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142 Treatment of Myelofibrosis Patients with the TGF-β 1/3 Inhibitor AVID200 (MPN-RC 118) Induces a Profound Effect on Platelet ProductionClinically Relevant Abstract

Program: Oral and Poster Abstracts
Type: Oral
Session: 634. Myeloproliferative Syndromes: Clinical and Epidemiological: Non-JAK inhibitor Therapies for Myelofibrosis
Hematology Disease Topics & Pathways:
Clinical Trials, Biological, Antibody Therapy, Clinical Research, Diseases, Therapies, Myeloid Malignancies
Saturday, December 11, 2021: 12:45 PM

John Mascarenhas, MD1, Heidi E. Kosiorek, MS2*, Rupali Bhave, MD3*, Jeanne M. Palmer, MD4, Andrew T. Kuykendall, MD5, Ruben A. Mesa, MD, FACP6, Raajit Rampal, MD, PhD7, Aaron T. Gerds, MD, MS8, Abdulraheem Yacoub, MD9, Kristen M. Pettit10, Moshe Talpaz, MD10, Rami S. Komrokji, MD5, Marina Kremyanskaya, MD, PhD11, Agapito Gonzalez12*, Frank Fabris1*, Lonette Sandy13*, Kathryn Johnson14*, Mikaela Doughtery1*, Erin McGovern, BA15*, Juan Arango Ossa16*, Dylan Domenico17*, Noushin Farnoud, PhD15*, Anna Rita Migliaccio, PhD18, Mohamed E Salama, MD19, Rona Singer Weinberg, PhD20, Amy Kong21*, Vesna Najfeld, PhD22, Carolyn Mead-Harvey, MS2*, Amylou C. Dueck, PhD2, Lilian Varricchio, PhD23* and Ronald Hoffman, MD24

1Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY
2Department of Health Sciences Research, Mayo Clinic, Scottsdale, AZ
3Wake Forest Baptist Health Comprehensive Cancer Center, Winston-Salem, NC
4Division of Hematology and Medical Oncology, Mayo Clinic, Phoenix, AZ
5Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
6UT Health San Antonio Cancer Center, San Antonio, TX
7Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Institute, New York, NY
8Leukemia Program, Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH
9The University of Kansas Cancer Center, Leawood, KS
10Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan, Ann Arbor, MI
11Tisch Cancer Institute, Mount Sinai School of Medicine, New York, NY
12University of Texas at San Antonio, San Antonio, TX
13Ichan School of Medicine At Mount Sinai, New York City, NY
14Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York
15Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, NY
16Computational Oncology Service, Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY
17Memorial Sloan Kettering Cancer Center, New York, NY
18Medicine and Surgery, University Campus Bio-Medico, Rome, Italy
19Mayo Clinic, Rochester, MN
20New York Blood Center, New York, NY
21Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY
22Departments of Pathology and Medicine, The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, Mount Sinai Health System, Inc., New York, NY
23Tisch Cancer Institute, Division of Hematology and Oncology, Icahn School of Medicine at Mount Sinai (ISMMS), New York, NY
24Tisch Cancer Institute, Icahn School of Medicine At Mount Sinai Medical Center, New York, NY

TGFβ plays a pivotal role in the pathobiology of myelofibrosis (MF) by not only promoting bone marrow fibrosis (BMF) but also by enhancing the dormancy of normal but not MF hematopoietic stem cells (HSCs). TGFβ has also previously been reported to inhibit normal megakaryocyte (MK) production (Bruno et al Blood 1998). TGFβ1 promotes the synthesis of collagen by normal human mesenchymal stromal cells (MSCs). Treatment of MSCs with AVID200, a potent TGFβ1/3 protein trap, significantly decreased MSC proliferation, phosphorylation of SMAD2, and collagen expression. Robust expression of pSMAD2 was observed in the absence of exogenous TGFβ in normal donor or MF-MKs, Addition of AVID200 to MKs decreased pSMAD2 without affecting total SMAD2/3 and led to increased numbers of MKs. Treatment of MF MNCs with AVID200 also led to increased numbers of progenitor cells with wild type JAK2 and a reduction of mutated colonies.

