ALBERT

Description: Background: Treatment of elderly AML patients considered unfit for conventional chemotherapy is inadequate and hypomethylating agents are commonly used alternatives. In the case of azacitidine, responses are typically seen after 3–6 cycles of therapy, and a recent large randomized trial in elderly unfit patients reported a complete response (CR)/CR with incomplete blood count recovery rate of 28% (Dombret et al, EHA 2014). Pevonedistat (MLN4924) is an investigational, first-in-class NEDD8-activating enzyme (NAE) inhibitor. A phase 1 trial previously reported pevonedistat single-agent clinical activity in relapsed/refractory AML patients. Preclinical studies of pevonedistat and azacitidine identified synergistic lethality in AML cell lines and murine xenografts. The current phase 1b dose-escalation study evaluated the safety and tolerability of pevonedistat combined with azacitidine in elderly AML patients considered unfit for conventional chemotherapy. Methods: The primary objective was to assess the safety and tolerability of pevonedistat combined with azacitidine. Secondary objectives included assessment of pevonedistat pharmacokinetics (PK) and clinical activity. Treatment-naïve AML patients aged ≥60 years who were considered unfit for standard induction therapy received pevonedistat via 1-hour IV infusion on days 1, 3, and 5 of 28-day cycles. Dose escalation began at 20 mg/m2 and used an adaptive Bayesian continual reassessment method. Azacitidine 75 mg/m2 was administered (IV or SC) on days 1–5 and 8–9. Patients were treated until disease progression or unacceptable toxicity. Adverse events (AEs) were graded per NCI-CTCAE v4.03. Responses were assessed according to International Working Group response criteria for AML. Serial blood samples were obtained for PK analysis following dosing on days 1 and 5 of cycle 1. Results: As of May 30, 2014, 25 patients (median age 75.0 years [range 63–85]; 16 [64%] male) had received pevonedistat 20 mg/m2 (n=22) and 30 mg/m2 (n=3). Primary diagnoses were 16 (64%) de novo AML and 9 (36%) secondary AML. Fourteen (56%) patients had intermediate- and 6 (24%) had adverse-risk cytogenetics (5 [20%] undetermined). During dose escalation, dose-limiting toxicity (DLT) at the 30 mg/m2 pevonedistat dose level included reversible grade 2 increased bilirubin (n=1) and grade 3/4 increased transaminases (n=1) without clinical sequelae. In 1 of the 22 patients treated at the maximum tolerated dose (20 mg/m2 pevonedistat plus 75 mg/m2 IV/SC azacitidine), 1 additional DLT (grade 4 AST/ALT elevation) was seen in the expansion cohort. This patient was successfully re-challenged with a reduced pevonedistat dose. The most common all-grade AEs are shown in table 1. Twelve (48%) patients experienced drug-related grade ≥3 AEs (table 1). The nature and frequency of the reported toxicities (excluding DLTs) were similar to previous reports for azacitidine alone. Preliminary PK data showed that addition of azacitidine did not alter the known PK profile of single-agent pevonedistat. In the 18 response-evaluable patients, there were 6 (33%) CRs and 4 (22%) PRs (table 2), for an overall response rate of 56%. Nine of the 10 responses occurred within the first two cycles of therapy and included 1 patient with bone marrow blasts 〉80%. Conclusions: Combination therapy with pevonedistat and azacitidine was generally well-tolerated. The characteristics of the observed responses suggest added benefit from the addition of pevonedistat compared with azacitidine alone. Table 1 Common all-grade AEs n (%) Most frequent (≥10%) drug-related grade ≥3 AEs n (%) Febrile neutropenia 9 (36) Febrile neutropenia 4 (16) Constipation 8 (32) Thrombocytopenia 3 (12) Decreased appetite 7 (28) – – Thrombocytopenia 7 (28) – – Table 2 Responders* Tumor Type Cytogenetic Risk Group Current Status Response Molecular CR 1st Response 1st CR 1 De novo AML Adverse C12 C4 – – 2 Undetermined C4† C1 C1 Y 3 Adverse C9 C1 C1 Y 4 Undetermined C5‡ C1 C2 Y 5 Intermediate C5† C1 C2 N 6 Intermediate C7 C1 C4 Y 7 Intermediate C2 C2 – – 8 Secondary AML Undetermined C4 C2 C2 – 9 Normal C4 C1 – – 10 De novo AML – C1 C1 – – Molecular CR, complete remission confirmed by molecular studies *All received 20 mg/m2 pevonedistat except #4, who started on 30 mg/m2 and had a dose reduction to 20 mg/m2. †Patient off study ‡Patient off treatment and in follow-up Disclosures Swords: Novartis: Consultancy; KaloBios Pharmaceuticals, Inc.: Consultancy; Millennium: The Takeda Oncology Company: Consultancy. Savona:Novartis: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences, Inc.: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Karyopharm Pharmaceuticals: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Erba:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Research Funding; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda Pharmaceuticals International Co.: Research Funding; Astellas Pharma: Research Funding; Celgene: Honoraria, Speakers Bureau; Seattle Genetics: Consultancy, Research Funding. Foran:Takeda Pharmaceuticals International Co.: Research Funding. Hua:Takeda Pharmaceuticals International Co.: Employment. Faessel:Takeda Pharmaceuticals International Co.: Employment, Equity Ownership. Dash:Takeda Pharmaceuticals International Co.: Employment. Sedarati:Takeda Pharmaceuticals International Co.: Employment. Dezube:Takeda Pharmaceuticals International Co.: Employment. Medeiros:Millennium: The Takeda Oncology Company: Consultancy, Honoraria; Takeda Pharmaceuticals International Co.: Research Funding.

