Transform-1: A Randomized, Double-Blind, Placebo-Controlled, Multicenter, International Phase 3 Study of Navitoclax in Combination with Ruxolitinib Versus Ruxolitinib Plus Placebo in Patients with Untreated Myelofibrosis
Blood, vol. 142, pp. 620
Abstract
Background: Janus kinase inhibitors (JAKis) provide symptom improvement and spleen volume reduction in patients with primary, post-polycythemia vera, and post-essential thrombocythemia myelofibrosis (MF). There remains a substantial unmet need for therapies that alter disease trajectory, improve outcomes, and enhance survival. The COMFORT-1 and -2 studies established JAKi monotherapy as standard-of-care with spleen volume reduction of ≥35% at Week 24 (SVR 35W24) of 42% and SVR 35W48 of 29%, respectively. In combination with the JAKi ruxolitinib, navitoclax, an orally available inhibitor of antiapoptotic B-cell lymphoma 2 proteins (BCL-X L, BCL-2, BCL-W), was shown to have pronounced antitumor activity in patients with MF in the phase 2 REFINE trial (NCT03222609). TRANSFORM-1 is an ongoing, phase 3, double-blind, placebo-controlled, multicenter, international study evaluating the safety and efficacy of navitoclax plus ruxolitinib (NAV + RUX) compared with placebo plus ruxolitinib (PBO + RUX) in JAK2i-naïve adults with MF. Methods: TRANSFORM-1 (NCT04472598) enrolled adult patients with intermediate-2 or high-risk MF with measurable splenomegaly, evidence of MF-related symptoms, no prior JAK2i treatment, and ECOG Performance Score ≤2. Patients were randomized 1:1 to receive NAV (starting dose of 200 mg [platelet {PLT} >150 × 10 9/L] or 100 mg escalated to 200 mg once daily if tolerated after ≥7 days [PLT ≤150 × 10 9/L]) or PBO, plus RUX at label dose, based on stratification factors of intermediate-2 vs high-risk MF and PLT ≤200 × 10 9/L vs >200 × 10 9/L. The primary endpoint was SVR 35W24. Secondary endpoints included change in total symptom score at Week 24 (TSS W24) assessed using 7-item MFSAF v4.0 (scale 0-70), SVR 35 at any time, duration of SVR 35, anemia response (per International Working Group criteria), reduction in marrow fibrosis, overall survival, leukemia-free survival, reduction in PROMIS Fatigue scale, and improvement in EORTC QLQ-C30 physical functioning scale. Exploratory endpoints include progression-free survival. Results: At data cutoff, April 13, 2023, 252 patients were enrolled with a median (range) follow-up of 14.9 (0.0-29.5) months; 125 patients were randomized to receive NAV + RUX and 127 to receive PBO + RUX. Most patients were male (57%), median (range) age was 69 (37-87) years, and patient demographics were similar between treatment arms ( Table 1). TRANSFORM-1 met its primary endpoint, with 79 patients (63.2%) in the NAV + RUX arm achieving SVR 35W24 compared with 40 patients (31.5%) in the PBO + RUX arm ( P<0.0001). Notably, SVR 35 at any time was achieved by 96 patients (77%) with NAV + RUX compared with 53 patients (42%) with PBO + RUX. Median (range) time to SVR 35 response was 12.3 (10.1-48.3) weeks with NAV + RUX versus 12.4 (11.3-72.3) weeks with PBO + RUX. Median duration of SVR 35 was not reached (NR) in the NAV + RUX arm compared with 19.4 months (95% CI 16.8, NR) in the PBO + RUX arm. At Week 24, the mean change in TSS from baseline was -9.7 (95% CI: -11.8, -7.6) with NAV + RUX compared with -11.1 (95% CI: -13.2, -9.1) with PBO + RUX arm ( P=0.2852). Grade ≥3 adverse events (AEs) were experienced by 85% of patients with NAV + RUX and 70% with PBO + RUX. The most common AEs (>30% of patients receiving NAV; Table 2) were thrombocytopenia, anemia, diarrhea, and neutropenia. Serious AEs were experienced by 26% of patients with NAV + RUX and 32% with PBO + RUX, including anemia (NAV + RUX: n=2; PBO + RUX: n=1), thrombocytopenia (NAV + RUX: n=2), and neutropenia (NAV + RUX: n=1). With NAV + RUX, AEs led to NAV dose reduction in 101 (81%) patients and NAV interruption in 87 (70%) patients of which 83 (67%) and 65 (52%) were due to thrombocytopenia, respectively. Of all enrolled patients, 83 (33%) discontinued study treatment; most common (>5% total patients) reason for NAV/PBO discontinuation were AEs (n=32; 39% of discontinuations) and physician decision (n=14; 17% of discontinuations). In each arm, 13 (10%) patients died; 6 with NAV + RUX and 5 with PBO + RUX died ≤30 days post-final dose. Conclusions: This first randomized trial in JAKi-naïve MF with NAV + RUX combination led to an SVR 35W24 rate that was twice as high as PBO + RUX ( P<0.0001). The responses were durable; AEs of thrombocytopenia and anemia were common but manageable with dose modification without any clinically significant sequalae. Additional evaluation is ongoing.
