Brentuximab Vedotin In Patients Research Articles

Brentuximab Vedotin (SGN-35) in Patients With Relapsed or Refractory Systemic Anaplastic Large-Cell Lymphoma: Results of a Phase II Study

Systemic anaplastic large-cell lymphoma (ALCL) is an aggressive subtype of T-cell lymphoma characterized by the uniform expression of CD30. The antibody-drug conjugate brentuximab vedotin delivers the potent antimicrotubule agent monomethylauristatin E to CD30-positive malignant cells. A phase II multicenter trial was conducted to evaluate the efficacy and safety of brentuximab vedotin in patients with relapsed or refractory systemic ALCL. Patients with systemic ALCL and recurrent disease after at least one prior therapy received brentuximab vedotin 1.8 mg/kg intravenously every 3 weeks over 30 minutes as an outpatient infusion. The primary end point of the study was overall objective response rate as assessed by independent central review. Of 58 patients treated in the study, 50 patients (86%) achieved an objective response, 33 patients (57%) achieved a complete remission (CR), and 17 patients (29%) achieved a partial remission. The median durations of overall response and CR were 12.6 and 13.2 months, respectively. Grade 3 or 4 adverse events in ≥ 10% of patients were neutropenia (21%), thrombocytopenia (14%), and peripheral sensory neuropathy (12%). Brentuximab vedotin induced objective responses in the majority of patients and CRs in more than half of patients with recurrent systemic ALCL. Targeted therapy with this CD30-directed antibody-drug conjugate may be an effective treatment for relapsed or refractory systemic ALCL and warrants further studies in front-line therapy.

Safety and efficacy of brentuximab vedotin in patients with Hodgkin lymphoma or systemic anaplastic large cell lymphoma.

Antibody-based immunotherapy has become an integral part of cancer therapeutics. However, monoclonal antibodies have their limitations as identifying an antigen selectively expressed on malignant cells and developing a high-affinity antibody may not by itself alter tumor growth. This is illustrated in the case of CD30; CD30 epitomizes many properties of an ideal pharmacologic target such as high expression on malignant cells and limited expression on normal tissues. However, until the advent of brentuximab vedotin, CD30 remained an elusive target as antibody-based anti-CD30 immunotherapy had been largely clinically unsuccessful. Brentuximab vedotin (cAC10-vcMMAE, SGN-35) is an antibody-drug conjugate consisting of a chimeric anti-CD30 monoclonal antibody whereupon the potent microtubule inhibitor monomethyl auristatin E (MMAE) is attached via a valine-citrulline linker. Once bound to CD30, brentuximab vedotin is internalized and MMAE is released with the action of lysosomal enzymes on the linker. In phase I studies in relapsed or refractory Hodgkin lymphoma and anaplastic large cell lymphoma, brentuximab vedotin induced unprecedented responses with manageable toxicity. In phase II studies, brentuximab vedotin induced overall response rates of 75% and 86% in relapsed or refractory Hodgkin lymphoma and anaplastic large cell lymphoma, respectively. The results of these trials led to the accelerated approval of the drug by the US Food and Drug Administration in a patient population with few other alternative options. Brentuximab vedotin has overall manageable toxicity profile; however, cumulative peripheral neuropathy constitutes an important clinical consideration as it may limit prolonged administration of the drug. The mechanism by which brentuximab vedotin exerts its antitumor activity is not entirely clear. Diffusion of MMAE in the tumor microenvironment and cytotoxicity on bystander cells may in part explain its activity, especially in Hodgkin lymphoma. Herein, we review the biology of CD30 and brentuximab vedotin, and the clinical data that has accumulated thus far with SGN-35.

