Dataset Information

Biological activity of weekly ONC201 in adult recurrent glioblastoma patients.

ABSTRACT:

Background

ONC201 is a dopamine receptor D2 (DRD2) antagonist that penetrates the blood-brain barrier. ONC201 efficacy has been shown in glioblastoma animal models and is inversely correlated with dopamine receptor DRD5 expression. ONC201 is well tolerated in adult recurrent glioblastoma patients with dosing every 3 weeks and has achieved an objective radiographic response in a patient harboring the H3 K27M mutation.

Methods

In a window-of-opportunity arm, 6 adult subjects initiated ONC201 prior to re-resection of recurrent glioblastoma with intratumoral concentrations as the primary endpoint. An additional 20 adults with recurrent glioblastoma received single agent weekly oral ONC201 at 625 mg, with progression-free survival at 6 months (PFS6) by Response Assessment in Neuro-Oncology (RANO) criteria as the primary endpoint.

Results

The window-of-opportunity arm achieved its primary endpoint with intratumoral ONC201 concentrations at ~24 hours following the second weekly dose ranging from 600 nM to 9.3 µM. Intratumoral pharmacodynamics assessed by activating transcriptional factor 4, death receptor 5, and apoptosis induction relative to archival samples were observed with the strongest intensity and uniformity among patients with low DRD5 tumor expression. The primary endpoint of PFS6 by RANO was not achieved at 5% in this molecularly unselected cohort; however, 1 of 3 patients enrolled with the H3 K27M mutation had a complete regression of enhancing multifocal lesions that remained durable for >1.5 years. No treatment modifications or discontinuations due to toxicity were observed, including in those who underwent re-resection.

Conclusions

Weekly ONC201 is well tolerated, and meaningful intratumoral concentrations were achieved. ONC201 may be biologically active in a subset of adult patients with recurrent glioblastoma.

SUBMITTER: Arrillaga-Romany I

PROVIDER: S-EPMC7080220 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Publications

Biological activity of weekly ONC201 in adult recurrent glioblastoma patients.

Arrillaga-Romany Isabel I Odia Yazmin Y Prabhu Varun V VV Tarapore Rohinton S RS Merdinger Krystal K Stogniew Martin M Oster Wolfgang W Allen Joshua E JE Mehta Minesh M Batchelor Tracy T TT Wen Patrick Y PY

Neuro-oncology 20200101 1

<h4>Background</h4>ONC201 is a dopamine receptor D2 (DRD2) antagonist that penetrates the blood-brain barrier. ONC201 efficacy has been shown in glioblastoma animal models and is inversely correlated with dopamine receptor DRD5 expression. ONC201 is well tolerated in adult recurrent glioblastoma patients with dosing every 3 weeks and has achieved an objective radiographic response in a patient harboring the H3 K27M mutation.<h4>Methods</h4>In a window-of-opportunity arm, 6 adult subjects initiat ...[more]

PMID: 31702782

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Project description:Glioblastoma multiforme is one of the most frequent and aggressive primary tumors in the central nervous system, representing >60% of all brain tumors in adults. Despite treatment, prognosis remains poor with most if not all patients experiencing disease recurrence and a 2-year survival rate of 27%. At present, no confirmed standard treatment exists for recurrent glioblastoma. Regorafenib is one of the few options available, based on results from the REGOMA trial. In the present study, a real-life retrospective investigation on the role of regorafenib in patients with recurrent glioblastoma (>60 years old) from two main Oncological Units in South Italy (Azienda Ospedaliera Universitaria Luigi Vanvitelli, Naples, Italy and Ospedale Civile San Giovanni di Dio, Frattamaggiore, Naples, Italy), was performed. The primary endpoint was overall survival (OS), whereas progression-free survival (PFS), objective response rate and disease control were secondary endpoints. Survival was then analyzed according to age, isocitrate dehydrogenase (IDH) and methylated methylguanine-DNA-methyltransferase (MGMT) status. A total of 56 patients met the eligibility criteria. The intention to treat population median PFS (mPFS) was 4.1 months and median OS (mOS) was 6.8 months. Age did not appear to have a significant influence on mPFS. mOS in MGMT-methylated patients was improved compared with that of the unmethylated group (7.7 months vs. 5.6 months). Both mOS and mPFS were longer in IDH-mutant patients. The present study was one of the first real life analyses of regorafenib in recurrent glioblastoma. The results were in line with the REGOMA trial. Age did not appear to be a prognostic factor, thus suggesting that treatment choice should not be different in elderly. MGMT methylation appeared to influence OS. To the best of our knowledge, this was the first report of regorafenib activity in older patients and, while the results were statistically significant, these should be confirmed in further studies.

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

Dataset Information

Biological activity of weekly ONC201 in adult recurrent glioblastoma patients.

Background

Methods

Results

Conclusions

Publications

Biological activity of weekly ONC201 in adult recurrent glioblastoma patients.

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