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Ranjana H Advani - One of the best experts on this subject based on the ideXlab platform.
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ipilimumab nivolumab and brentuximab Vedotin combination therapies in patients with relapsed or refractory hodgkin lymphoma phase 1 results of an open label multicentre phase 1 2 trial
The Lancet Haematology, 2020Co-Authors: Catherine Diefenbach, Ranjana H Advani, Fangxin Hong, Richard F Ambinder, Jonathon B Cohen, Michael J Robertson, Kevin A David, Timothy S Fenske, Stefan K BartaAbstract:Summary Background Recognising that the immune suppressive microenvironment promotes tumour growth in Hodgkin lymphoma, we hypothesised that activating immunity might augment the activity of targeted chemotherapy. We evaluated the safety and activity of combinations of brentuximab Vedotin with nivolumab or ipilimumab, or both in patients with relapsed or refractory Hodgkin lymphoma. Methods In this multicentre, open-label, phase 1/2 trial, patients with relapsed or refractory Hodgkin lymphoma aged 18 years or older who had relapsed after at least one line of therapy, with an Eastern Cooperative Oncology Group performance status of 2 or lower, and adequate organ and marrow function, with no pulmonary dysfunction were eligible for inclusion. Phase 1 primary objectives were to determine the maximum tolerated dose and dose limiting toxicities of brentuximab Vedotin combined with ipilimumab (ipilimumab group), nivolumab (nivolumab group), or both (triplet therapy group) using a 3 + 3 dose escalation design with expansion cohorts. During the dose escalation phase, patients were enrolled sequentially into one of six cohorts: in the ipilimumab group fixed brentuximab Vedotin 1·8 mg/kg with ipilimumab 1 mg/kg (cohort A) or 3 mg/kg (cohort B); in the nivolumab group fixed nivolumab 3 mg/kg with brentuximab Vedotin 1·2 mg/kg (cohort D) or 1·8 mg/kg (cohort E); and in the triplet therapy group fixed nivolumab 3 mg/kg and ipilimumab 1 mg/kg with brentuximab Vedotin 1·2 mg/kg (cohort G) or 1·8 mg/kg (cohort H). Additional patients were enrolled in the expansion phase at the same doses of cohorts B, E, and H. All drugs were given intravenously; brentuximab Vedotin and nivolumab were given every 3 weeks, ipilimumab was given every 6 weeks in the ipilimumab group and every 12 weeks in the triplet therapy group. All eligible and treated patients were included in the analysis. This phase 1/2 study is registered with ClinicalTrials.gov , NCT01896999 . The phase 2, randomised portion of the trial is still enrolling. Findings Between March 7, 2014, and Dec 28, 2017, 64 patients were enrolled; two patients in the ipilimumab group and one patient in the nivolumab group were excluded due to ineligibility after enrolment and 61 were evaluable. A total of six dose limiting toxicities were reported in four patients, and the doses used in cohorts B, E, and H were established as maximum tolerated doses and patients were subsequently enrolled onto expansion cohorts (C, F, and I) with these schedules. There were ten (43%) grade 3–4 treatment related adverse events in the ipilimumab group, three (16%) in the nivolumab group, and 11 (50%) in the triplet therapy group including: eight (13%) of 64 patients reporting rash, and colitis, gastritis, pancreatitis and arthritis, and diabetic ketoacidosis each occurring in one (2%) patient. There were two (3%) treatment related deaths, one in the nivolumab group and one in the triplet therapy group. The overall response rate was 76% (95% CI 53–92) in the ipilimumab group, 89% (65–99) in the nivolumab group, and 82% (60–95) in the triplet therapy group, and the complete response rate was 57% (95% CI 34–78%) in the ipilimumab group, 61% (36–83%) in the nivolumab group, and 73% (50–89%) in the triplet therapy group. With a median follow-up of 2·6 years (IQR 1·8–2·9) in the ipilimumab group, 2·4 years (2·2–2·6) in the nivolumab group, and 1·7 years (1·6–1·9) in the triplet therapy group, median progression-free survival is 1·2 years (95% CI 1·7–not reached) in the ipilimumab group, but was not reached in the other two treatment groups. Median overall survival has not been reached in any of the groups. Interpretation There are clear differences in activity and toxicity of the three combination regimens. The tolerability and preliminary activity for the two most active regimens, brentuximab Vedotin with nivolumab and the triplet therapy, are being compared in a randomised phase 2 trial ( NCT01896999 ). Funding Eastern Cooperative Oncology Group–American College of Radiology Imaging Network and the National Cancer Institute of the National Institutes of Health.
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response to brentuximab Vedotin by cd30 expression results from five trials in ptcl ctcl and b cell lymphomas
Journal of Clinical Oncology, 2019Co-Authors: Deepa Jagadeesh, Ranjana H Advani, Nancy L. Bartlett, Steven M Horwitz, Madeleine Duvic, Eric D Jacobsen, Ashish Gautam, Shangbang Rao, M Onsum, M FanaleAbstract:7543Background: Brentuximab Vedotin (BV), an antibody-drug conjugate targeting CD30, has been evaluated in multiple trials in patients (pts) with peripheral T-cell lymphoma (PTCL), cutaneous T-cell...
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response to a chp by cd30 expression in the echelon 2 trial
Journal of Clinical Oncology, 2019Co-Authors: Ranjana H Advani, Nancy L. Bartlett, Steven M Horwitz, Won Seog Kim, Tatyana Feldman, Herve Tilly, Swaminathan P Iyer, David Belada, Arpad Illes, Eric D JacobsenAbstract:7538Background: Brentuximab Vedotin (BV) is an antibody-drug conjugate that targets CD30. The ECHELON-2 (E-2) study demonstrated significantly longer progression-free and overall survival with BV p...
