A phase 1 study of PF-06840003, an oral indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor in patients with recurrent malign
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PHASE I STUDIES
A phase 1 study of PF-06840003, an oral indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor in patients with recurrent malignant glioma David A. Reardon 1 & Annick Desjardins 2 & Olivier Rixe 3 & Timothy Cloughesy 4 & Shilpa Alekar 5 & Jason H. Williams 5 & Ray Li 5 & Carrie Turich Taylor 5 & Andrew B. Lassman 6 Received: 7 April 2020 / Accepted: 10 May 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Summary Background PF-06840003 is a highly selective indoleamine 2, 3-dioxygenase (IDO1) inhibitor with antitumor effects in preclinical models. This first-in-human phase 1 study evaluated safety, pharmacokinetics/pharmacodynamics, and preliminary efficacy in recurrent malignant glioma to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D). Methods Patients (N = 17) received oral PF-06840003 in four dose-escalation groups: 125 mg once-daily (QD; n = 2); 250 mg QD (n = 4); 250 mg twice-daily (BID; n = 3); 500 mg BID (n = 8). A modified toxicity probability interval method determined the MTD. Results Four patients experienced serious adverse events (SAEs); one with treatment-related SAEs (grade 4 alanine and aspartate aminotransferase elevations). The dose-limiting toxicity (DLT) rate at 500 mg BID was 12.5% (n = 1/8); the MTD was not reached. Following PF-06840003 dosing, median time to maximum plasma concentration for the active enantiomer PF06840002 was 1.5–3.0 hr and mean elimination half-life was 2 to 4 hr (Cycle 1 Day 1). Urinary recovery of PF-06840002 was low (< 1%). At 500 mg BID, maximum mean percentage inhibition of 13C10 kynurenine vs endogenous kynurenine was 75% vs 24%. PF-06840002 CSF-to-plasma ratio was 1.00. Disease control occurred in eight patients (47%). Mean duration of stable disease (SD) was 32.1 (12.1–72.3) weeks. Two patients with SD discontinued the study at 450 and 561 days and continued PF-06840003 on compassionate use. Conclusion PF‑06840003 up to 500 mg BID was generally well tolerated with evidence of a pharmacodynamic effect and durable clinical benefit in a subset of patients with recurrent malignant glioma. ClinicalTrials.gov, NCT02764151, registered April 2016. Keywords Glioblastoma . IDO1 . Immuno-oncology . Kynurenine . Malignant glioma, tryptophan catabolism
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10637-020-00950-1) contains supplementary material, which is available to authorized users. * David A. Reardon [email protected] 1
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
2
Department of Neurosurgery, Duke University Medical Center, Durham, NC, USA
3
Quantum Santa Fe, Santa Fe, NM, USA
4
Department of Neurology, University of California Los Angeles Jonsson Comprehensive Cancer Center, Los Angeles, CA, USA
5
Pfizer Inc, New York, NY, USA
6
Department of Neurology and Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA
Introduction Malignant gliomas (World He
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