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1489 Adore: A Randomized, Open-Label, Phase 1/2 Open-Platform Study Evaluating Safety and Efficacy of Novel Ruxolitinib Combinations in Patients with MyelofibrosisClinically Relevant Abstract

Program: Oral and Poster Abstracts
Session: 634. Myeloproliferative Syndromes: Clinical and Epidemiological: Poster I
Hematology Disease Topics & Pathways:
Clinical Trials, Biological therapies, Adults, Non-Biological therapies, Workforce, Diversity, Equity, Inclusion, and Accessibility (DEI/DEIA) , Diseases, Therapies, Immunotherapy, Myeloid Malignancies, Monoclonal Antibody Therapy, Study Population
Saturday, December 11, 2021, 5:30 PM-7:30 PM

David M. Ross, MBBS, PhD, FRACP, FRCPA1*, Florian H. Heidel, MD2*, Andrew Charles Perkins, MBBS, PhD3, Caroline Riley, MD, PhD4*, Kate Burbury, MBBS, FRACP, FRCPA, DPhil5*, Thomas Lehmann, MD6*, Vikas Gupta, MD, FRCP, FRCPath7, Claire N. Harrison, DM8, Jean-Jacques Kiladjian, MD, PhD9*, Alessandro M. Vannucchi, MD10*, Marielle Wondergem, MD11, Bruyère Mahuzier, PharmD12*, Monika Wroclawska, MD13*, Celine Wilke, MD13*, Angela Zhang, PhD13* and Andreas Reiter, MD14

1Department of Haematology, Royal Adelaide Hospital and SA Pathology, Adelaide, Australia
2Klinik und Poliklinik für Innere Medizin C, Universitätsklinikum Greifswald, Greifswald, Germany
3Australian Centre for Blood Diseases, Monash University, Malvern, VIC, Australia
4Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
5Peter MacCallum Cancer Centre, Melbourne, Australia
6Clinic for Medical Oncology and Hematology, Cantonal Hospital St. Gallen, St. Gallen, Switzerland
7MPN Program, The Princess Margaret Cancer Centre, Toronto, ON, Canada
8Guy's and St Thomas' Hospital, London, United Kingdom
9Hôpital Saint-Louis & Université de Paris, Paris, France
10Center for Research and Innovation of Myeloproliferative Neoplasms – CRIMM, Azienda Ospedaliera Universitaria Careggi, University of Florence, Florence, Italy
11Department of Hematology, Amsterdam University Medical Centers, Amsterdam, Netherlands
12Novartis Pharma S.A.S, Rueil-Malmaison, France
13Novartis Pharma AG, Basel, Switzerland
14University Medical Centre Mannheim, Mannheim, Germany

Background

Myelofibrosis (MF) is a myeloproliferative neoplasm (MPN) that can develop de novo (primary MF) or from the progression of antecedent MPNs, in particular polycythemia vera (PPV-MF) or essential thrombocythemia (PET-MF). Ruxolitinib (RUX), a first-in-class JAK1/JAK2 inhibitor, is the standard of care for MF and demonstrated superiority over placebo (COMFORT-I) and best available therapy (COMFORT-II) in improving splenomegaly, MF-related symptoms, and quality of life. An overall survival benefit was also observed with RUX (Harrison CN, et al. Leukemia. 2016). However, RUX is not curative, cytopenias remain a challenge and some patients (pts) lose response or discontinue treatment due to adverse events. RUX combined with novel agents may offer superior disease control and transformative clinical benefits.

Methods

ADORE (NCT04097821) is a 3-part, open-label, multicenter, phase 1/2, platform study that will assess the safety and efficacy of RUX in combination with 5 novel compounds for the treatment of MF: siremadlin (HDM2 inhibitor), crizanlizumab (anti-P-selectin antibody), sabatolimab (anti-TIM-3 antibody), rineterkib (ERK1/2 inhibitor) and NIS793 (anti-TGFβ antibody) (Figure).