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five year outcomes for frontline brentuximab Vedotin with chp for cd30 expressing peripheral t cell lymphomas
Blood, 2018Co-Authors: Michelle A. Fanale, Ranjana H Advani, Barbara Pro, Nancy L. Bartlett, Steven M Horwitz, Andres Forerotorres, Timothy M Illidge, Robert W Chen, Andrew Davies, Mayur UttarwarAbstract:This phase 1 study evaluated frontline brentuximab Vedotin in combination with cyclophosphamide, doxorubicin, and prednisone (BV+CHP; 6 cycles, then up to 10 cycles of brentuximab Vedotin monotherapy) in 26 patients with CD30+ peripheral T-cell lymphoma, including 19 with systemic anaplastic large cell lymphoma. All patients (100%) achieved an objective response, with a complete remission (CR) rate of 92%; none received a consolidative stem cell transplant. After a median observation period of 59.6 months (range, 4.6-66.0) from first dose, neither the median progression-free survival (PFS) nor the median overall survival (OS) was reached. No progression or death was observed beyond 35 months. The estimated 5-year PFS and OS rates were 52% and 80%, respectively. Eighteen of 19 patients (95%) with treatment-emergent peripheral neuropathy (PN) reported resolution or improvement of symptoms. Thirteen patients (50%) remained in remission at the end of the study, with PFS ranging from 37.8+ to 66.0+ months. Eight of these 13 patients received the maximum 16 cycles of study treatment. These final results demonstrate durable remissions in 50% of patients treated with frontline BV+CHP, suggesting a potentially curative treatment option for some patients. This trial was registered at www.clinicaltrials.gov as #NCT01309789.
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five year results of brentuximab Vedotin in patients with relapsed or refractory systemic anaplastic large cell lymphoma
Blood, 2017Co-Authors: Barbara Pro, Jeffrey Matous, Ranjana H Advani, Michelle A. Fanale, Nancy L. Bartlett, Timothy M Illidge, Radhakrishnan Ramchandren, P Brice, Joseph D Rosenblatt, Joseph M. ConnorsAbstract:This pivotal phase 2 study evaluated the safety and efficacy of brentuximab Vedotin in patients with relapsed or refractory (R/R) systemic anaplastic large cell lymphoma (ALCL). After a median observation period of approximately 6 years from first treatment, we examined the durability of remission, progression-free survival (PFS), overall survival (OS), and safety outcomes of patients treated on this trial. Among all enrolled patients (n = 58), no progressions were observed beyond 40 months, and median OS was not reached. Patients with a complete response (CR), as assessed by the investigator (38 of 58, 66%), continued to demonstrate improved outcomes with neither median OS nor PFS reached. Of the 38 CR patients, 16 received a consolidative stem cell transplant (SCT) with median PFS not reached. Among patients who were on-study and in remission at study closure, 16 patients had not received any new treatment after single-agent brentuximab Vedotin other than consolidative SCT. Among this subset of 16 patients, 8 received SCT, and the remaining 8 patients (14% of all enrolled patients) remained in sustained remission without consolidative SCT or any new anticancer therapy. Thirty-three patients experienced peripheral neuropathy, among whom, the majority (30 of 33, 91%) had experienced resolution or improvement at their last assessment. These final results, which demonstrated a high rate of peripheral neuropathy resolution, and durable remissions in a subset of patients with relapsed or refractory systemic ALCL, provide evidence that single-agent brentuximab Vedotin may be a potentially curative treatment option. This trial was registered at www.clinicaltrials.gov as #NCT00866047.
Nancy L. Bartlett - One of the best experts on this subject based on the ideXlab platform.
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polatuzumab Vedotin in combination with immunochemotherapy in patients with previously untreated diffuse large b cell lymphoma an open label non randomised phase 1b 2 study
Lancet Oncology, 2019Co-Authors: Herve Tilly, Andy I Chen, Nancy L. Bartlett, Franck Morschhauser, A Mehta, Gilles Salles, Corinne Haioun, Javier Munoz, Kathryn S Kolibaba, Mark YanAbstract:Summary Background Polatuzumab Vedotin, an antibody–drug conjugate targeting the CD79b component of the B-cell receptor, has demonstrated activity as a single agent and in combination with rituximab in relapsed or refractory diffuse large B-cell lymphoma. In this study, we evaluated the safety and preliminary activity of polatuzumab Vedotin in combination with rituximab or obinutuzumab and cyclophosphamide, doxorubicin, and prednisone (CHP) in patients with previously untreated diffuse large B-cell lymphoma. Methods This was an open-label, non-randomised study composed of a phase 1b dose escalation and a phase 2 dose expansion at 11 hospitals and health centres in the USA and France. Patients aged 18 years or older with B-cell non-Hodgkin lymphoma were eligible. Exclusion criteria included peripheral neuropathy with grade greater than 1, major surgery within 4 weeks before enrolment, known CNS involvement of lymphoma, and uncontrolled heart disease. Phase 1b dose escalation had a three-plus-three design and established the recommended phase 2 dose. Phase 2 expansion evaluated the recommended phase 2 dose of polatuzumab Vedotin in patients with newly diagnosed diffuse large B-cell lymphoma with an International Prognostic Index (IPI) of 2–5. Patients received cyclophosphamide 750 mg/m2 on day 1 intravenously, doxorubicin 50 mg/m2 on day 1 intravenously, and prednisone 100 mg once daily on days 1–5 of each 21-day cycle orally (CHP), plus either rituximab 375 mg/m2 intravenously on day 1 of each cycle (R-CHP) or obinutuzumab 1000 mg intravenously on days 1, 8, and 15 of cycle 1 and on day 1 of the following cycles (G-CHP). Polatuzumab Vedotin was administered on day 2 of cycles 1 and 2, and on day 1 of the following cycles at 1·0–2·4 mg/kg during the escalation phase and at the recommended phase 2 dose during the expansion phase. Treatment could last six or eight cycles, depending on investigator preference. The primary endpoints of the study were safety and tolerability, and determination of the maximum tolerated dose (or recommended phase 2 dose) of polatuzumab Vedotin. All endpoints were analysed per protocol in the safety evaluable population, defined as all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT01992653. Findings Between Dec 4, 2013, and July 26, 2016, 85 patients were enrolled. 82 patients were included in the safety and activity evaluable populations, 25 in phase 1b and 57 in phase 2. In light of information from other studies using polatuzumab Vedotin reported during this study, in which the safety profile associated with exposure to polatuzumab Vedotin at doses higher than 1·8 mg/kg every 3 weeks was not outweighed by any clinical benefit, the recommended phase 2 dose was set to 1·8 mg/kg in the R-CHP cohort and no higher doses were explored in this study. 66 patients with newly diagnosed diffuse large B-cell lymphoma received the polatuzumab Vedotin recommended phase 2 dose (45 R-CHP; 21 G-CHP). In 66 patients with diffuse large B-cell lymphoma who received the recommended phase 2 dose, the most common adverse events of grade 3 or worse were neutropenia (20 [30%]), febrile neutropenia (12 [18%]), and thrombocytopenia (six [9%]). Among the 70 patients (any histology) who received the recommended phase 2 dose, 19 (27%) had grade 1 peripheral neuropathy, eight (11%) grade 2, and two (3%) grade 3. Four deaths were reported during follow-up: two treatment-related (one complication of atrial fibrillation and one septic shock) and two due to disease progression. As of the cutoff date of Dec 29, 2017, median follow-up time was 21·5 months (IQR 16·7–24·3) for the untreated diffuse large B-cell lymphoma cohort treated at the polatuzumab Vedotin recommended phase 2 dose. 59 (89%) patients achieved an overall response at end of treatment (51 [77%] patients had a complete response, and eight [12%] patients had a partial response). Interpretation The safety of incorporating polatuzumab Vedotin to R-CHP or G-CHP was as expected and managable. Preliminary clinical activity in newly diagnosed diffuse large B-cell lymphoma seems promising and encouraged a phase 3 trial comparing polatuzumab Vedotin with R-CHP to R-CHOP. Funding F Hoffmann-La Roche/Genentech.
