Phase 1b Study of Carfilzomib in Combination with Induction Chemotherapy in Children with Relapsed or Refractory Acute Lymphoblastic Leukemia (ALL)

Salvage options for children with relapsed ALL remain sub-optimal, particularly for T-cell ALL patients, and relapse remains the leading cause of death. Achieving complete remission (CR) after relapse is the first critical step to cure. Combining the proteasome inhibitor (PI) bortezomib with chemotherapy has previously shown promising results in achieving CR in pediatric phase 2 studies in ALL (Messinger 2012, Horton 2013, Bertaina 2017). In this ongoing dose-escalation phase 1 study, the second generation PI carfilzomib was combined with chemotherapy in children with relapsed ALL. Subjects received one 4-week cycle of induction chemotherapy with either UKALLR3 (dexamethasone, mitoxantrone, methotrexate, PEG-asparaginase, vincristine) or VXLD (vincristine, dexamethasone, PEG-asparaginase, daunorubicin) plus carfilzomib administered intravenously on days 1, 2, 8, 9, 15, and 16. The primary endpoint was dose limiting toxicities (DLTs) occurring during induction (grade 4 neutropenia or thrombocytopenia extending past day 45 or grade 4 non-hematological toxicity). Efficacy endpoints included CR (with or without hematological recovery) based on bone marrow (BM) and LP on day 29 of induction and consolidation. Subjects < 21 years of age and diagnosed with first early BM relapse (<36 months from diagnosis), multiply relapsed ALL, or primary induction failure were eligible; subjects with T-cell disease with any BM relapse were eligible. Subjects achieving ≥ stable disease could receive a cycle of modified BFM consolidation therapy (6-MP, cyclophosphamide, cytarabine, PEG-asparaginase, IT chemotherapy) plus carfilzomib at the same dose level and schedule given in induction therapy. Dose escalation was based on an evaluation of DLT's using a Bayesian logistic regression model. Ten subjects with B (n=9) or T- (n=1) cell ALL were treated with UKALLR3 at 2 carfilzomib dose levels (20 or 27 mg/m2, 5 subjects each). Among DLT-evaluable subjects, 3 DLTs (meningoencephalitis, hemolytic uremic syndrome and neutropenia) were observed, 2 at 27 and 1 at 20 mg/m2 dose levels with an MTD of 27 mg/m2. The UKALLR3 regimen was considered too toxic by the protocol steering committee and was replaced with VXLD in January 2016. The VXLD cohort started at 27 mg/m2 and is currently in the 56 mg/m2 dose level. Fifteen subjects (7 B-cell and 8 T-cell) were treated with VXLD at carfilzomib dose levels of 27 (n=3), 36 (n=7), 45 (n=4), and 56 (n=1) mg/m2. One DLT of posterior reversible encephalopathy syndrome (PRES) occurred in the 36 mg/m2 cohort, with no further DLTs identified after expansion to 7 subjects. Table 2 lists the patient characteristics of the 15 subjects in the VXLD cohort. Grade 3-4 hematological AEs were nearly universal for both UKALLR3 and VXLD. Non-hematological > Grade 3 AE's of note are listed in Table 1. PRES occurred in 2 subjects in the VXLD cohort (both with prior allogeneic SCT) and rapidly reversed in both cases. Re-challenge with carfilzomib in one case was tolerated without PRES recurrence. Serious AE's (SAE) were reported in 50% and 56% of subjects receiving carfilzomib in combination with UKALLR3 or VXLD, respectively, with the most common SAE's among all subjects being sepsis (16%), pancreatitis and PRES (8% each). In the UKALLR3 cohort, 60% of subjects (n=6) achieved a remission, however only 30% proceeded to consolidation. In the VXLD cohort, 53% of evaluable subjects (n=8) achieved remission and 13% were non-evaluable due to hypocellular BM at day 29 of induction. All responding subjects recovered hematological counts by day 42 without evidence of progression. Eight subjects (53%) proceeded to consolidation, including 2 subjects with non-evaluable BM results and 1 with 8% BM blasts after induction. All subjects entering consolidation were in remission on day 29 post-consolidation. The overall remission rate with VXLD-carfilzomib was 67% at the end of consolidation. Detailed response data are listed in Table 3. Carfilzomib in combination with VXLD chemotherapy was tolerable in a predominantly T-cell ALL population, very early or post stem cell transplant relapse. Efficacy is promising in this small cohort of patients with carfilzomib dose escalation continuing. Disclosures Burke: Amgen, Inc.: Consultancy, Speakers Bureau. Bautista Sirvent:EusaPharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending symposia; Takeda: Other: Support for attending symposia; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Honoraria, Other: Support for attending symposia; Amgen, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Gore:Amgen: Consultancy, Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel expenses; Novartis: Consultancy, Other: Service on Data Safety Monitoring Committee; travel, accommodations, expenses; Roche/Genentech: Consultancy, Honoraria, Other: travel expenses; Anchiano: Equity Ownership, Other: spouse employment and company leadership; Blueprint Medicines: Equity Ownership; Celgene: Equity Ownership, Other: DSMC member; Clovis: Equity Ownership; Mirati: Equity Ownership; Sanofi Paris: Equity Ownership. Locatelli:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Miltenyi: Honoraria; bluebird bio: Consultancy; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. O'Brien:BMS: Research Funding; Celgene: Research Funding; Pfizer: Research Funding; AbbVie: Research Funding; Amgen: Research Funding; BTG: Research Funding. Obreja:Amgen, Inc.: Employment, Equity Ownership. Morris:Amgen, Inc.: Employment, Equity Ownership. Baruchel:Novartis: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Bellicum: Consultancy; Celgene: Consultancy, Honoraria. OffLabel Disclosure: Kyprolis is a proteasomal inhibitor indicated in combination with dexamethasone or with lenalidomide plus dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma who have received one to three lines of therapy. It is also indicated as a single agent for the treatment of patients with relapsed or refractory multiple myeloma who have received one or more lines of therapy.

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First-in-Human, Phase 1/2 Trial to Assess the Safety and Clinical Activity of Subcutaneous GEN3013 (DuoBody®-CD3×CD20) in B-Cell Non-Hodgkin Lymphomas

Blood ◽

10.1182/blood-2019-121460 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 758-758 ◽

Cited By ~ 4

Author(s):

Pieternella Lugtenburg ◽

Rogier Mous ◽

Michael Roost Clausen ◽

Martine E.D. Chamuleau ◽

Peter Johnson ◽

...

Keyword(s):

