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Phase 0 Trial of AZD1775 in First-Recurrence Glioblastoma Patients.

ABSTRACT: Purpose: AZD1775 is a first-in-class Wee1 inhibitor with dual function as a DNA damage sensitizer and cytotoxic agent. A phase I study of AZD1775 for solid tumors suggested activity against brain tumors, but a preclinical study indicated minimal blood-brain barrier penetration in mice. To resolve this controversy, we examined the pharmacokinetics and pharmacodynamics of AZD1775 in patients with first-recurrence, glioblastoma.Patients and Methods: Twenty adult patients received a single dose of AZD1775 prior to tumor resection and enrolled in either a dose-escalation arm or a time-escalation arm. Sparse pharmacokinetic blood samples were collected, and contrast-enhancing tumor samples were collected intraoperatively. AZD1775 total and unbound concentrations were determined by a validated LC/MS-MS method. Population pharmacokinetic analysis was performed to characterize AZD1775 plasma pharmacokinetic profiles. Pharmacodynamic endpoints were compared to matched archival tissue.Results: The AZD1775 plasma concentration-time profile following a single oral dose in patients with glioblastoma was well-described by a one-compartment model. Glomerular filtration rate was identified as a significant covariate on AZD1775 apparent clearance. AZD1775 showed good brain tumor penetration, with a median unbound tumor-to-plasma concentration ratio of 3.2, and achieved potential pharmacologically active tumor concentrations. Wee1 pathway suppression was inferred by abrogation of G2 arrest, intensified double-strand DNA breakage, and programmed cell death. No drug-related adverse events were associated with this study.Conclusions: In contrast to recent preclinical data, our phase 0 study of AZD 1775 in recurrent glioblastoma indicates good human brain tumor penetration, provides the first evidence of clinical biological activity in human glioblastoma, and confirms the utility of phase 0 trials as part of an accelerated paradigm for drug development in patients with glioma. Clin Cancer Res; 24(16); 3820-8. ©2018 AACRSee related commentary by Vogelbaum, p. 3790.

SUBMITTER: Sanai N

PROVIDER: S-EPMC6865048 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Phase 0 Trial of AZD1775 in First-Recurrence Glioblastoma Patients.

Sanai Nader N Li Jing J Boerner Julie J Stark Karri K Wu Jianmei J Kim Seongho S Derogatis Alanna A Mehta Shwetal S Dhruv Harshil D HD Heilbrun Lance K LK Berens Michael E ME LoRusso Patricia M PM

Clinical cancer research : an official journal of the American Association for Cancer Research 20180524 16

<b>Purpose:</b> AZD1775 is a first-in-class Wee1 inhibitor with dual function as a DNA damage sensitizer and cytotoxic agent. A phase I study of AZD1775 for solid tumors suggested activity against brain tumors, but a preclinical study indicated minimal blood-brain barrier penetration in mice. To resolve this controversy, we examined the pharmacokinetics and pharmacodynamics of AZD1775 in patients with first-recurrence, glioblastoma.<b>Patients and Methods:</b> Twenty adult patients received a si ...[more]

PMID: 29798906

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Project description:Glioblastoma is an aggressive and almost universally fatal tumor. The prognosis at the time of recurrence has generally been poor, with overall survival typically in the range of 4-40 weeks. The merits of surgical resection (vs. open biopsy, to confirm recurrence via histology) in addition to conventional adjuvant chemotherapy have been the subject of longstanding debate. We wondered whether it would possible to conduct a trial at our institution to settle this question definitively with Class I evidence.Initially, we had hoped to conduct a randomized, unblinded prospective clinical trial. However on closer inspection it appeared that such an undertaking would pose significant practical challenges. Thus we present our protocol in draft form. In keeping with recommended outcomes for these tumors, the primary endpoint would be median progression free survival. Secondary end points would be: median overall survival (mOS, from time of recurrence) and change in Karnofsky Performance Status over time. Patients would be eligible at the time of first recurrence if they had received conventional treatment until that point and at least 1 month had elapsed since the time of radiation. All patients would be considered potentially eligible for enrollment (unless the decision regarding resection was already clear-cut in view of other factors). Using Cox's proportional hazards model, we estimate that at least 456 patients would be necessary to demonstrate an increase in the hazard ratio to 1.3 for those undergoing biopsy alone. This magnitude of benefit is estimated based on a review of retrospective studies.If restricted to our Institution alone, which sees approximately 100-150 new cases of glioblastoma each year, a trial of this nature would be likely to take around 10 years. Furthermore, there may be significant reluctance on the part of patients and physicians to participate. There is also the opportunity cost of excluding patients from other trials to consider. We recognize that the estimate of the magnitude of effect may be conservative. As things stand, we feel that multi-institutional collaboration would almost certainly be required for an undertaking of this kind.

