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671 Results from a Phase 2 Study of Navitoclax in Combination with Ruxolitinib in Patients with Primary or Secondary Myelofibrosis

Program: Oral and Poster Abstracts
Type: Oral
Session: 634. Myeloproliferative Syndromes: Clinical: JAK Inhibitors and Combination Therapies
Hematology Disease Topics & Pathways:
Diseases, Adult, Study Population, Clinically relevant, Myeloid Malignancies
Monday, December 9, 2019: 11:30 AM
W311EFGH, Level 3 (Orange County Convention Center)

Claire N Harrison, Professor1, Jacqueline S Garcia, MD2, Ruben A Mesa, MD3, Tim CP Somervaille, MD, PhD4, Rami S. Komrokji, MD5,6,7, Naveen Pemmaraju, MD8, Catriona Jamieson, MD, PhD9, Nikolaos Papadantonakis, MD, PhD, MSc10, James M. Foran, MD11, Casey L. O'Connell, MD12, Leanne Holes, BS, MBA,13*, Jia Jia, PhD, MBA13*, Jason Harb, PhD13*, Jessica Hutti, PhD13* and Josef T. Prchal, MD14

1Guy's and Saint Thomas' NHS Foundation Trust, London, United Kingdom
2Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
3University of Texas Health, San Antonio, TX
4Cancer Research UK Manchester Institute, The Christie NHS Foundation Trust, The University of Manchester, Manchester, United Kingdom
5Moffit Cancer Center, Tampa, FL
6Department of Malignant Hematology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL
7Division of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL
8The University of Texas MD Anderson Cancer Center, Houston, TX
9Moores Cancer Center, University of California, San Diego, La Jolla, CA
10University of Alabama at Birmingham, Birmingham, AL
11Mayo Clinic, Jacksonville, FL
12Keck School of Medicine, University of Southern California, Los Angeles, CA
13AbbVie Inc., North Chicago, IL
14Huntsman Cancer Institute, University of Utah and, Salt Lake City, UT

Background: Myelofibrosis (MF) is associated with bone marrow fibrosis (BMF), splenomegaly, a high symptom burden, and poor prognosis; the JAK/STAT pathway is the central pathway implicated in its pathogenesis. Ruxolitinib, a JAK1/2 inhibitor and the only FDA-approved pharmacotherapy for treatment (Tx) of MF patients (pts), improves splenomegaly, but is unable to control all clinical manifestations of disease. Navitoclax is an orally bioavailable, novel small-molecule that targets and binds with high affinity to multiple antiapoptotic B-cell lymphoma 2 (BCL2) family proteins, including BCL-XL, BCL2, and BCL-W. Preclinical studies have demonstrated cytotoxic activity of navitoclax against myeloproliferative neoplasm-derived cell lines. Herein, the results of a phase 2 study (NCT03222609) evaluating the combination of navitoclax with ruxolitinib in pts with MF are reported.

Methods: This phase 2 single-arm, multicenter, open-label study assessed the efficacy and safety of navitoclax combined with ruxolitinib in pts with MF. Eligible pts (18 yr, diagnosis of primary MF, post-essential thrombocythemia [PET]-MF, or post-polycythemia vera [PPV]-MF, ECOG 0–2, receiving at least 12 wk of continuous ruxolitinib therapy prior to study Tx initiation) received a starting dose of 50 mg navitoclax once-daily combined with the current stable dose of ruxolitinib (≥10 mg BID). Weekly intra-patient dose-escalation of navitoclax was allowed to a maximum daily dose of 300 mg based on tolerability and platelet count. Tx continued until the end of clinical benefit, unacceptable toxicity, or discontinuation. The primary efficacy endpoint was percentage reduction in splenic volume from baseline. Secondary endpoints included effect on total symptom score (TSS), overall response rate, rate of anemia response, improvement in BMF, and safety profile.