T Cell ◽

B Cells ◽

B Cell ◽

Board Of Directors ◽

Dose Escalation ◽

Research Funding ◽

Clinical Activity ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership

Introduction: CD20-specific monoclonal antibodies (mAbs) have demonstrated efficacy in the treatment of B-cell non-Hodgkin lymphomas (B-NHL); however, a significant proportion of patients (pts) present with refractory disease or will experience relapse. GEN3013 (DuoBody®-CD3×CD20) is the first subcutaneously administered IgG1 bispecific antibody (bsAb) that targets the T-cell surface antigen CD3 and the B-cell surface antigen CD20, triggering T-cell-mediated killing of B cells. In vitro, GEN3013 efficiently activates and induces cytotoxic activity of CD4+ and CD8+ T cells in the presence of B cells (Hiemstra et al. Blood 2018), and results in long-lasting depletion of B cells in cynomolgus monkeys. Subcutaneous (SC) GEN3013 in cynomolgus monkeys resulted in lower plasma cytokine levels, and similar bioavailability and B-cell depletion, compared with intravenous administration. GEN3013 has higher potency in vitro than most other CD3×CD20 bsAbs in clinical development (Hiemstra et al. HemaSphere 2019). SC GEN3013 in pts with B-NHL is being evaluated in a first-in-human, Phase 1/2 trial (NCT03625037), which comprises a dose-escalation part and a dose-expansion part. Here we report preliminary dose-escalation data. Methods: Pts with CD20+ B-NHL with relapsed, progressive, or refractory disease following anti-CD20 mAb treatment, and ECOG PS 0-2 were included. During dose escalation, pts received SC GEN3013 flat dose in 28-day cycles (q1w: cycle 1-2; q2w: cycle 3-6; q4w thereafter) until disease progression or unacceptable toxicity. Risk of cytokine release syndrome (CRS) was mitigated with the use of a priming dose and premedication with corticosteroids, antihistamines, and antipyretics. Primary endpoints were adverse events (AEs) and dose-limiting toxicities (DLTs). Secondary endpoints included pharmacokinetics (PK), immunogenicity (anti-drug antibodies [ADA]), pharmacodynamics (PD) (cytokine measures; laboratory parameters), and anti-tumor activity (tumor size reduction; objective and best response). Results: At data cut-off (June 28, 2019), 18 pts were enrolled into the dose-escalation part of the trial, with safety data available for pts receiving doses starting at 4 µg. Most pts had diffuse large B-cell lymphoma (DLBCL; n=14) and were heavily pre-treated; 10 pts had received ≥3 prior lines of therapy (overall median [range]: 3 [1-11]). The median age was 58.5 years (range: 21-80), and 13 pts were male. At a median follow-up of 1.9 months, pts received a median of 5 doses (range: 1-14); treatment is ongoing in 6 pts. Twelve pts discontinued treatment due to progressive disease. Six pts died (2 during treatment, 4 during survival follow-up), all due to disease progression and unrelated to treatment. The most common (n≥5) treatment-emergent AEs were pyrexia (n=8), local injection-site reactions (n=7), diarrhea (n=5), fatigue (n=5), and increased aspartate aminotransferase (n=5). The most common Grade (G) 3/4 AEs were anemia (n=3) and neutropenia (n=3). Despite increasing GEN3013 doses, all CRS events were non-severe (initial observation: 3/8 pts, G1: n=1, G2: n=2; following modification of premedication plan [corticosteroids for 3 days]: 6/10 pts, G1: n=4, G2: n=2). Increases in peripheral cytokine (IL6, IL8, IL10, IFNγ, TNFα) concentrations after GEN3013 dosing correlated with clinical symptoms of CRS in most pts. No pts had tumor lysis syndrome or neurological symptoms. No DLTs were observed. GEN3013 PK profiles reflect SC dosing; Cmax occurred 2-4 days after dosing. No ADAs were detected. PD effects following GEN3013 dosing were observed at dose levels as low as 40 µg and included rapid, complete depletion of circulating B cells (if present after prior anti-CD20 therapy) and peripheral T-cell activation and expansion. The first evidence of clinical activity was observed at a dose level of 120 µg, with complete metabolic response observed in a pt with DLBCL. Conclusions: Subcutaneously administered GEN3013, a potent CD3×CD20 bsAb, shows good tolerability and early evidence of clinical activity at low dose levels in heavily pretreated pts with relapsed or refractory B-NHL. All CRS events were non-severe and did not lead to discontinuation. No DLTs were observed. Dose escalation is ongoing; updated data will be presented. Dose expansion will begin upon determining the recommended Phase 2 dose (RP2D) (NCT03625037). Disclosures Lugtenburg: Janssen Cilag: Honoraria; Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria; Servier: Consultancy, Honoraria, Research Funding; Genmab: Consultancy, Honoraria; BMS: Consultancy; Takeda: Consultancy, Honoraria, Research Funding. Mous:Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Sandoz: Honoraria; Roche: Honoraria; Abbvie: Honoraria; Takeda: Honoraria, Research Funding; Janssen Cilag: Consultancy, Honoraria; MSD: Honoraria; Gilead: Consultancy, Honoraria, Research Funding. Clausen:Abbvie: Other: Travel grant to attend ASH 2019. Johnson:Boehringer Ingelheim: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Honoraria; Epizyme: Honoraria, Research Funding; Incyte: Honoraria; Takeda: Honoraria; Genmab: Honoraria; Bristol-Myers Squibb: Honoraria; Kite: Honoraria; Novartis: Honoraria. Rule:Janssen: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Astra-Zeneca: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria; Napp: Consultancy; Kite: Consultancy. Oliveri:Genmab: Employment, Equity Ownership. DeMarco:Genmab: Employment, Equity Ownership. Hiemstra:Genmab: Employment, Equity Ownership, Other: Warrants. Chen:Genmab: Employment. Azaryan:Genmab: Employment. Gupta:Genmab: Employment, Equity Ownership. Ahmadi:Genmab Inc: Employment, Other: stock and/or warrants. Hutchings:Incyte: Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Genmab: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Janssen: Research Funding; Pfizer: Research Funding.

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Phase 2 Study of Venetoclax Plus Carfilzomib and Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma

Blood ◽

10.1182/blood-2018-99-117026 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 303-303 ◽

Cited By ~ 10

Author(s):

Luciano J Costa ◽

Edward A. Stadtmauer ◽

Gareth Morgan ◽

Gregory Monohan ◽

Tibor Kovacsovics ◽

...

Keyword(s):

Multiple Myeloma ◽

Plasma Concentration ◽

Board Of Directors ◽

Median Time ◽

Dose Escalation ◽

Research Funding ◽

Phase 2 ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership

Abstract Introduction: Venetoclax (Ven), an oral agent that targets the antiapoptotic protein, BCL-2, has demonstrated efficacy, as monotherapy and combined with proteasome inhibitor (PI) bortezomib, in relapsed/refractory (R/R) multiple myeloma (MM). We report preliminary safety and efficacy data for Ven combined with the second generation PI carfilzomib (K) and dexamethasone (VenKd) in R/R MM. Methods: In this ongoing phase 2, dose escalation study (NCT02899052), patients with R/R MM and no prior K exposure received VenKd on 28-d cycles in 4 dose finding and one expansion cohorts: Ven 400 mg/day + K 27 mg/m2 Day 1, 2, 8, 9, 15, 16 + dex 40 mg Day 1, 8, 15, 22 (Cohort 1), same regimen but with Ven 800 mg/day (Cohort 2), Ven 800 mg/day + K 70 mg/m2 Day 1, 8, 15 + dex 40 mg Day 1, 8, 15, 22 (Cohort 3/expansion cohort), or Ven 800 mg + K 56 mg/m2 Day 1, 2, 8, 9, 15, 16 + dex 40 mg Day 1, 2, 8, 9, 15, 16, 22, 23 (Cohort 4). Treatment continued until progressive disease (PD) or unacceptable toxicity. Results: As of June 11, 2018, 42 patients were enrolled. The median age was 66.5 years (min, max: 37, 79), 63% had ISS II/III disease, and 8 patients (19%) had t(11;14). Patients received a median of 2 prior therapies (range: 1 - 3), 93% had received prior PI (50% refractory), 62% were refractory to immunomodulatory therapies, and 33% double refractory. At the data cut off, 29 patients were still active and had completed ≥2 cycles and 13 patients discontinued with the primary reason being disease progression (n=4), death (n=3), physician decision (n=2), withdrawal of consent (n=2), lack of efficacy (n=1), and AE (n=1). All patients experienced at least one AE, and grade 3/4 AEs experienced by >10% of subjects included: decreased lymphocyte count (26%), decreased neutrophil count (14%), and hypertension (12%). Thirteen subjects experienced at least one serious AE. Maximum tolerated dose was not reached and Ven 800 mg/day + K 70 mg/m2 was selected for expansion. Ven mean (% coefficient of variation) maximum plasma concentration (Cmax) and area under the plasma concentration-time curve over 24 hours (AUC24) on Cycle 1 Day 15 were 2.7 (57) mg/mL and 33.1 (54) mg×h/mL, respectively, at 400 mg venetoclax (n=4); and were 2.42 (53) mg/mL and 38.7 (51) mg×h/mL, respectively, at 800 mg venetoclax (n=13) in the dose escalation cohorts. The overall response rate (ORR) was 78% and the very good partial response (VGPR) or better rate was 56% (Table). Median time from first dose to the data cut or discontinuation was 5.7 months (range: 0.9 - 16.3) and the median time to first response was 1.9 months (95% CI: 0.9, 9.2). ORRs for subgroups of interest are reported in the Table. Conclusions: The combination of VenKd appears tolerable with no new safety signals or changes in Ven pharmacokinetics. VenKd shows promising preliminary efficacy in R/R MM patient subgroups. Response rates were comparable in all high risk subgroups and overall population. However, the subset of patients with t(11;14) had the highest response. Overall, these results demonstrate that VenKd is a safe and efficacious regimen in R/R MM and support the continued study of VenKd. Disclosures Costa: Abbvie: Research Funding; BMS: Research Funding; Karyopharm: Research Funding; Amgen: Honoraria, Research Funding; Sanofi: Honoraria; Celgene: Honoraria, Research Funding; Janssen: Research Funding. Stadtmauer:Celgene: Consultancy; AbbVie, Inc: Research Funding; Janssen: Consultancy; Takeda: Consultancy; Amgen: Consultancy. Morgan:Bristol-Myers Squibb: Consultancy, Honoraria; Janssen: Research Funding; Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Kovacsovics:Amgen: Honoraria, Research Funding; Abbvie: Research Funding. Jakubowiak:Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; SkylineDx: Consultancy, Honoraria; Adaptive Biotechnologies: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Kaufman:Roche: Consultancy; BMS: Consultancy; Karyopharm: Other: data monitoring committee; Janssen: Consultancy; Abbvie: Consultancy. Mobasher:Genentech Inc: Employment; F. Hoffmann-La Roche Ltd: Other: Ownership interests non-PLC. Freise:AbbVie, Inc: Employment, Equity Ownership. Ross:AbbVie, Inc: Employment, Equity Ownership. Pesko:AbbVie, Inc: Employment, Equity Ownership. Munasinghe:AbbVie, Inc: Employment, Equity Ownership. Gudipati:AbbVie, Inc: Employment, Equity Ownership. Mudd:AbbVie, Inc: Employment, Equity Ownership. Bueno:AbbVie, Inc: Employment, Equity Ownership. Kumar:Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: 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; Novartis: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: 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, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Safety, Clinical Activity, Pharmacokinetics, and Pharmacodynamics from a Phase I Study of PF-06863135, a B-Cell Maturation Antigen (BCMA)-CD3 Bispecific Antibody, in Patients with Relapsed/Refractory Multiple Myeloma (RRMM)