A phase 1b trial of AVID200 (NCT03895112) was performed and completed in INT-2/high risk MF patients resistant/intolerant to ruxolitinib (rux); baseline platelet count of ≥ 25 x 109/L, and grade 2/3 BMF. Subjects received AVID200 intravenously on Day 1 of a 21 day cycle. Response was assessed by IWG/ELN criteria after 6 cycles of AVID200. Subjects attaining at least a CI or SD with a decrease in BMF by ≥1 grade, continued AVID200.

We previously presented the results of the dose escalation study (Mascarenhas ASH 2020) demonstrating that AVID200 was well tolerated without dose limiting toxicities at 3 tested dose levels (Lots A and B) in dose cohorts of 180 mg (A), 550 mg (A)/70 mg (B), and 180 mg (B). Here we report updated safety and efficacy results of the phase 1b dose expansion stage at the two highest doses tested (70 mg (B) and 180 mg (B).

Twenty-two subjects were enrolled (1 withdrew before receiving treatment) and 9 were treated with AVID200 in the dose escalation phase and 12 in the dose expansion phase [Table1]. Median time after rux discontinuation was 7.4 months (0.5-59.9). The most common mutations observed at baseline in this cohort included JAK2V617F (71%), TET2 (29%) ASXL1 (24%) and CALR (19%). (Fig 1)

No DLTs were observed and Grade 3/4 AEs were observed in 16 (76.2%) subjects. Grade 3/4 non-hematologic AEs were observed in 8 (38.1%) subjects and included one subject in each case (epistaxis, mucositis, extraocular muscle paresis, fatigue, rash, duodenal hemorrhage, gastric hemorrhage, urinary tract infection, and syncope). Grade 3/4 hematologic AEs were anemia (6; 28.3%) and thrombocytopenia (2; 14.3%) [Table 2]. No fatal events were observed.

The median number of cycles received was 5 (range 2 - 13) and 7 (33%) patients received more than 6 cycles. For dose levels 2-3 at cycle 7, a CI was attained in one subject at dose level 2 [anemia, spleen and TSS], 5 subjects had SD, 3 subjects had PD and two subjects with 10% and 15% blasts at screening developed MPN-BP while on study based on central review. Reasons for discontinuation by local PI included PD (n=8), lack of response (n=5), study completed (n=2), other (n=2), patient decision (n=1).

Median % change in palpable spleen length was +10% (range -70% to +150%) and TSS change was -50% (-100% to +185.7%) The median platelet count at baseline was 114 x 109/L (range: 28-695) and 215 x 109/L (range: 66-263) after cycle 6 in 7 evaluable subjects (Fig 2A). Notably, 17 subjects had an increase in platelets from baseline during treatment and two subjects normalized their platelet counts. Maximum changes in platelets from baseline across all cycles was +63.8% [range -15.7%, +505.5%] (Fig 2B). Paired bone marrow biopsy pathology samples for 12 subjects were available for central review and showed no significant changes in BMF score or MK histo topography at end of treatment compared to baseline.

All patients had elevated plasma levels of TGF β1, but not TGFβ2/β3 levels as detected by ELISA, which were dramatically reduced 21 days after the last dose of AVID200.

AVID200 a TGFβ1/3 protein trap is well tolerated and clinical responses at cycle 7 of therapy in this advanced MF patient population were limited as judged by IWG/MRT response criteria. However, AVID200 therapy resulted in significant reduction in serum TGFβ levels and improvements in platelet counts indicating that TGF β1 plays a pivotal role in MF leading to thrombocytopenia which can be reversed with AVID200 therapy. We conclude that AVID200 may best be employed in combination therapy approaches in thrombocytopenic MF patients.

