POSTER A Phase 2, Multicenter, Open-Label Study of the Safety and Ef cacy of Luspatercept TPS7083 in Subjects With Myeloproliferative Neoplasm (MPN)-Associated Myelo brosis and Anemia With or Without RBC Transfusion Dependence Ruben A. Mesa1, Giovanni Barosi2, Claire N. Harrison3, Jean-Jacques Kiladjian4, Robert Peter Gale5, Abderrahmane Laadem5, Torsten Gerike5, Peter G. Linde6, Matthew L. Sherman6, Joseph Pariseau5, Srdan Verstovsek7 1UT Health San Antonio Cancer Center, San Antonio, TX, USA; 2IRCCS Policlinico San Matteo, Pavia, Italy; 3Guy’s and St Thomas’ NHS Foundation Trust, London, UK; 4Hôpital Saint-Louis and Université Paris Diderot, Paris, France; 5Celgene Corporation, Summit, NJ, USA; 6Acceleron Pharma, Cambridge, MA, USA; 7MD Anderson Cancer Center, Houston, TX, USA BACKGROUND STUDY DETAILS (cont.) STUDY DETAILS (cont.) • Myeloproliferative neoplasm (MPN)-associated myelo brosis (MF) is a clonal myeloid neoplasm characterized by bone marrow brosis, defective Figure 2. Study Design Figure 3. Clinical Sites in USA (A) and Europe (B) bone marrow function, extramedullary hematopoiesis, a propensity for Post-Treatment Screening 1 Follow-Up transformation to blast phase, and in ammation Period Treatment Period A Period 4 weeks • Anemia is an important complication of MPN-associated MF, eventually PrPimriamrya Pryh aPshease 3 years post developing in all patients2,3 1618 6d8a ydsays last dose • Anemia and red blood cell (RBC) transfusion dependence (TD) are independent Cohort 1 adverse prognostic and predictive variables for survival among these patients3,4 (Anemia only) 0 RBC units/84 days Luspatercept up to cycle 1, day 1 (n = 20) • Luspatercept is a recombinant fusion protein consisting of a modi ed activin receptor type IIB linked to the Fc domain of human If clinical Cohort 2 y 5,6 benefit d Day 169 u immunoglobulin G1 (IgG1) (Figure 1) (RBC-TD) Post-treatment t disease S Continue for Screening Mean 2–4 RBC follow-up f • Luspatercept acts as an erythroid maturation agent by binding speci c response o up to an period units/28 days assessment d transforming growth factor-β (TGF-β) superfamily ligands such as growth additional n (n = 20) 1.5 years E differentiation factor-11 (GDF11), blocking their inhibitory effect, and leading Parallel Enrolling B to increased RBC production6 Cohort 3 • In a recent phase 2 study, luspatercept was shown to be effective and (Patients on well tolerated for the treatment of anemia in patients with lower-risk ruxolitinib as part If no clinical 7 myelodysplastic syndromes of standard of benefit care therapy) Discontinue Anemia only (3a) treatment Figure 1. Mechanism of Action of Luspatercept and RBC-TD (3b) (n = 30) Erythropoietin-dependent RBC, red blood cell; TD, transfusion dependence. Luspatercept-responsive Hemoglobin Table. Study Endpoints Endpoints Cohorts 1 and 3a (Anemia Only) Cohorts 2 and 3b (RBC-TD) Primary ≥ 1.5 g/dL Hb increase from baseline RBC-TI over any consecutive 84-day BFU-E CFU-E Pro-E Baso-E Poly-E Ortho-E Reticulocyte RBCs over any consecutive 84-day period period Baso-E, basophilic erythroblast; BFU-E, burst-forming unit–erythroid; CFU-E, colony-forming unit–erythroid; Ortho-E, without an RBC transfusion orthochromatic erythroblast; Poly-E, polychromatophilic erythroblast; Pro-E, proerythroblast; RBC, red blood cell. Secondary • Time to anemia response • Time to anemia response • Duration of anemia response • Duration of anemia response OBJECTIVE • Symptom response improvement • Frequency of RBC transfusions Statistical Analyses (defi ned as ≥ 50% reduction (mean RBC units/4 weeks) • Descriptive statistical analyses will primarily be used • To evaluate the ef cacy and safety of luspatercept for the treatment of in fatigue symptoms or ≥ 50% • Frequency of RBC-TD (defi ned as • The Kaplan–Meier method may be used to estimate duration of anemia anemia in patients with MPN-associated MF with or without RBC-TD reduction in total symptom score reduction in transfusion burden by response by MF-SAF or MPN-SAF) ≥ 50% from baseline over any • No inferential comparisons between the cohorts will be performed STUDY DETAILS • HRQoL improvement consecutive 84-day period) • Safety • Symptom response improvement Study Status • • Enrollment began in November 2017 • This is an ongoing, multicenter, open-label, phase 2 study Pharmacokinetics (defi ned as ≥ 50% reduction • Antidrug antibodies in fatigue symptoms or ≥ 50% • Target enrollment is 70 patients with MPN-associated MF and anemia, with Study Population reduction in total symptom score or without RBC-TD • Inclusion criteria: by MF-SAF or MPN-SAF) • As of April 9, 2018 across 24 clinical sites (Figure 3), 12 patients have been – Age ≥ 18 years • HRQoL improvement enrolled into the study – MPN-associated