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 PF-06840002 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.
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This study was sponsored by Pfizer. Medical writing support was provided by David Sunter, PhD, CMPP, of Engage Scientific Solutions and funded by Pfizer. AB Lassman was supported in part by Voices Against Brain Cancer, the William Rhodes and Louise Tilzer-Rhodes Center for Glioblastoma at NewYork-Presbyterian Hospital, and grants P30CA013696 and UG1CA189960 from the National Cancer Institute (NCI). The content is solely the responsibility of the authors and does not necessarily represent the views of the NCI/NIH.
Conflict of interest
DA Reardon declares research support (paid to DFCI): Acerta Phamaceuticals, Agenus, Celldex, EMD Serono, Incyte, Inovio, Midatech, Omniox, and Tragara; Advisory/consultation (paid to Dr Reardon): AbbVie, Advantagene, Agenus, Amgen, Bayer, Bristol-Myers Squibb, Celldex, DelMar, EMD Serono, Genentech/Roche, Inovio, Merck, Merck KGaA, Monteris, Novocure, Oncorus, Oxigene, Regeneron, Stemline, and Taiho Oncology Inc; Honoraria (paid to Dr Reardon): AbbVie, Advantagene, Agenus, Bristol-Myers Squibb, Celldex, EMD Serono, Genentech/Roche, Inovio, Merck, Merck KGaA, Monteris, Novocure, Oncorus, Oxigene, Regeneron, Stemline, and Taiho Oncology Inc; A Desjardins declares research research support (paid to Duke): Orbus Therapeutics, Genentech/Roche, Triphase Accelerator, Symphogen A/S; has served as consultant/participated in advisory boards (paid to Dr Desjardins: Orbus Therapeutics and Istari Oncology; as stock options in Istari Oncology; and patent on the use of the oncolytic poliovirus for the treatment of solid tumors; T Cloughesy declares research support from AstraZeneca, honoraria from Roche for serving on the Speakers Bureau, has served as a consultant/participated in advisory boards for VBL, Bayer, GW Pharma, Tocagen, Del Mar, Amgen, QED, Merck, Karyopharm, Odonate, Pascal Biosciences, Agios, is a Board member for Global Coalition for Adaptive Research 501 ©3, has stock options with Notable Labs, has a provisional patent application for compositions and methods for treating cancer; O Rixe declares research support from: Kyowa/Kirin, Oxford Biotherapeutics, Nanobiotix, IMV Inc, Newlink, Seattle Genetics, has served on the advisory committee for Kyowa/Kirin, Bexion, and is a stock shareholder in Bexion; S Alekar is an employee of Pfizer and hold stock in Pfizer, JH Williams is an employee of Pfizer and hold stock in Pfizer, CT Taylor is an employee of Pfizer and hold stock in Pfizer, R Li is an employee of Pfizer and hold stock in Pfizer; AB Lassman declares grants and non-financial support from Pfizer, during the conduct of the study; personal fees and non-financial support from Bioclinica as an expert blinded independent reviewer of clinical and imaging data for a BMS-sponsored trial, grants, personal fees and non-financial support from Karyopharm, personal fees from Sapience, personal fees from Magnolia Innovation, personal fees and non-financial support from Guidepoint Global, personal fees and non-financial support from Abbott Molecular, grants, personal fees and non-financial support from QED Therapeutics, personal fees from GLG, personal fees from Olson Research Group, personal fees from Biostrategies Group, personal fees and non-financial support from Forma, personal fees from Clarion Health Care Consulting, grants, personal fees and non-financial support from Bayer, personal fees from Defined Health, personal fees from Research America, personal fees from Advanced Focus, personal fees from Expert Connect, personal fees from Elsevier, grants, personal fees and non-financial support from Orbus, personal fees and non-financial support from Northwest Biotherapeutics, grants, personal fees and non-financial support from AbbVie, personal fees from Bionest Partners, personal fees from Antheneum, personal fees from DecioBio, personal fees from Connected Research and Consulting, personal fees from Health Advisors Bureau/Medefield, grants, personal fees and non-financial support from Agios, personal fees from RICCA Group, personal fees from Medsurvey, personal fees from Focus Forward Incentives, personal fees from WebMD, personal fees from Celgene, personal fees from prIME Oncology, personal fees from marketplusresearch.com, personal fees from Market Strategies International, personal fees from MSI Survey, personal fees from Cortice Biosciences, grants, personal fees and non-financial support from Kadmon, personal fees from Schlesinger Associates, personal fees and non-financial support from Novocure, personal fees and non-financial support from Physicians' Education Resource/Chemotherapy Foundation Symposium, grants and non-financial support from Genentech/Roche, grants and non-financial support from Amgen, grants and non-financial support from Millienium, grants and non-financial support from Celldex, grants and non-financial support from Novartis, non-financial support from Keryx as legacy to Aeterna Zentaris, grants and non-financial support from VBI Vaccines, grants and non-financial support from Beigene, grants and non-financial support from Oncoceutics, non-financial support from Tocagen, outside the submitted work.
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Reardon, D.A., Desjardins, A., Rixe, O. et al. A phase 1 study of PF-06840003, an oral indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor in patients with recurrent malignant glioma. Invest New Drugs 38, 1784–1795 (2020). https://doi.org/10.1007/s10637-020-00950-1
- Malignant glioma, tryptophan catabolism