Brentuximab Vedotin in Front-Line Therapy of Hodgkin Lymphoma (HL) and CD30-Expressing Peripheral T-Cell Lymphoma (PTCL) in Adults Age 60 and Above

Background Despite the advances in therapy of classical Hodgkin lymphoma (cHL) and CD30-expressing peripheral T-cell lymphoma (PTCL) over the years, the outcomes seen in younger patients with the disease have not been attained in patients ≥60 years of age. Studies cite 5-year progression-free survival (PFS) and freedom from treatment failure rates of 30%-45% in older patients with HL, as compared to rates of 75%-80% expected in younger patients (Evens 2008; Proctor 2009). In a recent retrospective study of patients >60 years of age diagnosed with PTCL between 2008-2014, a multivariate analysis demonstrated that a Charlson Comorbidity Index (CCI) ≥2 and high IPI score (3-5) were independent risk factors for worse overall survival (OS) and PFS (Zhao 2016). Similarly, multivariate analysis of registry data from Sweden shows that a CCI ≥2, when adjusted for age, is independently associated with worse OS and PFS outcomes (Ellin 2018). There is no standard treatment regimen for elderly patients with cHL and PTCL, and co-morbidities including depressed cardiac and renal function limit the ability to use combination chemotherapy, and represent a high unmet need. Brentuximab vedotin (BV, ADCETRIS®) is a CD30-directed antibody-drug conjugate (ADC) consisting of the chimeric IgG1 antibody cAC10, specific for human CD30; the microtubule-disrupting agent monomethyl auristatin E (MMAE); and a protease-cleavable linker that covalently attaches MMAE to cAC10. Following the binding of BV to CD30-expressing cells, the ADC-CD30 complex is internalized, and MMAE released via proteolytic cleavage. Binding of MMAE to tubulin disrupts the microtubule network within the cell, subsequently inducing cell cycle arrest and apoptosis. Single-agent BV has demonstrated robust activity in patients with HL refractory to several lines of chemotherapy and the ECHELON-1 study (Connors 2017) established its efficacy in combination with chemotherapy for the front line treatment of HL. In a phase 2 study of single-agent BV in 27 patients aged ≥ 60 years with HL, there was an objective response rate of 92%, with 73% achieving complete remission (Forero-Torres, 2015). For CD30-expressing PTCL, single-agent BV is an active and well-tolerated treatment for patients with relapsed or refractory disease (Horwitz 2014) and the ECHELON-2 study showed that the addition of BV to combination chemotherapy in the frontline treatment improves both PFS and OS (Horwitz 2018). In the elderly patient populations who are not candidates for multi-agent chemotherapy, frontline treatment with single-agent BV may have the potential to be an active and well-tolerated treatment. Study Design Two additional cohorts have been added to the SGN35-015 phase 2 open-label study (NCT01716806) to evaluate the efficacy and tolerability of BV as monotherapy in treatment-naive patients with cHL, which excludes nodular lymphocyte-predominant HL (Part E) or treatment-naive patients with CD30-expressing PTCL (Part F). The primary objective of these cohorts is to assess objective response rates of single-agent BV as frontline therapy in patients ≥60 years of age and ineligible for conventional chemotherapy for HL (Part E) or CD30-expressing PTCL (Part F). Eligible patients in Parts E and F must be ≥75 years or ≥60 years of age and have one of the following: confirmed ejection fraction <45% or estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2 and <50 mL/min/1.73 m2, as determined by the Modification of Diet in Renal Disease study equation. Approximately 30 evaluable patients will be enrolled in Parts E and F of the study and administered BV 1.8 mg/kg as a single intravenous infusion on Day 1 of each 21-day cycle. Patients achieving a complete remission, partial remission, or stable disease will receive up to 16 cycles of treatment. Treatment response will be assessed by spiral CT scans of the chest, abdomen, and pelvis and PET scans at Cycles 2, 6, and 11. Response assessment will be determined by blinded independent central review. Disclosures Yasenchak: BMS: Consultancy; Seattle Genetics: Consultancy. Bordoni:Phillips & Gilmore: Honoraria; Genentech: Speakers Bureau; Merck: Speakers Bureau; Seattle Genetics, Inc.: Research Funding; Practice Point Communication: Honoraria; Deciphera: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Honoraria; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Yazbeck:Celgene: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Research Funding. Patel-Donnelly:Seattle Genetics, Inc.: Research Funding. Larson:Seattle Genetics, Inc.: Research Funding. Newhook:Seattle Genetics, Inc.: Employment. Ho:Seattle Genetics, Inc.: Employment, Equity Ownership. Mei:Seattle Genetics, Inc.: Research Funding.

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Long-Term Remissions Observed in an Ongoing Phase 2 Study of Brentuximab Vedotin in Patients with Relapsed or Refractory Systemic Anaplastic Large Cell Lymphoma.

Blood ◽

10.1182/blood.v120.21.2745.2745 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2745-2745 ◽

Cited By ~ 3

Author(s):

Barbara Pro ◽

Ranjana H. Advani ◽

Pauline Brice ◽

Nancy L. Bartlett ◽

Joseph D. Rosenblatt ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Objective Response ◽