Blood ◽

10.1182/blood-2019-121805 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1869-1869 ◽

Cited By ~ 13

Author(s):

Noopur S. Raje ◽

Andrzej Jakubowiak ◽

Cristina Gasparetto ◽

Robert F. Cornell ◽

Heike I. Krupka ◽

...

Keyword(s):

Phase I ◽

Board Of Directors ◽

Dose Escalation ◽

Research Funding ◽

Phase I Study ◽

Employment Equity ◽

Advisory Committees ◽

Best Response ◽

Equity Ownership ◽

Dose Levels

Introduction: PF-06863135 (PF-3135) is a bispecific, humanized, monoclonal antibody (mAb) consisting of BCMA- and CD3-targeting arms paired on an IgG2a backbone by hinge-mutation technology. PF-3135 binds BCMA+ myeloma cells and CD3+ T cells with affinities of 20 pM and ~40 nM, respectively (Panowski et al. Blood 2016). We report here findings from the dose-escalation portion of an ongoing, multi-center, open-label, phase I study (NCT03269136) of PF-3135 in patients with RRMM. Methods: Adult patients (≥18 years of age) with RRMM, previously treated with a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 mAb, received escalating, intravenous (IV) doses of PF-3135, once weekly. Prior BCMA-targeted bispecific T-cell engager or chimeric antigen receptor T-cell (CART) treatment was allowed by protocol. Patients had measurable disease per the International Myeloma Working Group (IMWG) updated criteria 2014. A modified toxicity probability interval method (mTPI), targeting a dose-limiting toxicity (DLT) rate of 25% (equivalence interval ± 5%) was used for dose escalation. The primary study objectives are to assess PF-3135 safety and tolerability, to determine the maximum tolerated dose (MTD) and select the recommended phase II dose (RP2D). Secondary objectives include evaluation of anti-myeloma activity, pharmacokinetics (PK), and immunogenicity of PF-3135. Results: As of April 9, 2019, 17 patients had received once weekly, non-continuous, IV infusion of PF-3135 in 6 dose-escalation groups. The majority were men (71%). The median age was 61 yrs (range, 47-82 yrs) and median disease duration since onset was 7 yrs (range, 1.1-13.3 yrs). Ten (59%) patients had ≥1 chromosomal abnormality and 5 (29%) had a normal karyotype (status not known for 2 [12%] patients). The median number of prior anti-myeloma therapies was 11; 5 (29%) patients had received prior BCMA-targeted therapy. Eight (47%) patients had relapsed MM and 8 (47%) had refractory disease (recurrence type not known for 1 [6%] patient). Ten (59%) patients experienced treatment-related (TR) AEs of any grade. Most TRAEs were grade 1-2, including cytokine release syndrome (CRS, 24%), thrombocytopenia (24%), anemia (18%), and pyrexia (18%). Three (18%) patients had grade 3 TRAEs (increased alanine aminotransferase/aspartate aminotransferase, leukocytopenia, neutropenia, and lymphopenia). One patient treated at the highest dose level, who had received prior BCMA CART therapy, developed treatment-related febrile neutropenia, a DLT, which may have been related to CRS and borderline/low neutrophil count at baseline. None of the patients had grade 4-5 TRAEs or discontinued treatment due to a TRAE. The median duration of treatment was 4 (range, 2-12) actual dosing days. Sixteen of the 17 patients were evaluable for response. At the time of data cut-off, one (6%) patient had a minimal response and 6 (35%) patients had stable disease (SD) across dose levels, as best response by investigator IMWG assessment; 9 (53%) patients experienced disease progression. The clinical benefit rate (defined as best response ≥SD) was 41% (95% CI: 18.4%, 67.1%). Conclusions: Treatment with IV PF-3135 was well tolerated at the dose levels evaluated. The observed CRS events were moderate and dose-dependent. Additional dose cohorts are accruing. The latest clinical, biomarker, and PK data will be presented for this ongoing study. Disclosures Raje: Medscape: Honoraria; Research to Practice: Honoraria; Takeda: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; AstraZeneca: Research Funding. Jakubowiak:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy, Honoraria; Juno: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; SkyLineDx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; KaryoPharm Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Gasparetto:Janssen: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; BMS: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; Celgene: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed . Cornell:KaryoPharm: Consultancy; Takeda: Consultancy. Krupka:Pfizer: Employment, Equity Ownership. Navarro:Pfizer: Employment, Equity Ownership. Forgie:Pfizer: Employment, Equity Ownership. Udata:Pfizer: Employment, Equity Ownership. Basu:Pfizer: Employment, Equity Ownership. Chou:Pfizer: Employment, Equity Ownership. Leung:Pfizer: Employment, Equity Ownership. Lesokhin:BMS: Consultancy, Honoraria, Research Funding; Serametrix Inc.: Patents & Royalties; Takeda: Consultancy, Honoraria; Genentech: Research Funding; Juno: Consultancy, Honoraria; GenMab: Consultancy, Honoraria; Janssen: Research Funding. OffLabel Disclosure: PF-06863135, investigational agent

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ACY-1215, a Selective Histone Deacetylase (HDAC) 6 Inhibitor, In Combination With Lenalidomide and Dexamethasone (dex), Is Well Tolerated Without Dose Limiting Toxicity (DLT) In Patients (Pts) With Multiple Myeloma (MM) At Doses Demonstrating Biologic Activity: Interim Results Of a Phase 1b Trial

Blood ◽

10.1182/blood.v122.21.3190.3190 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3190-3190 ◽

Cited By ~ 9

Author(s):

Andrew Yee ◽

Peter Vorhees ◽

William I. Bensinger ◽

Jesus Berdeja ◽

Jeffrey G Supko ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Progressive Disease ◽