Authors 24
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The University of Texas MD Anderson Cancer Center
Affiliation as printed
1Department of Leukemia, MD Anderson Cancer Center, Houston, TX
MD Anderson Cancer Center [Houston] (1515 Holcombe Blvd, Houston, TX 77030 - United States)
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Churchill Hospital · National Institute for Health and Care Research · University of Oxford · MRC Weatherall Institute of Molecular Medicine · Oxford University Hospitals NHS Trust · MRC Molecular Haematology Unit · Medical Research Council
Affiliation as printed
2Medical Research Council (MRC) Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, NIHR, Biomedical Research Centre, University of Oxford, Oxford, United Kingdom
3Cancer and Haematology Centre, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom
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University of Manchester · Cancer Research UK Manchester Institute · The Christie NHS Foundation Trust
Affiliation as printed
4Cancer Research UK Manchester Institute, The University of Manchester and The Christie NHS Foundation Trust, Manchester, United Kingdom
Cancer Research UK Manchester Institute (Cancer Research UK Manchester Institute The University of Manchester Alderley Park SK10 4TG - United Kingdom)
The Christie NHS Foundation Trust [Manchester, Royaume-Uni] (United Kingdom)
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Affiliation as printed
5Department of Leukemia, John Theurer Cancer Center at Hackensack Meridian Health, Hackensack, NJ
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IRCCS Azienda Ospedliero-Universitaria di Bologna Policlinico di Sant'Orsola
Affiliation as printed
6Istituto di Ematologia “Seràgnoli”, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
AOUB - IRCCS Azienda Ospedaliero-Universitaria di Bologna (Area S.Orsola - Via Massarenti, Bologna - Italy)
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Affiliation as printed
7Department of Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Medical Faculty, RWTH Aachen University, Aachen, Germany
8Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Aachen, Germany
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Affiliation as printed
9Hadassah Medical Center, Jerusalem, Israel
Hadassah Hebrew University Medical Center [Jerusalem] (Kiryat Hadassah, POB 12000 Jerusalem, 91120 - Israel)
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Affiliation as printed
10Division of Hematology, Juravinski Cancer Center, Hamilton, Canada
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China Medical University · China Medical University Hospital
Affiliation as printed
11Division of Hematology and Oncology, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
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Universidad de Las Palmas de Gran Canaria · Hospital Universitario de Gran Canaria Doctor Negrín
Affiliation as printed
12Hospital Universitario de Gran Canaria Dr. Negrín. Universidad de Las Palmas de Gran Canaria., Las Palmas de Gran Canaria, Spain
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University Medical Center Groningen · University of Groningen
Affiliation as printed
13Department of Hematology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands
University of Groningen [Groningen] (PO Box 72 , 9700 AB Groningen - Netherlands)
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Pusan National University Hospital · Pusan National University
Affiliation as printed
14Department of Hematology-Oncology, Pusan National University Hospital, Pusan National University School of Medicine, Busan, Korea, Republic of (South)
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Affiliation as printed
15Department of Hematology and Oncology, University of Yamanashi, Chuo, Japan
Yamanashi University (Kofu Campus 4-4-37, Takeda, Kofu, Yamanashi, 400-8510 Japan - Japan)
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Centre Hospitalier Universitaire de Nîmes
Affiliation as printed
16Hematologie Clinique, CHU de Nimes, Nimes, France
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Universitair Ziekenhuis Leuven · KU Leuven
Affiliation as printed
17Department of Hematology, University Hospitals Leuven, Leuven, Belgium
18Department of Microbiology and Immunology, Laboratory of Molecular Immunology (Rega Institute), KU Leuven, Leuven, Belgium
UZ Leuven - Universitair Ziekenhuis Leuven = University Hospital of Leuven = Hopital universitaire de Louvain (Herestraat 49, 3000 Leuven - Belgium)
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Affiliation as printed
19Department of Haematology, Royal Perth Hospital, Perth, Australia
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University Hospital St. Ivan Rilski
Affiliation as printed
20Clinic of Haematology, St.Ivan Rilski University Multidisciplinary Hospital, ., Bulgaria
St. Ivan Rilski University Hospital = University Hospital St. Ivan Rilski (Sofia - Bulgaria)
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University of Belgrade · Univerzitetski Klinički Centar Srbije
Affiliation as printed
21Faculty of Medicine, University of Belgrade, Belgrade, Serbia
22Clinic of Hematology, University Clinical Center Serbia, Belgrade, Serbia
University of Belgrade [Belgrade] (Studentski Trg 1, 11000 Belgrade - Serbia)
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Affiliation as printed
23AbbVie Inc., North Chicago, IL
Abbvie Inc. [North Chicago] (1400 Sheridan Rd, North Chicago, IL 60064 - United States)
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Affiliation as printed
23AbbVie Inc., North Chicago, IL
Abbvie Inc. [North Chicago] (1400 Sheridan Rd, North Chicago, IL 60064 - United States)
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Affiliation as printed
23AbbVie Inc., North Chicago, IL
Abbvie Inc. [North Chicago] (1400 Sheridan Rd, North Chicago, IL 60064 - United States)
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Affiliation as printed
23AbbVie Inc., North Chicago, IL
Abbvie Inc. [North Chicago] (1400 Sheridan Rd, North Chicago, IL 60064 - United States)
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Affiliation as printed
24AbbVie Inc, North Chicago, IL
Abbvie Inc. [North Chicago] (1400 Sheridan Rd, North Chicago, IL 60064 - United States)
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University of Milan · Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
Affiliation as printed
25Dipartimento di Oncologia ed Ematologia, Università degli Studi di Milano, Policlinico di Milano, Ospedale Maggiore, Fondazione I.R.C.C.S. Ca Granda, Milano, Italy
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