Large Cell ◽

Brentuximab Vedotin ◽

Advisory Committees ◽

Frontline Treatment ◽

Long Term Follow Up ◽

Alk Positive

Abstract Abstract 2745 Background: Systemic anaplastic large cell lymphoma (sALCL) is a CD30-positive malignancy that accounts for 2–5% of all non-Hodgkin lymphoma (NHL) cases. Approximately 40–65% of patients with sALCL develop recurrent disease after frontline treatment and few effective treatment options exist for this population. Brentuximab vedotin (ADCETRIS®) comprises an anti-CD30 antibody conjugated by a protease-cleavable linker to monomethyl auristatin E (MMAE), a microtubule-disrupting agent. Brentuximab vedotin selectively induces apoptotic death of CD30-positive cells by binding, internalizing, and releasing 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); long-term follow-up data from this ongoing trial are presented. Methods: Patients received 1.8 mg/kg brentuximab vedotin every 3 weeks as a 30-minute outpatient IV infusion for up to 16 cycles. The primary endpoint was the objective response rate (ORR) per independent review according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Results: 58 patients were enrolled at 22 clinical sites in the US, Canada, and Europe. The median age was 52 years (range 14–76) and 57% were male. 72% 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 ORR was 86% (50 of 58 patients) and the CR rate was 59% (34 of 58 patients). At the time of this analysis (datacut April 2012), all patients had discontinued treatment and the median observation time from first dose was 22.8 months (range, 0.8–32.2). The median duration of objective response for all patients was 13.2 months (range, 0.1–27.7+) and the median duration of response for patients who obtained a CR has not yet been met (range, 0.7–27.7+). Of the patients who achieved a CR, over half (18 of 34; 53%) were in continued remission at the time of this analysis. The median progression-free survival (PFS) for all patients was 14.6 months and the median overall survival has not yet been reached. After discontinuing treatment in the study, 16 patients (28%) received a hematopoietic SCT (8 allogeneic, 8 autologous). The median PFS has not yet been met for the group of patients who achieved a CR and received a subsequent SCT (range, 8.1–29+), while the median PFS for the group who achieved a CR and did not receive post-treatment SCT was 18.4 months (range, 2.6–26+). 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. Median PFS did not appear to be influenced by ALK status; in the subgroup of ALK-positive patients (n=16) PFS was 14.6 months versus 14.3 months for ALK-negative patients (n=42). The median overall survival has not yet been met for either ALK-positive or ALK-negative patients. The most common (reported in ≥20% of patients) adverse events (AEs) observed in the study were peripheral sensory neuropathy (41%), nausea (40%), fatigue (38%), pyrexia (34%), diarrhea (29%), rash (24%), constipation (22%), and neutropenia (21%). The majority of AEs were Grade 1 or 2 in severity. Ten patients (17%) experienced Grade 3 events of peripheral neuropathy as defined by a Standardised MedDRA Query; no Grade 4 events were observed. Resolution or at least 1 grade of improvement in peripheral neuropathy has occurred in 79% of patients with neuropathy events (26 of 33 patients) and the median time to resolution or improvement was 13.4 weeks (range, 0.3–48.7). Conclusions: 34 of 58 patients (59%) with relapsed or refractory sALCL obtained a durable CR with brentuximab vedotin and treatment was associated with manageable toxicity. PFS did not appear to be influenced by ALK status. These long-term follow-up results underscore the durability of clinical benefit obtained with brentuximab vedotin. A randomized phase 3 study is planned to evaluate brentuximab vedotin in combination with cyclophosphamide, doxorubicin, and prednisone for frontline treatment of CD30-positive mature T-cell lymphomas. Disclosures: Pro: Seattle Genetics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Advani:Seattle Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Pharmacyclics: Research Funding; Abbott: Research Funding. Brice:Seattle Genetics, Inc.: Honoraria, Research Funding; Roche: Honoraria. Bartlett:Seattle Genetics, Inc.: Consultancy, Research Funding, Travel expenses Other. Rosenblatt:Seattle Genetics, Inc.: Research Funding. Illidge:Seattle Genetics, Inc.: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Honoraria. Matous:Seattle Genetics, Inc.: Research Funding, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Speakers Bureau. Ramchandren:Seattle Genetics, Inc.: Research Funding, Speakers Bureau. Fanale:Seattle Genetics, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Travel expenses Other. Connors:Seattle Genetics, Inc.: Research Funding. Yang:Seattle Genetics, Inc.: Employment, Equity Ownership. Kennedy:Seattle Genetics, Inc.: Employment, Equity Ownership. Shustov:Seattle Genetics, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

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A Phase 2 Study of Brentuximab Vedotin in Patients with Relapsed or Refractory CD30-Positive Non-Hodgkin Lymphomas: Interim Results.

Blood ◽

10.1182/blood.v120.21.2746.2746 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2746-2746 ◽

Cited By ~ 7

Author(s):

Eric D. Jacobsen ◽

Ranjana H. Advani ◽

Yasuhiro Oki ◽

Jeff Sharman ◽

Steven M. Horwitz ◽

...

Keyword(s):

Antitumor Activity ◽

B Cell ◽

Board Of Directors ◽

Research Funding ◽

Nk Cell ◽

Cell Lymphoma ◽

Objective Response ◽

Brentuximab Vedotin ◽

Grey Zone ◽

Advisory Committees

Abstract Abstract 2746 Background: Brentuximab vedotin (ADCETRIS®) is a CD30-directed antibody-drug conjugate approved for the treatment of relapsed Hodgkin lymphoma and systemic anaplastic large cell lymphoma (ALCL). Several non-Hodgkin lymphoma (NHL) subtypes such as diffuse large B-cell lymphoma (DLBCL) and peripheral T-cell lymphomas (PTCL) have variable quantitative and qualitative expression of CD30. As a result of the high objective response rate (86%) and durable complete remissions (CR) observed in a pivotal phase 2 study in ALCL, a study was initiated to investigate the efficacy and safety of brentuximab vedotin in other NHLs that express the CD30 antigen. Methods: A phase 2, open-label, single-arm, multicenter study is currently ongoing to evaluate the antitumor activity of brentuximab vedotin in approximately 75 patients with relapsed or refractory CD30-positive NHL (ClinicalTrials.gov NCT01421667). Brentuximab vedotin, 1.8 mg/kg, is administered every 3 weeks by IV infusion. Patients who achieve at least stable disease are eligible to receive continued treatment until disease progression or unacceptable toxicity. The primary efficacy endpoint is objective response rate (ORR) as assessed by the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Efficacy variables will be analyzed by total patients, WHO NHL classification, DLBCL (excluding peripheral mediastinal large B-cell lymphoma [PMBL] due to differing treatment paradigms and outcomes for this DLBCL subtype), and by each individual disease. The correlation between antitumor activity and quantitative CD30 expression is also being explored. Results: Fifty-three patients with various CD30-positive NHLs have been enrolled to date (35 with B-cell neoplasms and 18 with mature T-/NK-cell neoplasms). Twenty-nine (55%) patients had refractory disease, 19 (36%) had relapsed since their most recent prior therapy, and 5 (9%) had primary refractory disease (did not achieve a CR with frontline therapy or relapsed within 3 months of completing frontline therapy). Diagnoses include DLBCL (assorted disease subtypes, n=22), angioimmunoblastic T-cell lymphoma (AITL, n=9), PTCL-NOS (n=8), grey zone lymphoma (n=5), PMBL (n=4), follicular lymphoma (n=3), post-transplant lymphoproliferative disorder (n=1), and cutaneous T-cell lymphoma (n=1). The median age is 64 years (range 16–83) and 30 patients (57%) are male. Patients have received a median of 3 prior systemic therapies and 6 patients have received prior stem cell transplants. Of the 36 patients who have had a response assessment to date, 12 (33%) have achieved an objective response (5 CR, 7 partial remissions [PR]). The ORR for B-cell NHLs is 36% (9/25), and 27% (3/11) for mature T-/NK-cell NHLs. Thus far, responses are particularly noteworthy in DLBCL (excluding PMBL) where 7 of 15 patients (47%) have responded (3 CR, 4 PR), in AITL where 3 of 5 patients (60%) have responded (2 CR, 1 PR), and in grey zone lymphoma where 2 of 5 patients (40%) have achieved a PR. Median duration of response has not been reached. Of the 12 responding patients, 7 remain on treatment, 3 discontinued due to a patient decision (non-adverse event), and 2 due to adverse events of neutropenia (related) and pneumocystis jiroveci pneumonia (unrelated). CD30 expression levels for patients with a CR or PR were widely variable and ranged from <1% to 90%. Treatment-emergent adverse events (TEAEs) occurring in ≥10% of patients include fatigue (26%), diarrhea (16%), nausea (16%), pyrexia (16%), neutropenia (14%), dyspnea (12%), and abdominal pain (10%), and TEAEs considered related to study drug include fatigue (16%) and neutropenia (14%). Most AEs have been Grade 1 or 2. Grade 3 dyspnea, hyponatremia, and decreased white blood cell count have occurred in 2 patients each, while Grade 3 neutropenia has occurred in 3 patients. Two patients have experienced Grade 4 neutropenia. Peripheral neuropathy events have been Grade 1 or 2. Conclusions: In this interim analysis of 53 patients (36 with response evaluations), compelling antitumor activity has been demonstrated in both B-cell and mature T-/NK-cell NHLs, in particular DLBCL, AITL, and grey zone lymphoma. Due to the range of CD30 expression in patients achieving an objective response, more data are needed to determine if there is a correlation between CD30 expression and antitumor activity. Preliminary safety data are consistent with the safety profile of brentuximab vedotin. Disclosures: Jacobsen: Seattle Genetics, Inc.: Research Funding. Off Label Use: Brentuximab vedotin is indicated for treatment of patients with Hodgkin lymphoma after failure of autologous stem cell transplant or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not ASCT candidates and for the treatment of patients with systemic anaplastic large cell lymphoma after failure of at least one prior multi-agent chemotherapy regimen. These indications are based on response rate. There are no data available demonstrating improvement in patient reported outcomes or survival with brentuximab vedotin. Advani:Seattle Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Pharmacyclics: Research Funding; Abbott: Research Funding. Oki:Seattle Genetics, Inc.: Research Funding. Sharman:Seattle Genetics, Inc.: Research Funding. Horwitz:Seattle Genetics, Inc.: Consultancy, Research Funding; Novartis: Consultancy; Millennium: Consultancy; Celgene: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy; Allos Therapeutics: Consultancy, Research Funding; Merck: Honoraria; Genzyme: Research Funding; Infinity Pharmaceuticals: Research Funding. Forero-Torres:Seattle Geentics, Inc.: Research Funding, Speakers Bureau. O'Connor:Seattle Genetics, Inc.: Consultancy, Research Funding; Millennium: Consultancy, Research Funding. Shustov:Seattle Genetics, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Siddiqi:Seattle Genetics, Inc.: Consultancy, Research Funding. Grove:Seattle Genetics, Inc.: Employment, Equity Ownership. Bartlett:Seattle Genetics, Inc.: Consultancy, Research Funding, Travel expenses Other.

