Phase 1b/2a study of galunisertib, a small molecule inhibitor of transforming growth factor-beta receptor I, in combination with standard temozolomide-based radiochemotherapy in patients with newly diagnosed malignant glioma

Antje Wick, Annick Desjardins, Cristina Suarez, Peter Forsyth, Ivelina Gueorguieva, Tiana Burkholder, Ann Louise Cleverly, Shawn T Estrem, Shuaicheng Wang, Michael M Lahn, Susan C Guba, David Capper, Jordi Rodon, Antje Wick, Annick Desjardins, Cristina Suarez, Peter Forsyth, Ivelina Gueorguieva, Tiana Burkholder, Ann Louise Cleverly, Shawn T Estrem, Shuaicheng Wang, Michael M Lahn, Susan C Guba, David Capper, Jordi Rodon

Abstract

Purpose Galunisertib, a TGF-β inhibitor, has demonstrated antitumor effects in preclinical and radiographic responses in some patients with malignant glioma. This Phase 1b/2a trial investigated the clinical benefit of combining galunisertib with temozolomide-based radiochemotherapy (TMZ/RTX) in patients with newly diagnosed malignant glioma (NCT01220271). Methods This is an open-label, 2-arm Phase 1b/2a study (N = 56) of galunisertib (intermittent dosing: 14 days on/14 days off per cycle of 28 days) in combination with TMZ/RTX (n = 40), versus a control arm (TMZ/RTX, n = 16). The primary objective of Phase 1b was to determine the safe and tolerable Phase 2 dose of galunisertib. The primary objective of Phase 2a was to confirm the tolerability and pharmacodynamic profile of galunisertib with TMZ/RTX, and the secondary objectives included determining the efficacy and pharmacokinetic (PK) profile of galunisertib with TMZ/RTX in patients with glioblastoma. This study also characterized the changes in the major T-cell subsets during TMZ/RTX plus galunisertib treatment. Results In the Phase 2a study, efficacy results for patients treated with galunisertib plus TMZ/RTX or TMZ/RTX were: median overall survival (18.2 vs 17.9 months), median progression-free survival (7.6 vs 11.5 months), and disease control rate (80% [32/40] vs 56% [9/16] patients) respectively. PK profile of galunisertib plus TMZ/RTX regimen was consistent with previously published PK data of galunisertib. The overall safety profile across treatment arms was comparable. Conclusion No differences in efficacy, safety or pharmacokinetic variables were observed between the two treatment arms.

Keywords: Biomarkers; Galunisertib; Glioblastoma; Radiochemotherapy; T cells.

Conflict of interest statement

AD serves on Advisory Board for Orbus Therapeutics, and Celgene, holds stock options from ISTARI Oncology, and letters of patent for Oncolytic Poliovirus for human tumors. AD’s institution receives research funding from Genentech/Roche, Celldex, Triphase Accelerator Corp., Eli Lilly and Company, Symphogen A/S, Pfizer, and Orbus Therapeutics. CS serves on Advisory Board for Pfizer, IPSEN, BMS, Astellas, Sanofi, Bayer, and MSD; is a speaker for BMS, Pfizer, IPSEN, and Astellas; received travel reimbursement from BMS, Pfizer, and Roche; reports receiving research/clinical funding from Roche. PF is consultant for AbbVie Inc., Ziopharm, Tocagen Inc., BMS and L.E.K. JR reports non-financial support and reasonable reimbursement for travel from European Journal of Cancer, Vall d’Hebron Institut of Oncology, Chinese University of Hong Kong, SOLTI, Elsevier, GLAXOSMITHKLINE; receiving consulting and travel fees from Novartis, Eli Lilly and Company, Orion Pharmaceuticals, Servier Pharmaceuticals, Peptomyc, Merck Sharp & Dohme, Kelun Pharmaceutical/Klus Pharma, Spectrum Pharmaceuticals Inc., Pfizer, Roche Pharmaceuticals, Ellipses Pharma (including serving on the scientific advisory board from 2015-present), receiving research funding from Bayer and Novartis, and serving as investigator in clinical trials with Spectrum Pharmaceuticals, Tocagen, Symphogen, BioAtla, Pfizer, GenMab, CytomX, KELUN-BIOTECH, Takeda-Millenium, GLAXOSMITHKLINE, IPSEN and travel fees from ESMO, US Department of Defense, Louisiana State University, Hunstman Cancer Institute, Cancer Core Europe, Karolinska Cancer Institute and King Abdullah International Medical Research Center (KAIMRC). SE, IG, and TB are employees of Eli Lilly and Company and may hold company stocks. ML, SG, and ALC are former employees of Eli Lilly and Company and hold company stocks. The other authors report no conflicts of interest.

Figures

Fig. 1
Fig. 1
Patient dispositions from treatment. Abbreviations: TMZ = temozolomide; RTX = radiation. aAEs not-related to study treatment as AEs happened >30 days after discontinuation of study treatment.
Fig. 2
Fig. 2
Summary of treatment responses. Kaplan-Meier estimates of OS (a), and PFS (b). Summary of OS, PFS, TTF, TTP, and DTR (c). Abbreviations: m = months; OS = overall survival; PFS = progression-free survival; TFF = time-to-treatment failure; TTP = time-to-tumor progression; DTR = duration of tumor response; Gal = galunisertib; TMZ = temozolomide; RTX = radiation; NR = Not reported
Fig. 3
Fig. 3
Characterization of the changes in the major T cell subsets in Phase 2a. a Absolute numbers of CD4 + CD25 + CD127-FoxP3+ T (Tregs), CD4+, and CD8+ T cells are reported over time from the first dose of treatment. Each gray line represents a patient. Solid and dashed lines connect the geometric mean (error bars, 90% CI) at baseline, Day 42 (end of radiation phase), and Day 182 (adjuvant phase). Vertical dotted line indicates the end of the chemoradiotherapy treatment and the beginning of the adjuvant phase. b Geometric mean, with 90% confidence interval, at baseline, Day 42, and Day 182. The p value from Pair-wise t-Test compares baseline and Day 42 within each arm. Note: Day42 = End of Radiation Phase, Cycle 2 Day 14; Day182 = Cycle 7 day 14; P value = Pair-wise t-Test for Comparing Baseline and Day42. Abbreviations: Gal = galunisertib; TMZ = temozolomide; RTX = radiation

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