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response to a chp by cd30 expression in the echelon 2 trial
Journal of Clinical Oncology, 2019Co-Authors: Ranjana H Advani, Nancy L. Bartlett, Steven M Horwitz, Won Seog Kim, Tatyana Feldman, Herve Tilly, Swaminathan P Iyer, David Belada, Arpad Illes, Eric D JacobsenAbstract:7538Background: Brentuximab Vedotin (BV) is an antibody-drug conjugate that targets CD30. The ECHELON-2 (E-2) study demonstrated significantly longer progression-free and overall survival with BV p...
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response to brentuximab Vedotin by cd30 expression results from five trials in ptcl ctcl and b cell lymphomas
Journal of Clinical Oncology, 2019Co-Authors: Deepa Jagadeesh, Ranjana H Advani, Nancy L. Bartlett, Steven M Horwitz, Madeleine Duvic, Eric D Jacobsen, Ashish Gautam, Shangbang Rao, M Onsum, M FanaleAbstract:7543Background: Brentuximab Vedotin (BV), an antibody-drug conjugate targeting CD30, has been evaluated in multiple trials in patients (pts) with peripheral T-cell lymphoma (PTCL), cutaneous T-cell...
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five year outcomes for frontline brentuximab Vedotin with chp for cd30 expressing peripheral t cell lymphomas
Blood, 2018Co-Authors: Michelle A. Fanale, Ranjana H Advani, Barbara Pro, Nancy L. Bartlett, Steven M Horwitz, Andres Forerotorres, Timothy M Illidge, Robert W Chen, Andrew Davies, Mayur UttarwarAbstract:This phase 1 study evaluated frontline brentuximab Vedotin in combination with cyclophosphamide, doxorubicin, and prednisone (BV+CHP; 6 cycles, then up to 10 cycles of brentuximab Vedotin monotherapy) in 26 patients with CD30+ peripheral T-cell lymphoma, including 19 with systemic anaplastic large cell lymphoma. All patients (100%) achieved an objective response, with a complete remission (CR) rate of 92%; none received a consolidative stem cell transplant. After a median observation period of 59.6 months (range, 4.6-66.0) from first dose, neither the median progression-free survival (PFS) nor the median overall survival (OS) was reached. No progression or death was observed beyond 35 months. The estimated 5-year PFS and OS rates were 52% and 80%, respectively. Eighteen of 19 patients (95%) with treatment-emergent peripheral neuropathy (PN) reported resolution or improvement of symptoms. Thirteen patients (50%) remained in remission at the end of the study, with PFS ranging from 37.8+ to 66.0+ months. Eight of these 13 patients received the maximum 16 cycles of study treatment. These final results demonstrate durable remissions in 50% of patients treated with frontline BV+CHP, suggesting a potentially curative treatment option for some patients. This trial was registered at www.clinicaltrials.gov as #NCT01309789.
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five year results of brentuximab Vedotin in patients with relapsed or refractory systemic anaplastic large cell lymphoma
Blood, 2017Co-Authors: Barbara Pro, Jeffrey Matous, Ranjana H Advani, Michelle A. Fanale, Nancy L. Bartlett, Timothy M Illidge, Radhakrishnan Ramchandren, P Brice, Joseph D Rosenblatt, Joseph M. ConnorsAbstract:This pivotal phase 2 study evaluated the safety and efficacy of brentuximab Vedotin in patients with relapsed or refractory (R/R) systemic anaplastic large cell lymphoma (ALCL). After a median observation period of approximately 6 years from first treatment, we examined the durability of remission, progression-free survival (PFS), overall survival (OS), and safety outcomes of patients treated on this trial. Among all enrolled patients (n = 58), no progressions were observed beyond 40 months, and median OS was not reached. Patients with a complete response (CR), as assessed by the investigator (38 of 58, 66%), continued to demonstrate improved outcomes with neither median OS nor PFS reached. Of the 38 CR patients, 16 received a consolidative stem cell transplant (SCT) with median PFS not reached. Among patients who were on-study and in remission at study closure, 16 patients had not received any new treatment after single-agent brentuximab Vedotin other than consolidative SCT. Among this subset of 16 patients, 8 received SCT, and the remaining 8 patients (14% of all enrolled patients) remained in sustained remission without consolidative SCT or any new anticancer therapy. Thirty-three patients experienced peripheral neuropathy, among whom, the majority (30 of 33, 91%) had experienced resolution or improvement at their last assessment. These final results, which demonstrated a high rate of peripheral neuropathy resolution, and durable remissions in a subset of patients with relapsed or refractory systemic ALCL, provide evidence that single-agent brentuximab Vedotin may be a potentially curative treatment option. This trial was registered at www.clinicaltrials.gov as #NCT00866047.
Anas Younes - One of the best experts on this subject based on the ideXlab platform.