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

Blood ◽

10.1182/blood.v118.21.443.443 ◽

2011 ◽

Vol 118 (21) ◽

pp. 443-443 ◽

Cited By ~ 9

Author(s):

Ranjana H. Advani ◽

Andrei R. Shustov ◽

Pauline Brice ◽

Nancy L. Bartlett ◽

Joseph D. Rosenblatt ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Cell Lymphoma ◽

Objective Response ◽

Large Cell ◽

Brentuximab Vedotin ◽

Employment Equity ◽

Advisory Committees ◽

Phase 2 Study ◽

Equity Ownership

Abstract 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.

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Phase 1b Results of a Phase 1b/2 Study of Obinutuzmab, Ibrutinib, and Venetoclax in Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL)

Blood ◽

10.1182/blood.v128.22.639.639 ◽

2016 ◽

Vol 128 (22) ◽

pp. 639-639 ◽

Cited By ~ 21

Author(s):

Jeffrey A. Jones ◽

Jennifer Woyach ◽

Farrukh T. Awan ◽

Kami J. Maddocks ◽

Thomas Whitlow ◽

...

Keyword(s):

Adverse Events ◽

Board Of Directors ◽

Research Funding ◽

Single Agent ◽

Objective Response ◽

Response Assessment ◽

Phase 2 ◽

Advisory Committees ◽

Once Daily ◽

Phase 1B

Abstract BACKGROUND Venetoclax(VEN), a once daily oral inhibitor of BCL2, has demonstrated high response rates and acceptable toxicity in patients with relapsed or refractory (R/R) CLL both as a single agent and in combination with the anti-CD20 monoclonal antibodies rituximab and obinutuzumab (formerly GA-101, G), where minimal residual disease (MRD) negative responses have been observed in the majority of patients. Ibrutinib (IBR), a once daily oral inhibitor of the Brutontyrosine kinase, likewise induces remissions in the majority of treated patients, but complete response (CR) is uncommon even after prolonged administration. Early genetic studies have demonstrated that BCL2 over-expression rescues BTK deficient XID murine B-cells from spontaneous apoptosis (J Immunol 1996), so we hypothesized that combination therapy would more efficiently achieve deep response endpoints. We report phase 1b results of a single-institution phase 1b/2 study of G, IBR, and VEN to characterize the safety and preliminary efficacy of the combination. METHODS Patients with CLL relapsed after or refractory to ≥1 prior therapy and who required treatment were eligible. Enrolled patients had ECOG ≤1 and preserved end-organ function, including creatinine clearance ≥50 mL/min/m2. Patients with chronic viral hepatitis infection, uncontrolled autoimmunecytopenia, active Richter transformation, and known cysteine-481 BTK mutation or clinical disease progression during treatment with a cysteine-481-binding BTK inhibitor were excluded. G, IBR, and VEN were started sequentially over the first 3 of fourteen 28-day cycles as detailed in the table. To establish the safety of VEN in combination with OBIN and IBR, VEN dose was escalated in 3 x 3 cohorts (100, 200, 400 mg) to a maximum planned dose of 400 mg daily. Dose limiting toxicity (DLT) was defined during the third cycle. Risk assessment for VEN dose ramp-up was conducted according to US prescribing information. Adverse events were assessed and graded using CTCAE v4.03. Response assessment according to IWCLL 2008 criteria, including bone marrow biopsy with 4-colorimmunophenotyping of marrow and peripheral blood (PB) for MRD, occurs after cycles 8 and 14. RESULTS Twelve R/R patients have been treated in the phase 1b portion of the trial. Median age was 57 years (range: 42-70) and median prior therapies was 1 (range: 1-7). Baseline genetic risk features includedunmutatedIGHV in 11 (92%),del(17p) in 1 (8%), del(11q) in 8 (67%), and complex abnormal karyotype in 5 (42%) patients. Tumor lysis (TLS) risk was low in 1 (8%), medium in 7 (58%), and high in 4 (33%) patients at study entry. In general, observed toxicities for the combination were consistent with those reported for the single agents. DLTs were not observed at any VEN dose level, establishing VEN 400 mg daily as safe in combination with standard doses of G and IBR. The most common grade ≥3 adverse events (regardless of attribution) were neutropenia (50%), lymphopenia (33%),hypertension(25%), and fatigue (17%). Grade 1/2 adverse events occurring in over half the patients included bruising (all grade 1, 83%), infusion related reaction (75%), hypertension (67%), headache (67%), hyperuricemia (all grade 1, 75%), hypocalcemia (75%), and diarrhea (all grade 1, 67%), AST and/or ALT elevation (58%), and rash (50%). No cases of either clinical or laboratory TLS were observed. All patients remain on therapy and 6 have reached response assessment after completing 8 cycles of therapy. All 6 have achieved objective response: 5 PR, including 1 MRD-negative in PB (VEN 100) and 1 MRD-negative in both PB and marrow (VEN 100), and 1 CR with MRD-negative PB and marrow (VEN 200). CONCLUSIONS G, IBR, and VEN can be safely administered in combination at doses standard for the treatment of CLL. DLTs were not observed, establishing VEN 400 mg as the recommended phase 2 dose in combination with G and IBR. Adverse events were manageable and largely consistent with those reported in the single agent phase 2 studies. Objective responses, including MRD-negative responses, have been observed among all R/R patients from the first dose cohorts. Accrual continues to parallel phase 2 cohorts of R/R (n=25) and TN (n=25) patients. Updated phase 1b toxicity and response data will be presented. Table. Table. Disclosures Jones: Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Awan:Pharmacyclics: Consultancy; Novartis Oncology: Consultancy; Innate Pharma: Research Funding.

