ALBERT

Description: Background: Belantamab mafodotin is a humanized, afucosylated, anti-B-cell maturation antigen (BCMA) monoclonal antibody conjugated to monomethyl auristatin F via a maleimidocaproyl linker (mcMMAF). Upon binding to BCMA on the surface of plasma cells, it is rapidly internalized and the cytotoxic moiety (cys-mcMMAF) is released, antibody-dependent cellular cytotoxicity is enhanced, and immunogenic cell death occurs. In vitro and in vivo cytotoxic activity against both myeloma cell lines and primary patient cells has been demonstrated in preclinical studies. In the first-in-human phase 1 study (DREAMM-1/BMA117159, NCT02064387), belantamab mafodotin had a manageable safety profile and demonstrated a rapid, deep, and durable clinical response as a monotherapy in patients with relapsed/refractory multiple myeloma (RRMM). In a cohort of 35 heavily pretreated patients with RRMM (57% with ≥5 lines of prior therapy) who received belantamab mafodotin 3.4 mg/kg by intravenous (IV) infusion every 3 weeks (Q3W) overall response rate (ORR) of 60% (95% confidence interval [CI]: 42.1, 76.1) was demonstrated. The median progression-free survival (PFS) was 12.0 months (95% CI: 3.1, not estimable [NE]) and the median duration of response (DoR) was 14.3 months (95% CI: 10.6, NE). Belantamab mafodotin monotherapy in patients with RRMM is being further evaluated against the standard-of-care pomalidomide/dexamethasone (Pom/Dex) regimen in the DREAMM-3 study. Methods: The phase 3, multicenter, randomized, open-label DREAMM-3 study will evaluate the efficacy and safety of belantamab mafodotin monotherapy compared with Pom/Dex, an established standard-of-care regimen in RRMM. In this global study, patients treated with ≥2 prior lines of therapy, including ≥2 consecutive cycles of both lenalidomide and a proteasome inhibitor, and refractory to the last line of treatment, will be eligible for inclusion. Participants with prior allogeneic transplant will be excluded, as will those with prior exposure to BCMA-targeted therapies and Pom. Approximately 320 participants will be randomized (2:1) to receive either belantamab mafodotin or Pom/Dex and will be stratified by age, exposure to anti-CD38 therapy, and number of prior lines of treatment. Belantamab mafodotin will be administered IV Q3W, at the dose confirmed in the ongoing DREAMM-2 study (NCT03525678). Pom will be administered orally at 4 mg on Days 1-21 of each 28-day cycle, with Dex 40 or 20 mg (depending on age) on Days 1, 8, 15, and 22. Treatment in both arms will continue until progressive disease, unacceptable toxicity, or death. The primary endpoint is PFS, and overall survival is a key secondary endpoint. Additional secondary endpoints include ORR, time to response, minimal residual disease negativity rate (10-5 threshold assessed by next-generation sequencing), DoR, safety, and health-related quality of life. Bone marrow and blood samples will be collected for biomarker research. The study is planned to start in late 2019. Acknowledgments: Editorial assistance was provided by Sarah Hauze, PhD, at Fishawack Indicia Ltd, UK, and funded by GlaxoSmithKline. Study is funded by GlaxoSmithKline (ID: 207495); drug linker technology is licensed from Seattle Genetics; monoclonal antibody is produced using POTELLIGENT Technology licensed from BioWa. Disclosures Weisel: Sanofi: Consultancy, Honoraria, Research Funding; Adaptive Biotech: Consultancy, Honoraria; GSK: Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Juno: Consultancy; Bristol-Myers Squibb: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Hopkins:GSK: Employment, Equity Ownership. Fecteau:GSK: Employment, Equity Ownership. Bao:GSK: Employment, Equity Ownership. Quigley:GSK: Employment, Equity Ownership. Jewell:GSK: Employment, Equity Ownership. Nichols:GSK: Employment, Equity Ownership. Opalinska:GSK: Employment, Equity Ownership.