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brentuximab Vedotin with chemotherapy for stage iii or iv hodgkin s lymphoma
The New England Journal of Medicine, 2017Co-Authors: Joseph M. Connors, Anas Younes, Stephen M. Ansell, Andrea Gallamini, Won Seog Kim, Arpad Illes, Wojciech Jurczak, David J Straus, Sergey Alekseev, Marco PicardiAbstract:Abstract Background Brentuximab Vedotin is an anti-CD30 antibody–drug conjugate that has been approved for relapsed and refractory Hodgkin’s lymphoma. Methods We conducted an open-label, multicenter, randomized phase 3 trial involving patients with previously untreated stage III or IV classic Hodgkin’s lymphoma, in which 664 were assigned to receive brentuximab Vedotin, doxorubicin, vinblastine, and dacarbazine (A+AVD) and 670 were assigned to receive doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). The primary end point was modified progression-free survival (the time to progression, death, or noncomplete response and use of subsequent anticancer therapy) as adjudicated by an independent review committee. The key secondary end point was overall survival. Results At a median follow-up of 24.6 months, 2-year modified progression-free survival rates in the A+AVD and ABVD groups were 82.1% (95% confidence interval [CI], 78.8 to 85.0) and 77.2% (95% CI, 73.7 to 80.4), respectively, a difference of...
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brentuximab Vedotin in patients aged 60 years or older with relapsed or refractory cd30 positive lymphomas a retrospective evaluation of safety and efficacy
Leukemia & Lymphoma, 2014Co-Authors: Ajay K Gopal, Jeffrey Matous, Anas Younes, Nancy L. Bartlett, Andres Forerotorres, Robert T Chen, Scott E Smith, Jonathan W Friedberg, Andrei R Shustov, Jasmine ZainAbstract:AbstractOlder adults constitute a significant proportion of the cancer population, but are underrepresented in clinical trials. We conducted a retrospective analysis of the safety and efficacy of brentuximab Vedotin in adults ≥ 60 years with relapsed CD30-positive lymphomas. Baseline characteristics and safety data were compared for older (median age 66) and younger patients (< 60 years, median age 32). Exposure to brentuximab Vedotin was comparable. Older patients had more preexisting conditions (median 11 vs. 6) and were receiving more concomitant medications (median 7.5 vs. 4). Higher rates of anemia (30% vs. 10%), peripheral sensory neuropathy (60% vs. 46%), fatigue (58% vs. 43%) and adverse events ≥ grade 3 (70% vs. 56%) occurred in older patients. Objective response rates were 56% and 100% in older patients with Hodgkin lymphoma and systemic anaplastic large cell lymphoma, respectively. With appropriate monitoring, brentuximab Vedotin may represent a meaningful clinical option for older patients wit...
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Brentuximab Vedotin combined with ABVD or AVD for patients with newly diagnosed Hodgkin's lymphoma: a phase 1, open-label, dose-escalation study
The Lancet. Oncology, 2013Co-Authors: Anas Younes, Michelle A. Fanale, Joseph M. Connors, Steven I. Park, Megan M. O'meara, Naomi N. H. Hunder, Dirk Huebner, Stephen M. AnsellAbstract:Summary Background Roughly 70–80% of patients with advanced stage Hodgkin's lymphoma are cured with various first-line and second-line treatments, including ABVD, BEACOPP, and stem-cell transplantation. Brentuximab Vedotin has shown significant clinical activity, with a manageable safety profile, in patients with relapsed or refractory Hodgkin's lymphoma. We aimed to assess the safety and early clinical efficacy of this drug as first-line treatment in combination with standard or modified-standard treatment in patients with previously untreated Hodgkin's lymphoma. Methods We did a phase 1, open-label, dose-escalation safety study comparing brentuximab Vedotin in combination with standard (ABVD) or a modified-standard (AVD) treatment. Patients were enrolled into the groups sequentially. Main entry criteria were newly diagnosed, treatment-naive, CD30-positive patients with Hodgkin's lymphoma who had histologically confirmed stage IIA bulky disease or stage IIB–IV disease and an Eastern Cooperative Oncology Group performance status of two or less. Patients received doses of 0·6, 0·9, or 1·2 mg/kg brentuximab Vedotin by intravenous infusion every 2 weeks with either ABVD (25 mg/m 2 doxorubicin, 10 units/m 2 bleomycin, 6 mg/m 2 vinblastine, and 375 mg/m 2 dacarbazine) or AVD (ABVD modified regimen without the inclusion of bleomycin) for up to six cycles. Our primary objectives were to assess the safety profile and establish the maximum tolerated dose (MTD) of brentuximab Vedotin in combination with ABVD and AVD. The safety profile and MTD was assessed for the safety population. The study has completed and the final analysis is presented. This study was registered with ClinicalTrials.gov, number NCT01060904. Findings Between Jan 29, 2010, and Sept 17, 2012, 51 patients were enrolled and received at least one dose of brentuximab Vedotin. The maximum tolerated dose of brentuximab Vedotin when combined with ABVD or AVD was not exceeded at 1·2 mg/kg. 21 (95%) of 22 patients given brentuximab Vedotin and ABVD achieved complete remission, as did 24 (96%) of 25 patients given brentuximab Vedotin and AVD. Adverse events were generally grade 1 or 2; however, an unacceptable number of patients in the brentuximab Vedotin and ABVD groups had pulmonary toxic effects (11 [44%] of 25), which exceeded the historical incidence for ABVD alone. No patients experienced pulmonary toxic effects when treated with brentuximab Vedotin plus AVD. The most common grade 3 or worse events were neutropenia (20 [80%] of 25 patients in the brentuximab Vedotin and ABVD group vs 20 [77%] of 26 patients in the brentuximab Vedotin and AVD group), anaemia (five [20%] vs three [12%]), febrile neutropenia (five [20%] vs two [8%]), pulmonary toxic effects (six [24%] vs 0), syncope (three [12%] vs two [8%]), dyspnoea (three [12%] vs one [4%]), pulmonary embolism (three [12%] vs 0), fatigue (one [4%] each), and leucopenia (one [4%] each). Serious events occured in 41% of all patients (14 [56%] in the brentuximab Vedotin and ABVD group and seven [27%] in the brentuximab Vedotin and AVD group). Serious events occurring in 10% of patients or more overall were febrile neutropenia (four [16%] in the brentuximab Vedotin and ABVD group vs two [8%] in the brentuximab Vedotin and AVD group), and, in the brentuximab Vedotin and ABVD group only, pulmonary toxic effects (six [24%]). Interpretation Brentuximab Vedotin should not be given with bleomycin in general or specifically as first-line therapy for patients with treatment naive, advanced stage Hodgkin's lymphoma. 1·2 mg/kg brentuximab Vedotin combined with AVD given every 2 weeks was generally well tolerated by patients. At present, a phase 3 trial comparing brentuximab Vedotin plus AVD to ABVD alone is ongoing (ClinicalTrials.gov, number NCT01712490) and will formally assess whether brentuximab Vedotin plus AVD might redefine therapy in treatment-naive patients with Hodgkin's lymphoma. Funding Seattle Genetics Inc and Takeda Pharmaceuticals International Co.