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Brentuximab Vedotin (BV) and Lenalidomide (Len) in Relapsed and Refractory (r/r) Cutaneous (CTCL) and Peripheral (PTCL) T-Cell Lymphomas; A Planned Interim Analysis of Phase II Trial

Blood ◽

10.1182/blood-2019-123801 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2853-2853

Author(s):

Basem M. William ◽

Ying Huang ◽

Amy Johnson ◽

Jonathan E Brammer ◽

John C. Reneau ◽

...

Keyword(s):

T Cell ◽

Board Of Directors ◽

Phase Ii ◽

Research Funding ◽

Cell Lymphoma ◽

Single Agent ◽

Large Cell ◽

Median Number ◽

Brentuximab Vedotin ◽

Advisory Committees

Background: Patients with r/r tumor stage CTCL and/or PTCL have a poor prognosis. BV is currently FDA approved for CD30 positive CTCL and anaplastic large cell lymphoma (ALCL) with single agent activity in additional PTCL subtypes. Len also has single agent activity in patients with r/r CTCL/PTCL. The safety of the combination was established in a phase I trial in patients with r/r diffuse large B-cell lymphoma. Methods: We conducted a single-institution phase II trial to determine the safety and efficacy of BV+Len combination in patients with r/r CTCL/PTCL. Simon's 2-stage optimal design was followed to test the null hypothesis of overall response rate (ORR) ≤0.3 versus the alternative hypothesis of ORR≥0.5. Patients with ≥ 1 line of systemic therapy or 2 lines of skin directed therapy, at least stage IB (for CTCL), and no prior progression on BV were eligible regardless of CD30 staining. All patients were treated with BV 1.2 mg/kg IV and Len 20 mg PO daily q3 weeks for a maximum 16 cycles. After 7 patients were treated, we reduced Len to 10 mg given safety/tolerability concerns. Responses are assessed by the International Society for Cutaneous Lymphomas and the cutaneous lymphoma task force of the European Organization of Research and Treatment of Cancer (ISCL/EORTC) Global response criteria (for CTCL) and Cheson year criteria (for PTCL). The effect of treatment on quality of life is assessed by Skindex-16. Results: As of July 1, 2019, 17 subjects were treated; 10 (59%) with mycosis fungoides (MF), 2 (12%) with Sezary syndrome (SS), 2 (12%) with CD30+ lymphoproliferative disorder, and 3 (18%) with PTCL. Median age was 60 (49-90) years and 76% were males. CD30 was completely negative (<1%) in 3 (18%) of patients and median CD30 staining (by immunohistochemistry) was 7.5% (range 1-75%). Of 12 patients with MF/SS, 5 (42%) had evidence of large cell transformation at accrual. Of 14 patients with CTCL, median baseline mSWAT was 54.5 (range 4.4-190). Median number of prior therapies was 5 (range 1-9). Grade 3 adverse events (AEs) were reported in 11/17 patients; including neutropenia (4), thrombocytopenia (1), bronchitis (1), dyspnea (1), abdominal pain (2), vertigo (1), , DRESS (Drug Rash with Eosinophilia and Systemic Symptoms) syndrome (1), urinary tract infection (1), and tumor flare (2). Median number of cycles received was 4 (range 1-17). Best response in 14 evaluable patients were 2 (14%) complete response, 3 (21%) partial response, and 8 (57%) stable disease with ORR of 33% (95% confidence interval:12-62%). Of 17 patients, 5 (29%) remain on treatment, and 12 (71%) discontinued treatment because of disease progression (7; 58%), AEs (4; 33%), or patient preference (1; 2%). Median duration of response was 3.2 (range 2.5-13) months. Of note, 7/14 patients (50%) patients with CTCL had >50% reduction in their Skindex-16 scores after a median of 2 cycles (range 1-3). Conclusions: BV + Len is combination is safe and efficacious in a heavily pre-treated patients with T-cell lymphomas. Len doses higher than 10 mg daily are poorly tolerated and associated with excess tumor flare. Recruitment of both CTCL and PTCL patients for this trial is ongoing. Disclosures William: Guidepoint Global: Consultancy; Kyowa Kirin, Inc.: Consultancy; Defined Health: Consultancy; Techspert: Consultancy; Celgene Corporation: Consultancy. Brammer:Verastem, Inc: Research Funding; Viracta Therapeutics, Inc.: Research Funding; Bioniz Therapeutics, Inc.: Research Funding. Grantier:Pharmacyclics LLC and Janssen Oncology: Other: Advisory Board. Hoffman:Pharmacyclics LLC and Janssen Oncology: Other: Advisory Board. Baiocchi:Prelude: Consultancy. Epperla:Pharmacyclics: Honoraria; Verastem Oncology: Speakers Bureau. Christian:Triphase: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Immunomedics: Research Funding; Acerta: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding; Cephalon: Research Funding; Merck: Research Funding; Janssen: Research Funding; Millennium Pharmaceuticals Inc: Research Funding. Maddocks:BMS: Research Funding; Merck: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Brentuximab vedotin is being used off-label for CD30 negative peripheral and cutaneous T-cell lymphoma. Lenalidomide is being used off-label for both conditions (within a phase II clinical trial)

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A Phase 1b Study Investigating the Combination of the Tetravalent Bispecific NK Cell Engager AFM13 and Pembrolizumab in Patients with Relapsed/Refractory Hodgkin Lymphoma after Brentuximab Vedotin Failure: Updated Safety and Efficacy Data

Blood ◽

10.1182/blood-2018-99-118506 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1620-1620 ◽

Cited By ~ 7

Author(s):

Nancy L. Bartlett ◽

Robert W. Chen ◽

Eva Domingo-Domenech ◽

Andres Forero-Torres ◽

Ramon Garcia-Sanz ◽

...

Keyword(s):