A Phase I Weekly Dosing Study of Brentuximab Vedotin in Patients with Relapsed/Refractory CD30-Positive Hematologic Malignancies

The antibody-drug conjugate (ADC) brentuximab vedotin comprises a CD30-directed antibody covalently attached to the potent antimicrotubule agent monomethyl auristatin E (MMAE) via a protease-cleavable linker. This study explored the safety, maximum-tolerated dose (MTD), and activity of weekly dosing of brentuximab vedotin in patients with relapsed or refractory CD30-positive hematologic malignancies. In this phase I dose-escalation study, brentuximab vedotin was administered intravenously on Days 1, 8, and 15, of each 28-day cycle at doses ranging from 0.4 to 1.4 mg/kg. Forty-four patients were enrolled: 38 with Hodgkin lymphoma, five with systemic anaplastic large cell lymphoma, and one with peripheral T-cell lymphoma not otherwise specified. Doses were escalated in increments of 0.2 mg/kg until dose-limiting toxicity (DLT) was observed. Patients were monitored for antitherapeutic antibodies and pharmacokinetic parameters. Antitumor assessments were carried out every two cycles. The MTD was 1.2 mg/kg. The most common adverse events were peripheral sensory neuropathy, fatigue, nausea, diarrhea, arthralgia, and pyrexia; and the majority of events were mild to moderate in severity. Tumor regression occurred in 85% of patients and the overall objective response rate was 59% (n = 24), with 34% (n = 14) complete remissions. The median duration of response was not reached at a median follow-up of 45 weeks on study. Weekly administration of brentuximab vedotin resulted in tumor regression and durable remissions in patients with CD30-positive malignancies. This ADC was associated with manageable toxicity, including peripheral neuropathy. Further study in CD30-positive malignancies is warranted.

Brentuximab Vedotin (SGN-35) in Patients with Relapsed or Refractory Systemic Anaplastic Large Cell Lymphoma: A Phase 2 Study Update

Abstract 443 Background:Systemic anaplastic large cell lymphoma (sALCL) is a T-cell non-Hodgkin lymphoma (NHL) characterized by the uniform expression of CD30. sALCL accounts for 2–5% of all cases of NHL; approximately 40–65% of patients experience recurrent disease after frontline treatment with few effective treatment options. Brentuximab vedotin (SGN-35) comprises an anti-CD30 antibody conjugated by a protease-cleavable linker to the potent antimicrotubule agent, monomethyl auristatin E (MMAE). A phase 2 study was conducted to determine the efficacy and safety of brentuximab vedotin in patients with relapsed or refractory sALCL (ClinicalTrials.gov #NCT00866047); updated results of this trial are presented. Methods:Brentuximab vedotin 1.8 mg/kg was administered every 3 weeks as a 30-minute outpatient IV infusion for up to 16 cycles of treatment. Determination of efficacy was based on objective response assessments per independent review according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Patients were enrolled between June 2009 and May 2010 at 22 clinical sites in the US, Canada, and Europe. Results:58 patients with a median of 2 prior therapies (range 1–6) were treated; 57% were male and the median age was 52 years (range 14–76). Seventy-two percent of patients had ALK-negative disease, 62% had primary refractory disease (defined as no complete remission (CR) or relapse within 3 months of frontline therapy), and 26% had failed a prior autologous stem cell transplant (SCT). As previously reported, the objective response rate (ORR) was 86%, the CR rate was 57%, and 97% of patients had a reduction in tumor volume postbaseline. At the time of this updated analysis (data cut May 2011), all but 2 patients had discontinued treatment with brentuximab vedotin; the median number of treatment cycles was 7 (range 1–16). The median duration of objective response was 13.0 months (range 0.1–19.1+) and the median duration of response for patients achieving a CR was 17.1 months (range 0.7–19.1+). Median progression-free survival (PFS) was 14.6 months and median overall survival was not yet reached. Per investigator assessment, the median PFS with brentuximab vedotin was significantly longer than the median PFS achieved with the most recent prior therapy (20.0 months vs. 5.9 months; P value <0.001). All subgroups of patients analyzed in the study achieved a similar level of antitumor activity, regardless of baseline disease characteristics, tumor burden, or prior treatment history. Responses were particularly noteworthy in patients who had never responded to any previous therapy (n=13); in this subgroup of patients, 10 achieved an objective response (77%) and 4 a CR (31%). After discontinuing treatment in the study, 16 patients (28%) received a hematopoietic SCT (8 allogeneic, 8 autologous). The most common adverse events observed in the study were peripheral sensory neuropathy (41%), nausea (40%), fatigue (38%), pyrexia (34%), diarrhea (29%), rash (24%), constipation (22%), and neutropenia (21%). Most AEs in the study were Grade 1 or 2 in severity. Ten patients (17%) experienced Grade 3 events of peripheral neuropathy as defined in a Standardised MedDRA Query; no Grade 4 events were observed. In patients with neuropathy, 79% (26 of 33) have experienced resolution or some improvement and the median time to resolution or improvement was 13.3 weeks (range 0.3–48.7). Conclusions:Durable complete remissions were achieved with brentuximab vedotin, and treatment was associated with manageable toxicity, in patients with relapsed or refractory sALCL. Approximately half of the responding patients (24 of 50) continued in remission at the time of this analysis; updated results of efficacy and long term safety will be presented at the meeting. Based on the results from this study, a trial evaluating the safety of brentuximab vedotin administered in sequence and in combination with multiagent chemotherapy was initiated and is currently ongoing in frontline sALCL. Disclosures:Advani:Seattle Genetics, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Brentuximab vedotin (SGN-35) comprises an anti-CD30 antibody conjugated by a protease-cleavable linker to the potent antimicrotubule agent, monomethyl auristatin E (MMAE). It is an investigational agent that is being studied in CD30+ malignancies. Shustov:Millennium: Honoraria; Seattle Genetics, Inc.: Consultancy, Research Funding. Brice:Roche: Honoraria; Seattle Genetics, Inc.: Honoraria, Research Funding. Bartlett:Seattle Genetics, Inc.: Consultancy, Research Funding, Travel Expenses. Rosenblatt:Seattle Genetics, Inc.: Research Funding. Illidge:Seattle Genetics, Inc.: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Honoraria. Matous:Cephalon: Speakers Bureau; Celgene: Speakers Bureau; Seattle Genetics, Inc.: Research Funding; Millennium: Speakers Bureau. Ramchandren:Seattle Genetics, Inc.: Research Funding. Fanale:Seattle Genetics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Connors:Seattle Genetics, Inc.: Research Funding. Yang:Seattle Genetics, Inc.: Employment, Equity Ownership. Kennedy:Seattle Genetics, Inc.: Employment, Equity Ownership. Pro:Seattle Genetics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Results from a pivotal phase II study of brentuximab vedotin (SGN-35) in patients with relapsed or refractory Hodgkin lymphoma (HL).