Results: As of May 1, 2019, 34 pts (primary MF, n=16; PET-MF, n=5; PPV-MF, n=13) had received 1 dose of navitoclax in combination with ruxolitinib. Median age was 68 yr (range 42–86), 68% were male, and 9 pts (26%) had 3 prior lines of MF therapy. The median duration of prior ruxolitinib exposure was 745 days (range 134–4549). Of the 34 pts enrolled, 27 (79%) had JAK2 and 7 pts (21%) had CALR mutations. There were no pts enrolled with triple-negative MF. Of 33 pts with available baseline testing, 17 (52%) had high molecular risk, defined by mutations within ASXL1, EZH2, IDH1/2, SRSF2, or U2AF1. The mean baseline platelet count was 231 x 109/L (range 99-706); mean baseline Hgb was 10.8 g/dL; 19 (56%) pts had elevated WBC at baseline (>1.5× ULN). Maximal navitoclax dose of 300 mg was achieved in 23 pts (68%). Of the 25 (74%) pts that enrolled on ruxolitinib doses >10 mg BID, 22 (88%) subsequently had the dose of ruxolitinib reduced to 10 mg BID. At the time of this analysis, 24 pts were evaluable for efficacy, with 20 pts completing ≥24 wk on study and 4 pts with Tx discontinuations prior to 24 wk. At wk 24, 7 of 24 pts (29%) achieved a spleen volume reduction of ≥35% (SVR35) from baseline by MRI as determined by prespecified central review; the median TSS was 7.4 (range 0–23), a 20% improvement from baseline. A SVR35 at any time on study was achieved in 10 pts (42%). Reductions in driver mutation allelic burden of >5% were observed in 10 (42%) pts; 6 pts (25%) had BMF improvement of 1 grade. One pt (4%) had an anemia response; the mean Hgb at wk 24 was slightly improved over baseline at 11.3 g/dL. Of the 19 pts with elevated baseline WBC, 16 (84%) reduced to within normal limits during Tx, with a median WBC reduction of 17.7 × 109/L. All pts experienced a Tx-emergent adverse event (TEAE); most common (20%) were thrombocytopenia (82%), diarrhea (62%), fatigue (53%), anemia (27%), nausea (27%), contusion (24%), and vomiting (21%). Grade 3 TEAEs occurred in 26 pts (77%); most common were thrombocytopenia (n=15, 44%; Grade 4 n=1, 3%) and anemia (n=8, 24%; no Grade 4). Five pts (15%) experienced serious AEs that resolved including anemia, upper abdominal pain, vomiting, chest pain, increased C-reactive protein, and abnormal liver function test (3% each). There were no significant episodes of bleeding and no TEAE-related deaths.

Conclusions: Navitoclax in combination with ruxolitinib was well tolerated with clinically meaningful spleen responses, allelic burden reductions, TSS improvements, and encouraging improvements in BMF in pts with MF who have received prior Tx with ruxolitinib.

Disclosures: Harrison: CTI: Speakers Bureau; Promedior: Honoraria; Roche: Honoraria; Celgene: Honoraria, Speakers Bureau; Gilead: Speakers Bureau; Shire: Speakers Bureau; Incyte: Speakers Bureau; Sierra Oncology: Honoraria; Janssen: Speakers Bureau. Garcia: Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Pfizer: Research Funding; Eli Lilly: Research Funding. Mesa: Incyte: Research Funding; Genentech: Research Funding; Abbvie: Research Funding; CTI: Research Funding; Samus: Consultancy; Celgene: Research Funding; Novartis: Consultancy; La Jolla: Consultancy; Sierra Oncology: Consultancy. Somervaille: Novartis: Consultancy. Komrokji: pfizer: Consultancy; celgene: Consultancy; DSI: Consultancy; Incyte: Consultancy; Agios: Consultancy; JAZZ: Consultancy; Novartis: Speakers Bureau; JAZZ: Speakers Bureau. Pemmaraju: sagerstrong: Research Funding; celgene: Consultancy, Honoraria; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; samus: Research Funding; novartis: Consultancy, Research Funding; plexxikon: Research Funding; incyte: Consultancy, Research Funding; abbvie: Consultancy, Honoraria, Research Funding; mustangbio: Consultancy, Research Funding; cellectis: Research Funding; affymetrix: Research Funding. Papadantonakis: Agios: Consultancy, Honoraria. Foran: Agios: Honoraria, Research Funding. O'Connell: Astex: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Shionogi: Membership on an entity's Board of Directors or advisory committees. Holes: AbbVie Inc: Employment, Other: Stock/stock options. Jia: AbbVie: Employment, Other: Stock/stock options. Harb: AbbVie Inc: Employment, Other: Stock/stock options. Hutti: AbbVie: Employment, Other: Stock/stock options.

*signifies non-member of ASH