Employment Equity ◽

Advisory Committees ◽

Acetylated Tubulin ◽

Phase 1B ◽

Equity Ownership ◽

Grade 3 ◽

Dose Levels

Abstract Background ACY-1215 is the first selective HDAC6 inhibitor in clinical trials and is well-tolerated as monotherapy up to 360 mg/day, the maximum dose examined. Cmax ≥ 1µM was achieved at dose levels >80 mg. Unlike nonselective HDAC inhibitors, which are associated with severe fatigue, vomiting, diarrhea and myelosuppression, DLTs have not been observed with ACY-1215. ACY-1215 synergizes in in vitro with both lenalidomide and dex in MM cell lines providing the rationale to conduct a phase 1b trial of ACY-1215 in combination with these agents. Methods Relapsed and relapsed and refractory pts who have progressed on at least one prior treatment regimen, who have creatinine clearance >50 mg/mL/min, adequate bone marrow and hepatic function, and who gave informed consent were enrolled. In Part A, patients were treated with escalating doses of oral ACY-1215 on days 1-5 and 8-12 of a 28 day cycle with lenalidomide 25 mg d 1-21 and dex 40 mg weekly. In Part B, the schedule includes ACY-1215 on days 15-19. Subsequent cohorts will explore twice daily dosing based on emerging clinical, pharmacokinetic (PK) and pharmacodynamic (PD) data. Peripheral blood samples were obtained for PK and PD analysis. PD assessment measured the fold increase of acetylated tubulin (a marker of HDAC6 inhibition) and acetylated histones (a marker of class 1 HDAC inhibition) in peripheral blood mononuclear cells (PBMC). Results As of July 3, 2013, 15 pts who progressed after 1 to >3 prior therapies have been enrolled; 8 were relapsed and 7 were refractory to the most recent therapy. Patients were treated daily at up to 240 mg ACY-1215. Fourteen pts had received prior lenalidomide of which 6 were previously refractory as defined by having less than a minimal response (MR) to therapy (1) or progressive disease on either full dose or maintenance therapy (5). Pts have completed 0 to 11+ cycles of therapy with 10 pts continuing on therapy. Five pts have discontinued therapy due to progressive disease (PD) (3), travel difficulties (1), or missed doses of lenalidomide (1). The latter pt was replaced. The most common treatment emergent events were fatigue (43%), upper respiratory infection (36%), anemia and peripheral edema (21% each), neutropenia (29%) and muscle spasms (21%). Most were grade 1 and 2 and there was no dose relationship to ACY-1215. There were 9 grade 3-4 events in 6 pts, primarily hematologic, as well as fatigue and asymptomatic laboratory investigations. Only 1 event, grade 3 neutropenia, was considered possibly related to ACY-1215 by the investigator. PK and PD data is available from 12 pts up to 160 mg dose level. PK for ACY-1215 is similar to the analogous dose levels in phase 1a monotherapy suggesting coadministration of lenalidomide does not significantly impact the PK of ACY-1215. Maximal levels were ≥ 1µM at ≥ 80 mg correlating with measurable increases >2x in acetylated tubulin with a minimal increase in acetylated histones. Twelve pts, at doses up to 160 mg ACY-1215, are evaluable for response (after at least two cycles). In addition, 1 pt who discontinued therapy after one cycle had response data available. Nine patients (69%) have ≥ PR, including 1 CR, 4 VGPR, 3 PR, and 1 PRu. Two pts had MR and 2 had SD as the best response. Reponses are durable up to 11+ cycles of therapy. Of the 6 patients who were refractory to lenalidomide, best responses included 1 PR, 1 VGPR, 2 MR and 2 SD. Conclusions ACY-1215 at doses which have biological activity (as determined by PD data in PBMC) can be safely combined with lenalidomide and dex with favorable toxicity to date. Significant responses were observed in pts, and responses have been seen in pts previously refractory to lenalidomide. Future cohorts will explore longer duration of exposure as well as a twice daily dosing schedule for ACY-1215. Disclosures: Vorhees: Acetylon Pharmaceuticals, Inc: Research Funding; GlaxcoSmithKline: Consultancy, Research Funding; Millenium: Research Funding; Celgene: Consultancy, Research Funding; Merck: Research Funding; Janssen: Research Funding; Prolexys: Research Funding; Abbott: Consultancy. Bensinger:Celgene: Consultancy, Honoraria, Research Funding. Supko:Acetylon Pharmaceuticals, Inc: Research Funding. Richardson:Celgene: Membership on an entity’s Board of Directors or advisory committees; Millenium: Membership on an entity’s Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity’s Board of Directors or advisory committees. Jones:Acetylon Pharmaceuticals, Inc: Employment, Equity Ownership. Patrick:Acetylon Pharmaceuticals, Inc: Employment, Equity Ownership. Wheeler:Acetylon Pharmaceuticals, Inc: Employment, Equity Ownership. Raje:Acetylon Pharmaceuticals, Inc: Research Funding; Eli Lilly: Research Funding; Celgene: Consultancy; Millenium: Consultancy; Onyx: Consultancy; Amgen: Consultancy.

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Safety and Efficacy of Venetoclax (ABT-199/GDC-0199) in Combination with Bortezomib and Dexamethasone in Relapsed/Refractory Multiple Myeloma: Phase 1b Results

Blood ◽

10.1182/blood.v126.23.3038.3038 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3038-3038 ◽

Cited By ~ 15

Author(s):

Philippe Moreau ◽

Asher Chanan-Khan ◽

Andrew W. Roberts ◽

Amit B. Agarwal ◽

Thierry Facon ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Dose Escalation ◽

