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Preclinical modeling of a phase 0 clinical trial: qualification of a pharmacodynamic assay of poly (ADP-ribose) polymerase in tumor biopsies of mouse xenografts.

ABSTRACT: The National Cancer Institute has completed a first-in-human clinical pharmacodynamic trial of the targeted agent ABT-888, a poly (ADP-ribose) polymerase (PARP) inhibitor, under the auspices of the U.S. Food and Drug Administration's Exploratory Investigational New Drug Application. Performance of the study design, needle biopsy procedure, and validated pharmacodynamic assay were evaluated in human tumor xenograft models.A validated ELISA was used to quantify PAR, a product of the PARP 1/2 enzyme activity. Sampling variability from tumor heterogeneity was determined by comparing PAR content in multiple tumors, and in different areas of the same tumor in a particular animal, collected under anesthesia by needle biopsy or resection before and after administration of nontoxic doses of ABT-888. The degree of PARP inhibition following single-dose treatment was evaluated in the time frame anticipated for biopsy in humans.Sampling variability around the mean (approximately 50%) for untreated and vehicle-treated animals was random and due to specimen heterogeneity. PAR levels in initial and repeat tumor biopsies, separated by 1 week, were not altered by the stress induced by daily handling of the animals. A single ABT-888 dose (3 or 12.5 mg/kg) reduced intratumor PAR levels by >95%. ABT-888 (1.56-25 mg/kg) significantly decreased PAR levels at 2 h post-dosing.The detailed methodologies developed for this study facilitated the design of a phase 0, first-in-human clinical trial of ABT-888 and could serve as a model for developing proof-of-principle clinical trials of molecularly targeted anticancer agents.

SUBMITTER: Kinders RJ

PROVIDER: S-EPMC2766769 | biostudies-literature | 2008 Nov

REPOSITORIES: biostudies-literature

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Preclinical modeling of a phase 0 clinical trial: qualification of a pharmacodynamic assay of poly (ADP-ribose) polymerase in tumor biopsies of mouse xenografts.

Kinders Robert J RJ Hollingshead Melinda M Khin Sonny S Rubinstein Larry L Tomaszewski Joseph E JE Doroshow James H JH Parchment Ralph E RE

Clinical cancer research : an official journal of the American Association for Cancer Research 20081101 21

<h4>Purpose</h4>The National Cancer Institute has completed a first-in-human clinical pharmacodynamic trial of the targeted agent ABT-888, a poly (ADP-ribose) polymerase (PARP) inhibitor, under the auspices of the U.S. Food and Drug Administration's Exploratory Investigational New Drug Application. Performance of the study design, needle biopsy procedure, and validated pharmacodynamic assay were evaluated in human tumor xenograft models.<h4>Experimental design</h4>A validated ELISA was used to q ...[more]

PMID: 18980982

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Project description:Purpose To demonstrate that positron emission tomography (PET) with fluorine 18 (18F) fluorthanatrace (FTT) depicts activated poly (adenosine diphosphate-ribose)polymerase (PARP) expression and is feasible for clinical trial evaluation. Materials and Methods All studies were conducted prospectively from February 2012 through July 2015 under protocols approved by the local animal studies committee and institutional review board. The area under the receiver operating characteristic curve (AUC, in g/mL· min) for 18F-FTT was assessed in normal mouse organs before and after treatment with olaparib (n = 14), a PARP inhibitor, or iniparib (n = 11), which has no PARP inhibitory activity. Murine biodistribution studies were performed to support human translational studies. Eight human subjects with cancer and eight healthy volunteers underwent imaging to verify the human radiation dosimetry of 18F-FTT. The Wilcoxon signed rank test was used to assess for differences among treatment groups for the mouse studies. Results In mice, olaparib, but not iniparib, significantly reduced the 18F-FTT AUC in the spine (median difference before and after treatment and interquartile range [IQR]: -17 g/mL· min and 10 g/mL · min, respectively [P = .0001], for olaparib and -3 g/mL · min and 13 g/mL · min [P = .70] for iniparib) and in nodes (median difference and interquartile range [IQR] before and after treatment: -23 g/mL · min and 13 g/mL · min [P = .0001] for olaparib; -9 g/mL · min and 17 g/mL · min [P = .05] for iniparib). The effective dose was estimated at 6.9 mSv for a 370-MBq 18F-FTT dose in humans. In humans, the organs with the highest uptake on images were the spleen and pancreas. Among five subjects with measurable tumors, increased 18F-FTT uptake was seen in one subject with pancreatic adenocarcinoma and another with liver cancer. Conclusion The results suggest that 18F-FTT uptake reflects PARP expression and that its radiation dosimetry profile is compatible with those of agents currently in clinical use. © RSNA, 2016 Online supplemental material is available for this article.

Project description:Poly(ADP-ribose) polymerase (PARP) facilitates DNA repair and PARP inhibitors may potentiate the effect of DNA-damaging chemotherapeutic agents in patients with cancer. Collection of peripheral blood mononuclear cells (PBMCs) as a surrogate tissue to monitor PARP inhibitor pharmacodynamic effects has several advantages over tumor biopsy collection, including minimally invasive sample collection and the ability to collect multiple samples for longitudinal assessment of drug effect.Using our previously validated immunoassay for measuring poly(ADP-ribose) (PAR), a product of PARP, in tumor biopsies, we validated a method to quantify PAR levels in PBMCs to monitor the pharmacodynamic effects of the PARP inhibitor ABT-888 in clinical trials. The inter-individual variation in PAR levels was large. No significant difference (P?=?0.67) was measured between median baseline PAR levels in 144 healthy volunteers (131.7 pg/1×10(7) PBMCs [interquartile range, 79.5-241.6]) and 49 patients with cancer (149.2 pg/1×10(7) PBMCs [interquartile range, 83.2-249.3]). In addition, PAR levels monitored in healthy volunteers over 3 weeks had considerable intra- and inter-individual variation (range, 44-1073 pg PAR/1×10(7) PBMCs). As a pharmacodynamic model, we quantified changes in PAR levels in human PBMCs treated ex vivo with clinically relevant concentrations of ABT-888. Of 40 healthy volunteer PBMC samples treated with ABT-888, 47.5% had greater than 50% PAR reduction compared to vehicle-treated controls. Considerable inter-sample heterogeneity in PAR levels was measured, and several ABT-888-insensitive samples were identified.Our results emphasize the importance of using a validated method to measure PAR levels, and support further investigation into the role of PARP in PBMCs. To this end, the PAR immunoassay has been validated for use with PBMCs and incorporated into clinical trials to assess PBMCs as a potential pharmacodynamic surrogate for tumor biopsies in clinical trials of PARP inhibitors.

Dataset Information

Preclinical modeling of a phase 0 clinical trial: qualification of a pharmacodynamic assay of poly (ADP-ribose) polymerase in tumor biopsies of mouse xenografts.

Publications

Preclinical modeling of a phase 0 clinical trial: qualification of a pharmacodynamic assay of poly (ADP-ribose) polymerase in tumor biopsies of mouse xenografts.

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