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A phase 1 study of PF-06840003, an oral indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor in patients with recurrent malignant glioma.

Publication ,  Conference
Reardon, DA; Desjardins, A; Rixe, O; Cloughesy, T; Alekar, S; Williams, JH; Li, R; Taylor, CT; Lassman, AB
Published in: Invest New Drugs
December 2020

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.

Duke Scholars

Published In

Invest New Drugs

DOI

EISSN

1573-0646

Publication Date

December 2020

Volume

38

Issue

6

Start / End Page

1784 / 1795

Location

United States

Related Subject Headings

  • Young Adult
  • Tryptophan
  • Treatment Outcome
  • Succinimides
  • Oncology & Carcinogenesis
  • Neoplasm Recurrence, Local
  • Middle Aged
  • Male
  • Kynurenine
  • Indoles
 

Citation

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Reardon, D. A., Desjardins, A., Rixe, O., Cloughesy, T., Alekar, S., Williams, J. H., … Lassman, A. B. (2020). A phase 1 study of PF-06840003, an oral indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor in patients with recurrent malignant glioma. In Invest New Drugs (Vol. 38, pp. 1784–1795). United States. https://doi.org/10.1007/s10637-020-00950-1
Reardon, David A., Annick Desjardins, Olivier Rixe, Timothy Cloughesy, Shilpa Alekar, Jason H. Williams, Ray Li, Carrie Turich Taylor, and Andrew B. Lassman. “A phase 1 study of PF-06840003, an oral indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor in patients with recurrent malignant glioma.” In Invest New Drugs, 38:1784–95, 2020. https://doi.org/10.1007/s10637-020-00950-1.
Reardon DA, Desjardins A, Rixe O, Cloughesy T, Alekar S, Williams JH, et al. A phase 1 study of PF-06840003, an oral indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor in patients with recurrent malignant glioma. In: Invest New Drugs. 2020. p. 1784–95.
Reardon, David A., 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, vol. 38, no. 6, 2020, pp. 1784–95. Pubmed, doi:10.1007/s10637-020-00950-1.
Reardon DA, Desjardins A, Rixe O, Cloughesy T, Alekar S, Williams JH, Li R, Taylor CT, Lassman AB. 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. 2020. p. 1784–1795.
Journal cover image

Published In

Invest New Drugs

DOI

EISSN

1573-0646

Publication Date

December 2020

Volume

38

Issue

6

Start / End Page

1784 / 1795

Location

United States

Related Subject Headings

  • Young Adult
  • Tryptophan
  • Treatment Outcome
  • Succinimides
  • Oncology & Carcinogenesis
  • Neoplasm Recurrence, Local
  • Middle Aged
  • Male
  • Kynurenine
  • Indoles