Research Funding ◽

Fixed Dose ◽

Investigational Drug ◽

Fish Analysis ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership

Abstract Background: The anti-apoptotic proteins BCL-2 and MCL-1 promote multiple myeloma (MM) cell survival. Bortezomib (BTZ) can inhibit MCL-1 activity by stabilizing the MCL-1 antagonist, NOXA. Venetoclax is an orally bioavailable, highly selective BCL-2 inhibitor, which enhances BTZ efficacy in MM xenograft models. This Phase 1 study evaluates venetoclax with BTZ and dexamethasone (Dex) in patients (pts) with relapsed/refractory MM. Methods: Objectives include safety, pharmacokinetics, preliminary efficacy and maximum therapeutic dose of venetoclax with BTZ and Dex. A fixed dose of venetoclax ranging from 50 to 800 mg PO daily, according to dose cohort assignment, was given in combination in cycles (C) 1-11 and alone in C12 and beyond. Dose escalation decisions were made using the continual reassessment method. Pts received BTZ (1.3 mg/m2 SC, days [D] 1, 4, 8, 11) and Dex (20 mg PO, D1, 2, 4, 5, 8, 9, 11, 12) in cycles (C)1-8 (21D), then BTZ + Dex (D1, 8, 15, 22) in C9-11 (35D). Results: Forty-one pts were enrolled as of June 15, 2015 (pts in each cohort: 50 mg, n=3; 100 mg, n=5; 200 mg, n=6; 300 mg, n=7; 400 mg, n=6; 500 mg, n=7; 600 mg, n=5; 800 mg, n=2). Median age was 65 (38-79); 15/26 F/M. 14 were ISS stage I, 11 stage II, 11 stage III, 5 missing. Median (range) number of prior lines of therapy was 5 (1-15). Thirty-five pts had received prior BTZ (10 refractory), 34 prior lenalidomide (22 refractory); 29 had undergone stem cell transplantation. Based on FISH analysis, 5 pts had MM with t(11;14); 3 with t(4;14), 20 with del 17p, and 10 with del 13q. Treatment-emergent AEs occurring in ≥20% of pts were constipation (37%), diarrhea (37%), thrombocytopenia (32%), asthenia (29%), insomnia (29%), anemia (27%), peripheral neuropathy (27%), dyspnea (24%), peripheral edema (22%), and nausea (20%). Grade 3/4 AEs in ≥10% of pts were thrombocytopenia (20%), and anemia (17%). SAEs occurred in 18 pts; SAEs in ≥2 pts were cardiac failure, embolism, pyrexia, respiratory failure, sepsis, thrombocytopenia (n=2 each, no SAEs were venetoclax-related). Twenty-nine pts have discontinued treatment: 23 due to PD, 2 due to AEs [adenocarcinoma; cardiac and respiratory decompensation attributed to Dex (DLT at 300 mg)], and 4 withdrew consent. Three deaths occurred (all due to PD). No TLS occurred. In preliminary PK analyses (n=41), dose-normalized venetoclax exposure when given with BTZ+Dex was similar when compared to venetoclax monotherapy in MM as well as CLL and NHL pts. Forty of 41 pts were evaluable for efficacy. All responses occurred in BTZ sensitive or naïve pts. Median (range) duration or response was 5.9 (0-14.1) months in all pts, 8.5 (2.3-11.4) months in BTZ naïve pts, and 4.7 (0-14.1) months in BTZ-sensitive pts. Conclusions: Venetoclax with BTZ and Dex has an acceptable safety profile in heavily pretreated MM pts; no new safety signals were identified compared to other venetoclax studies. These early data suggest the combination of proteasome and BCL-2 inhibition resulted in anti-tumor activity. Responses were observed only in pts naïve or sensitive to prior BTZ (ORR = 100% and 58%, respectively) and occurred in all dose cohorts. The study is currently enrolling pts in the 1000 mg dose escalation cohort. Figure 1. Figure 1. Disclosures Moreau: Celgene, Janssen, Takeda, Novartis, Amgen: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Venetoclax is an investigational drug that is not yet approved in this indication. Roberts:AbbVie and Genentech: Research Funding; Walter and Eliza Hall Institute of Medical Research: Employment. Agarwal:Amgen, Millennium: Consultancy; Celgene, Onyx: Speakers Bureau; AbbVie: Research Funding. Facon:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millenium: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Pierre Fabre: Membership on an entity's Board of Directors or advisory committees. Kumar:Skyline, Noxxon: Honoraria; Celgene, Millennium, Onyx, Janssen, Noxxon, Sanofi, BMS, Skyline: Consultancy; Celgene, Millennium, Onyx, Novartis, Janssen, Sanofi: Research Funding. Touzeau:AbbVie: Research Funding. Darden:AbbVie: Employment, Equity Ownership. Morris:AbbVie: Employment, Equity Ownership. Ross:AbbVie: Employment, Equity Ownership. Salem:AbbVie: Employment, Equity Ownership. Munasinghe:AbbVie: Employment, Equity Ownership. Zhu:AbbVie: Employment, Equity Ownership. Leverson:AbbVie: Employment, Equity Ownership. Maciag:AbbVie: Employment, Equity Ownership. Enschede:AbbVie: Employment, Equity Ownership. Verdugo:AbbVie: Employment, Equity Ownership. Humerickhouse:AbbVie: Employment, Equity Ownership. Harrison:Celgene: Honoraria, Research Funding; Janssen: Research Funding, Speakers Bureau; AbbVie: Research Funding.

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Immune Profiling of Relapsed or Refractory Multiple Myeloma Patients Treated with Pomalidomide and Low-Dose Dexamethasone in Combination with Daratumumab

Blood ◽

10.1182/blood-2018-99-111554 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2012-2012 ◽

Cited By ~ 2

Author(s):

William E. Pierceall ◽

Nizar Bahlis ◽

David S Siegel ◽

Gary J. Schiller ◽

Christy J. Samaras ◽

...

Keyword(s):

Multiple Myeloma ◽

T Cells ◽

T Cell ◽

Nk Cells ◽

Board Of Directors ◽

Research Funding ◽

Employment Equity ◽

Advisory Committees ◽

Ki 67 ◽

Equity Ownership

Abstract Background: Multiple myeloma clinical trial CC-4047-MM-014 (NCT01946477) is a Phase II study designed to test the safety and efficacy of pomalidomide and low-dose dexamethasone alone (arm A) or in combination with daratumumab, an anti-CD38 antibody, (arm B) subjects with relapsed or refractory multiple myeloma who have received a first or second line treatment of lenalidomide-based therapy. Immunomodulatory agents (IMiD® compounds) continue to be the backbone of multiple myeloma therapy especially when combined with monoclonal antibodies, more specifically pomalidomide had been shown previously to enhance T cell- and NK cell-mediated immunity. We sought to characterize on-treatment pharmacodynamic changes of immune biomarkers associated with POM + LoDEX + DARA administration (arm B) using multicolor flow cytometry panels designed to characterize T-cell subsets and CD38+ expressing cells. IMiD agents are the backbone of combination regimens in the treatment of patients with newly diagnosed or relapsed and/or refractory multiple myeloma. The anti-myeloma properties of these agents derive from a dual mechanism of pro-apoptotic effects on tumor cells as well as enhanced immune stimulation. An understanding of how IMiD agents interact with new monoclonal antibodies to modify patient immune profiles offers key insights into the role of such in innate and adaptive immunity in determining patient outcomes. Methods and Results: Peripheral blood samples were collected at screening, Cycle1 Days 1, 8, and 15, and Cycle 2 Days 1 and 15 to monitor pharmacodynamic changes in populations of T cells, NK cells, monocytes and MDSCs by flow cytometry. From 112 patients enrolled in Arm B, 98 patients had baseline and post-treatment specimens available for these analyses. As expected, combination treatment with POM + LoDEX + DARA led to decreased peripheral counts of CD56+CD16+ NK cells as well as CD4+CD38+ and CD8+CD38+ T cell subpopulations. Decreased counts were also noted in CD3-CD19+ B cells. In contrast, total counts of CD14+ monocytes and CD3+CD4+ or CD3+CD8+ T cells were stably maintained and pronounced increases were observed in proliferating CD4+Ki-67+ and CD8+Ki-67+ T cells. Further, when examined as a percent of total counts, increases were observed in CD14+ monocytes, CD3+CD4+ and CD3+CD8+ T-cells, with decreases in CD3-CD19+ B-cells and CD3-CD56+CD16+ NK cells. Correlation of these pharmacodynamic changes with clinical outcomes will be presented. In addition, baseline immune profiling of specific cell population subsets and associations with best overall response and progression-free survival is currently being analyzed. Conclusions: The triplet regimen POM + LoDEX + DARA has shown notable clinical activity with deep and durable responses in relapsed multiple myeloma patients progressed and are or refractory to lenalidomide. Immune characterization here is consistent with a model for clinical activity in which the loss of CD56+CD16+ NK cells along with a concomitant immune suppression by loss of CD38+CD4+ and CD38+CD8+ T- cells is offset by an increase in proliferating cytotoxic CD4+Ki-67+ and CD8+Ki-67+ T-cell populations. Our results demonstrate that patients treated with the POM + LoDEX + DARA combination do not demonstrate impairment in the innate and adaptive immune compartments and, in contrast, show significant proliferative activity in the subsets of CD4, CD8 and NK cells following treatment. Pomalidomide had been shown previously to enhance T cell- and NK cell-mediated immunity; these data are consistent with a mechanism of action in which pomalidomide administration facilitates the ability to overcome immunosuppressive effects of Dara and LoDex. Potential associations of immune biomarkers with patient outcomes is ongoing and will be updated. Disclosures Pierceall: Celgene Corporation: Employment, Equity Ownership. Bahlis:Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Siegel:Merck: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Karyopharm: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau. Schiller:Astellas Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; bluebird bio: Research Funding. Sebag:Amgen Canada: Membership on an entity's Board of Directors or advisory committees; Takeda Canada: Membership on an entity's Board of Directors or advisory committees; Janssen Inc.: Membership on an entity's Board of Directors or advisory committees; Celgene Canada: Membership on an entity's Board of Directors or advisory committees. Berdeja:Takeda: Research Funding; Genentech: Research Funding; Sanofi: Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Glenmark: Research Funding; Amgen: Research Funding; Novartis: Research Funding; Poseida Therapeutics, Inc.: Research Funding; Bluebird: Research Funding; Teva: Research Funding. Ganguly:Amgen: Consultancy; Daiichi Sankyo: Research Funding; Janssen: Consultancy; Seattle Genetics: Speakers Bureau. Matous:Celgene: Consultancy, Honoraria, Speakers Bureau. Srinivas:VAHCSNJ: Employment. Bar:Celgene: Consultancy. Quick:CTI BioPharma: Research Funding. Fonseca:Celgene: Speakers Bureau. Reece:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Merck: Honoraria, Research Funding; Otsuka: Research Funding. Serbina:Celgene: Employment. Zafar:Celgene: Employment. Agarwal:Celgene Corporation: Employment, Equity Ownership. Thakurta:Celgene Corporation: Employment, Equity Ownership.

