Brentuximab Vedotin for Patients With Refractory Lymphomatoid Papulosis: An Analysis of Phase 2 Results.
ABSTRACT: Importance:Brentuximab vedotin is a monomethyl auristatin E-conjugated monoclonal antibody directed against CD30. It represents a potential treatment for the CD30+ lymphoproliferative disorder lymphomatoid papulosis (LyP), which currently has no approved treatment. Objective:To assess the efficacy and safety of brentuximab vedotin for the treatment of LyP. Design, Setting, and Participants:In this study conducted at The University of Texas MD Anderson Cancer Center from May 10, 2011, to March 31, 2017, a total of 12 patients with LyP received brentuximab vedotin. All patients were 18 years or older with a diagnosis of LyP and were also required to have scarring, more than 10 lesions, or active lesions on the face, hands, or feet. Nine patients were enrolled in a physician-initiated, open-label, single-center, phase 2 clinical trial of brentuximab vedotin for CD30+ cutaneous T-cell lymphomas and LyP from 2011 to 2013. Three patients were later treated outside of the trial from 2013 to 2017. Five patients continued to be followed up as of March 2017. Interventions:Intravenous brentuximab vedotin 1.8 mg/kg infused over 30 minutes every 21 days. Main Outcomes and Measures:The primary end point was the overall response rate. Complete response was defined as zero lesions, and partial response was defined as a 50% or greater reduction in lesion count from baseline. A relapse was defined as loss of partial response. Results:All 12 patients (8 men and 4 women; median age, 46 years) responded to brentuximab vedotin, and 7 exhibited a complete response. Time to response was 3 weeks in all patients. The median duration of response was 20 weeks (range, 6-103 weeks). For 5 patients who relapsed, the median time to relapse was 12 weeks (range, 6-41 weeks). One patient who relapsed was retreated and has remained in partial response for more than 23 months. Grade 1 to 2 neuropathy occurred in 10 patients but resolved in 5. Adverse events of grade 3 or higher were neutropenia (n?=?2) and dizziness/vertigo (n?=?1). Three patients withdrew owing to adverse events. Conclusions and Relevance:Brentuximab vedotin is effective in treating LyP (overall response rate, 100%; complete response rate, 58%), but its use should be reserved for patients with truly severe and refractory LyP. More work is needed to optimize its dosing to minimize adverse events, such as peripheral neuropathy. Trial Registration:clinicaltrials.gov Identifier: NCT01352520.
Project description:This phase 2, open-label, multicenter study evaluated the efficacy and safety of brentuximab vedotin, a CD30-directed antibody-drug conjugate, in relapsed/refractory CD30(+) non-Hodgkin lymphomas. The primary end point was objective response rate (ORR). Key secondary end points included safety, correlation of CD30 expression with response, response duration, and progression-free survival (PFS). Brentuximab vedotin 1.8 mg/kg was administered every 3 weeks until progression or unacceptable toxicity. This planned subset analysis included patients with peripheral T-cell lymphomas (PTCLs; n = 35), specifically angioimmunoblastic T-cell lymphoma (AITL; n = 13) and PTCL not otherwise specified (n = 22). Median age was 64 years; 63% were refractory to most recent therapy. Of 34 evaluable patients, ORR was 41% (8 complete remissions [CRs], 6 partial remissions [PRs]), and ORR was 54% in AITL (5 CRs, 2 PRs) with median PFS of 6.7 months thus far. No correlation between CD30 expression per central review and response was observed. Safety data were consistent with the known profile of brentuximab vedotin, and included at least grade 3 events of neutropenia (14%), peripheral sensory neuropathy, and hyperkalemia (9% each). In summary, brentuximab vedotin showed antitumor activity in patients with relapsed PTCL particularly AITL. This trial was registered at www.clinicaltrials.gov as #NCT01421667.
Project description: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).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.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.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.Retreatment with brentuximab vedotin monotherapy is associated with response rates in 68% (39% CR) of patients with relapsed HL and systemic ALCL.United States registry and results database ClinicalTrials.gov NCT00947856.
