Preclinical and clinical investigation of intratumoral chemotherapy pharmacokinetics in DIPG using gemcitabine

Adam L Green; Patrick Flannery; Todd C Hankinson; Brent O'Neill; Vladimir Amani; John DeSisto; Aaron Knox; Hannah Chatwin; Rakeb Lemma; Lindsey M Hoffman; Jean Mulcahy Levy; Jennifer Raybin; Molly Hemenway; Ahmed Gilani; Carl Koschmann; Nathan Dahl; Michael Handler; Angela Pierce; Sujatha Venkataraman; Nicholas Foreman; Rajeev Vibhakar; Michael F Wempe; Kathleen Dorris

doi:10.1093/noajnl/vdaa021

Preclinical and clinical investigation of intratumoral chemotherapy pharmacokinetics in DIPG using gemcitabine

Neurooncol Adv. 2020 Feb 24;2(1):vdaa021. doi: 10.1093/noajnl/vdaa021. eCollection 2020 Jan-Dec.

Authors

Adam L Green^{1

2

3}, Patrick Flannery¹, Todd C Hankinson^{1

2

4}, Brent O'Neill^{1

4}, Vladimir Amani¹, John DeSisto¹, Aaron Knox¹, Hannah Chatwin¹, Rakeb Lemma¹, Lindsey M Hoffman^{1

2

3}, Jean Mulcahy Levy^{1

2

3}, Jennifer Raybin^{1

2

3}, Molly Hemenway^{1

2

3}, Ahmed Gilani^{1

2

5}, Carl Koschmann⁶, Nathan Dahl^{1

2

3}, Michael Handler^{1

2

4}, Angela Pierce¹, Sujatha Venkataraman^{1

3}, Nicholas Foreman^{1

2

3}, Rajeev Vibhakar^{1

2

3}, Michael F Wempe⁷, Kathleen Dorris^{1

2

3}

Affiliations

¹ Morgan Adams Foundation Pediatric Brain Tumor Research Program, Aurora, Colorado, USA.
² Center for Cancer and Blood Disorders, Children's Hospital Colorado, Aurora, Colorado, USA.
³ Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado, USA.
⁴ Department of Neurosurgery, University of Colorado School of Medicine, Aurora, Colorado, USA.
⁵ Department of Pathology, University of Colorado School of Medicine, Aurora, Colorado, USA.
⁶ University of Michigan, Ann Arbor, Michigan, USA.
⁷ University of Colorado School of Pharmacy and Pharmaceutical Sciences, Aurora, Colorado, USA.

Abstract

Background: Hundreds of systemic chemotherapy trials in diffuse intrinsic pontine glioma (DIPG) have not improved survival, potentially due to lack of intratumoral penetration, which has not previously been assessed in humans.

Methods: We used gemcitabine as a model agent to assess DIPG intratumoral pharmacokinetics (PK) using mass spectrometry.

Results: In a phase 0 clinical trial of i.v. gemcitabine prior to biopsy in children newly diagnosed with DIPG by MRI, mean concentration in 4 biopsy cores in patient 1 (H3K27M diffuse midline glioma) was 7.65 µM. These compare favorably to levels for patient 2 (mean 3.85 µM, found to have an H3K27-wildtype low-grade glioma on histology), and from a similar study in adult glioblastoma (adjusted mean 3.48 µM). In orthotopic patient-derived xenograft (PDX) models of DIPG and H3K27M-wildtype pediatric glioblastoma, gemcitabine levels and clearance were similar in tumor, pons, and cortex and did not depend on H3K27 mutation status or tumor location. Normalized gemcitabine levels were similar in patient 1 and the DIPG PDX.

Conclusions: These findings, while limited to one agent, provide preliminary evidence for the hypotheses that lack of intratumoral penetration is not why systemic chemotherapy has failed in DIPG, and orthotopic PDX models can adequately model intratumoral PK in human DIPG.

Keywords: DIPG; PDX; chemotherapy; clinical trial; pharmacokinetics.