best ORR was 71%, with 51% of patients in CR. In multivariable analysis, only the relapse status after the last regimen (relapse vs refractory) was associated with ORR, relapsed patients having a better ORR (83% vs 57% in refractory patients, p=.014, OR=3.70 (95%CI:1.3-10.5)). Median DoR was 15.4 months in patients with CR but differed significantly whether patients were transplanted or not (Not reached vs 8.4 months, p=.0055). Twenty-two patients (30% of patients ≤ 70 years of age) were transplanted (6 autologous and 16 allogenic). With a median follow-up of 9 months, the median PFS and OS were 8.3 and 26.3 months respectively. In multivariable analysis, only 2 factors had a significant impact on PFS and OS: best response (CR/PR vs SD/PD with a median PFS of 17.4 vs 1.9 months, p<.0001, and a median OS Not Reached vs 5,9 months, p<.0001) and transplantation (for patients in CR, median PFS was Not Reached in transplanted patients vs 13.1 months; p=.0410, and median OS was Not Reached vs 34, 6 months; p=.0304) (Fig1). Histological subgroups was also significantly associated with PFS (p=.012) but not with OS (p=.26) in multivariable analysis. Patients with PTCL NOS/Other subtypes had worse PFS than patients with TFH subtypes (HR=2.89 (95%CI: 1.4-5.8), p=.0029). Interestingly the CD30 status (positive vs negative) had no impact on ORR or survival. Fifty-nine percent of patients experienced a grade 3 to 4 adverse event which was mainly hematologic toxicity. Treatment had to be stopped in 11% of patients. Conclusion: To the best of our knowledge, this is the first study reporting on the combination of BBV in the treatment of R/R PTCL in such a large cohort. The results are very encouraging with a high response rate, long DoR in responding patients and a very good outcome. Furthermore, patients in CR who are eligible for transplant have the best outcome, making this combination a good candidate as salvage therapy before transplant consolidation in these high-risk lymphomas with limited treatment options. Figure 1 Figure 1. Disclosures Bouabdallah: Kite/Gilead: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Herbaux: Takeda: Honoraria, Research Funding; Janssen: Honoraria; Roche: Honoraria; Abbvie: Honoraria, Research Funding. Brice: MSD: Research Funding; Amgen: Other: Travel/accommodations/expenses; Roche: Other: Travel/accommodations/expenses; Takeda: Research Funding. Sibon: Abbvie: Consultancy; Janssen: Consultancy; Roche: Consultancy; iQone: Consultancy; Takeda: Consultancy. Laribi: AstraZeneca: Other: Personal Fees; AbbVie: Other: Personal Fees, Research Funding; IQONE: Other: Personal Fees; Astellas Phama, Inc.: Other: Personal Fees; BeiGene: Other: Personal Fees; Takeda: Other: Personal Fees, Research Funding; Novartis: Other: Personal Fees, Research Funding; Le Mans Hospital: Research Funding; Jansen: Research Funding. Damaj: roche: Consultancy, Honoraria; takeda: Consultancy, Honoraria. OffLabel Disclosure: Brentuximab Vedotin and Bendamustine

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

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

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

Purpose Romidepsin is a structurally unique, potent class 1 selective histone deacetylase inhibitor. The primary objective of this international, pivotal, single-arm, phase II trial was to confirm the efficacy of romidepsin in patients with relapsed or refractory peripheral T-cell lymphoma (PTCL). Patients and Methods Patients who were refractory to at least one prior systemic therapy or for whom at least one prior systemic therapy failed received romidepsin at 14 mg/m2 as a 4-hour intravenous infusion on days 1, 8, and 15 every 28 days. The primary end point was the rate of complete response/unconfirmed complete response (CR/CRu) as assessed by an independent review committee. Results Of the 131 patients enrolled, 130 had histologically confirmed PTCL by central review. The median number of prior systemic therapies was two (range, one to eight). The objective response rate was 25% (33 of 130), including 15% (19 of 130) with CR/CRu. Patient characteristics, prior stem-cell transplantation, number or type of prior therapies, or response to last prior therapy did not have an impact on response rate. The median duration of response was 17 months, with the longest response ongoing at 34+ months. Of the 19 patients who achieved CR/CRu, 17 (89%) had not experienced disease progression at a median follow-up of 13.4 months. The most common grade ≥ 3 adverse events were thrombocytopenia (24%), neutropenia (20%), and infections (all types, 19%). Conclusion Single-agent romidepsin induced complete and durable responses with manageable toxicity in patients with relapsed or refractory PTCL across all major PTCL subtypes, regardless of the number or type of prior therapies. Results led to US Food and Drug Administration approval of romidepsin in this indication.

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