Description: Background: Patients with RRMM who have relapsed through multiple prior lines of therapy need novel, effective, targeted agents. B-cell maturation antigen (BCMA) is a cell-surface receptor required for plasma cell survival that is ubiquitously expressed on MM cells, but virtually absent on naïve and memory B cells. Belantamab mafodotin (GSK2857916) is a BCMA-directed immuno-conjugate with an afucosylated, humanized anti-BCMA monoclonal antibody (mAb) conjugated by a protease-resistant cysteine linker to a microtubule disrupting agent, monomethyl auristatin F (MMAF). Belantamab mafodotin specifically binds to BCMA, eliminating MM cells by a multimodal mechanism including delivering MMAF to BCMA-expressing malignant cells, enhancing antibody-dependent cellular cytotoxicity, and leveraging immunogenic cell death. In an open-label, phase 1 study (DREAMM-1), belantamab mafodotin monotherapy had a manageable safety profile and demonstrated rapid, deep and durable clinical response (60% overall response rate, 14.3 months duration of response) with significant progression free-survival (PFS; 12 months) in patients with heavily pretreated MM. Belantamab mafodotin is being evaluated in clinical trials in various lines of MM therapy, either as monotherapy or in combination. The DREAMM-5 platform trial is a phase 1/2 study that incorporates an efficient design with 1 master protocol, wherein multiple belantamab mafodotin-containing combinations will be evaluated in separate substudies to identify effective doublet combinations versus a shared belantamab mafodotin monotherapy control arm. Initial substudies will include combinations with the T-cell activating checkpoint mAbs GSK3359609 (an IgG4 inducible T-cell costimulatory [ICOS] agonist antibody that is Fc optimized to selectively enhance T-cell function to enable antitumor responses), GSK3174998 (a humanized wild-type IgG1 anti-OX40 agonistic mAb), and a gamma-secretase inhibitor, Nirogacestat (PF-03084014, SpringWorks Therapeutics). Furthermore, as treatment paradigms evolve, including potential genomic subsets of patients with RRMM and actionable mutations, other control arms may be introduced. The combination agent for evaluation in each substudy will be selected based on scientific rationale and/or results of preclinical experiments with the selected agent in combination with belantamab mafodotin. Methods: Patients with RRMM will be eligible if they have received ≥3 prior lines of therapy (consisting of an immunomodulatory drug, proteasome inhibitor, and an anti-CD38 mAb), have measurable disease (as measured by M-protein and free light chain), and acceptable hematologic and vital organ functions. Participants previously treated with an anti-BCMA targeted therapy are eligible except for prior belantamab mafodotin treatment and chimeric antigen receptor (CAR) T-cell therapy within 3 months of screening. Each substudy will have 2 sequential phases to evaluate safety and efficacy (Figure). The dose exploration (DE) phase will evaluate the safety and tolerability of belantamab mafodotin administered in combination with a partner agent. Each DE phase will consist of multiple dosing cohorts (N≤10 per cohort), 1 cohort per doublet combination. The primary objective is to identify a recommended phase 2 dose for each doublet combination based on safety and preliminary efficacy. Once a substudy is selected for the cohort expansion (CE) phase (N=35 per substudy), the objective is to compare the response rate between the doublet combination and the shared belantamab mafodotin monotherapy control arm. Secondary objectives in CE are to assess AEs, durability of response, PFS, and overall survival. Exploratory objectives include assessment of PK for belantamab mafodotin with each partner agent, bone marrow minimal residual disease status, and plasma soluble BCMA levels as candidate prognostic and predictive biomarkers. DREAMM-5 is designed to efficiently identify novel, highly effective belantamab mafodotin-containing doublet combinations for evaluation in pivotal trials against current standard-of-care MM agents. Acknowledgments: Editorial assistance provided by Sarah Hauze, PhD, at Fishawack Indicia Ltd and funded by GSK. Study funded by GSK (208887); drug linker technology licensed from Seattle Genetics; monoclonal antibody produced using POTELLIGENT Technology licensed from BioWa. Figure Disclosures Richardson: Oncopeptides: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Sanofi: 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; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Biswas:GSK: Employment, Equity Ownership. Holkova:GlaxoSmithKline: Employment, Equity Ownership. Jackson:GlaxoSmithKline: Employment, Equity Ownership. Netherway:GlaxoSmithKline: Employment, Equity Ownership. Bao:GSK: Employment, Equity Ownership. Ferron-Brady:GlaxoSmithKline: Employment, Equity Ownership. Yeakey:GlaxoSmithKline: Employment, Equity Ownership. Shelton:GlaxoSmithKline: Employment, Equity Ownership. Montes De Oca:GlaxoSmithKline: Employment. Ahlers:GlaxoSmithKline: Employment, Equity Ownership. Franco:GlaxoSmithKline: Employment, Equity Ownership. Ballas:GlaxoSmithKline: Employment, Equity Ownership; Bristol-Myers Squibb: Equity Ownership; AstraZeneca: Patents & Royalties: Uncompensated copyrights. Paul:GlaxoSmithKline: Employment, Equity Ownership. Luptakova:GlaxoSmithKline: Employment, Equity Ownership. Gupta:GlaxoSmithKline: Employment, Equity Ownership. Opalinska:GSK: Employment, Equity Ownership.