8031 Background: CD30 expression by Reed-Sternberg cells is a defining feature of HL. Brentuximab vedotin comprises an anti-CD30 antibody conjugated by a plasma-stable linker to the potent antimicrotubule agent, monomethyl auristatin E (MMAE). Brentuximab vedotin selectively induces apoptotic death of CD30+ cells by binding, internalizing, and releasing MMAE. Methods: A pivotal, phase II, single-arm, multicenter study evaluated the efficacy and safety of brentuximab vedotin in patients (pts) with relapsed or refractory HL after autologous stem cell transplant (SCT). Pts received brentuximab vedotin 1.8 mg/kg q3 weeks (wks) as a 30‐minute outpatient IV infusion for up to 16 cycles. The primary endpoint was the objective response rate (ORR) per an independent review facility (IRF) according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Results: 102 pts were enrolled; 53% were female and median age was 31 yrs (range, 15–77 yrs). Pts had received a median of 3.5 (range 1–13) prior cancer-related systemic therapies excluding autologous SCT. 71% of pts had primary refractory disease and 42% had not responded to their most recent prior therapy. The ORR per IRF assessment was 75% (76 of 102 pts), with complete remissions (CRs) in 34% of pts (n=35). At the time of database lock (August 2010), the median duration of follow up from first dose was ~9 months (for responders). The median duration of response for pts with CR per IRF has not yet been reached (range 0.3+ to 61.4+ wks); follow up continues and 6+ months of additional data will be available for presentation. The most common (≥15%) treatment-related adverse events (AEs) of any grade were peripheral sensory neuropathy, nausea, fatigue, neutropenia, and diarrhea. AEs ≥ Grade 3 occurring in ≥5% of pts were neutropenia, peripheral sensory neuropathy, thrombocytopenia, and anemia. Conclusions: With manageable AEs, single-agent brentuximab vedotin induced objective responses in 75% of pts with relapsed or refractory HL. In this heavily pretreated population, 35 of 102 pts (34%) achieved a durable CR, with more than 65% of pts remaining in CR.