Adverse Events ◽

Nk Cells ◽

Board Of Directors ◽

Salvage Therapy ◽

Research Funding ◽

Nk Cell ◽

Single Agent ◽

Brentuximab Vedotin ◽

Advisory Committees ◽

Phase 1B

Abstract Background AFM13 is a bispecific, tetravalent NK cell-engaging antibody construct binding to CD30 on CD30+ tumor cells and CD16A on NK cells. By engaging CD16A-positive NK cells, AFM13 leads to NK cell-mediated killing of CD30-positive lymphoma cells (Reusch et al., 2014) making it an attractive agent to target classical Hodgkin lymphoma (HL). Pembrolizumab is a PD-1 blocking antibody which has shown high single-agent response rates in patients (pts) with relapsed/refractory HL (RRHL; Armand et al., 2016, Chen et al., 2017). AFM13 has shown clinical activity in RRHL as a single agent in a preceding Phase 1 study (Rothe et al., 2015). Preclinical in vivo data of the combination of AFM13 with PD-1 blockade showed synergistic activity and the potential for induction of cross-talk between innate and adaptive immunity (Zhao et al., 2016). We hypothesize that the combination of the two agents could improve outcomes in pts with RRHL. Methods This Phase 1b study is evaluating the safety and tolerability of the combination of AFM13 with pembrolizumab (Keytruda) as salvage therapy after failure of standard therapies including brentuximab vedotin (BV) in HL (NCT02665650). Pts receive escalating doses of AFM13 in combination with pembrolizumab at a dose of 200 mg flat administered every 3 weeks following a classical 3+3 design, followed by enrollment into an extension cohort at the maximum tolerated dose (MTD)/maximum administered dose (MAD). Response assessment is performed every 12 weeks by PET/CT according to the Lugano Classification (Cheson et al., 2014). The main objectives of the study is to ascertain the MTD/MAD along with the preliminary efficacy of the combination. Results As of June 29, 2018, 30 pts have been enrolled into the study. The median age is 34 years (range, 18-73), with a median of 4 (range 3-7) prior lines of therapy. All pts had relapsed or refractory disease (43% relapsed, 57% refractory) and had failed standard treatments including BV and 43% of pts (13/30) had BV as their latest therapy. Thirty seven percent (11/30) had undergone prior autologous stem cell transplantation. All 30 pts have completed the 6-week dose-limiting toxicity (DLT) observation period. Twelve pts were enrolled into the dose escalation cohorts (Cohorts 1 (n=3), 2 (n=3), and 3 (n=6)) and 18 into the Extension Cohort, with a total of 24 patients treated at the MAD (dose level 3). One DLT was observed in Cohort 3 (missing ≥25% of AFM13 during the DLT period) and another observed in the Extension Cohort (G4 infusion-related reaction; IRR). The most common related adverse events (AEs) were IRRs (80%), rash (30%), pyrexia (23%), nausea (23%), diarrhea (20%), fatigue (17%), headache (17%), increased aspartate aminotransferase (13%), and increased alanine aminotransferase (10%). Treatment related G3/4 AEs included IRRs (13%), elevated AST (3%), gastritis (3%), hypotension (3%), nausea (3%), neutropenia (3%), and vomiting (3%). The majority of IRRs were manageable with standard of care measures and did not lead to treatment discontinuations. Included in the efficacy analysis were the best response from 29 evaluable pts who had at least one post-baseline disease assessment as of the data cutoff on June 29, 2018. The overall response rate (ORR) and complete response (CR) rate for evaluable pts treated at the dose and schedule chosen for expansion (n=23; Cohort 3 and Extension Cohort) were 87% and 35% by the investigator-confirmed assessment, respectively. Independent assessment resulted in an ORR of 87% and CR rate of 39% for these pts. Updated data for all 30 patients will be presented at the meeting. Conclusions The combination of AFM13 and pembrolizumab is a well-tolerated salvage therapy in pts with RRHL. IRRs were the most frequently observed adverse events; however, most of these events were of mild or moderate severity and manageable. Both the ORR and CR rate compare favorably to monotherapy pembrolizumab in a similar RRHL population (Chen et al., 2017). The combination of AFM13 and pembrolizumab could be a potential new therapeutic option for HL patients. Disclosures Bartlett: Immune Design: Research Funding; Affimed: Research Funding; Bristol-Meyers Squibb: Research Funding; Merck & Co: Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding; Pharmacyclics: Research Funding; Genentech: Research Funding; Forty Seven: Research Funding; Novartis: Research Funding; Novartis: Research Funding; Millennium: Research Funding; ImaginAB: Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees. Chen:Affimed: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Genentech Inc.: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Merck & Co., Inc.: Consultancy, Research Funding, Speakers Bureau; Millennium Pharmaceuticals: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding. Domingo-Domenech:Affimed: Research Funding. Forero-Torres:Affimed: Research Funding. Garcia-Sanz:Affimed: Research Funding. Devata:Affimed: Research Funding. Rodriguez Izquierdo:Affimed: Research Funding. Lossos:Affimed: Research Funding. Reeder:Affimed: Research Funding. Sher:Affimed: Research Funding. Choe-Juliak:Affimed: Employment. Prier:Affimed: Research Funding. Schwarz:Affimed: Employment. Strassz:Affimed: Employment. Alland:Affimed: Employment. Ansell:Bristol-Myers Squibb: Research Funding; Celldex: Research Funding; LAM Therapeutics: Research Funding; Trillium: Research Funding; Pfizer: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; Merck & Co: Research Funding; Affimed: Research Funding; Takeda: Research Funding.

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Allogeneic Transplant Following Brentuximab Vedotin Treatment in Patients with Relapsed or Refractory CD30+ Lymphomas

Blood ◽

10.1182/blood.v118.21.3091.3091 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3091-3091 ◽

Cited By ~ 5

Author(s):

Tim Illidge ◽

Reda Bouabdallah ◽

Robert W. Chen ◽

Ajay K. Gopal ◽

Craig H. Moskowitz ◽

...

Keyword(s):