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phase 3 study of brentuximab Vedotin plus doxorubicin vinblastine and dacarbazine a avd versus doxorubicin bleomycin vinblastine and dacarbazine abvd as front line treatment for advanced classical hodgkin lymphoma hl echelon 1 study
Journal of Clinical Oncology, 2013Co-Authors: Stephen M. Ansell, Anas Younes, Joseph M. Connors, Nancy L. Bartlett, Andrea Gallamini, Won Seog Kim, Jonathan W Friedberg, Tatyana Feldman, Graham P Collins, Jingyuan WangAbstract:TPS8612 Background: Brentuximab Vedotin, a CD30-targeted antibody-drug conjugate, has conditional approval in Europe for relapsed/refractory (RR) CD30-positive HL following autologous stem cell transplant (ASCT) or following ≥2 prior therapies when ASCT or multi-agent chemotherapy is not a treatment option. ABVD, a common front-line regimen for advanced HL, achieves complete response (CR) rates of 70–80%. However, 10–20% of patients (pts) are refractory to front-line treatment and up to 35% relapse after front-line multi-modality therapy. In pts with relapsed HL post-ASCT, single-agent brentuximab Vedotin yields an objective response rate of 75% (CR, 33%; Chen ASH 2012). In a phase 1 study in treatment-naive HL pts, A+AVD was associated with manageable toxicity and a CR rate of 96%; brentuximab Vedotin + ABVD was contraindicated due to pulmonary toxicity (Ansell ASH 2012). We hypothesized that substituting bleomycin with brentuximab Vedotin would eliminate bleomycin-associated pulmonary toxicity and impro...
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results of a pivotal phase ii study of brentuximab Vedotin for patients with relapsed or refractory hodgkin s lymphoma
Journal of Clinical Oncology, 2012Co-Authors: Anas Younes, Stephen M. Ansell, Nancy L. Bartlett, Ajay K Gopal, Radhakrishnan Ramchandren, Scott E Smith, Joseph D Rosenblatt, Kerry J Savage, Bruce D Cheson, Sven De VosAbstract:Purpose Brentuximab Vedotin is an antibody-drug conjugate (ADC) that selectively delivers monomethyl auristatin E, an antimicrotubule agent, into CD30-expressing cells. In phase I studies, brentuximab Vedotin demonstrated significant activity with a favorable safety profile in patients with relapsed or refractory CD30-positive lymphomas. Patients and Methods In this multinational, open-label, phase II study, the efficacy and safety of brentuximab Vedotin were evaluated in patients with relapsed or refractory Hodgkin’s lymphoma (HL) after autologous stem-cell transplantation (auto-SCT). Patients had histologically documented CD30-positive HL by central pathology review. A total of 102 patients were treated with brentuximab Vedotin 1.8 mg/kg by intravenous infusion every 3 weeks. In the absence of disease progression or prohibitive toxicity, patients received a maximum of 16 cycles. The primary end point was the overall objective response rate (ORR) determined by an independent radiology review facility. Results The ORR was 75% with complete remission (CR) in 34% of patients. The median progression-free survival time for all patients was 5.6 months, and the median duration of response for those in CR was 20.5 months. After a median observation time of more than 1.5 years, 31 patients were alive and free of documented progressive disease. The most common treatment-related adverse events were peripheral sensory neuropathy, nausea, fatigue, neutropenia, and diarrhea. Conclusion The ADC brentuximab Vedotin was associated with manageable toxicity and induced objective responses in 75% of patients with relapsed or refractory HL after auto-SCT. Durable CRs approaching 2 years were observed, supporting study in earlier lines of therapy. J Clin Oncol 30:2183-2189. © 2012 by American Society of Clinical Oncology
Michelle A. Fanale - One of the best experts on this subject based on the ideXlab platform.
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five year outcomes for frontline brentuximab Vedotin with chp for cd30 expressing peripheral t cell lymphomas
Blood, 2018Co-Authors: Michelle A. Fanale, Ranjana H Advani, Barbara Pro, Nancy L. Bartlett, Steven M Horwitz, Andres Forerotorres, Timothy M Illidge, Robert W Chen, Andrew Davies, Mayur UttarwarAbstract:This phase 1 study evaluated frontline brentuximab Vedotin in combination with cyclophosphamide, doxorubicin, and prednisone (BV+CHP; 6 cycles, then up to 10 cycles of brentuximab Vedotin monotherapy) in 26 patients with CD30+ peripheral T-cell lymphoma, including 19 with systemic anaplastic large cell lymphoma. All patients (100%) achieved an objective response, with a complete remission (CR) rate of 92%; none received a consolidative stem cell transplant. After a median observation period of 59.6 months (range, 4.6-66.0) from first dose, neither the median progression-free survival (PFS) nor the median overall survival (OS) was reached. No progression or death was observed beyond 35 months. The estimated 5-year PFS and OS rates were 52% and 80%, respectively. Eighteen of 19 patients (95%) with treatment-emergent peripheral neuropathy (PN) reported resolution or improvement of symptoms. Thirteen patients (50%) remained in remission at the end of the study, with PFS ranging from 37.8+ to 66.0+ months. Eight of these 13 patients received the maximum 16 cycles of study treatment. These final results demonstrate durable remissions in 50% of patients treated with frontline BV+CHP, suggesting a potentially curative treatment option for some patients. This trial was registered at www.clinicaltrials.gov as #NCT01309789.