Description: Background Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of aggressive non-Hodgkin lymphomas (NHL). PTCL accounts for approximately 10% of all NHL cases in the US and Europe, and may be as high as 24% in Asia. The most common frontline treatment of PTCL is anthracycline-based chemotherapy with CHOP or CHOP-like regimens which do not produce durable remissions in the majority of subtypes, including ALK+ systemic anaplastic large cell lymphoma (sALCL) with high International Prognostic Index (IPI) scores. Brentuximab vedotin is an antibody-drug conjugate directed against CD30 currently approved for the treatment of relapsed or refractory sALCL with demonstrated antitumor activity in frontline PTCL. A phase 1 trial combining brentuximab vedotin with cyclophosphamide, doxorubicin, and prednisone (CHP [CHOP without vincristine to eliminate additive neurotoxicity]) as frontline treatment of PTCL demonstrated estimated 5-year progression-free survival (PFS) and overall survival (OS) rates of 52% and 79% (Fanale 2018). Based on the encouraging activity and manageable safety profile of the combination, the ECHELON-2 trial was initiated to compare the efficacy and safety of brentuximab vedotin in combination with CHP (A+CHP) versus standard CHOP for the treatment of patients (pts) with PTCL (ClinicalTrials.gov No. NCT01777152). Here we report the blinded, pooled analyses per investigator of the ECHELON-2 trial. Methods ECHELON-2 is a phase 3, randomized, double-blind, active-controlled, multicenter study. Adults with newly diagnosed CD30+ (≥10% of neoplastic cells by local review) PTCL were enrolled. Pts with ALK+ sALCL were required to have an IPI ≥2. The primary endpoint of ECHELON-2 is PFS per an independent review facility. Pts were randomized 1:1 to receive 21-day cycles of either CHOP or A+CHP for 6 to 8 cycles. Consolidative SCT or radiotherapy was permitted at the investigator's discretion after end of treatment. Results A total of 452 pts across 17 countries were randomized between January 2013 and November 2016 in Europe (44%), North America (29%), and other (26%) regions including Asia and Australia. The median age was 58 years (range, 18-85) and 63% were male. Most pts were white (62%) or Asian (22%). Most pts entering the study had an ECOG performance status of 0 or 1 (39% each) and the remaining 22% of pts had a performance status of 2. Most pts had advanced-stage disease (Stage III [27%] or IV [53%]) at diagnosis and 78% had IPI scores ≥2 (2 [34%], 3 [29%], 4 [12%]. 5 [3%]). PTCL subtypes included sALCL (316 pts [70%]: ALK+ 98 pts [22%]; ALK- 218 pts [48%]), PTCL - not otherwise specified (72 pts [16%]), angioimmunoblastic T-cell lymphoma (54 pts [12%]), adult T-cell leukemia/lymphoma (7 pts [2%]), and enteropathy-associated T-cell lymphoma (3 pts [1%]). Of the 452 randomized pts, 449 received at least 1 dose of study treatment and all pts had either completed (82%) or discontinued treatment as of April 2017. Treatment was discontinued for adverse events (AEs) (7%), progressive disease (7%), investigator decision (2%), and patient decision (2%). Preliminary results by investigator assessment, show an overall blinded pooled objective response rate (ORR) following completion of the frontline treatment of 79% (95% CI: 75.4-83.1) with 64% achieving a complete response (CR) (95% CI: 59.1-68.2). With a median follow-up of 35.2 mos, the 3-year PFS and OS for all pts were 52.9% (95% CI: 47.7-57.7) and 73.1% (95% CI: 68.3-77.2). The incidence of AEs was consistent with the known safety profiles of brentuximab vedotin and CHOP chemotherapy, including the AE of interest, peripheral sensory neuropathy (43%). Grade 3 or higher AEs reported in ≥10% of pts were neutropenia (33%), febrile neutropenia (17%), and anemia (12%). Conclusions ECHELON-2 is the largest prospective, randomized, double-blind study to compare the efficacy and safety of standard CHOP with an alternative regimen that includes a CD30-targeted agent in frontline treatment of sALCL and other CD30+ PTCLs. Blinded pooled data from ECHELON-2 show that the treatment was well tolerated with encouraging 3-year PFS and OS rates. The primary analysis by treatment regimen will be unblinded prior to the meeting and presented at the conference. Disclosures Horwitz: Seattle Genetics: Consultancy, Research Funding; Aileron Therapeutics: Consultancy, Research Funding; Innate Pharma: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Forty Seven: Consultancy, Research Funding; Corvus: Consultancy; Mundipharma: Consultancy; ADC Therapeutics: Consultancy, Research Funding; Trillium: Consultancy; Celgene: Consultancy, Research Funding; Portola: Consultancy; Infinity/Verastem: Consultancy, Research Funding; Spectrum: Research Funding; Kyowa-Hakka-Kirin: Consultancy, Research Funding. O'Connor:Seattle Genetics: Research Funding; Celgene: Research Funding; ADC Therapeutics: Research Funding. Pro:kiowa: Honoraria; Takeda Pharmaceuticals: Honoraria, Other: Travel expenses; Seattle Genetics: Consultancy, Other: Travel expenses, Research Funding; portola: Honoraria. Illidge:Nordic Nanovector: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Research Funding; Takeda: Consultancy, Honoraria. Fanale:Amgen: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Merck & Co: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Takeda: Honoraria, Other: Travel expenses, Research Funding. Advani:Agensys: Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Astra Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Merck: Research Funding; Janssen: Research Funding; Autolus: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Celgene: Research Funding; Kyowa: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Regeneron: Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Infinity: Research Funding; Kura: Research Funding; Celgene: Research Funding; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Gilead/Kite: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Cell Medica: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Millenium: Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Forty Seven Inc.: Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board. Bartlett:KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding; Astra Zeneca: Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; ImaginAB: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck & Co: Research Funding; Immune Design: Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Forty Seven: Research Funding; Affimed: Research Funding; Celgene: Research Funding; Novartis: Research Funding; Pharmacyclics: Research Funding; Novartis: Research Funding; Bristol-Meyers Squibb: Research Funding; Millennium: Research Funding. Christensen:Seattle Genetics: Research Funding. Morschhauser:Janssen: Other: Scientific Lectures; BMS: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, 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; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees. Domingo-Domenech:Affimed: Research Funding. Rossi:Novartis: Honoraria; Jazz: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Teva: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses; Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses; Janssen: Membership on an entity's Board of Directors or advisory committees, Travel expenses; Roche: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Mundipharma: Honoraria; Sandoz: Honoraria; Seattle Genetics: Research Funding; Alexion: Other: Travel expenses. Feldman:Portola: Research Funding; Celgene: Speakers Bureau; Pharmacyclics: Speakers Bureau; Seattle Genetics: Research Funding, Speakers Bureau; KITE: Speakers Bureau; Johnson and Johnson: Speakers Bureau; Janssen: Speakers Bureau. Lennard:Janssen: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Research Funding. Belada:Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead Sciences: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Illés:Takeda: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. Tobinai:Zenyaku Kogyo: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; SERVIER: Research Funding; Abbvie: Research Funding; GlaxoSmithKline: Research Funding; Takeda: Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding; Kyowa Hakko Kirin: Honoraria, Research Funding; HUYA Bioscience International: Consultancy, Honoraria; Chugai Pharma: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Tsukasaki:Celgene: Honoraria; Eisai: Research Funding; Chugai Pharma: Honoraria, Research Funding; HUYA: Consultancy, Research Funding; Ono Pharma: Consultancy; Daiich-Sankyo: Consultancy; Mundy Pharma: Honoraria; Kyowa-hakko/Kirin: Honoraria; Seattle Genetics: Research Funding. Yeh:GNT Biotech & Medicals Crop.: Research Funding. Shustov:Seattle Genetics: Research Funding. Hüttmann:Roche: Other: Travel expenses; Celgene: Other: Travel expenses. Savage:Verastem: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Servier: Consultancy. Yuen:Seattle Genetics: Research Funding. Zinzani:MSD: Honoraria, Speakers Bureau; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SERVIER: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astra Zeneca: Speakers Bureau; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hua:Takeda Pharmaceuticals International Co.: Employment. Little:Takeda Pharmaceuticals: Employment. Rao:Seattle Genetics: Employment, Equity Ownership. Woolery:Seattle Genetics: Employment, Equity Ownership. Manley:Seattle Genetics: Employment, Equity Ownership. Trümper:Seattle Genetics: Research Funding.