Project description:INTRODUCTION:Brentuximab vedotin (SGN-35), an anti-cluster of differentiation (CD)-30 antibody conjugated to the anti-tubulin agent monomethyl auristatin E, has demonstrated promising efficacy and tolerability in relapsed and heavily treated Hodgkin lymphoma (HL). In this study, we report the Asian experience with brentuximab vedotin in patients with relapsed or refractory CD30-positive (CD30+) HL. METHODS:This is an observational, multicenter, retrospective study. Between October 2011 and June 2013, a total of 22 patients were treated with brentuximab vedotin under a named patient program in Asia. Patients received a 30 min infusion of brentuximab vedotin at a dose of 1.8 mg/kg of body weight every 3 weeks. RESULTS:Four patients (18.2%) showed a complete response, and the overall response rate was 72.7%. The median duration of response was 4.4 months (range 1.0-17.4). The median progression-free survival was 5.7 months, and the median overall survival has not yet been reached. The 1-year expected survival rate was 67.2%. The most common grade 3/4 adverse events were neutropenia (n=7; 31.8%). No patients experienced grade 3/4 sensory neuropathy. CONCLUSIONS:These results confirm that brentuximab vedotin as a single agent is also effective and well tolerated when used in Asian patients with relapsed and refractory CD30+ HL.
Project description:Brentuximab vedotin (ADCETRIS®), an antibody-drug conjugate, comprises an anti-CD30 antibody conjugated by a protease-cleavable linker to a microtubule-disrupting agent, monomethyl auristatin E (MMAE). In vitro studies showed that MMAE does not interfere with hERG K+ channels at clinically relevant concentrations. In pivotal phase 2 clinical trials in patients with relapsed or refractory Hodgkin lymphoma and systemic anaplastic large cell lymphoma, brentuximab vedotin has shown substantial efficacy and an acceptable safety profile. This phase 1 open-label study was designed to evaluate the effect of brentuximab vedotin on the duration of cardiac ventricular repolarization.Patients with CD30-positive hematologic malignancies were treated with 1.8 mg/kg brentuximab vedotin by intravenous infusion every 3 weeks for up to 16 cycles. The primary endpoint was the change from baseline to Cycle 1 Days 2, 3, and 4 in the duration of ventricular repolarization using Fridericia's corrected QT interval (QTcF).There was no clinically meaningful change from baseline in the duration of ventricular repolarization as measured by QTcF in the 46 evaluable patients out of 52 total patients treated with brentuximab vedotin. There was no evidence of treatment-emergent cardiac safety abnormalities. Brentuximab vedotin was generally well tolerated with a response rate and an adverse event profile consistent with prior studies.There is no significant prolongation of the QT/QTc interval with brentuximab vedotin in patients with CD30-positive hematologic malignancies.
Project description:In contrast to Hodgkin lymphoma and systemic anaplastic large-cell lymphoma, CD30 expression of malignant lymphocytes in mycosis fungoides (MF) and Sézary syndrome (SS) is quite variable. Clinical activity and safety of brentuximab vedotin, a CD30 targeting antibody-drug conjugate, was evaluated in MF and SS. Tissue and blood biomarkers of clinical response were explored.In this phase II study, patients with MF or SS with negligible to 100% CD30 expression levels were treated with brentuximab vedotin (1.8 mg/kg) every 3 weeks for a maximum of sixteen doses. The primary end point was overall global response rate. Secondary end points included correlation of tissue CD30 expression level with clinical response, time to response, duration of response, progression-free and event-free survivals, and safety.Of the 32 patients enrolled and treated, 30 patients had available efficacy evaluations. Objective global response was observed in 21 (70%) of 30 patients (90% CI, 53% to 83%). CD30 expression assessed by immunohistochemistry was highly variable, with a median CD30max of 13% (range, 0% to 100%). Those with <5% CD30 expression had a lower likelihood of global response than did those with 5% or greater CD30 expression (P < .005). CD163 positive tumor-associated macrophages, many of which coexpress CD30, were abundant in tissue. Peripheral neuropathy was the most common adverse event.Brentuximab vedotin demonstrated significant clinical activity in treatment-refractory or advanced MF or SS with a wide range of CD30 expression levels. Additional biomarker studies may help optimize rational design of combination therapies with brentuximab vedotin.