Durable remissions with brentuximab vedotin (SGN-35): Updated results of a phase II study in patients with relapsed or refractory systemic anaplastic large cell lymphoma (sALCL).

8032 Background: sALCL is a CD30-expressing malignancy comprising ~2-3% of all NHL cases. Brentuximab vedotin consists of an anti-CD30 antibody conjugated by a plasma-stable linker to the potent antimicrotubule agent, monomethyl auristatin E (MMAE). Brentuximab vedotin selectively induces apoptotic death of CD30+ cells by binding, internalizing, and releasing MMAE. Methods: A phase II, single-arm, multicenter study evaluated the efficacy and safety of brentuximab vedotin in patients (pts) with relapsed or refractory sALCL. Pts received brentuximab vedotin 1.8 mg/kg q3 weeks (wks) as a 30‐minute outpatient IV infusion for up to 16 cycles. The primary endpoint was the objective response rate (ORR) per an independent review facility (IRF) according to Cheson 2007. Results: 58 pts were enrolled; 57% were male, median age was 52 yrs (range 14–76 yrs). 72% of pts had ALK negative sALCL. Pts had received a median of 2 (range 1–6) prior systemic therapies. 62% of pts had primary refractory disease, 50% were refractory to their most recent prior therapy, and 22% had never responded to any prior therapy. At the time of primary efficacy analysis, ORR per IRF was 86% (50 of 58 pts) with CRs in 53% of pts (31 of 58). Median duration of objective response had not yet been reached; the duration ranged from 0.3 to 45.3 wks. Of 15 pts with malignant cutaneous lesions at baseline, 14 (93%) had resolution of all lesions; median time to resolution was 4.9 wks. After achieving a remission with brentuximab vedotin, 7 pts received an allogeneic stem cell transplant (SCT) and 7 pts had an autologous SCT. Treatment-related adverse events (AEs) of any grade in ≥15% of pts were peripheral sensory neuropathy (36%), nausea (24%), fatigue (22%), diarrhea (19%), and neutropenia (17%). AEs ≥ Grade 3 in ≥10% of patients were neutropenia (21%); thrombocytopenia (14%), and peripheral sensory neuropathy (10%). No treatment-related Grade 5 events were observed. Conclusions: Brentuximab vedotin induced objective responses in 86% of pts with highly refractory sALCL, including a high proportion of CRs, with manageable AEs. Updated response durability and safety will be presented at the meeting.

Complete Remissions with Brentuximab Vedotin (SGN-35) in Patients with Relapsed or Refractory Systemic Anaplastic Large Cell Lymphoma