Board Of Directors ◽

Median Time ◽

Research Funding ◽

Objective Response ◽

Sensory Neuropathy ◽

Brentuximab Vedotin ◽

Peripheral Sensory Neuropathy ◽

Advisory Committees ◽

Peripheral Sensory

Abstract Abstract 3091 Background: Allogeneic stem cell transplant (allo-SCT) for relapsed or refractory lymphoma is often limited by the amount of residual tumor burden following cytoreductive therapy. Brentuximab vedotin (SGN-35) comprises an anti-CD30 antibody conjugated by a protease-cleavable linker to the potent antimicrotubule agent, monomethyl auristatin E (MMAE). In recent phase 2 trials, brentuximab vedotin induced objective responses in 75% of patients with Hodgkin lymphoma (HL) (Chen 2011) and 86% of patients with systemic ALCL (sALCL) (Pro 2011). Fifteen of 160 patients (9%) who participated in these two phase 2 studies received an allo-SCT as their first subsequent antitumor therapy after treatment with brentuximab vedotin. This case series describes the initial experience of these patients. Methods: Patients received 1.8 mg/kg brentuximab vedotin administered every 3 weeks as a 30-minute outpatient IV infusion for up to 16 cycles of treatment. Antitumor activity was based on objective response assessments according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). After discontinuing brentuximab vedotin, patients were followed for survival/disease status and information regarding subsequent therapy, including allo-SCT, was collected. Results: Fifteen patients (7 with HL and 8 with sALCL) received an allo-SCT as their first subsequent antitumor therapy following brentuximab vedotin treatment. The median age was 28.0 years (range 17–61 years) and the majority (67%) were female. The median time since initial HL/sALCL diagnosis was 27.3 months (range 6.2–108 months). The median number of therapies patients had received prior to brentuximab vedotin was 3.0 (range 2–5) and 12 patients had previously received an autologous SCT. Patients received a median of 9.0 cycles (range 4–16) of brentuximab vedotin and all 15 patients achieved an objective response per independent radiological review; best response was CR for 12 patients (5 with HL and 7 with sALCL) and PR for 3 patients (2 with HL and 1 with sALCL). The median time to objective response was 1.4 months (range 1.2–2.6 months) and all 15 patients maintained an objective response at the time of the last assessment prior to allo-SCT. The median time between the last dose of brentuximab vedotin and the start of the SCT conditioning regimen was 1.4 months (range 0.6–3.3 months). Thirteen of the 15 patients (87%) are alive and remain in follow-up post allo-SCT. The median duration of follow-up from first dose of brentuximab vedotin is 16.9 months (range 8.2–21.1 months). Five patients (1 with HL and 4 with sALCL) have either progressed or died post-transplant. Four of these 5 patients had achieved a CR with brentuximab vedotin treatment. Of the 2 patients who died (both patients with sALCL who had achieved a CR with brentuximab vedotin treatment), one death was disease-related (not formally restaged) and the other was due to transplant-related complications. The median PFS at the time of this analysis is 21.1 months (range 8.2–21.1 months). Treatment-emergent adverse events that occurred prior to allo-SCT in >20% of patients were peripheral sensory neuropathy and pyrexia (53%; n=8), diarrhea and neutropenia (47%; n=7), nausea (33%; n=5), and chills and dyspnea (27%; n=4). Thirteen of 15 patients (87%) experienced AEs of ≥ Grade 3 prior to allo-SCT; the most common (reported in >10% of patients) were neutropenia (47%; n=7), anemia and thrombocytopenia (27%; n=4), and abdominal pain, pain, and peripheral sensory neuropathy (13%; n=2). Two patients discontinued brentuximab vedotin treatment due to an AE (peripheral sensory neuropathy) before subsequently receiving allo-SCT. Conclusions: Treatment with brentuximab vedotin provided cytoreduction in patients with relapsed or refractory HL and sALCL, many of whom had failed a prior autologous SCT. Thirteen of the 15 patients (87%) achieved an objective response with brentuximab vedotin treatment prior to allo-SCT and remain in follow-up at the time of this analysis. Ten of the 15 patients (67%) remain in remission. Our results suggest that brentuximab vedotin may be an option for reducing tumor burden to facilitate a consolidative allo-SCT and warrants further study. Disclosures: Illidge: Seattle Genetics, Inc.: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Honoraria. 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. Bouabdallah:Seattle Genetics, Inc.: Research Funding. Chen:Seattle Genetics, Inc.: Consultancy, Research Funding, Travel Expenses. Gopal:Seattle Genetics: Consultancy, Honoraria, Research Funding; Millennium: Honoraria, Speakers Bureau; Cephalon: Research Funding; Spectrum: Research Funding; Piramal: Research Funding; Merck: Research Funding; Calistoga: Research Funding; Abbott: Research Funding; Pfizer: Research Funding; SBIO: Research Funding; Gilead: Research Funding; Genzyme: Speakers Bureau; Amgen: Speakers Bureau; Cellular Therapeutics Inc.: Speakers Bureau. Moskowitz:Seattle Genetics, Inc.: Consultancy, Research Funding; Cephalon: Research Funding; Genentech: Research Funding; Plexxicon: Research Funding. Ramchandren:Seattle Genetics, Inc.: Research Funding. Rosenblatt:Seattle Genetics, Inc.: Research Funding. Shustov:Seattle Genetics, Inc.: Consultancy, Research Funding; Millennium: Honoraria. Tilly:Genentech: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau, Travel/accommodations/meeting expenses; Seattle Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Research Funding, Speakers Bureau; Pfizer: Speakers Bureau; Janssen Cilag: Speakers Bureau. Trippett:Seattle Genetics, Inc.: Research Funding; OSI Pharmaceuticals: DSMB Chair. Grove:Seattle Genetics, Inc.: Employment; Seattle Genetics, Inc.: Equity Ownership. Advani:Seattle Genetics, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Prolonged Treatment with Brentuximab Vedotin (SGN-35) in Patients with Relapsed or Refractory Hodgkin Lymphoma (HL) or Systemic Anaplastic Large Cell Lymphoma (sALCL),

Blood ◽

10.1182/blood.v118.21.3711.3711 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3711-3711 ◽

Cited By ~ 7

Author(s):

Andres Forero-Torres ◽

R. Brian Berryman ◽

Ranjana H. Advani ◽

Nancy L. Bartlett ◽

Robert W. Chen ◽

...

Keyword(s):

Peripheral Neuropathy ◽

Board Of Directors ◽

Median Duration ◽

Research Funding ◽

Objective Response ◽

Case Series ◽

Brentuximab Vedotin ◽

Extension Study ◽

Prolonged Treatment ◽

Advisory Committees

Abstract Abstract 3711 Background: Brentuximab vedotin (SGN-35) comprises an anti-CD30 antibody conjugated by a protease-cleavable linker to the potent antimicrotubule agent, monomethyl auristatin E (MMAE). Trials with brentuximab vedotin have previously reported results in patients with relapsed or refractory HL or sALCL. In a pivotal HL trial, complete remissions (CRs) were observed in 35 of 102 patients (34%) with a median duration of 20.5 months (Chen 2011). Thirty-three of 58 patients (57%) with sALCL achieved CRs with a median duration of 13.2 months in a phase 2 trial (Pro 2011). In both of these studies, a maximum of 16 cycles was permitted; patients with HL received a median of 10 cycles and those with sALCL, 7 cycles. This case series presents a retrospective analysis on a subset of patients who have received prolonged treatment (>16 cycles) with brentuximab vedotin in a treatment-extension study (ClinicalTrials.gov #NCT00947856). Methods: Brentuximab vedotin 1.2 or 1.8 mg/kg was administered every 3 weeks as a 30-minute outpatient IV infusion for up to 16 cycles of treatment in 1 of 4 preceding studies. Consecutive cycles of treatment were then administered in the extension study until disease progression, unacceptable toxicity, or withdrawal of consent. Antitumor activity in this case series was based on objective response assessments per the investigator according to the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Results: Fifteen patients have received >16 consecutive cycles of treatment with brentuximab vedotin. The median age of patients was 35 years (range 14–74); 9 patients were female. Patients had relapsed or refractory CD30-positive HL (10) or sALCL (5) and had received a median of 3 prior therapies (range 1–14). Nine patients had previously failed autologous stem cell transplant (SCT), and 2 of these patients had additionally failed an allogeneic SCT. The median number of treatment cycles was 19 (range 17–29). At the time of the analysis, 2 patients had discontinued treatment; neither patient had discontinued due to an adverse event (AE). AEs among patients were generally mild, which enabled continued treatment beyond the initial study. Across all cycles of treatment, AEs in >30% of patients were peripheral sensory neuropathy (73%), fatigue (53%), upper respiratory tract infection (53%), cough (40%), alopecia, diarrhea, neutropenia, and pyrexia (33% each). The only AE which occurred for the first time after Cycle 16 in more than 1 patient was neutropenia (n=2). Peripheral neuropathy events (by Standardised MedDRA Query) of Grade 1 or 2 were experienced by 87% of patients; no Grade 3 or 4 events of peripheral neuropathy were observed. Peripheral neuropathy was managed with dose reductions and dose delays; resolution or improvement of peripheral neuropathy was observed in over half of the patients (7 of 13) with a median time to resolution or improvement of 3.1 weeks (range 0.1–8). Best clinical responses in patients were 11 CRs, including CRs achieved by all 5 patients with sALCL, 2 partial remissions (PRs), and 2 patients with stable disease. Four of 11 patients evolved from a PR to achieve a CR; the median time from first dose to achievement of CR was 12 weeks (range 5.4–48.9). The median duration of objective response has not been reached; the durations ranged from 6.5+ to 21.8+ months. At the time of the analysis, 14 patients were alive and free of documented progression, and the median progression-free survival had not been reached (range 11.8+ to 23+ months). Conclusions: Among patients with relapsed or refractory HL or sALCL who have enrolled in a treatment-extension study, 15 have received >16 consecutive cycles of treatment with brentuximab vedotin. The safety profile of brentuximab vedotin did not meaningfully change with treatment beyond 16 cycles. Durations of response (11 CR and 2 PR) ranged from 6.5+ to 21.8+ months, with 13 patients still receiving treatment. Updated safety and durability of response will be presented at the meeting. Disclosures: Forero-Torres: Seattle Genetics, Inc.: 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. Berryman:Seattle Genetics, Inc.: Research Funding; Soligenix: Research Funding; Gloucester Pharmaceuticals: Research Funding. Advani:Seattle Genetics, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Bartlett:Seattle Genetics, Inc.: Consultancy, Research Funding, Travel Expenses. Chen:Seattle Genetics, Inc.: Consultancy, Research Funding, Travel Expenses. Fanale:Seattle Genetics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Gopal:Seattle Genetics: Consultancy, Honoraria, Research Funding; Millennium: Honoraria, Speakers Bureau; Cephalon: Research Funding; Spectrum: Research Funding; Piramal: Research Funding; Merck: Research Funding; Calistoga: Research Funding; Abbott: Research Funding; Pfizer: Research Funding; SBIO: Research Funding; Gilead: Research Funding; Genzyme: Speakers Bureau; Amgen: Speakers Bureau; Cellular Therapeutics Inc.: Speakers Bureau. O'Connor:Seattle Genetics, Inc.: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Allos: Consultancy, Research Funding; Purdue Pharma: Consultancy; Celgene: Consultancy; Merck: Research Funding. Olshefski:Seattle Genetics, Inc.: Research Funding. Smith:Seattle Genetics, Inc.: Research Funding; Cephalon: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Spectrum: Consultancy; GSK: Speakers Bureau. Grove:Seattle Genetics, Inc.: Equity Ownership; Seattle Genetics, Inc.: Employment. Matous:Seattle Genetics, Inc.: Research Funding; Celgene: Speakers Bureau; Cephalon: Speakers Bureau; Millennium: Speakers Bureau.