The study includes pts ≥18 years with primary MF, PPV-MF, or PET-MF, splenomegaly (a palpable spleen ≥5 cm from the left costal margin or spleen volume ≥450 cm3 by MRI or CT scan), hemoglobin level <11 g/dL, and platelet count ≥75 × 109/L (≥50 × 109/L in Parts 2/3). Pts must have received RUX for ≥24 weeks and at a stable dose for ≥8 weeks prior to study entry. Key exclusion criteria include splenic irradiation within 6 months or blood platelet transfusion within 28 days of study start.

Part 1 (phase 1b; Safety) includes a dose escalation arm to determine the recommended phase 2 dose for siremadlin + RUX and rineterkib + RUX, and a safety run-in for RUX + crizanlizumab, RUX + sabatolimab and RUX + NIS793. RUX will be administered at the same stable dose used prior to study entry. Pts will be treated for ≥24 weeks (8 cycles in NIS793 arm or 6 cycles in other arms). Part 1 primary endpoint is the incidence of dose-limiting toxicities within the first 2 cycles. Combinations evaluated as safe and tolerable in Part 1 may be selected for Part 2.

In Part 2 (phase 2; Selection), pts will be randomized to one of the selected combinations or RUX monotherapy (control) and treated for ≥48 weeks. Interim analysis of preliminary efficacy after ≥48 weeks of combination treatment will determine if the combination treatment will proceed to Part 3.

In Part 3 (phase 2; Expansion), pts will be randomized to the combination treatment, RUX cessation, or RUX monotherapy and treated for ≥48 weeks. Pts in the RUX cessation arm will be treated with combination therapy for 12 weeks, followed by RUX tapering and novel agent monotherapy.

The primary endpoint for Parts 2 and 3 is the response rate (a composite of anemia improvement [increase in hemoglobin of ≥1.5 g/dL], no spleen volume progression, and no symptom worsening) at the end of cycle 8 (NIS793 arms) or cycle 6 (other arms) (24 weeks). The study will end 24 months after the last pt has initiated Part 3. Assuming all five combination treatments enter Part 2 and one combination treatment is expanded in Part 3, a total of 240 patients are planned to be enrolled. The study is open for enrolling into Part 1.

Disclosures: Ross: Sierra: Research Funding; Novartis: Honoraria, Research Funding; Kartos: Research Funding; BMS: Research Funding; Imago Biosciences: Research Funding; Keros: Research Funding; Avance Clinical: Consultancy; Roche: Research Funding; Abbvie: Research Funding. Heidel: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CTI: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene/BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AOP: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees. Perkins: Novartis: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy; Abbvie: Honoraria, Speakers Bureau. Lehmann: Janssen: Other; Abbvie: Other: Financial support for congress and conference travel ; Amgen: Honoraria; BMS: Honoraria; Novartis: Research Funding; Swedish Orphan Biovitrum AG: Honoraria; Celgene: Research Funding; Incyte: Honoraria; Amgen: Other: Financial support for congress and conference travel ; AbbVie: Honoraria; Roche: Other; Janssen: Honoraria. Gupta: Constellation Pharma: Consultancy, Honoraria; Sierra Oncology: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy; Pfizer: Consultancy; AbbVie: Consultancy, Honoraria; BMS-Celgene: Consultancy, Honoraria, 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, Research Funding; Incyte: Honoraria, Research Funding. Harrison: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte Corporation: Speakers Bureau; Galacteo: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Keros: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Constellation Pharmaceuticals: Research Funding; Geron: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sierra Oncology: Honoraria; AOP Orphan Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Promedior: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead Sciences: 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, Speakers Bureau. Kiladjian: Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; AP Orphan: Membership on an entity's Board of Directors or advisory committees; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; PharmaEssentia: Membership on an entity's Board of Directors or advisory committees. Vannucchi: AbbVie: Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Wondergem: Novartis: Honoraria. Mahuzier: Novartis: Current Employment. Wroclawska: Novartis: Current Employment. Wilke: Novartis: Current Employment, Current holder of individual stocks in a privately-held company. Zhang: Novartis: Current Employment. Reiter: Deciphera: Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses; Abbvie: Membership on an entity's Board of Directors or advisory committees; AOP Orphan Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; Celgene/BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Research Funding; Blueprint Medicines: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses; Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses.

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