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A Phase 1, Multicenter Study of Pomalidomide, Bortezomib, and Low-Dose Dexamethasone in Patients with Proteasome Inhibitor Exposed and Lenalidomide-Refractory Myeloma (Trial MM-005)

Blood ◽

10.1182/blood.v126.23.3036.3036 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3036-3036 ◽

Cited By ~ 10

Author(s):

Paul G. Richardson ◽

Craig Hofmeister ◽

Noopur S. Raje ◽

David Siegel ◽

Sagar Lonial ◽

...

Keyword(s):

Board Of Directors ◽

Dose Escalation ◽

Research Funding ◽

Phase 1 ◽

Median Number ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership ◽

Immunomodulatory Drug ◽

Grade 3

Abstract Background: The combination of an immunomodulatory drug with the proteasome inhibitor (PI), bortezomib (BORT), and low-dose dexamethasone (LoDEX) has demonstrated preclinical synergy and considerable clinical activity in relapsed and refractory multiple myeloma (RRMM; Mitsiades et al Blood, 2002; Richardson et al Blood, 2014). Treatment (Tx) with the immunomodulatory drug pomalidomide (POM) + LoDEX has been shown to delay disease progression and extend survival in patients (pts) with myeloma previously treated with lenalidomide (LEN) and BORT (Richardson et al Blood, 2014; San Miguel et al Lancet Oncol, 2013). This approach was tested using POM + BORT + LoDEX (PVd) in MM-005; preliminary results showed that PVd was effective and well tolerated in LEN-refractory and BORT-exposed pts. Subcutaneous (SC) BORT was shown to be non-inferior to intravenous (IV) BORT and had an improved safety profile in RRMM (Moreau et al Lancet Oncol, 2011). In addition to a cohort of PVd with IV BORT, MM-005 included a cohort of PVd with SC BORT. Methods: In this phase 1 dose-escalation trial, pts must have received 1-4 lines of prior Tx, with ≥ 2 consecutive cycles of LEN plus a PI. Pts had to be PI exposed and refractory to LEN but not to BORT. A 3 + 3 design with 21-day cycles was used to determine the maximum tolerated dose (MTD). Cycles 1-8 of dose-escalation cohorts received POM (1-4 mg/day on days 1-14), IV or SC BORT (1-1.3 mg/m2 on days 1, 4, 8, and 11), and LoDEX (20 mg/day, or 10 mg/day for pts aged > 75 years, on days 1, 2, 4, 5, 8, 9, 11, and 12) until progressive disease (PD) or unacceptable adverse event (AE). After cycle 8, BORT was administered on days 1 and 8, and LoDEX was administered on days 1, 2, 8, and 9. The primary endpoint was MTD, and secondary endpoints included safety, overall response rate (ORR; ≥ partial response [PR]), duration of response (DOR), and time to response. Results: Of the 34 pts enrolled from March 2012 to August 2014, the median age was 58.5 years (range, 36-76 years) and 59% were male. The median number of prior antimyeloma Tx lines (PAMTL) was 2 (range, 1-4), the proportion of pts with ≥ 2 PAMTL was 56%, and the Eastern Cooperative Oncology Group performance status was ≤ 1 for all pts. All pts were refractory to LEN, and all were exposed to prior PI (33 pts [97%] received prior BORT and 2 pts [6%] received prior ixazomib). All pts discontinued Tx, most commonly due to PD (n = 23), but none due to Tx-related AEs. No dose-limiting toxicities were reported in the dose-escalation cohorts or at the maximum planned dose (MPD) of POM 4 mg, BORT 1.3 mg/m2, and LoDEX 20 mg (10 mg for pts aged > 75 years). The median number of Tx cycles received was 9 (range, 2-36) for all pts and was 11 (range, 2-19) vs 8 (range, 3-15) in the MPD with IV BORT (n = 10) vs SC BORT (n = 12) cohorts. The ORR for all pts was 65% (n = 22), with 2 complete responses (CRs), 1 stringent CR, 10 very good PRs (VGPRs), and 9 PRs; all pts achieved at least stable disease. The median DOR for the 22 responders was 7.4 months. Commonly reported grade 3/4 AEs were more frequent at the MPD level with IV BORT vs SC BORT (90% vs 75%), including neutropenia (60% vs 17%), thrombocytopenia (40% vs 8%), and pneumonia (30% vs 8%). There were no reports of grade 3/4 peripheral neuropathy (PN) or deep vein thrombosis (DVT) in any of the cohorts. Conclusions: PVd was effective, with an ORR of 65% in pts with LEN-refractory and PI-exposed myeloma. PVd was well tolerated, with no grade 3/4 PN or DVT and no Tx discontinuation due to Tx-related AE; toxicities were well managed. Moreover, AEs were generally less frequent with SC vs IV BORT. Thus, the favorable tolerability and efficacy of PVd, which could be a highly attractive therapeutic option in pts with RRMM, is under further evaluation in the large ongoing phase 3 trial MM-007. Disclosures Richardson: Millennium Takeda: Membership on an entity's Board of Directors or advisory committees; Gentium S.p.A.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Pomalidomide in combination with bortezomib. Raje:BMS: Consultancy; Takeda: Consultancy; Millenium: Consultancy; Novartis: Consultancy; Celgene Corporation: Consultancy; Onyx: Consultancy; Eli Lilly: Research Funding; Amgen: Consultancy; AstraZeneca: Research Funding; Acetylon: Research Funding. Siegel:Celgene Corporation: Consultancy, Speakers Bureau; Amgen: Speakers Bureau; Takeda: Speakers Bureau; Novartis: Speakers Bureau; Merck: Speakers Bureau. Lonial:Janssen: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Millennium: Consultancy, Research Funding. Laubach:Novartis: Research Funding; Millennium: Research Funding; Onyx: Research Funding; Celgene Corporation: Research Funding. Vesole:Celgene Corporation: Speakers Bureau; Idera Pharmaceuticals: Research Funding. Nooka:Spectrum Pharmaceuticals: Consultancy; Onyx: Consultancy. Zaki:Celgene Corporation: Employment, Equity Ownership. Herring:Celgene Corporation: Employment. Li:Celgene Corporation: Employment, Equity Ownership. Shah:Celgene Corporation: Employment, Equity Ownership. Chen:Celgene Corporation: Employment, Equity Ownership. Anderson:Oncocorp: Equity Ownership; Celgene Corporation: Consultancy; acetylon pharmaceuticals: Equity Ownership; Gilead: Consultancy; BMS: Consultancy; Millennium: Consultancy.

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Selinexor-Containing Regimens for the Treatment of Patients with Multiple Myeloma Refractory to Chimeric Antigen Receptor T-Cell (CAR-T) Therapy

Blood ◽

10.1182/blood-2019-128887 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1854-1854 ◽

Cited By ~ 3

Author(s):

Ajai Chari ◽

Dan T. Vogl ◽

Sundar Jagannath ◽

Jagoda K. Jasielec ◽

Andrew DeCastro ◽

...