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A Phase 2 Study Of Brentuximab Vedotin In Patients With Relapsed Or Refractory CD30-Positive Non-Hodgkin Lymphomas: Interim Results In Patients With DLBCL and Other B-Cell Lymphomas

Blood ◽

10.1182/blood.v122.21.848.848 ◽

2013 ◽

Vol 122 (21) ◽

pp. 848-848 ◽

Cited By ~ 22

Author(s):

Nancy L. Bartlett ◽

Jeff P. Sharman ◽

Yasuhiro Oki ◽

Ranjana H. Advani ◽

Celeste M. Bello ◽

...

Keyword(s):

B Cell ◽

Board Of Directors ◽

Research Funding ◽

Response Rate ◽

Cell Lymphoma ◽

Objective Response ◽

B Cell Lymphoma ◽

Brentuximab Vedotin ◽

Advisory Committees ◽

Board Membership

Abstract Background Brentuximab vedotin (ADCETRIS®) is an anti-CD30 monoclonal antibody conjugated by a protease-cleavable linker to a microtubule-disrupting agent, monomethyl auristatin E. Variable CD30 expression has been demonstrated in several B-cell non-Hodgkin lymphoma (NHL) subtypes such as diffuse large B-cell lymphoma (DLBCL) and primary mediastinal B-cell lymphoma (PMBL). Methods A phase 2, open-label, single-arm study is ongoing to evaluate the antitumor activity of brentuximab vedotin in relapsed or refractory CD30-positive NHL, including B-cell neoplasms (Clinical Trials.gov NCT01421667). CD30 expression is determined by immunohistochemistry per local laboratory; any level of CD30-positive expression is permitted for enrollment. Brentuximab vedotin, 1.8 mg/kg, is administered every 3 weeks by IV infusion. Patients who achieve at least stable disease are eligible to receive continued treatment until disease progression or unacceptable toxicity. The primary efficacy endpoint is objective response rate (ORR) as assessed by the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Correlation between antitumor activity and quantitative CD30 expression is also being explored. This subset analysis presents interim data for patients with relapsed/refractory Bcell neoplasms. Results Sixty-two B-cell lymphoma patients with variable CD30 expression by central review (range 0–100%) have been enrolled to date. Diagnoses include DLBCL (n=44) and other B-cell neoplasms (n=18) [grey zone lymphoma (n=6), PMBL (n=6), follicular lymphoma (n=3), and post-transplant lymphoproliferative disorder (n=3)]. The median age of all patients was 55 years (range, 16–85 years), and the majority had an ECOG performance status of 0/1 (92%). Patients had received a median of 2 prior therapies (range, 1 to 19); 11 (18%) had received prior stem cell transplant. Forty patients (65%) had primary refractory disease, and 47 patients (76%) were refractory to their most recent prior therapy. Fourteen patients (23%) had never responded to any prior therapy. At the time of this analysis, patients had received a median of 3 cycles of treatment (range, 1–17 cycles), with a median duration of treatment of 10.5 weeks (range, 2.4 to 57.1 weeks). Twelve (19%) patients remain on treatment. Of the 43 efficacy evaluable DLBCL patients, 40% achieved an objective response [7 complete remission (CR), 10 partial remission (PR)]; the median duration of objective response was 36 weeks (range, 0.1+ to 62.3+ weeks). Of the 18 efficacy evaluable patients with other Bcell neoplasms, 22% achieved an objective response: PMBL (1 CR), PTLD (1 CR), and grey zone lymphoma (2 PRs). The median duration of objective response was 21.7 weeks (range, 6.1 to 37.1 weeks). CD30 expression levels for patients with a CR or PR were variable and ranged from <1% to 90%. There was no statistical correlation between CD30 expression and response rate. Treatment-emergent adverse events (AEs) occurring in >20% of patients included fatigue (40%), nausea and neutropenia (37% each), pyrexia (32%), diarrhea (31%), peripheral sensory neuropathy (26%), vomiting (23%), and anemia and constipation (21% each). Peripheral neuropathy events have been primarily Grade 1 or 2. Neutropenia (29%) was the only Grade 3/4 related AE observed in >10% of patients. AEs led to treatment discontinuation in 6 patients; the most common reason was peripheral sensory neuropathy (2 patients). Conclusions In this interim analysis of 62 patients with highly refractory B-cell lymphomas, compelling antitumor activity has been observed with brentuximab vedotin. Forty percent of DLBCL patients achieved an objective response, with median remission duration of >8 months and a notable proportion of complete remissions. No correlation between CD30 expression and response rate has been observed to date. Safety data are consistent with the profile of brentuximab vedotin. This study continues to enroll patients and updated results will be presented at the meeting. Disclosures: Bartlett: Seattle Genetics, Inc.: Advisory/scientific board membership and travel expenses Other, Research Funding. Off Label Use: Brentuximab vedotin is indicated for treatment of patients with Hodgkin lymphoma after failure of autologous stem cell transplant or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not ASCT candidates and for the treatment of patients with systemic anaplastic large cell lymphoma after failure of at least one prior multi-agent chemotherapy regimen. Sharman:Seattle Genetics, Inc.: Research Funding, Travel expenses Other; Genentech: Research Funding; Gilead: Research Funding. Oki:Seattle Genetics, Inc.: Research Funding. Advani:Millennium: Advisory/scientific board membership, Advisory/scientific board membership Other, Research Funding; Seattle Genetics, Inc.: Advisory/scientific board membership Other, Research Funding; Genentech: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Pharmacyclics, Inc.: Research Funding; Janssen R&D: Research Funding; Allos Therapeutics: Research Funding; Celgene: Membership on an entity’s Board of Directors or advisory committees; Abbott: Research Funding. Bello:Seattle Genetics, Inc.: Research Funding, Speakers Bureau; Celgene: Membership on an entity’s Board of Directors or advisory committees; Spectrum pharmaceuticals: Speakers Bureau. Winter:Seattle Genetics, Inc.: Research Funding. Yang:Seattle Genetics, Inc.: Employment, Equity Ownership. Kennedy:Seattle Genetics, Inc.: Employment, Equity Ownership. Jacobsen:Seattle Genetics, Inc.: Advisory/scientific board membership Other, Research Funding.

