Abstract
Background: LGH447 is a novel, specific pan-Pim kinase inhibitor in development for the treatment of patients with multiple myeloma (MM) and other hematologic malignancies. The PIM (Provirus Integration site for Moloney leukemia) kinase gene family encodes 3 serine/threonine protein kinases that have roles in cell cycle progression and survival. In human disease, elevated levels of Pim1 and Pim2 are associated with hematologic malignancies, with MM showing the highest level of Pim2 expression. In preclinical studies, a majority of MM cell lines proved sensitive in vitro to LGH447-mediated Pim inhibition, exhibiting a dose-dependent decrease in cell proliferation. LGH447 demonstrated significant tumor growth inhibition in xenograft mouse models of MM as compared with control animals, supporting the clinical development of LGH447 in MM patients.
Methods: Patients with relapsed/refractory MM for whom no effective treatment options exist were enrolled on this first-in-human, multicenter, open-label phase 1 dose-escalation study (CLGH447X2101). Escalating doses of single-agent LGH447 were administered orally on a continuous daily dosing schedule. Treatment continued until disease progression, unacceptable toxicity, consent withdrawal, or death. The primary objective was to estimate the maximum tolerated dose (MTD) of LGH447 administered as a single agent, orally, once daily. Secondary objectives included assessing the safety, tolerability, preliminary anti-myeloma activity, and pharmacokinetics of LGH447. Dose escalation followed a Bayesian logistic regression model based on dose-limiting toxicities (DLTs) occurring in cycle 1. Adverse events (AEs) were graded according to NCI-CTCAE v4.03. Efficacy assessments were made by investigators according to International Myeloma Working Group (IMWG) uniform response criteria with modifications.
Results:At the data cutoff, 54 patients have been treated at the following doses: 70 mg (n = 5), 150 mg (n = 6), 200 mg (n = 6), 250 mg (n = 7), 300 mg (n = 4), 350 mg (n=10), 500 mg (n=10), 700 mg (n=6), with the MTD determined to be 500 mg once daily. Median age was 65 years (range, 41-87 years). Most patients (92.6%) presented with baseline Eastern Cooperative Oncology Group performance status 0-1. Patients were heavily pretreated with a median of 4 prior lines of therapy (range, 1-16). 81.5% had received prior proteasome inhibitor therapy, 83.3% had received prior immunomodulatory therapy (70.4% lenalidomide and 48.1% thalidomide), 68.5% were treated with both proteasome inhibitor and immunomodulatory therapies, and 87.0% had received prior stem cell transplant. Seventeen patients are ongoing at doses between 250-700 mg, with a median duration of exposure of 10.6 weeks (range, 0.1-56.1 weeks), and 37 patients discontinued (disease progression [n = 29], AEs [n = 4], withdrawal of consent [n = 4]). There were 8 DLTs, consisting of four grade 3/4 thrombocytopenia (1 each at 200, 250, 350, 500 mg dose levels), two grade 3 fatigue (1 each at 500 and 700 mg dose levels), one grade 3 hypophosphatemia (300 mg), and one episode of vaso-vagal syncope (700 mg). This last event was the only reported unexpected serious AE that was suspected to be due to LGH447 treatment. The majority of AEs regardless of study drug relationship were grade 1/2. Most common grade 3/4 AEs were thrombocytopenia (18.5%), anemia (18.5%), neutropenia (13%), and fatigue (11.1%). No deaths have occurred on study. Forty-eight individuals (70-500 mg) were evaluable for disease response assessments. Evidence of single agent activity was noted at doses ≥ 150 mg, including 1 VGPR at 200 mg (exposure duration > 55 weeks) and 4 PRs noted at doses ranging from 150-500 mg (respective exposure durations of 32, 29, 24, and 21 weeks). Five additional patients achieved MR, resulting in a clinical benefit rate (≥ MR) of 20.8%, and 23 patients were noted to have SD, resulting in a remarkable disease control rate (≥ SD) of 68.8%. In addition, of those patients with SD, 8 had exposure durations for > 20 weeks.
Conclusions:In heavily treated patients with relapsed/refractory MM, LGH447 was generally well tolerated and exhibited evidence of durable single-agent efficacy in multiple patients, with the best response being a VGPR. These findings validate Pim kinase inhibition as a promising therapeutic rationale in MM patients and support further clinical development in patients.
Disclosures
Ocio: Novartis: Honoraria. Thomas:Novartis: Research Funding; Celgene: Consultancy, Research Funding; Millennium: Research Funding; Idera Pharmaceuticals: Research Funding; Immunomedics: Research Funding. Günther:Novartis: Consultancy, Research Funding. Goh:Gilead Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jannsen Pharmaceuticals: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Lebovic:Celgene: Consultancy, Research Funding, Speakers Bureau; Onyx: Research Funding, Speakers Bureau; Millennium: Consultancy. Jakubowiak:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Consultancy, 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; SkylineDx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Song:Novartis: Employment. Xiang:Novartis: Employment. Patel:Novartis: Employment. Vanasse:Novartis: Employment, Equity Ownership. Kumar:Celgene: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; Novartis: Research Funding; Array: Research Funding; Cephalon: Research Funding.
Phase 1 study of the selective BTK inhibitor zanubrutinib in B-cell malignancies and safety and efficacy evaluation in CLL