Description: Background: Ruxolitinib, a Janus kinase (JAK) 1/2 inhibitor, has been shown to effectively reduce splenomegaly, manage myelofibrosis (MF)-related symptoms, and improve survival, but has limited anticlonal activity. Inhibition of hedgehog signaling via therapy with sonidegib, a selective inhibitor of smoothened (SMO), in combination with ruxolitinib reduced white blood cell (WBC) and platelet counts, JAK2 mutant allele burden, and bone marrow (BM) fibrosis in preclinical MF models more than ruxolitinib alone (Bhagwat, ASH 2013). The maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of sonidegib in combination with ruxolitinib for patients (pts) with MF is being assessed in the phase 1b portion of this phase 1b/2 study (NCT01787552). The safety-expansion cohort is currently ongoing; updated data will be presented. Methods: Adults with primary or secondary (post–polycythemia vera or –essential thrombocythemia) intermediate- or high-risk MF with palpable splenomegaly not previously treated with JAK or SMO inhibitors were eligible. Pts received oral doses of sonidegib once daily (QD) and ruxolitinib twice daily (BID). The first dose level enrolled was sonidegib 400 mg QD + ruxolitinib 10 mg BID. Dose escalations were guided by a Bayesian logistic regression model. In addition to safety and pharmacokinetics (PK), spleen length was assessed by palpation at screening, wk 1, every 2 wk until wk 13, monthly after wk 13, and at the end of treatment. BM fibrosis was assessed in biopsies collected every 24 wk. Results: As of March 26, 2014, 23 pts (16 male) with a median age of 67 y (range, 42-77 y) were treated at 3 dose levels (1: sonidegib 400 mg QD + ruxolitinib 10 mg BID [n = 8]; 2: sonidegib 400 mg QD + ruxolitinib 15 mg BID [n = 10]; 3: sonidegib 400 mg QD + ruxolitinib 20 mg BID [n = 5]). Median (range) levels for hemoglobin, platelet count, and WBC count at baseline (BL) were 102 g/L (64-142 g/L), 232 × 109/L (81-900 × 109/L) and 21 x 109/L (2-59 x 109/L), respectively. Median (range) palpable spleen size at BL was 13 cm (5-38 cm) below costal margin. According to the International Prognosis Scoring System, 5, 7, and 11 pts were intermediate-1, intermediate-2, and high-risk, respectively. At data cutoff, 4 pts had discontinued treatment due to an adverse event (AE), physician decision, progressive disease, or patient decision (n = 1 each). PK parameters and trough levels for both agents generally aligned with single-agent data. Fatigue was the most commonly reported AE regardless of causality (Table). Six serious AEs were reported, 4 at dose level 1 (face edema, hyponatremia, pyrexia, right ventricular failure; n = 1 each) and 2 at dose level 2 (blood creatine kinase [CK] increased; n = 2). Dose-limiting toxicities of grade 3 and 4 CK elevations were reported in 2 pts at dose level 2. At data cutoff, 65% of pts achieved a ≥ 50% reduction in palpable spleen length from BL and 9 pts had resolution of splenomegaly. Conclusions: The evaluated combination doses of sonidegib and ruxolitinib were generally well tolerated in pts with MF, and preliminary efficacy data appear promising. Sonidegib and ruxolitinib in combination did not appear to affect the PK of either agent. Once the MTD and/or RP2D are determined, the safety and efficacy of this combination will be further evaluated in the phase 2 study. Abstract 712. Table.Dose Level 1Sonidegib 400 mg QD +Ruxolitinib 10 mg BID(n = 8)Dose Level 2Sonidegib 400 mg QD +Ruxolitinib 15 mg BID(n = 10)Dose Level 3Sonidegib 400 mg QD +Ruxolitinib 20 mg BID(n = 5)All(N = 23)AEs of any cause reported in 〉 10% of all pts, n (%)AllGrade 3/4AllGrade 3/4AllGrade 3/4AllGrade 3/4Fatigue5 (63)1 (13)3 (30)0008 (35)1 (4)Anemia5 (63)5 (63)00005 (22)5 (22)Dysgeusia3 (38)02 (20)0005 (22)0Abdominal pain2 (25)02 (20)01 (20)05 (22)0Alopecia1 (13)04 (40)0005 (22)0Muscle spasms1 (13)04 (40)1 (10)005 (22)1 (4)Thrombocytopenia2 (25)1 (13)1 (10)01 (20)04 (17)1 (4)Diarrhea3 (38)01 (10)0004 (17)0Hyponatremia2 (25)2 (25)1 (10)1 (10)003 (13)3 (13)Blood CK increased1 (13)02 (20)2 (20)003 (13)2 (9)Muscular weakness1 (13)02 (20)1 (10)003 (13)1 (4)Aspartate aminotransferase increased002 (20)1 (10)1 (20)03 (13)1 (4)Decreased appetite3 (38)000003 (13)0Nausea2 (25)01 (10)0003 (13)0Constipation2 (25)01 (10)0003 (13)0Asthenia1 (13)02 (20)0003 (13)0Upper respiratory tract infection1 (13)02 (20)0003 (13)0Headache003 (30)0003 (13)0Myalgia003 (30)0003 (13)0Alanine aminotransferase increased002 (20)01 (20)03 (13)0 Disclosures Gupta: Incyte Corporation: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Koschmieder:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Travel, Accomodation, Expenses Other; Novartis Foundation: Research Funding. Harrison:SBio: Consultancy; Gilead: Honoraria; CTI: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Shire: Speakers Bureau. Cervantes:Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees. Heidel:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Drummond:Novartis: Consultancy, Honoraria, Speakers Bureau. Rey:Novartis: Consultancy. Hurh:Novartis NIBR: Employment. Bao:Novartis Pharmaceuticals Corporation: Employment. Rampersad:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership. Kalambakas:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Description: Background: Ruxolitinib, a Janus kinase (JAK) 1/2 inhibitor, has been approved for the treatment of disease-related splenomegaly or symptoms in adults with primary myelofibrosis (MF), post-polycythemia vera (PPV) MF, and post-essential thrombocythemia (PET) MF. In a murine model of MF, ruxolitinib in combination with the hedgehog pathway inhibitor (HPI) sonidegib, improved splenomegaly and bone marrow (BM) fibrosis more than ruxolitinib monotherapy (Bhagwat, ASH 2013). Building on these data, ruxolitinib and sonidegib combination therapy is being assessed in a phase 1b/2 study in patients (pts) with MF (NCT01787552). Findings from the phase 1b portion of this study determined the recommended phase 2 dose (RP2D) to be sonidegib 400 mg once daily and ruxolitinib 20 mg twice daily (Gupta, ASH 2014). Combination treatment was generally well tolerated; the maximum tolerated dose was not reached, and the only observed dose-limiting toxicity was creatine kinase (CK) elevation. In this report, safety and efficacy data from the analysis performed 24 weeks after the last pt enrollment (data cutoff, 08 May 2015) are presented for pts treated at the RP2D. Methods: Eligible pts includedadults with primary or secondary (PPV or PET) intermediate (Int)- or high-risk MF with palpable splenomegaly who were not previously treated with a JAK inhibitor or HPI. The primary objective was to assess the efficacy of co-administration of ruxolitinib and sonidegib determined by reduction in spleen volume per MRI/CT by central review at the end of weeks 24 and 48. Results: Overall, 27 pts with primary MF (n = 16; 59.3%), PET-MF (n = 7; 25.9%), and PPV-MF (n = 4; 14.8%) were treated at the RP2D (median exposure, 28.6 weeks). The median age was 69 years (range, 44 to 83 years), 70.4% of pts were male, and 85.2% were JAK2 V617F positive. According to the International Prognosis Scoring System, 1 pt (3.7%) was low risk, 4 pts (14.8%) were Int-1, 4 pts (14.8%) were Int-2, and 18 pts (66.7%) were high risk. At data cutoff, 20 pts (74.1%) remained on treatment; 5 pts discontinued treatment due to an adverse event (AE), and 1 pt each due to pt decision and death (multi-organ failure unrelated to study treatment occurring 2 days after discontinuation). Overall, the most common AEs regardless of causality (all grade; grade 3/4; Table) were anemia (52%; 33%) and muscle spasms (48%; 4%). AEs requiring dose adjustment or interruption were experienced by 17 pts (63%), with the most common being increased CK (19% [n = 5]) and myalgia (19% [n = 5]). The mean hemoglobin level at baseline (BL) was ≈ 100 g/L and it remained relatively stable throughout treatment. Mean platelet count decreased from BL levels of ≈ 300 × 109/L to ≈ 150 × 109/L by week 4, and then remained relatively stable at ≈ 200 × 109/L. At the end of week 24, 12 pts (44.4%) had a ≥ 35% reduction in spleen volume as measured by MRI/CT and 15 pts (55.6%) achieved a ≥ 35% reduction in spleen volume at any time on treatment (Figure 1). A ≥ 50% reduction in palpable spleen length was achieved by 15 pts (55.6%) at the end of week 24; a best response of ≥ 50% reduction in spleen length at any time on treatment was achieved by 25 pts (92.6%), with 15 pts (55.6%) having a non-palpable spleen (Figure 2). The mean change in JAK2 V617F allele burden was -9.0% (range, -56.5% to 7.0%) from BL to the end of week 24. Investigator-assessed changes in BM fibrosis in pts with BL and post-BL values indicated that 2 pts had an improvement (from grade 3 to grade 2), 8 pts remained stable, and 3 pts had a worsening from BL by the end of week 24. Pharmacokinetics of the combination will be presented. Conclusions: The combination of ruxolitinib and sonidegib has activity in pts with MF and may provide improved benefit over ruxolitinib monotherapy. Combination treatment was generally well tolerated, with ≈ 74% of pts remaining on treatment at data cutoff. Table. Most Common Adverse Events Sonidegib 400 mg Once Daily + Ruxolitinib 20 mg Twice Daily(n = 27) AEs of any cause in ≥ 10% of pts, n (%) All Grade 3/4 Anemia 14 (52) 9 (33) Muscle spasms 13 (48) 1 (4) Increased CK 10 (37) 5 (19) Myalgia 8 (30) 2 (7) Dysgeusia 8 (30) - Thrombocytopenia 7 (26) 3 (11) Diarrhea 7 (26) 1 (4) Fatigue 7 (26) 0 Pyrexia 6 (22) 1 (4) Alopecia 6 (22) - Constipation 5 (19) 0 Nausea 5 (19) 0 Abdominal pain 4 (15) 0 Dizziness 4 (15) 0 Headache 4 (15) 0 Decreased platelet count 3 (11) 1 (4) Asthenia 3 (11) 0 Cough 3 (11) 0 Decreased weight 3 (11) 0 Dry mouth 3 (11) 0 Dyspnea 3 (11) 0 Extremity pain 3 (11) 0 Increased creatinine 3 (11) 0 Disclosures Gupta: Incyte: Honoraria, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Off Label Use: Ruxolitinib is a kinase inhibitor indicated for treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential thrombocythemia myelofibrosis. Sonidegib is approved for the treatment of locally advanced basal cell carcinoma. Harrison:Novartis: Honoraria, Research Funding, Speakers Bureau; CTI Biopharma: Consultancy, Honoraria, Speakers Bureau; Gilead: Honoraria; Shire: Speakers Bureau; Sanofi: Honoraria, Speakers Bureau. Hasselbalch:Novartis: Research Funding. Koschmieder:Novartis Foundation: Research Funding; Baxalta/CTI: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel reimbursement for scientific conferences ; Janssen Cilag: Other: Travel reimbursement for scientific conferences ; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel reimbursement for scientific conferences , Research Funding. Cervantes:Novartis: Consultancy, Speakers Bureau; CTI-Baxter: Consultancy, Speakers Bureau; Sanofi-Aventis: Consultancy. Bao:Novartis Pharmaceuticals Corporation: Employment. Kalambakas:Novartis: Employment, Equity Ownership. Atienza:Novartis Pharmaceuticals Corporation: Employment. Gopalakrishna:Novartis Pharma AG: Employment. Heidel:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.