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The Oral Selective Inhibitor of Nuclear Export (SINE) Selinexor (KPT-330) Demonstrates Broad and Durable Clinical Activity in Relapsed / Refractory Non Hodgkin’s Lymphoma (NHL)

Blood ◽

10.1182/blood.v124.21.396.396 ◽

2014 ◽

Vol 124 (21) ◽

pp. 396-396 ◽

Cited By ~ 17

Author(s):

John Kuruvilla ◽

John C. Byrd ◽

Joseph M Flynn ◽

Ramiro Garzon ◽

Pierluigi Porcu ◽

...

Keyword(s):

Board Of Directors ◽

Nuclear Export ◽

Research Funding ◽

Phase 1 ◽

Single Agent ◽

Objective Response ◽

Employment Equity ◽

Advisory Committees ◽

Heavily Pretreated ◽

Equity Ownership

Abstract Background: The nuclear export protein, XPO1 is overexpressed in all types of malignant lymphoma. The SINE selinexor (KPT-330) is a slowly reversible XPO1 antagonist that forces the nuclear retention and activation of over 10 tumor suppressor proteins (TSP) such as p53, IkB, FOXO and p21. In addition, selinexor inhibits the nuclear export and the translation of oncogenic mRNAs such as c-myc and Bcl-XL levels. Together these effects result in apoptosis of cancer cells in preclinical models of both T- and B- cell NHL. In DLBCL cell lines (n=10), selinexor induced potent cytotoxicity against both germinal center (GCB) and nonGCB including those with high MYC and/or BCL2/6 protein levels. Methods: Selinexor was administered orally for 4-10 doses in a 28-day cycle in this phase 1 study. Serial tumor biopsies were performed. Response evaluation was performed in cycle 1 and 2 and then every 2 cycles. All pts had heavily pretreated NHL with documented progressive disease (PD) on study entry. Results: 58 pts (34 males 24 females; median age 62 yrs; ECOG PS 0/1/2: 19/35/4; median prior regimens: 3) received selinexor across 13 dose levels (3 to 80 mg/m2). The recommended Phase 2 dose is 60 mg/m2 based on results across all Phase 1 studies. Grade 3/4 events (>5%) include thrombocytopenia (31%), neutropenia (22%), fatigue (10%), and anemia (7%). The most common Grade 1/2 AEs were: nausea (66%), anorexia (47%), fatigue (40%), and vomiting (40%) that were manageable with supportive care and were seen less frequently following cycle 1. Increases in XPO1 mRNA levels were observed at all doses and sustained for 4-48 hours, supporting twice weekly dosing. Tumor biopsies confirmed TSP nuclear localization, c-myc reductions, and apoptosis induction of cancer cells. Objective responses were observed in all classes of NHL studied (Table 1). An objective response rate (ORR) of 31% was observed across all NHL types. An ORR of 40% was observed in pts with rel/ref aggressive B-NHL (DLBCL, Follicular NHL grade 3b (FLgrd3b) and transformed NHL) at doses ³60 mg/m2 vs an ORR of 33% at 23-50 mg/m2 and 25% at ²20 mg/m2. Across all NHL types, time to best response was delayed, including 5 complete responses (CR) (4 in DLBCL and 1 T-NHL). Nine pts out of 34 have remained on therapy for >6-23 months without clinically significant cumulative toxicities or major organ dysfunction. Conclusions: Selinexor treatment is generally well tolerated with supportive care and can be given over a prolonged period. Durable single agent activity in pts with heavily pretreated NHL has been observed. Phase 2 studies in DLBCL, Richter's transformation and T-NHL of single agent selinexor as well as in combination with other agents including CD20 antibodies are expected to begin in the near future. Abstract 396. Table 1 Cancer Type Selinexor Dose (mg/m2) N* ORR (%) CR (%) PR (%) SD (%) PD (%) WC/NE (%) Aggressive B-NHL (DLBCL, FLgrd3b, Transformed) ≤20 4 1 (25%) -- 1 (25%) 1 (25%) 2 (50%) -- 20 – 50 21 7 (33%) 4 (19%) 3 (14%) 5 (24%) 6 (29%) 3 (14%) ≥60* 10 4 (40%) -- 4 (40%) 4 (40%) -- 2 (20%) Follicular & Other Indolent NHL ≤30 4 -- -- -- 4 (100%) -- -- ≥35 4 2 (50%) -- 2 (50%) 1 (25%) -- 1 (25%) Mantle Cell Lymphoma ≤30 2 1 (50%) -- 1 (50%) 1 (50%) -- -- ≥35 2 -- -- -- -- 1 (50%) 1 (50%) T-Cell Lymphoma ≤30 4 -- -- -- 2 (50%) -- 2 (50%) ≥35 1 1 (100%) 1 (100%) -- -- -- -- Richter's Transformation ≤30 3 1 (33%) -- 1 (33%) 2 (67%) -- -- ≥35 3 1 (33%) -- 1 (33%) -- -- 2 (67%) TOTAL 58 18 (31%) 5 (9%) 13 (22%) 20 (34%) 9 (16%) 11 (19%) * First pt in this population was dosed on 23-July-2012 ORR=Objective Response Rate; CR=Complete Response; PR=Partial Response; SD=Stable Disease; PD=Progressive Disease; WC=Withdrew Consent; NE=Non-Evaluable Disclosures Byrd: Pharmacyclics, Genentech: Research Funding. Porcu:Infinity: Research Funding; Seattle genetics: Research Funding; Actelion: Honoraria; Celgene: Honoraria; United States Cutaneous Lymphoma Consortium: Membership on an entity's Board of Directors or advisory committees; Cutaneous Lymphoma Foundation: Membership on an entity's Board of Directors or advisory committees. Stone:AbbVie, Inc: Consultancy; Agios: Consultancy; Amgen: Consultancy; Celator: Consultancy; Celgene: Consultancy; Roche: Consultancy. Baz:Celgene: Research Funding; Millennium: Research Funding; Bristol Myers Squibb: Research Funding; Karyopharm: Research Funding; Sanofi: Research Funding. Flinn:AstraZeneca: Research Funding. Kukreti:Celgene: Honoraria. Landesman:Karyopharm Therapeutics: Employment. Klebanov:Karyopharm Therpeutics: Employment. Shacham:Karyopharm Therapeutics: Employment. Saint-Martin:Karyopharm Therpeutics: Employment. Marshall:Karyopharm Therpeutics: Employment. McCartney:Karyopharm Therpeutics: Employment. McCauley:Karyopharm Therapeutics: Employment, Equity Ownership. Carlson:Karyopharm Therapeutics: Employment. Norori:Karyopharm Therpeutics: Consultancy. Savona:Karyopharm Therpeutics: Membership on an entity's Board of Directors or advisory committees. Rashal:Karyopharm Therapeutics: Employment. Mirza:Karyopharm Therpeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kauffman:Karyopharm Therapeutics: Employment, Equity Ownership. Shacham:Karyopharm Therpeutics: Employment, Equity Ownership.

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