Project description:Intravenous brentuximab vedotin (ADCETRIS®) is a targeted antibody-drug conjugate (ADC) active against CD30-positive cancer cells such as those associated with classical Hodgkin lymphoma (HL). In noncomparative, phase 2 trials and in the real-world setting, salvage therapy with brentuximab vedotin resulted in high objective response (complete plus partial remission) rates in patients with relapsed or refractory CD30-positive HL, including as retreatment in patients who had an objective response to previous brentuximab vedotin therapy and subsequently relapsed. These beneficial outcomes were durable during long-term follow-up. As consolidation therapy after autologous haematopoietic stem cell transplant (ASCT) in the multinational, phase 3 AETHERA trial, brentuximab vedotin prolonged progression-free-survival (PFS) compared with placebo at a median follow-up of 30 months (primary analysis), with a 43% reduction in the risk of disease progression or death. The beneficial effects of brentuximab vedotin consolidation therapy were maintained during long-term follow-up. In the clinical trial and real-world setting, brentuximab vedotin had an acceptable tolerability and safety profile, with most adverse events manageable with dose reductions and/or delays [including peripheral sensory neuropathy (PSN) and neutropenia]. With a paucity of treatments available for many patients with relapsed or refractory HL, brentuximab vedotin represents an important option for the management of patients who have failed high-dose chemotherapy/ASCT or at least two prior chemotherapy regimens and as post-ASCT consolidation therapy in patients who are at increased risk/high-risk of relapse or progression after ASCT.
Project description:Brentuximab vedotin is an antibody-drug conjugate designed to selectively deliver monomethyl auristatin E, a microtubule-disrupting agent, to CD30-expressing cells. Brentuximab vedotin induces durable objective responses in patients with relapsed or refractory Hodgkin lymphoma (HL) after autologous stem cell transplantation (ASCT). The objective of this post-hoc analysis was to characterize the safety and efficacy of brentuximab vedotin for patients with relapsed or refractory HL who refused or were ineligible for ASCT.This case series included 20 transplant-naïve patients who were enrolled in two phase I multicenter studies. Patients received brentuximab vedotin intravenously every 3 weeks or every week for 3 out of 4 weeks.The majority of patients were transplant-naïve because of chemorefractory disease. Median age was 31.5 years (range, 12-87 years). Treatment-emergent adverse events in >20% of patients were peripheral neuropathy, fatigue, nausea, pyrexia, diarrhea, weight decreased, anemia, back pain, decreased appetite, night sweats, and vomiting; most events were grade 1 or 2. Six patients obtained objective responses: two complete remissions and four partial remissions. Median duration of response was not met; censored durations ranged from >6.8 to >13.8 months. Three of six responders subsequently received ASCT.Brentuximab vedotin was associated with manageable adverse events in transplant-naïve patients with relapsed or refractory HL. The objective responses observed demonstrate that antitumor activity is not limited to patients who received brentuximab vedotin after ASCT. The promising activity observed in this population warrants further study.
Project description:<h4>Purpose</h4>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.<h4>Patients and methods</h4>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.<h4>Results</h4>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.<h4>Conclusion</h4>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.
Project description:PURPOSE:In classical Hodgkin lymphoma, the malignant Reed-Sternberg cells express the cell surface marker CD30. Brentuximab vedotin is an antibody-drug conjugate (ADC) that selectively delivers a potent cytotoxic agent, monomethyl auristatin E (MMAE), to CD30-positive cells. Although brentuximab vedotin elicits a high response rate (75%) in relapsed/refractory Hodgkin lymphoma, most patients who respond to brentuximab vedotin eventually develop resistance. PATIENTS AND METHODS:We developed two brentuximab vedotin-resistant Hodgkin lymphoma cell line models using a pulsatile approach and observed that resistance to brentuximab vedotin is associated with an upregulation of multidrug resistance-1 (MDR1). We then conducted a phase I trial combining brentuximab vedotin and cyclosporine A (CsA) in patients with relapsed/refractory Hodgkin lymphoma. RESULTS:Here, we show that competitive inhibition of MDR1 restored sensitivity to brentuximab vedotin in our brentuximab vedotin-resistant cell lines by increasing intracellular MMAE levels, and potentiated brentuximab vedotin activity in brentuximab vedotin-resistant Hodgkin lymphoma tumors in a human xenograft mouse model. In our phase I trial, the combination of brentuximab vedotin and CsA was tolerable and produced an overall and complete response rate of 75% and 42% in a population of patients who were nearly all refractory to brentuximab vedotin. CONCLUSIONS:This study may provide a new therapeutic strategy to combat brentuximab vedotin resistance in Hodgkin lymphoma. This is the first study reporting an effect of multidrug resistance modulation on the therapeutic activity of an ADC in humans. The expansion phase of the trial is ongoing and enrolling patients who are refractory to brentuximab vedotin to confirm clinical activity in this population with unmet need.
Project description: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 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.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%).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).