AbstractAbstract 961 Background:Systemic anaplastic large cell lymphoma (sALCL) is a CD30-expressing malignancy comprising approximately 2–3% of all cases of non-Hodgkin lymphoma. The antibody-drug conjugate (ADC) brentuximab vedotin (SGN-35) delivers the highly potent antimicrotubule agent monomethyl auristatin E (MMAE) to CD30-positive malignant cells by binding specifically to CD30 on the cell surface and releasing MMAE inside the cell via lysosomal degradation. Binding of MMAE to tubulin disrupts the microtubule network within the cell, induces cell cycle arrest, and results in apoptotic death of the CD30-expressing tumor cell. In phase 1 studies, brentuximab vedotin demonstrated good tolerability and notable antitumor activity in patients with relapsed or refractory sALCL: 6 of 7 treated patients achieved complete remissions (CR). Methods:A phase 2, single-arm, multicenter study was conducted to evaluate the efficacy and safety of brentuximab vedotin in patients with relapsed or refractory sALCL. Brentuximab vedotin 1.8 mg/kg was administered every 3 weeks as a 30-minute outpatient IV infusion for up to 16 cycles of treatment. Determination of antitumor efficacy was based on objective response assessments according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Results:A total of 58 patients were treated in this study; interim data are presented for the first 30 treated patients. 53% of patients were female and median age was 55 years (range 14–71). The majority of patients had ALK-1 negative tumor (70%, or n=21) and 4 patients (13%) had bone marrow involvement at baseline. The median number of prior chemotherapy regimens was 2 (range 1–6) and 8 patients (27%) had failed previous autologous hematopoietic stem cell transplant (SCT). 19 patients (63%) had primary refractory disease, and 16 patients (53%) had not responded to the most recent prior therapy. The objective response rate (ORR) by investigator assessment was 87%; 57% of patients achieved a CR (n=17) and 30% of patients achieved a partial remission (PR; n=9). The remaining patients had stable disease (n=3) or were not evaluable for response (n=1). Similar proportions of ALK-1 negative and ALK-1 positive patients achieved CR and PR. Reduction in tumor burden was observed in 97% of patients. The median time to objective response was 6 weeks (range 5–12) and the duration of objective responses currently range from 4–36 weeks, with responses ongoing in 18 patients. B symptoms resolved in 9 of 10 patients (90%) who had these symptoms at baseline. After achieving a CR with brentuximab vedotin, 10 patients (33%) went on to receive an autologous or allogeneic SCT. The most common (>20%) adverse events (AEs) of any grade were nausea (47%), diarrhea (40%), peripheral sensory neuropathy (40%), pyrexia (33%), dyspnea (30%), fatigue (27%), insomnia (23%), and neutropenia (23%). Grade 3/4 AEs considered related to brentuximab vedotin observed in >1 patient were neutropenia (17%), peripheral sensory neuropathy (13%), diarrhea (7%), and anemia (7%); no treatment-related Grade 5 events were observed. 7 patients (23%) discontinued treatment due to an AE. Conclusion:In this interim analysis of 30 patients with relapsed or refractory sALCL, the investigator-assessed ORR was 87% and the CR rate was 57%. Brentuximab vedotin treatment was associated with manageable AEs; the most common in the study were nausea, diarrhea, and peripheral sensory neuropathy. The rate of complete remissions observed thus far in this study with single-agent treatment suggests that brentuximab vedotin has potential for the treatment of sALCL. Results of the independent assessment of response for all patients, duration of response, progression-free survival, and updated safety data will be presented at the meeting. Disclosures:Shustov:Seattle Genetics, Inc.: Research Funding, Steering Committee member. Off Label Use: The clinical trial uses an investigational drug, brentuximab vedotin (SGN-35). Advani:Seattle Genetics, Inc.: Research Funding. Brice:Seattle Genetics, Inc.: Research Funding. Bartlett:Seattle Genetics, Inc.: Research Funding. Rosenblatt:Seattle Genetics, Inc.: Research Funding. Illidge:Seattle Genetics, Inc.: Research Funding; Roche: Consultancy; Biogen Idec: Consultancy; Amgen: Consultancy. Matous:Seattle Genetics, Inc.: Research Funding; Celgene: Honoraria, Speakers Bureau; Millennium: Speakers Bureau; Cephalon: Speakers Bureau. Ramchandren:Seattle Genetics, Inc.: Research Funding. Fanale:Seattle Genetics, Inc.: Research Funding. Connors:Seattle Genetics, Inc.: Research Funding. Yang:Seattle Genetics, Inc.: Employment. Sievers:Seattle Genetics, Inc.: Employment, Equity Ownership. Kennedy:Seattle Genetics, Inc.: Employment, Equity Ownership. Pro:Seattle Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Results of a Pivotal Phase 2 Study of Brentuximab Vedotin (SGN-35) in Patients with Relapsed or Refractory Hodgkin Lymphoma