Disclosures: Mascarenhas: Constellation: Consultancy, Membership on an entity's Board of Directors or advisory committees; Promedior: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Geron: Consultancy, Research Funding; Forbius: Research Funding; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; PharmaEssentia: 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; Galecto: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Prelude: Consultancy; Kartos: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; CTI Biopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Geron: Consultancy; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merus: Research Funding. Palmer: PharmaEssentia: Research Funding; Sierra Oncology: Consultancy, Research Funding; Incyte: Research Funding; CTI BioPharma: Consultancy, Research Funding; Protagonist: Consultancy, Research Funding. Kuykendall: Abbvie: Honoraria; Novartis: Honoraria, Speakers Bureau; Celgene/BMS: Honoraria, Research Funding, Speakers Bureau; CTI Biopharma: Honoraria; BluePrint Medicines: Honoraria, Research Funding, Speakers Bureau; Incyte: Consultancy; PharmaEssentia: Honoraria; Prelude: Research Funding; Protagonist: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Mesa: Genentech: Research Funding; Promedior: Research Funding; Samus: Research Funding; Gilead: Research Funding; CTI: Research Funding; Abbvie: Research Funding; Sierra Oncology: Consultancy, Research Funding; Celgene: Research Funding; Novartis: Consultancy; Pharma: Consultancy; CTI: Research Funding; Constellation Pharmaceuticals: Consultancy, Research Funding; AOP: Consultancy; La Jolla Pharma: Consultancy; Incyte Corporation: Consultancy, Research Funding. Rampal: Pharmaessentia: Consultancy; Kartos: Consultancy; Incyte: Consultancy, Research Funding; Disc Medicine: Consultancy; Stemline: Consultancy, Research Funding; BMS/Celgene: Consultancy; Novartis: Consultancy; Sierra Oncology: Consultancy; CTI: Consultancy; Abbvie: Consultancy; Memorial Sloan Kettering: Current Employment; Constellation: Research Funding; Jazz Pharmaceuticals: Consultancy; Blueprint: Consultancy. Gerds: PharmaEssentia Corporation: Consultancy; Sierra Oncology: Consultancy; CTI BioPharma: Research Funding; Constellation: Consultancy; Celgene/Bristol Myers Squibb: Consultancy; AbbVie: Consultancy; Novartis: Consultancy. Yacoub: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees; ACCELERON PHARMA: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Dynavex: Current equity holder in publicly-traded company; Cara: Current equity holder in publicly-traded company; Ardelyx: Current equity holder in publicly-traded company; Seattle Genetics: Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau; Hylapharm: Current equity holder in publicly-traded company. Talpaz: Imago: Consultancy; Constellation: 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; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Other: Grant/research support ; Celgene: Consultancy. Komrokji: Acceleron: Consultancy; Taiho Oncology: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy; BMSCelgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; PharmaEssentia: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Geron: Consultancy; Jazz: Consultancy, Speakers Bureau. Kremyanskaya: Astellas: Research Funding; Astex: Research Funding; Chimerix: Research Funding; Bristol Myers Squibb: Research Funding; Constellation: Research Funding; Protagonist Therapeutics: Consultancy, Research Funding; Incyte: Research Funding. Salama: Mayo Clinic: Current Employment, Other: Mayo Clinic had the contractual work for the central pathology review for this study and I was one of the reviewing pathologists; Constellation Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Hoffman: Kartos Therapeutics, Inc.: Research Funding; Protagonist Therapeutics, Inc.: Consultancy; Novartis: Other: Data Safety Monitoring Board, Research Funding; AbbVie Inc.: Other: Data Safety Monitoring Board, Research Funding.

OffLabel Disclosure: AVID200 is a TGFb trap and is in clinical testing for fibrotic diseases. It does not have an approved indication at this time.

*signifies non-member of ASH