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five year results of brentuximab Vedotin in patients with relapsed or refractory systemic anaplastic large cell lymphoma
Blood, 2017Co-Authors: Barbara Pro, Jeffrey Matous, Ranjana H Advani, Michelle A. Fanale, Nancy L. Bartlett, Timothy M Illidge, Radhakrishnan Ramchandren, P Brice, Joseph D Rosenblatt, Joseph M. ConnorsAbstract:This pivotal phase 2 study evaluated the safety and efficacy of brentuximab Vedotin in patients with relapsed or refractory (R/R) systemic anaplastic large cell lymphoma (ALCL). After a median observation period of approximately 6 years from first treatment, we examined the durability of remission, progression-free survival (PFS), overall survival (OS), and safety outcomes of patients treated on this trial. Among all enrolled patients (n = 58), no progressions were observed beyond 40 months, and median OS was not reached. Patients with a complete response (CR), as assessed by the investigator (38 of 58, 66%), continued to demonstrate improved outcomes with neither median OS nor PFS reached. Of the 38 CR patients, 16 received a consolidative stem cell transplant (SCT) with median PFS not reached. Among patients who were on-study and in remission at study closure, 16 patients had not received any new treatment after single-agent brentuximab Vedotin other than consolidative SCT. Among this subset of 16 patients, 8 received SCT, and the remaining 8 patients (14% of all enrolled patients) remained in sustained remission without consolidative SCT or any new anticancer therapy. Thirty-three patients experienced peripheral neuropathy, among whom, the majority (30 of 33, 91%) had experienced resolution or improvement at their last assessment. These final results, which demonstrated a high rate of peripheral neuropathy resolution, and durable remissions in a subset of patients with relapsed or refractory systemic ALCL, provide evidence that single-agent brentuximab Vedotin may be a potentially curative treatment option. This trial was registered at www.clinicaltrials.gov as #NCT00866047.
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brentuximab Vedotin in the front line treatment of patients with cd30 peripheral t cell lymphomas results of a phase i study
Journal of Clinical Oncology, 2014Co-Authors: Michelle A. Fanale, Ranjana H Advani, Dirk Huebner, Nancy L. Bartlett, Steven M Horwitz, Andres Forerotorres, Robert Chen, A G Davies, Timothy M Illidge, Dana A KennedyAbstract:Purpose Front-line treatment of peripheral T-cell lymphomas (PTCL) involves regimens such as cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) and results in a 5-year overall survival (OS) rate of less than 50%. This phase I open-label study evaluated the safety and activity of brentuximab Vedotin administered sequentially with CHOP or in combination with CHP (CHOP without vincristine) as front-line treatment in patients with CD30+ PTCL. Patients and Methods Patients received sequential treatment (once every 3 weeks) with brentuximab Vedotin 1.8 mg/kg (two cycles) followed by CHOP (six cycles) or brentuximab Vedotin 1.8 mg/kg plus CHP (BV+CHP) for six cycles (once every 3 weeks). Responders received single-agent brentuximab Vedotin for eight to 10 additional cycles (for a total of 16 cycles). The primary objective was assessment of safety; secondary end points included objective response rate, complete remission (CR) rate, progression-free survival rate (PFS), and OS. There were no prespecifie...
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brentuximab Vedotin in the front line treatment of patients with cd30 peripheral t cell lymphomas results of a phase i study
Journal of Clinical Oncology, 2014Co-Authors: Michelle A. Fanale, Ranjana H Advani, Barbara Pro, Nancy L. Bartlett, Steven M Horwitz, Andres Forerotorres, Timothy M Illidge, Robert W Chen, Andrew Davies, Dirk HuebnerAbstract:Purpose Front-line treatment of peripheral T-cell lymphomas (PTCL) involves regimens such as cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) and results in a 5-year overall survival (OS) rate of less than 50%. This phase I open-label study evaluated the safety and activity of brentuximab Vedotin administered sequentially with CHOP or in combination with CHP (CHOP without vincristine) as front-line treatment in patients with CD30(+) PTCL. Patients and methods Patients received sequential treatment (once every 3 weeks) with brentuximab Vedotin 1.8 mg/kg (two cycles) followed by CHOP (six cycles) or brentuximab Vedotin 1.8 mg/kg plus CHP (BV+CHP) for six cycles (once every 3 weeks). Responders received single-agent brentuximab Vedotin for eight to 10 additional cycles (for a total of 16 cycles). The primary objective was assessment of safety; secondary end points included objective response rate, complete remission (CR) rate, progression-free survival rate (PFS), and OS. There were no prespecified comparisons of the two treatment approaches. Results After sequential treatment, 11 (85%) of 13 patients achieved an objective response (CR rate, 62%; estimated 1-year PFS rate, 77%). Grade 3/4 adverse events occurred in eight (62%) of 13 patients. At the end of combination treatment, all patients (n = 26) achieved an objective response (CR rate, 88%; estimated 1-year PFS rate, 71%). All seven patients without anaplastic large-cell lymphoma achieved CR. Grade 3/4 adverse events (≥ 10%) in the combination-treatment group were febrile neutropenia (31%), neutropenia (23%), anemia (15%), and pulmonary embolism (12%). Conclusion Brentuximab Vedotin, administered sequentially with CHOP or in combination with CHP, had a manageable safety profile and exhibited substantial antitumor activity in newly diagnosed patients with CD30(+) PTCL. A randomized phase III trial is under way, comparing BV+CHP with CHOP (clinical trial No. NCT01777152).
