Faculty Bibliography

ONC201, the first clinical bitopic DRD2 antagonist for clinical oncology, is in multiple Phase II advanced cancer clinical trials. The recommended phase 2 dose (RP2D) of 625mg ONC201 Q1W has been established in adult patients as a biologically active dose. ONC201 efficacy has been shown in high-grade glioma preclinical models and durable responses with single agent ONC201 have been reported in adult recurrent H3 K27M-mutant glioma patients. These observations, along with the subsequently discovered increased susceptibility of H3 K27Mmutant gliomas to ONC201, we initiated a Phase I pediatric clinical trial of ONC201 scaled by body weight. This multi-center, open-label, dose-escalation and dose-expansion clinical trial (NCT03416530) was designed to determine the pediatric RP2D of ONC201 administered as an oral capsule in post-radiation H3 K27M-mutant glioma (Arm A) or newly diagnosed DIPG (Arm B) patients. Molecular evaluations include assessment of intratumoral concentrations of ONC201 in pediatric midline gliomas patients (Arm C) and the effects of ONC201 in H3 K27M DNA levels in circulating CSF (Arm D). The single agent safety of ONC201 administered as an oral Ora-Sweet solution was also evaluated (Arm E). Enrollment as of May 22, 2019: 21 evaluable patients in Arm A, 8 patients in Arm B, 2 patients in Arm C, 9 patients in Arm D, 6 patients in Arm E. Arm A has accrued with a median age of 8 (range: 3-18) years. As of May 22, 2019, patients have received a median of 18 (range: 3-54) doses without any dose-limiting toxicities. Pharmacokinetic profiles were comparable to those observed in adults (Cmax ~2.1ug/mL; AUC ~2.3hr*ug/mL; Tmax ~1.9hr; T1/2 ~8hr) and exposure was similar across body weights. Safety, PK, PD, molecular correlatives, and clinical outcomes will be reported

ONC201, the first bitopic DRD2 antagonist for clinical oncology, has shown efficacy in H3 K27M-mutant glioma. We performed an integrated preclinical and clinical analysis of ONC201 in thalamic H3 K27Mmutant glioma. ONC201 was effective in mouse intra-uterine electroporation (IUE)-generated H3 K27M-mutant gliomas, with an in vitro IC50 of 500 nM and 50% prolongation of median survival in vivo (p=0.02, n=14). Elevated DRD2 expression was found in the thalamus of non-malignant brain tissue, leading to the hypothesis that thalamic tumors may be a particularly ONC201-sensitive sub-group. We analyzed thalamic H3 K27Mmutant glioma patients treated with ONC201 as of the 05/22/2019 cutoff date, which included patients who had recurrent disease prior to initiating ONC201 (n=20; 15-73 years old) and post-radiation non-recurrent patients (n=11; 5-19 years old). As of 5/22/2019, 10 of 20 recurrent patients and 9 of 11 non-recurrent patients remain on-treatment. Median PFS has not been reached for either cohort: median follow-up of 2.2 months (range: 0.6-37.9) for recurrent patients and 10.6 months (range: 4.3-20.5) from diagnosis for non-recurrent patients. Best response so far by RANO includes 1 CR, 2 PR, 7 SD, 9 PD, 1 NE for recurrent patients and 1 PR, 7 SD, 3 PD for non-recurrent patients. Additionally, 3 recurrent (-66%, -47%, -34%) and 2 non-recurrent (-40%, -10%) patients experienced regressions but are not yet confirmed PRs. For recurrent patients, median onset of response is 3.5 months (range: 2.2-3.8) and median duration of response has not been reached with a median follow-up of 12.5 months (range: 8.1-32.8). Preliminary analyses demonstrated a strong correlation of cell-free tumor DNA in plasma and CSF with MRI response. In summary, ONC201 demonstrates promising clinical efficacy in thalamic H3 K27M-mutant glioma patients, regardless of age. Micro-environmental DRD2 expression may enhance the overall ONC201 response and extend its therapeutic utility beyond H3 K27M-mutant glioma