MF (primary MF, post-polycythemia vera MF, • Safety • Enrollment is currently ongoing (ClinicalTrials.gov identi er NCT03194542) or post-essential thrombocythemia MF) • Pharmacokinetics • If you have a patient who could bene t from participation in this trial, please – Anemia, de ned as: • Antidrug antibodies contact the Associate Director of Clinical Trial Disclosure (+1-888-260-1599 Cohorts 1 and 3a: ≥ 3 hemoglobin (Hb) levels ≤ 9.5 g/dL on ≥ 3 days (including day of dosing), with no RBC transfusions in the 84 days prior to cycle 1 day 1 (C1D1); Hb, hemoglobin; HRQoL, health-related quality of life; MF-SAF, Myelofi brosis Symptom Assessment Form; MPN-SAF, Myeloproliferative or [email protected]) ≥ 42 days between measurements will be excluded Neoplasm Symptom Assessment Form; RBC, red blood cell; TD, transfusion dependence; TI, transfusion independence. Cohorts 2 and 3b: average RBC transfusion frequency of 2–4 RBC units/28 days over ≥ 84 days prior to C1D1, with no interval > 42 days without ≥ 1 RBC transfusion; Post-Treatment Follow-Up Period REFERENCES Hb < 13 g/dL on C1D1 prior to luspatercept administration • After treatment discontinuation, follow-up safety data will be collected up to 1. Mesa RA, et al. Leuk Res. 2011;35(1):12-13. 5. Attie KM, et al. Am J Hematol. 2014;89(7):766-770. – Eastern Cooperative Oncology Group performance status ≤ 2 42 days after the last dose of study treatment 2. Cervantes F, et al. Blood. 2009;113(13):2895-2901. 6. Suragani RN, et al. Nat Med. 2014;20(4):408-414. Study Design and Treatment 3. Passamonti F, et al. Blood. 2010;115(9):1703-1708. 7. Platzbecker U, et al. Lancet Oncol. 2017;18(10):1338-1347. • Safety data will then be collected every 3 months for up to 3 years after the last 4. Elena C, et al. Haematologica. 2011;96(1):167-170. • The study comprises 3 periods (Figure 2): dose of study treatment or until death, consent withdrawal, or loss to follow-up – Screening period Endpoints ACKNOWLEDGEMENTS AND DISCLOSURES – Treatment period (primary phase, disease response assessment at • Primary and secondary endpoints are listed in the Table day 169, and extension phase) This study was sponsored by Celgene Corporation, Summit, NJ, USA. The authors received editorial assistance and printing – Post-treatment follow-up period • Exploratory endpoints include treatment exposure–response, biomarkers, support in the preparation of this poster from Excerpta Medica (Daniel Gilmartin, PhD), supported by Celgene Corporation. and mutational analyses The authors are fully responsible for all content and editorial decisions. Screening Period R.A.M.: Celgene Corporation, CTI, Genentech, Gilead Sciences, Incyte, NS Pharma, P zer, PharmaEssentia, Promedior • All ef cacy analyses will be performed primarily on the intent-to-treat – research funding; AOP Orphan Pharmaceuticals, Incyte, Novartis – travel/accommodations/expenses; AOP Orphan • All screening procedures are conducted ≤ 28 days prior to enrollment Pharmaceuticals, Novartis, Shire – honoraria; Baxalta, Galena Biopharma, Incyte, Novartis – consulting or advisory role. population, de ned as all patients enrolled G.B.: no con icts of interest to disclose. C.N.H.: Celgene Corporation, Novartis – research funding; Celgene Corporation, Treatment Period • Con rmatory ef cacy analyses will be performed on the ef cacy-evaluable Gilead Sciences, Novartis – honoraria; Novartis – speakers bureau. J.J.K.: AOP Orphan Pharmaceuticals, Novartis – research funding; Incyte, Novartis, Shire – travel/accommodations/expenses; Novartis, Shire – honoraria; Incyte, Novartis, Shire – • All patients will receive luspatercept 1 mg/kg subcutaneously on day 1 population, de ned as all patients who: consulting or advisory role. R.P.G., T.G., J.P.: Celgene Corporation – employment, stock and other ownership interests, travel/ of each 21-day cycle – Received ≥ 3 cycles of study treatment and remain on study for accommodations/expenses. A.L.: Celgene Corporation – employment, stock and other ownership interests, honoraria. P.G.L.: Acceleron Pharma – employment; Abbott Laboratories, AbbVie, Acceleron Pharma, FibroGen – stock and other ownership • Patients will be enrolled in cohorts according to RBC transfusion requirement: ≥ 21 days after the third study dose OR interests. M.L.S.: Acceleron Pharma – employment, patents/royalties/other intellectual property; Acceleron Pharma, Pulmatrix – leadership, stock and other ownership interests. S.V.: Gilead Sciences, Incyte, Novartis – honoraria; Incyte, Novartis – – Cohorts 1 and 3a (anemia only) – Achieved Hb > 13 g/dL in < 3 cycles consulting or advisory role; AstraZeneca, BioPharma Corp., Blueprint Medicines Corp., Bristol-Myers Squibb, Celgene – Cohorts 2 and 3b (RBC-TD) • Safety analyses will be performed on