Description: Background NEDD8-activating enzyme (NAE) regulates the NEDD8 conjugation pathway, and is required for activity of the cullin-RING E3 ligases (CRLs). CRLs control proteasomal degradation of several substrates involved in cell-cycle regulation, signal transduction, DNA replication and stress response including proteins important for survival of AML cells. MLN4924, a first-in-class NAE inhibitor, has shown antitumor activity in preclinical AML models. This study evaluated safety and tolerability of MLN4924 given on multiple dosing schedules. A maximum tolerated dose (MTD) of 59 mg/m2 given on days 1, 3 and 5 of a 21-day cycle (schedule A) was previously reported (Erba et al, EHA 2011); complete responses were observed in 4/27 patients for this schedule (most common AE: diarrhea [44%], most common Gr ≥3 AE: febrile neutropenia [33%]). Here we report on two additional schedules. Methods Adults with AML or MDS and good performance status received MLN4924 as a 60-min IV infusion on one of two schedules for up to 1 year or until disease progression. Schedule B patients received escalating doses of MLN4924 on days 1, 4, 8 and 11 every 21 days. Schedule E patients received a fixed dose of MLN4924 on days 1, 3 and 5 every 21 days. Adverse events (AEs) and responses were graded according to published guidelines. Serial blood samples were obtained during cycle 1 for pharmacokinetic (PK) and pharmacodynamic analyses. Results On schedule B: 26 patients were enrolled (77% male), median age was 70.5 yrs, 23 had AML and 3 had MDS (2 had advanced disease with marrow blasts exceeding 10%). Patients received MLN4924 at 83 (n=19), 110 (n=4), and 147 mg/m2 (n=3). On Schedule E: 16 patients (69% male) received 50 mg/m2 MLN4924, median age was 70.5 yrs, 14 AML and 2 MDS (1 with advanced disease). Three patients on schedule B had dose-limiting toxicities (DLTs): 1 patient at 110 mg/m2; orthostatic hypotension (Gr 3); 2 patients at 147 mg/m2; cardiac failure (Gr 4; n=1), fatal lactic acidosis, hypotension, gastrointestinal necrosis, acute renal failure and myocardial ischemia (each Gr 4; n=1). On schedule E, 2 patients had DLTs: morbilliform rash (Gr 3; n=1); and increased aspartate/alanine aminotransferases (Gr 2/3; n=1). Most common all-grade and Gr ≥3 AEs are shown in the table. The MTD for Schedule B was determined as 83 mg/m2. On schedules B/E, 3/2 patients received ≥4 cycles, 0/4 remain on treatment; discontinuations were due to progressive disease (11/10), AEs (8/0), and other reasons (7/2) respectively. In 17 patients treated at 83 mg/m2 on schedule B and 16 patients on schedule E, individual PK profiles showed a biphasic disposition phase following completion of the first infusion. MLN4924 plasma concentrations were detectable 24–48 hours (schedule B) and 24 hours (schedule E) post dosing. Schedule B geometric mean (%CV) Cmax was 1255 ng/mL (25.1%), AUC24hr was 3936 ng•h/mL (22.6%); schedule E values were Cmax of 669 ng/mL (24.4%) and AUC24hr of 2614 ng•h/mL (21.4%). Observed increases in mean Cmax and AUC24hr were dose-proportional between 50 and 83 mg/m2 after single dosing. Pharmacodynamic data demonstrated evidence of target and pathway inhibition for all patients on both schedules. On schedule B, of 20 response-evaluable patients (18 AML, 2 MDS), 2 (11%) AML patients had partial responses (PR), 13 (72%) had stable disease. On schedule E, of 12 response-evaluable patients (11 AML, 1 MDS), 1 (8%) AML patient had a PR, 7 (59%) maintained stable disease and the MDS patient (8%) had a response. Conclusions Both schedules appeared to be generally well tolerated and NAE inhibition with MLN4924 resulted in clinical activity in highly refractory/multiply relapsed patients. Based on safety and observed clinical activity across schedules, the recommended phase 2 dose for single agent MLN4924 in AML/MDS is 50 mg/m2 given on days 1, 3 and 5 of a 21-day cycle. A study of MLN4924 with azacitidine in treatment-naïve AML patients older than 60 years is ongoing (NCT01814826). Disclosures: Off Label Use: Investigational agent MLN4924 for the treatment of patients with AML and high-grade or low-grade MDS. Hua:Millennium: The Takeda Oncology Company: Employment. Blakemore:Millennium: The Takeda Oncology Company: Employment. Faessel:Millennium: The Takeda Oncology Company: Employment. Dezube:Millennium: The Takeda Oncology Company: Employment. Medeiros:Millennium: The Takeda Oncology Company: Research Funding.