Keyword(s):

Multiple Myeloma ◽

T Cell ◽

Board Of Directors ◽

Chimeric Antigen Receptor ◽

Research Funding ◽

Treatment Options ◽

Employment Equity ◽

Advisory Committees ◽

Car T ◽

Equity Ownership

Introduction: There are limited data on treatment options for patients with multiple myeloma whose disease has progressed after chimeric antigen receptor T-cell (CAR-T) therapy. Selinexor is a novel, oral selective inhibitor of nuclear export (SINE) that forces nuclear retention and activation of tumor suppressor proteins. Selinexor plus low dose dexamethasone (Sel-dex) was recently approved in the United States based on data from the STORM study wherein, Sel-dex induced an overall response rate (ORR) of 26.2% in patients with penta-exposed, triple-class refractory multiple myeloma. The activity of Sel-dex was preserved regardless of specific prior therapies, as expected given its unique and novel mechanism of action. The efficacy of selinexor after CAR-T therapy remains unknown. Here, we report on observations of the efficacy of Sel-dex alone or administered as a triplet in combination with bortezomib or carfilzomib in patients with multiple myeloma whose disease has progressed after CAR-T therapy. Methods: We identified 7 patients across all selinexor myeloma trials who had received lymphodepleting conditioning (fludarabine/cyclophosphamide n=6; Cyclophosphamide n=1) followed by an effective dose of CAR-T cell therapy (>108 CAR-positive cells targeting B-cell maturation antigen) for their multiple myeloma prior to being enrolled in a trial using a selinexor-containing regimen. Four were female and 3 were male. Median age was 64 years (range: 35-70 years). One patient was treated in the STORM study, with selinexor (starting at 80 mg twice-weekly) and dexamethasone (20 mg twice-weekly), 1 patient was treated with selinexor (100 mg once-weekly) plus bortezomib (1.3 mg/m2 once-weekly for 4 of 5 weeks) and dexamethasone (40 mg once-weekly) and 5 patients were treated with selinexor (100 mg once-weekly) plus carfilzomib (20/56 mg/m2 or 20/70 mg/m2) and dexamethasone (40 mg once-weekly or 20 mg twice-weekly). Response was assessed by the treating physician per International Myeloma Working Group (IMWG) criteria. Results: Patients had a median of 10 prior therapeutic regimens (range:5-15), all had high-risk cytogenetics, and 6 of the 7 had rapidly progressing disease as indicated by the percent increase in paraprotein (17-91%) between screening and Cycle 1 Day 1 (range: 7-22 days). All patients responded to treatment, including 1 unconfirmed complete response (uCR), 2 very good partial responses (VGPR), 3 partial responses (PR), and 1 minimal response (MR). Responses were rapid and typically occurred within the first cycle of treatment (median 28 days; range 14-83 days). At the time of data cutoff, the median time on a selinexor-based regimen was 4.1 monthsange: 2.5-8.0 months); 2 patients' disease had progressed, 1 patient had withdrawn consent, and 4 patients were still responding on therapy. Adverse events were consistent with what has previously been reported with selinexor-containing regimens in heavily-pretreated patients with multiple myeloma and included nausea, fatigue, thrombocytopenia, neutropenia, and anemia. Conclusions: These results suggest that Sel-dex alone or in combination with bortezomib or carfilzomib may offer therapeutic benefit for patients who have exhausted available treatment options, have rapidly progressing disease, and who have progressed after CAR-T therapy. Importantly patients are able to tolerate and remain on therapy with weekly Sel-dex in combination with bortezomib or carfilzomib, with time on therapy of >4 months and 4/7 patients remaining on therapy. Although based on a small sample size, the findings of this analysis are intriguing and warrant further investigation in a larger study. Disclosures Chari: Sanofi: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncoceutics: Research Funding; Novartis Pharmaceuticals: Research Funding; GlaxoSmithKline: Research Funding; Array Biopharma: Research Funding; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium/Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy. Vogl:Karyopharm Therapeutics: Consultancy; Takeda: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Janssen: Consultancy; Active Biotech: Consultancy. Jagannath:Merck: Consultancy; Celgene: Consultancy; BMS: Consultancy; Medicom: Speakers Bureau; Multiple Myeloma Research Foundation: Speakers Bureau; Novartis: Consultancy. DeCastro:Karyopharm Therapeutics: Employment, Equity Ownership. Unger:Karyopharm Therapeutics: Employment, Equity Ownership. Shah:Karyopharm Therapeutics: Employment, Equity Ownership. Jakubowiak:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Juno: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; SkyLineDx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy, Honoraria; KaryoPharm Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

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A Phase 1b Study of Oprozomib with Dexamethasone or Pomalidomide and Dexamethasone in Patients with Relapsed or Refractory Multiple Myeloma

Blood ◽

10.1182/blood-2018-99-112610 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 803-803 ◽

Cited By ~ 2

Author(s):

Parameswaran Hari ◽

Mark A. Schroeder ◽

James R Berenson ◽

Andrzej Jakubowiak ◽

Jonathan L Kaufman ◽

...

Keyword(s):

Multiple Myeloma ◽

Partial Response ◽

Board Of Directors ◽

Research Funding ◽

Objective Response ◽

Employment Equity ◽

Advisory Committees ◽

Phase 1B ◽

Equity Ownership ◽

Grade 3

Abstract Introduction: Oprozomib is a selective oral tripeptide epoxyketone inhibitor of the chymotrypsin-like subunit of the constitutive proteasome and immunoproteasome. This phase 1b study evaluated the safety and tolerability of two new formulations of oprozomib in combination with dexamethasone (Odex) or pomalidomide and dexamethasone (OPomD) in patients with relapsed or refractory multiple myeloma (RRMM). Methods: Adult patients with RRMM who had received at least 2 prior lines of therapy and whose prior treatment included both lenalidomide and a proteasome inhibitor were eligible for inclusion. Patients received either immediate-release (IR) or extended-release gastroretentive (GR) oprozomib, orally, in combination with dexamethasone (20 mg) alone or pomalidomide (4 mg) and dexamethasone (20 mg) in 4-week cycles. Oprozomib was given according to a 2/7 schedule on days 1, 2, 8, 9, 15, 16, 22, and 23 of each 4-week cycle. In part 1 of the study, patients received Odex with either IR oprozomib at 150 mg/day or GR oprozomib at 150 mg/day. In part 2 of the study, patients received OPomD at increasing dose levels. Dosing for the IR formulation began at 150 mg/day and could be increased to 300 mg/day in increments of 25 mg as needed; at least one cohort could be enrolled at each dose level of oprozomib. Dosing for the GR formulation was determined based on the efficacy and safety data observed in the initial IR dose escalation and was at least one dose level lower than the highest dose tested of the IR formulation. The primary objectives of the study were to identify the maximum tolerated dose (MTD) and to evaluate the safety and tolerability of the OPomD formulations. Results: Overall, 34 patients were assessed at the time of this analysis. Baseline patient demographics and disease characteristics are shown in Table 1. Fourteen patients (41%) received prior carfilzomib, and 10 of these were carfilzomib-refractory; 27 patients (79%) received prior bortezomib and 14 were bortezomib-refractory. Patients were enrolled into 6 cohorts and received either IR 150 mg/day (n=5) or GR 150 mg/day (n=8) Odex, or IR 150 mg/day (n=4), IR 200 mg/day (n=8), IR 225 mg/day (n=5), or GR 150 mg/day (n=4) OPomD. Median (interquartile range) number of cycles of oprozomib received for each cohort was 2.0 (1.0-11.0), 3.5 (1.5-4.0), 6.5 (2.5-9.5), 4.5 (3.0-5.5), 1.0 (1.0-1.0), and 2.0 (1.5-2.0), respectively. Three patients experienced dose-limiting toxicities (IR 150 mg/day OPomD, increased lipase; IR 200 mg/day OPomD, acute kidney injury; GR 150 mg/day OPomD, febrile neutropenia). At the time of this analysis the MTD was not yet reached for either the IR or GR formulation. Most patients (97%) experienced ≥1 treatment-emergent adverse event (AE) and 23 (68%) experienced ≥1 treatment-emergent grade ≥3 AE. AEs that occurred in ≥50% of patients in any cohort are listed in Table 2; the most common overall were nausea (62% any grade; 3% grade ≥3), diarrhea (50% any grade; 6% grade ≥3), and vomiting (47% any grade; 6% grade ≥3). Four patients (12%) experienced treatment-emergent AEs leading to discontinuation of study drug; no fatal AEs occurred. Seven patients who received OPomD had an objective response at the time of this analysis (IR 150 mg/day, n=1 [33%], median duration of response [DOR]=169 days; IR 200 mg/day, n=6 [67%], median DOR=86.5 days; DOR assessments ongoing). Of the seven patients with an objective response, six had a partial response (IR 150 mg/day and IR 200 mg/day) and one had a very good partial response (IR 200 mg/day). Progression-free survival data were not yet mature. In total, 16 of 34 patients continue to receive oprozomib therapy. The results reported are based on preliminary data available at the time of analysis. The study is ongoing and updated results will be provided at the meeting. Conclusion: Results from this study showed that treatment with OPomD had manageable toxicity in patients with RRMM. The most common AEs observed were gastrointestinal disorders, and most of these were grade 1-2 with no gastrointestinal bleeding reported. Furthermore, OPomD therapy showed promising efficacy, with an objective response rate of 67% for patients in the IR 200-mg/day cohort. Disclosures Hari: Sanofi: Honoraria, Research Funding; Janssen: Honoraria; Bristol-Myers Squibb: Consultancy, Research Funding; Amgen Inc.: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Kite Pharma: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Research Funding; Spectrum: Consultancy, Research Funding. Schroeder:Amgen Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees. Berenson:Amgen Inc.: Consultancy, Honoraria, Research Funding. Jakubowiak:Takeda: Consultancy, Honoraria; Adaptive Biotechnologies: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; SkylineDx: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Kaufman:BMS: Consultancy; Roche: Consultancy; Abbvie: Consultancy; Karyopharm: Other: data monitoring committee; Janssen: Consultancy. Voorhees:Amgen Inc.: Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: served on an IRC; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TeneoBio: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: served on an IRC; Novartis: Consultancy, Other: served on an IRC. Fujii:Amgen Inc.: Employment, Equity Ownership. Yang:Amgen Inc.: Employment, Equity Ownership. Galimi:Amgen Inc.: Employment, Equity Ownership.