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retreatment with brentuximab Vedotin in patients with cd30 positive hematologic malignancies
Journal of Hematology & Oncology, 2014Co-Authors: Nancy L. Bartlett, Jeffrey Matous, Ranjana H Advani, Michelle A. Fanale, Ajay K Gopal, Radhakrishnan Ramchandren, Robert T Chen, P Brice, Scott E Smith, Joseph D RosenblattAbstract:Background: Brentuximab Vedotin is a CD30-directed antibody-drug conjugate. Retreatment with brentuximab Vedotin monotherapy was investigated in patients with CD30-positive Hodgkin lymphoma (HL) or systemic anaplastic large cell lymphoma (ALCL) who relapsed after achieving complete or partial remission (CR or PR) with initial brentuximab Vedotin therapy in a previous study (ClinicalTrials.gov NCT00947856). Methods: Twenty-one patients with HL and 8 patients with systemic ALCL were retreated; 3 patients with systemic ALCL were retreated twice. Patients generally received brentuximab Vedotin 1.8 mg/kg intravenously approximately every 3 weeks over 30 minutes as an outpatient infusion. The primary objectives of this study were to assess safety and to estimate antitumor activity of brentuximab Vedotin retreatment. Results: The objective response rate was 60% (30% CR) in HL patients and 88% (63% CR) in systemic ALCL patients. The estimated median duration of response for patients with an objective response was 9.5 months (range, 0.0+ to 28.0+ months) at the time of study closure. Of the 19 patients with objective response, 7 patients had not had an event of disease progression or death at the time of study closure; duration of response for these patients ranged from 3.5 to 28 months. Of the 11 patients with CR, 45% had response durations of over 1 year. Adverse events (AEs) occurring in ≥25% of patients during the retreatment period were generally similar in type and frequency to those observed in the pivotal trials of brentuximab Vedotin monotherapy, with the exception of peripheral neuropathy, which is known to have a cumulative effect. Grade 3 or higher events were observed in 48% of patients; these were generally transient and managed by dose modifications or delays. Deaths due to AEs occurred in 3 HL patients; none were considered to be related to brentuximab Vedotin retreatment. Discussion: With the exception of a higher rate of peripheral motor neuropathy, retreatment with brentuximab Vedotin was associated with similar side effects seen in the pivotal trials. Conclusions: Retreatment with brentuximab Vedotin monotherapy is associated with response rates in 68% (39% CR) of patients with relapsed HL and systemic ALCL. Trial registration: United States registry and results database ClinicalTrials.gov NCT00947856.
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five year results of brentuximab Vedotin in patients with relapsed or refractory systemic anaplastic large cell lymphoma
Blood, 2017Co-Authors: Barbara Pro, Jeffrey Matous, Ranjana H Advani, Michelle A. Fanale, Nancy L. Bartlett, Timothy M Illidge, Radhakrishnan Ramchandren, P Brice, Joseph D Rosenblatt, Joseph M. ConnorsAbstract:This pivotal phase 2 study evaluated the safety and efficacy of brentuximab Vedotin in patients with relapsed or refractory (R/R) systemic anaplastic large cell lymphoma (ALCL). After a median observation period of approximately 6 years from first treatment, we examined the durability of remission, progression-free survival (PFS), overall survival (OS), and safety outcomes of patients treated on this trial. Among all enrolled patients (n = 58), no progressions were observed beyond 40 months, and median OS was not reached. Patients with a complete response (CR), as assessed by the investigator (38 of 58, 66%), continued to demonstrate improved outcomes with neither median OS nor PFS reached. Of the 38 CR patients, 16 received a consolidative stem cell transplant (SCT) with median PFS not reached. Among patients who were on-study and in remission at study closure, 16 patients had not received any new treatment after single-agent brentuximab Vedotin other than consolidative SCT. Among this subset of 16 patients, 8 received SCT, and the remaining 8 patients (14% of all enrolled patients) remained in sustained remission without consolidative SCT or any new anticancer therapy. Thirty-three patients experienced peripheral neuropathy, among whom, the majority (30 of 33, 91%) had experienced resolution or improvement at their last assessment. These final results, which demonstrated a high rate of peripheral neuropathy resolution, and durable remissions in a subset of patients with relapsed or refractory systemic ALCL, provide evidence that single-agent brentuximab Vedotin may be a potentially curative treatment option. This trial was registered at www.clinicaltrials.gov as #NCT00866047.
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brentuximab Vedotin with chemotherapy for stage iii or iv hodgkin s lymphoma
The New England Journal of Medicine, 2017Co-Authors: Joseph M. Connors, Anas Younes, Stephen M. Ansell, Andrea Gallamini, Won Seog Kim, Arpad Illes, Wojciech Jurczak, David J Straus, Sergey Alekseev, Marco PicardiAbstract:Abstract Background Brentuximab Vedotin is an anti-CD30 antibody–drug conjugate that has been approved for relapsed and refractory Hodgkin’s lymphoma. Methods We conducted an open-label, multicenter, randomized phase 3 trial involving patients with previously untreated stage III or IV classic Hodgkin’s lymphoma, in which 664 were assigned to receive brentuximab Vedotin, doxorubicin, vinblastine, and dacarbazine (A+AVD) and 670 were assigned to receive doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). The primary end point was modified progression-free survival (the time to progression, death, or noncomplete response and use of subsequent anticancer therapy) as adjudicated by an independent review committee. The key secondary end point was overall survival. Results At a median follow-up of 24.6 months, 2-year modified progression-free survival rates in the A+AVD and ABVD groups were 82.1% (95% confidence interval [CI], 78.8 to 85.0) and 77.2% (95% CI, 73.7 to 80.4), respectively, a difference of...
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five year survival and durability results of brentuximab Vedotin in patients with relapsed or refractory hodgkin lymphoma
Blood, 2016Co-Authors: Robert Chen, Joseph M. Connors, Stephen M. Ansell, Ajay K Gopal, Scott E Smith, Joseph D Rosenblatt, Kerry J Savage, Andreas Engert, Emily K Larsen, Dirk HuebnerAbstract:Presented here are the 5-year end-of-study results from the pivotal phase 2 trial of brentuximab Vedotin in patients with relapsed/refractory (R/R) Hodgkin lymphoma (HL) after failed hematopoietic autologous stem cell transplantation. At 5 years, the overall patient population (N = 102) had an estimated overall survival (OS) rate of 41% (95% confidence interval [CI]: 31-51) and progression-free survival (PFS) rate of 22% (95% CI: 13-31). Patients who achieved a complete response (CR) to brentuximab Vedotin (N = 34) had estimated OS and PFS rates of 64% (95% CI: 48-80%) and 52% (95% CI: 34-69%), respectively. The median OS and PFS were not reached in CR patients, with 13 patients (38% of all CR patients) remaining in follow-up and in remission at study closure. Of the 13 patients, 4 received consolidative hematopoietic allogeneic stem cell transplant, and 9 (9% of all enrolled patients) remain in sustained CR without receiving any further anticancer therapy after treatment with brentuximab Vedotin. Of the patients who experienced treatment-emergent peripheral neuropathy, 88% experienced either resolution (73%) or improvement (14%) in symptoms. These 5-year follow-up data demonstrate that a subset of patients with R/R HL who obtained CR with single-agent brentuximab Vedotin achieved long-term disease control and may potentially be cured. The trial was registered at www.clinicaltrials.gov as #NCT00848926.