AbstractAbstract 283 Background:Hodgkin lymphoma (HL) is characterized by the presence of CD30-positive Hodgkin Reed-Sternberg cells. The antibody-drug conjugate (ADC) brentuximab vedotin (SGN-35) delivers the highly potent antimicrotubule agent monomethyl auristatin E (MMAE) to CD30-positive malignant cells by binding specifically to CD30 on the cell surface and releasing MMAE inside the cell via lysosomal degradation. Binding of MMAE to tubulin disrupts the microtubule network within the cell, induces cell cycle arrest, and results in apoptotic death of the CD30-expressing tumor cell. In a previous phase 1 study with brentuximab vedotin dosing every third week, 11 of 12 patients (92%) treated at the maximum tolerated dose of 1.8 mg/kg had tumor reductions and 6 of 12 patients (50%) achieved an objective response (complete remission [CR] + partial remission [PR]). Methods:A pivotal, phase 2, single-arm, multicenter study was conducted to evaluate the efficacy and safety of brentuximab vedotin in patients with relapsed or refractory HL post autologous stem cell transplant (ASCT). Brentuximab vedotin 1.8 mg/kg was administered every 3 weeks as a 30-minute outpatient IV infusion for up to 16 cycles of treatment. The primary endpoint was the overall objective response rate (ORR) as assessed by an independent review facility according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Results:A total of 102 patients with relapsed or refractory HL were treated at 26 study centers. Median age was 31 years (range 15–77) and approximately half of the patients were female (53%). Eastern Cooperative Oncology Group (ECOG) performance status at baseline was 0 (41%) or 1 (59%). All patients had previously received an ASCT and the median number of prior chemotherapy regimens was 4 (range 1–13). More than 70% of the patients had primary refractory disease, defined as failure to achieve a CR or progression within 3 months of completing frontline therapy. In addition, 39% of patients had lymphoma that was refractory to the most recent salvage therapy excluding ASCT. The median duration of brentuximab vedotin treatment on this study was 27 weeks (range 3–54) and the median number of cycles was 9 (range 1–16). The most common (>15%) treatment-related adverse events (AEs) of any grade were peripheral sensory neuropathy (43%), fatigue (40%), nausea (35%), neutropenia (19%), diarrhea (18%), and pyrexia (16%); most events were Grade 1 or 2. Grade 3 treatment-related AEs reported in >1 patient were neutropenia (14%), peripheral sensory neuropathy (5%), thrombocytopenia and hyperglycemia (3% each), and fatigue (2%). The only Grade 4 treatment-related events were neutropenia (4%), and thrombocytopenia, abdominal pain, and pulmonary embolism (1% each). No related Grade 5 events were observed. 18 patients discontinued treatment due to an AE. Consistent with findings from the phase 1 study, 97 patients (95%) had a reduction in tumor size per investigator assessment. Of the 35 patients who had B symptoms at baseline, 29 (83%) experienced resolution of these symptoms. The median time to B symptom resolution was 3 weeks (range <1–16 weeks). To date, 5 patients have received an allogeneic stem cell transplant as their first therapy after discontinuing treatment in the study; all of these patients remain in follow up. Per protocol, no interim analyses were planned for the primary endpoint of ORR by independent review. Independent assessment of ORR is being conducted and final efficacy results will be presented at the meeting. Conclusions:Brentuximab vedotin was associated with manageable adverse events and, based on investigator assessment, demonstrated encouraging activity in heavily pretreated patients with relapsed or refractory HL. Tumor shrinkage was observed in 95% of patients and the B symptom resolution rate was 83%. Final results of the independent assessment of ORR, as well as duration of response, progression-free survival, and updated safety data, will be presented at the meeting. Disclosures:Chen: Seattle Genetics, Inc.: Research Funding. Off Label Use: This clinical trial uses the investigational drug, brentuximab vedotin (SGN-35). Gopal:Seattle Genetics, Inc.: Research Funding. Smith:Seattle Genetics, Inc.: Research Funding. Ansell:Seattle Genetics, Inc.: Research Funding. Rosenblatt:Seattle Genetics, Inc.: Research Funding. Klasa:Seattle Genetics, Inc.: Research Funding. Connors:Seattle Genetics, Inc.: Research Funding. Engert:Seattle Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding. Larsen:Seattle Genetics, Inc.: Employment, Equity Ownership. Kennedy:Seattle Genetics, Inc.: Employment, Equity Ownership. Sievers:Seattle Genetics, Inc.: Employment, Equity Ownership. Younes:Seattle Genetics, Inc.: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; SBIO: Honoraria, Research Funding.