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CD20-Tcb (RG6026), a Novel "2:1" Format T-Cell-Engaging Bispecific Antibody, Induces Complete Remissions in Relapsed/Refractory B-Cell Non-Hodgkin's Lymphoma: Preliminary Results from a Phase I First in Human Trial

Blood ◽

10.1182/blood-2018-99-110207 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 226-226 ◽

Cited By ~ 11

Author(s):

Martin Hutchings ◽

Gloria Iacoboni ◽

Franck Morschhauser ◽

Fritz Offner ◽

Anna Sureda ◽

...

Keyword(s):

T Cell ◽

Board Of Directors ◽

Dose Escalation ◽

Research Funding ◽

Bispecific Antibody ◽

Advisory Board ◽

Cytokine Release ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership

Abstract Despite advancements in outcomes with the introduction of anti-CD20 monoclonal antibody therapy, a substantial proportion of B-cell Non-Hodgkin's Lymphoma (B-NHL) patients do not sustain a durable response to standard of care treatment. T-cell bispecific antibodies (TCBs) represent a new class of disease-targeting agents shown to activate T-cells to kill cancer cells, offering this exciting mechanism of action with 'off the shelf' availability. CD20-TCB (RG6026) is a novel T-cell-engaging bispecific antibody whose "2:1" format possesses two CD20 binders in addition to a CD3 binder, enabling increased tumor antigen avidity, rapid T-cell activation, and enhanced tumor cell killing. NP30179 is a multicenter phase I dose escalation trial investigating the safety, tolerability, pharmacokinetics (PK), biomarker responses, and antitumor activity (assessed by overall response rate [ORR] and complete response rate [CR] per Lugano 2014 criteria) of single agent CD20-TCB. Patients receive escalating doses of CD20-TCB as intravenous infusions with dose escalation guided by a model implementing the Bayesian continuous reassessment method with overdose control. In order to reduce the potential risk of cytokine release syndrome (CRS) induced by CD20-TCB mediated systemic T-cell activation, a single dose of 1000 mg obinutuzumab (G) pretreatment (Gpt) is administered seven days prior to start of CD20-TCB and has preclinically been shown to debulk peripheral B cells and reduce systemic cytokine release (Bacac et al. Clin Canc Res 2018). As of July 29th 2018 a total of 64 patients (pts) with aggressive r/r B-NHL (DLBCL/PMBCL/trFL/Richter´s transformation (n=47)) and indolent r/r B-NHL (FL(n=17)) received CD20-TCB doses ranging from 5 µg to 1800 µg in a Q2W schedule. Median age was 64 years (range 28-82), 61% were male, median prior lines of therapy was 3 (range 1-10). A single DLT (myocardial infarction) was observed at 220 µg and until the maximum tested dose CD20-TCB was well tolerated. The most reported AEs were pyrexia (n=14, all Gr 1 and 2), neutropenia (all grades n=17, Gr 3 and 4 n=14) and cytokine release syndrome (CRS, n=14, all Grade 1-2 according to the criteria by Lee et al. Blood 2014). Two patients received tocilizumab for CRS management all CRS events were manageable and resolved, without leading to dose reduction or study withdrawal. No CNS toxicity was reported so far in this study. Fifty-five pts had at least one post-baseline response assessment and were eligible for efficacy analysis. Responses were observed from 15 µg onwards, and complete responses (CR) occurred from 300 µg onwards following two cycles of treatment. At doses of 300 µg or above (n=29) the ORR and CR rate by investigator assessment was 38% and 24%, respectively (FL: 3/5 pts and 2/5 pts respectively, aggressive B-NHL: 8/24 pts and 5/24 pts respectively). All CRs are sustained thus far with a median follow up 96 days (range 26-152). Responses were seen across various NHL subtypes and across prognostic factors such as prior lines of therapy, refractoriness to the most recent line of therapy, tumor burden, and IPI or FLIPI. CD20-TCB exposure and receptor occupancy increased dose-dependently across the investigated dose range; dose-escalation is continuing to optimize these factors. No anti-drug-antibodies have occurred. CD20-TCB is a novel 2:1 format T-cell-engaging bispecific antibody which already at suboptimal doses displays promising clinical activity in heavily-pretreated B-NHL. In addition, Gpt has shown clinical proof of principle as an approach to efficiently mitigate CRS. An update on safety and efficacy as well as biomarker data will be presented. Disclosures Hutchings: Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche/Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Iacoboni:Celgene: Other: Travel funding; Roche: Honoraria. Morschhauser:Janssen: Other: Scientific Lectures; BMS: Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy; Roche: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees. Sureda:Takeda: Consultancy, Honoraria, Speakers Bureau; Roche: Honoraria; Merck: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Sanofi: Honoraria. Salles:Janssen: Honoraria; Merck: Honoraria; Gilead Sciences: Honoraria; Epizyme: Honoraria; Amgen: Honoraria; Acerta: Honoraria; Abbvie: Honoraria; Celgene: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Morphosys: Honoraria; Pfizer: Honoraria; Servier: Honoraria; Takeda: Honoraria. Carlo-Stella:Rhizen Pharmaceuticals: Research Funding; Boehringer Ingelheim: Consultancy; Sanofi: Consultancy; MSD: Other: Advisory Board; Genenta Science: Other: Advisory Board; BMS: Other: Advisory Board; Amgen: Other: Advisory Board; Janssen: Other: Advisory Board; AstraZeneca: Other: Advisory Board; ADC Therapeutics: Other: Advisory Board. Martinez Lopez:Celgene: Research Funding, Speakers Bureau; BMS: Research Funding, Speakers Bureau; Jansen: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Thomas:Roche: Employment, Equity Ownership. Morcos:Roche: Employment, Equity Ownership. Quackenbush:Roche: Employment. Ferlini:Roche: Employment. Bacac:F. Hoffmann-La Roche Ltd.: Employment, Other: stock, Patents & Royalties. Broeske:Roche: Employment, Equity Ownership. Dimier:Roche: Employment, Equity Ownership. Moore:Roche: Employment. Weisser:Roche: Employment, Equity Ownership, Patents & Royalties. Dickinson:GSK: Consultancy.

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