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durable remissions in a pivotal phase 2 study of brentuximab Vedotin in relapsed or refractory hodgkin lymphoma
Blood, 2015Co-Authors: Ajay K Gopal, Joseph M. Connors, Stephen M. Ansell, Robert Chen, Scott E Smith, Joseph D Rosenblatt, Kerry J Savage, Andreas Engert, Emily K Larsen, Xuedong ChiAbstract:We present response and survival outcomes of a pivotal phase 2 trial of the antibody-drug conjugate brentuximab Vedotin in patients with relapsed/refractory Hodgkin lymphoma following autologous stem cell transplant (N = 102) after a median observation period of approximately 3 years. Median overall survival and progression-free survival were estimated at 40.5 months and 9.3 months, respectively. Improved outcomes were observed in patients who achieved a complete remission (CR) on brentuximab Vedotin, with estimated 3-year overall survival and progression-free survival rates of 73% (95% confidence interval [CI]: 57%, 88%) and 58% (95% CI: 41%, 76%), respectively, in this group (medians not reached). Of the 34 patients who obtained CR, 16 (47%) remain progression-free after a median of 53.3 months (range, 29.0 to 56.2 months) of observation; 12 patients remain progression-free without a consolidative allogeneic stem cell transplant. Younger age, good performance status, and lower disease burden at baseline were characteristic of patients who achieved a CR and were favorable prognostic factors for overall survival. These results suggest that a significant proportion of patients who respond to brentuximab Vedotin can achieve prolonged disease control. The trial was registered at www.clinicaltrials.gov as #NCT00848926.
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Brentuximab Vedotin combined with ABVD or AVD for patients with newly diagnosed Hodgkin's lymphoma: a phase 1, open-label, dose-escalation study
The Lancet. Oncology, 2013Co-Authors: Anas Younes, Michelle A. Fanale, Joseph M. Connors, Steven I. Park, Megan M. O'meara, Naomi N. H. Hunder, Dirk Huebner, Stephen M. AnsellAbstract:Summary Background Roughly 70–80% of patients with advanced stage Hodgkin's lymphoma are cured with various first-line and second-line treatments, including ABVD, BEACOPP, and stem-cell transplantation. Brentuximab Vedotin has shown significant clinical activity, with a manageable safety profile, in patients with relapsed or refractory Hodgkin's lymphoma. We aimed to assess the safety and early clinical efficacy of this drug as first-line treatment in combination with standard or modified-standard treatment in patients with previously untreated Hodgkin's lymphoma. Methods We did a phase 1, open-label, dose-escalation safety study comparing brentuximab Vedotin in combination with standard (ABVD) or a modified-standard (AVD) treatment. Patients were enrolled into the groups sequentially. Main entry criteria were newly diagnosed, treatment-naive, CD30-positive patients with Hodgkin's lymphoma who had histologically confirmed stage IIA bulky disease or stage IIB–IV disease and an Eastern Cooperative Oncology Group performance status of two or less. Patients received doses of 0·6, 0·9, or 1·2 mg/kg brentuximab Vedotin by intravenous infusion every 2 weeks with either ABVD (25 mg/m 2 doxorubicin, 10 units/m 2 bleomycin, 6 mg/m 2 vinblastine, and 375 mg/m 2 dacarbazine) or AVD (ABVD modified regimen without the inclusion of bleomycin) for up to six cycles. Our primary objectives were to assess the safety profile and establish the maximum tolerated dose (MTD) of brentuximab Vedotin in combination with ABVD and AVD. The safety profile and MTD was assessed for the safety population. The study has completed and the final analysis is presented. This study was registered with ClinicalTrials.gov, number NCT01060904. Findings Between Jan 29, 2010, and Sept 17, 2012, 51 patients were enrolled and received at least one dose of brentuximab Vedotin. The maximum tolerated dose of brentuximab Vedotin when combined with ABVD or AVD was not exceeded at 1·2 mg/kg. 21 (95%) of 22 patients given brentuximab Vedotin and ABVD achieved complete remission, as did 24 (96%) of 25 patients given brentuximab Vedotin and AVD. Adverse events were generally grade 1 or 2; however, an unacceptable number of patients in the brentuximab Vedotin and ABVD groups had pulmonary toxic effects (11 [44%] of 25), which exceeded the historical incidence for ABVD alone. No patients experienced pulmonary toxic effects when treated with brentuximab Vedotin plus AVD. The most common grade 3 or worse events were neutropenia (20 [80%] of 25 patients in the brentuximab Vedotin and ABVD group vs 20 [77%] of 26 patients in the brentuximab Vedotin and AVD group), anaemia (five [20%] vs three [12%]), febrile neutropenia (five [20%] vs two [8%]), pulmonary toxic effects (six [24%] vs 0), syncope (three [12%] vs two [8%]), dyspnoea (three [12%] vs one [4%]), pulmonary embolism (three [12%] vs 0), fatigue (one [4%] each), and leucopenia (one [4%] each). Serious events occured in 41% of all patients (14 [56%] in the brentuximab Vedotin and ABVD group and seven [27%] in the brentuximab Vedotin and AVD group). Serious events occurring in 10% of patients or more overall were febrile neutropenia (four [16%] in the brentuximab Vedotin and ABVD group vs two [8%] in the brentuximab Vedotin and AVD group), and, in the brentuximab Vedotin and ABVD group only, pulmonary toxic effects (six [24%]). Interpretation Brentuximab Vedotin should not be given with bleomycin in general or specifically as first-line therapy for patients with treatment naive, advanced stage Hodgkin's lymphoma. 1·2 mg/kg brentuximab Vedotin combined with AVD given every 2 weeks was generally well tolerated by patients. At present, a phase 3 trial comparing brentuximab Vedotin plus AVD to ABVD alone is ongoing (ClinicalTrials.gov, number NCT01712490) and will formally assess whether brentuximab Vedotin plus AVD might redefine therapy in treatment-naive patients with Hodgkin's lymphoma. Funding Seattle Genetics Inc and Takeda Pharmaceuticals International Co.
