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1254 Rationale for and Results of a Phase I Study of the TGF-β 1/3 Inhibitor AVID200 in Subjects with Myelofibrosis: MPN-RC 118 Trial

Program: Oral and Poster Abstracts
Session: 634. Myeloproliferative Syndromes: Clinical: Poster I
Hematology Disease Topics & Pathways:
Biological, Adult, Diseases, Therapies, blood banking, MPN, thrombocythemia, Study Population, Myeloid Malignancies, Clinically relevant, pathways
Saturday, December 5, 2020, 7:00 AM-3:30 PM

John Mascarenhas, MD1,2,3,4,5, Heidi E. Kosiorek, MS6,7*, Lilian Varricchio, PhD8*, Rupali Bhave, M.D.9*, Andrew T. Kuykendall, MD10,11,12,13, Rami Komrokji, MD14, Aaron T. Gerds, MD, MS15,16,17,18,19,20,21,22,23,24, Jeanne M. Palmer, Md25,26,27, Amelia R. Gabler1,28,29,30,31,32*, Lonette Sandy33*, Anna Rita Migliaccio, PhD34,35,36,37, Mohamed E Salama, MD38,39, Rona Singer Weinberg, PhD40, Maureen O'Connor-McCourt, PhD41*, Gilles Tremblay, PhD42*, Paul I. Nadler, MD43, Amylou C. Dueck, PhD2,44,45,46, Ruben A. Mesa, MD, FACP47 and Ronald Hoffman, MD2,48,49,50

1Icahn School of Medicine at Mount Sinai, New York, NY
2MPN Research Consortium, New York, NY
3Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY
4Hematology, Mount Sinai School of Medicine, New York, NY
5Division of Hematology/Medical Oncology, Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute, New York, NY
6Mayo Clinic, Scottsdale, AZ
7Department of Biostatistics, Mayo Clinic, Phoenix, AZ
8Division of Hematology and Oncology, Tish Cancer Institute, Ichan School of Medicine at Mount Sinai, New York
9Comprehensive Cancer Center of Wake Forest Baptist Health, Winston-Salem, NC
10Division of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
11Division of Malignant Hematology, Moffitt Cancer Center, Tampa, FL
12Department of Malignant Hematology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL
13Moffitt Cancer Center, University of South Florida, Tampa, FL
14Moffitt Cancer Center, Tampa, FL
15Cleveland Clinic Taussig Cancer Institute, Cleveland, OH
16Leukemia & Myeloid Disorders Program, Cleveland Clinic, Cleveland, OH
17Department of Hematology and Medical Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH
18Taussig Cancer Institute, Department of Hematology & Medical Oncology, Cleveland Clinic, Cleveland, OH
19Blood and Marrow Transplant Program, Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH
20Hematology and Medical Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH
21Department of Hematology/Oncology, Cleveland Clinic, Cleveland, OH
22Blood and Marrow Transplant Program, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH
23Cleveland Clinic Taussig Cancer Institute, Shaker Heights, OH
24Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH
25Mayo Clinic, Phoenix, AZ
26Division of Hematology and Medical Oncology, Department of Medicine, Mayo Clinic, Phoenix, AZ
27Division of Hematology/Oncology, Mayo Clinic, Phoenix, AZ
28Icahn School of Medicine at Mount Sinai, The Tisch Cancer Institute, New York, NY
29Icahn School of Medicine at Mount Sinai, Division of Hematology and Medical Oncology, New York, NY
30Icahn School of Medicine at Mount Sinai, Myeloproliferative Neoplasms Research Consortium, New York, NY
31Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD
32Memorial Sloan Kettering Cancer Center, New York, NY
33Ichan School of Medicine At Mount Sinai, New York City, NY
34Biomedical and Neuromotorial Sciences, Alma Mater Studiorum University, Bologna, Italy
35Department of Biomedical and Neuromotorial Sciences, Mount Sinai School of Medicine, New York, NY
36Division of Hematology/Oncology, Tisch Cancer Institute, Ichan School of Medicine at Mount Sinai, New York, Italy
37Myeloproliferative Neoplasm-Research Consortium, New York, NY
38Mayo Medical Laboratories, Rochester, MN
39Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
40New York Blood Center, New York, NY
41Forbius, Montreal, Canada
42Formation Biologics, Montreal, QC, Canada
43Nadler Pharma Associates, LLC, Randolph, NJ
44Mayo Clinic Arizona, Phoenix, AZ
45Section of Biostatistics, Mayo Clinic, Scottsdale, AZ
46Department of Health Sciences Research, Mayo Clinic, Scottsdale, AZ
47Mays Cancer Center at UT Health San Antonio, San Antonio, TX
48Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY
49Tisch Cancer Institute, Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY
50Hematology/Oncology, Mount Sinai School of Medicine, New York, NY

Preclinical Rationale: Myelofibrosis (MF) is a chronic myeloproliferative neoplasm for which there are limited therapies. TGFβ plays a pivotal role in the pathobiology of MF by not only promoting bone marrow fibrosis (BMF) and collagen deposition, 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) and activates the TGFβ receptor I/SMAD pathway as well as non-canonical TGFβ pathways. We generated MKs from MF subject mononuclear cells (MNCs) and showed that they elaborated significantly greater levels of TGFβ1 than TGFβ2/3 TGFβ1 treatment reduced the numbers of hematopoietic colonies generated by normal but not MF MNCs. 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, indicating that AVID200 blocks the effects of autocrine TGFβ produced by MKs and led to increased numbers of MKs. Moreover, treatment of primary MF MNCs with AVID200 led to increased numbers of progenitor cells with wild type JAK2 and a reduction of mutated colonies. AVID200 blocked TGFβ1-induced p57Kip2 expression and SMAD2 activation by MF MNCs allowing the normal progenitor cells to preferentially cycle, proliferate, and form hematopoietic colonies.