BACKGROUND: The EMulate Therapeutics Halo system is an investigational non-sterile, non-invasive, non-thermal, non-ionizing, portable, home-use medical device that uses a specific, localized ultra-low radio frequency energy (ulRFER) cognate for the treatment of pediatric brain tumors.
METHOD(S): Sixteen patients with brain tumors consisting of diffuse midline glioma/diffuse intrinsic pontine glioma (DMG/DIPG, n=14), recurrent medulloblastoma (n=1), or anaplastic astrocytoma (n=1) - were treated with the Halo under FDA's single-patient compassionate use pathway, as protocol deviations in a glioblastoma trial, or under TGA's Special Access Scheme. Baseline information and on-treatment safety and exposure data were collected.
RESULT(S): Patients ranged in age from 4 to 28 years (median = 8 years) and were diagnosed 91 - 1399 days (median = 397 days) prior to treatment with the Halo system. Patients were treated for 2 - 52 weeks (median = 15 weeks), with 4 patients still alive (all with a diagnosis of DMG/DIPG), and 3 still on treatment (ranging 18 - 52 weeks). Two out of the 16 patients reported mild-moderate adverse events - one patient reported nausea, fatigue, and excessive sleepiness, and one patient reported vomiting. No device-related serious adverse events were reported. Other adverse events reported were generally associated with progressive disease. Unsolicited, anecdotal reports from some parents/caregivers noted improvements in mobility, speech, and visual acuity while on treatment.
CONCLUSION(S): The Halo system appears to be safe and feasible for the treatment of pediatric brain tumors. Given that therapy is delivered non-invasively and no device-related serious adverse events were reported, further prospective study of the investigational device is warranted

BACKGROUND:H3 K27M-mutant diffuse midline glioma is a fatal malignancy with no proven medical therapies. The entity predominantly occurs in children and young adults. ONC201 is a small molecule selective antagonist of dopamine receptor D2/3 (DRD2/3) with an exceptional safety profile. Following up on a durable response in the first H3 K27M-mutant diffuse midline glioma patient who received ONC201 (NCT02525692), an expanded access program was initiated. METHODS:Patients with H3 K27M-mutant gliomas who received at least prior radiation were eligible. Patients with leptomeningeal spread were excluded. All patients received open-label ONC201 orally once every week. Safety, radiographic assessments, and overall survival were regularly assessed at least every 8 weeks by investigators. As of August 2018, a total of 18 patients with H3 K27M-mutant diffuse midline glioma or DIPG were enrolled to single patient expanded access ONC201 protocols. Among the 18 patients: seven adult (> 20 years old) and seven pediatric (< 20 years old) patients initiated ONC201 with recurrent disease and four pediatric patients initiated ONC201 following radiation, but prior to disease recurrence. FINDINGS/RESULTS:Among the 14 patients with recurrent disease prior to initiation of ONC201, median progression-free survival is 14 weeks and median overall survival is 17 weeks. Three adults among the 14 recurrent patients remain on treatment progression-free with a median follow up of 49.6 (range 41-76.1) weeks. Among the 4 pediatric patients who initiated adjuvant ONC201 following radiation, two DIPG patients remain progression-free for at least 53 and 81 weeks. Radiographic regressions, including a complete response, were reported by investigators in a subset of patients with thalamic and pontine gliomas, along with improvements in disease-associated neurological symptoms. INTERPRETATION/CONCLUSIONS:The clinical outcomes and radiographic responses in these patients provide the preliminary, and initial clinical proof-of-concept for targeting H3 K27M-mutant diffuse midline glioma with ONC201, regardless of age or location, providing rationale for robust clinical testing of the agent.

BACKGROUND:The dismal outcome in children with high-grade brainstem gliomas (BSG) accentuates the need for effective therapeutic strategies. We investigated the role of intensive, including marrow-ablative, chemotherapy regimens in the treatment of young children with newly-diagnosed high-grade BSG. METHODS:Between 1991-and-2002, 15 eligible children less than 10 years of age with a diagnosis of high-grade BSG were treated on "Head-Start" I and II protocols (HSI and HSII). Treatment included Induction with 4-5 cycles of one of three intensive chemotherapy regimens followed by Consolidation with one cycle of marrow-ablative chemotherapy (thiotepa, carboplatin and etoposide) with autologous hematopoietic cell rescue (AHCR). Irradiation was required for children over 6 years of age or for those with residual tumor at the end of Consolidation. RESULTS:We had two long-term survivors who were found retrospectively to harbor low-grade glial tumors and thus were not included in the survival analysis. Of the remaining 13 patients, the 1-year event-free (EFS) and overall (OS) survival for these children were 31% (95% CI 9-55%) and 38% (95% CI 14-63%), respectively. Median EFS and OS were 6.6 (95% CI 2.7, 12.7) and 8.7 months (95% CI 6.9, 20.9), respectively. Eight patients developed progressive disease during study treatment (seven during Induction and one at the end of Consolidation). Ten children received focal irradiation, five for residual tumor (three following Induction and two following Consolidation) and five due to disease progression. CONCLUSIONS:Children with high-grade BSG did not benefit from this intensive chemotherapy strategy administered prior to irradiation.