Project description:Abstract BACKGROUND CDK4/6-dependent cell-cycle regulation is disrupted in 78% of glioblastoma patients. We conducted a Phase 0/2 clinical trial (NCT02933736) of ribociclib, a selective CDK4/6-inhibitor, to examine the plasma and tumor pharmacokinetics (PK) and pharmacodynamics (PD) of recurrent glioblastoma. METHODS Eligible patients with intact RB expression and CDKN2A deletion or CDK4/6 amplification were enrolled into the Phase 0 component to receive ribociclib (900mg daily) for 5 days prior to tumor resection. Plasma, tumor, and CSF samples were collected to determine drug concentrations using validated LC-MS/MS methods. PD effects, including RB and FoxM1 phosphorylation, were compared to archival tissue. Patients with favorable PK and PD outcomes were transitioned into the Phase 2 component. RESULTS Twelve patients were enrolled into three presurgical time-escalation groups (2-hours, 8-hours, 24-hours). Ribociclib penetrated both enhancing and non-enhancing regions of the tumor. In non-enhancing tissue, median unbound brain-to-plasma ratio was 1.78 and median ribociclib concentration was 0.54 nmol/mL, exceeding the in vitro IC50 for CDK4/6 (0.04 nmol/mL). Suppression of G1-to-S phase was inferred by a decrease in RB phosphorylation (p<0.01) and cell proliferation (p<0.05). Six patients (50%) were graduated to the Phase 2 component and demonstrated a median progression-free survival of 9.7 weeks (95% CI, 6.3 to 40 weeks). Tissue samples from re-resection following Phase 2 study identified mTOR pathway upregulation as a candidate resistance mechanism to ribociclib monotherapy. CONCLUSION: Ribociclib penetrates the tumor-brain barrier, achieving pharmacologically-active concentrations in human glioblastoma and suppressing tumor proliferation. Phase 2 study results suggest ribociclib is ineffective as a monotherapy, but analysis of ribociclib-resistant tumors identified the addition of an mTOR inhibitor as a dual-drug strategy for recurrent glioblastoma.

Project description:Background There is much discussion in the cancer drug development community about how to incorporate molecular tools into early-stage clinical trials to assess target modulation, measure anti-tumor activity, and enrich the clinical trial population for patients who are more likely to benefit. Small, molecularly focused clinical studies offer the promise of the early definition of optimal biologic dose and patient population. Methods and Findings Based on preclinical evidence that phosphatase and tensin homolog deleted on Chromosome 10 (PTEN) loss sensitizes tumors to the inhibition of mammalian target of rapamycin (mTOR), we conducted a proof-of-concept Phase I neoadjuvant trial of rapamycin in patients with recurrent glioblastoma, whose tumors lacked expression of the tumor suppressor PTEN. We aimed to assess the safety profile of daily rapamycin in patients with glioma, define the dose of rapamycin required for mTOR inhibition in tumor tissue, and evaluate the antiproliferative activity of rapamycin in PTEN-deficient glioblastoma. Although intratumoral rapamycin concentrations that were sufficient to inhibit mTOR in vitro were achieved in all patients, the magnitude of mTOR inhibition in tumor cells (measured by reduced ribosomal S6 protein phosphorylation) varied substantially. Tumor cell proliferation (measured by Ki-67 staining) was dramatically reduced in seven of 14 patients after 1 wk of rapamycin treatment and was associated with the magnitude of mTOR inhibition (p = 0.0047, Fisher exact test) but not the intratumoral rapamycin concentration. Tumor cells harvested from the Ki-67 nonresponders retained sensitivity to rapamycin ex vivo, indicating that clinical resistance to biochemical mTOR inhibition was not cell-intrinsic. Rapamycin treatment led to Akt activation in seven patients, presumably due to loss of negative feedback, and this activation was associated with shorter time-to-progression during post-surgical maintenance rapamycin therapy (p < 0.05, Logrank test). Conclusions Rapamycin has anticancer activity in PTEN-deficient glioblastoma and warrants further clinical study alone or in combination with PI3K pathway inhibitors. The short-term treatment endpoints used in this neoadjuvant trial design identified the importance of monitoring target inhibition and negative feedback to guide future clinical development. Keywords: Comparative Genomic Hybridization

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Phase 0 Trial of AZD1775 in First-Recurrence Glioblastoma Patients.

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Phase 0 Trial of AZD1775 in First-Recurrence Glioblastoma Patients.

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