Clinical Trial Design: Based on these findings, a phase 1 trial of AVID200 is ongoing in INT-2/high risk MF subjects resistant or intolerant to ruxolitinib; baseline platelet count of ≥ 25 x 109/L, and grade 2/3 BMF. Subjects received intravenous AVID200 (Lots A and B) in dose cohorts of 180 mg/m2 (A), 550 mg/m2 (A), 180 mg/m2 (B) on Day 1 of a 21 day cycle. Cohorts of 3 subjects with a target toxicity rate of 30% were enrolled to estimate the maximum tolerated dose (MTD). A modified toxicity probability interval design was used. 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.

Clinical Trial Results: 10 subjects were enrolled (1 withdrew before receiving treatment) and 9 were treated with AVID200 and were evaluable for DLT assessment [Table1]. Median time after ruxolitinib discontinuation was 3.5 months (0.5-12.2).

No DLTs were observed. Grade 3/4 AEs (regardless of attribution) were observed in 6 (66.7%) subjects. Grade 3/4 non-hematologic AEs observed were epistaxis (1, 11.1%),
extraocular muscle paresis (1, 11.1%), fatigue (1, 11.1%) and rash (1, 11.1%). Grade 3/4 hematologic AEs were anemia (3, 33.3%) and thrombocytopenia (2, 22.2%) [Table 2].

The median number of cycles received was 5.7 (range 0 - 12). 5 subjects received 6+ cycles and were evaluable. CI occurred in 2 subjects [anemia, spleen and TSS (n=1); TSS (n=1)] 1 of which is still being treated, 2 subjects had SD, 1 subject with 21% blasts prior to study treatment had progressive MPN-BP.

4 subjects failed to reach response evaluation after 6 cycles, 2 had PD due to increasing splenomegaly, 1 subject received an allogeneic transplant and 1 is still being treated [Cycle 2].

The median platelet count at baseline was 114 (range: 42-290) and 159 after cycle 6 [Figure 1]. Maximum changes in platelets from baseline was +64% [range -73%, 169%] in all subjects. 7 subjects had an increase in platelets from baseline during treatment. 2 subjects normalized their platelet count from thrombocytopenic levels. The effect of AVID200 on BMF is currently being examined. 2 subjects remain on treatment.

Conclusions: AVID200 a TGFβ1/3 protein trap is well tolerated in advanced MF subjects. Clinical responses were observed at the 550 mg dose and the expansion efficacy cohorts at doses 2 and 3 are enrolling 12 additional subjects. Furthermore, AVID200 therapy improved thrombocytopenia in MF subjects which may be due to AVID200 inhibiting the effects of TGFβ1 on normal MKpoiesis. Updated subject safety and efficacy data along with correlative data will be presented.

Disclosures: Mascarenhas: Celgene, Prelude, Galecto, Promedior, Geron, Constellation, and Incyte: Consultancy; Incyte, Kartos, Roche, Promedior, Merck, Merus, Arog, CTI Biopharma, Janssen, and PharmaEssentia: Other: Research funding (institution). Kuykendall: Blueprint Medicines: Research Funding; BMS: Research Funding; Incyte: Research Funding; Novartis: Research Funding. Komrokji: Jazz: Honoraria, Speakers Bureau; Abbvie: Honoraria; Agios: Speakers Bureau; BMS: Honoraria, Speakers Bureau; Geron: Honoraria; Incyte: Honoraria; Acceleron: Honoraria; Novartis: Honoraria. Gerds: Gilead Sciences: Research Funding; Imago Biosciences: Research Funding; Sierra Oncology: Research Funding; Celgene: Consultancy, Research Funding; Roche/Genentech: Research Funding; CTI Biopharma: Consultancy, Research Funding; Apexx Oncology: Consultancy; AstraZeneca/MedImmune: Consultancy; Pfizer: Research Funding; Incyte Corporation: Consultancy, Research Funding. Migliaccio: Novartis: Research Funding. O'Connor-McCourt: Forbius: Current Employment. Tremblay: Forius: Current Employment. Nadler: Forbius: Consultancy; Nadler Pharma Associates: Current Employment; Symphogen: Consultancy; Iksuda Therapeutics: Consultancy; Tessa Therapeutics: Consultancy. Mesa: Celgene: Research Funding; Genetech: Research Funding; Samus: Research Funding; Promedior: Research Funding; CTI: Research Funding; LaJolla Pharma: Consultancy; Incyte: Research Funding; Sierra Onc: Consultancy; Abbvie: Research Funding; Novartis: Consultancy. Hoffman: Forbius: Consultancy; Abbvie: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Dompe: Research Funding; Protagonist: Consultancy.

*signifies non-member of ASH