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CLINICAL EFFICACY AND PREDICTIVE BIOMARKERS OF ONC201 IN H3K27M-MUTANT DIFFUSE MIDLINE GLIOMA [Meeting Abstract]

Kawakibi, A R; Tarapore, R; Gardner, S; Chi, A; Kurz, S; Wen, P Y; Arrillaga-Romany, I; Batchelor, T; Butowski, N; Sumrall, A; Shonka, N; Harrison, R; DeGroot, J; Mehta, M; Odia, Y; Hall, M; Daghistani, D; Cloughesy, T; Ellingson, B; Kim, M; Umemura, Y; Garton, H; Franson, A; Schwartz, J; Li, S; Cartaxo, R; Ravi, K; Cantor, E; Cummings, J; Paul, A; Walling, D; Dun, M; Cain, J; Li, J; Filbin, M; Zhao, L; Kumar-Sinha, C; Mody, R; Chinnaiyan, A; Kurokawa, R; Pratt, D; Venneti, S; Grill, J; Kline, C; Mueller, S; Resnick, A C; Nazarian, J; Waszak, S; Allen, J E; Koschmann, C
Patients with H3K27M-mutated diffuse midline glioma (DMG) have no proven effective therapies beyond radiation. ONC201, a DRD2 antagonist and mitochondrial ClpP agonist, has shown promise in this population. Clinical and genetic variables associated with ONC201 response in H3K27M-mutant DMG continue to be investigated. A combined clinical and genetic study evaluated patients with H3K27M-DMG treated with single-agent ONC201 at the established phase 2 dose. Clinical outcomes of patients treated on two recently completed multi-site clinical studies (NCT03416530 and NCT03134131, n = 75) were compared with historical control data from patients with confirmed H3K27M-DMG (n = 391 total, n = 119 recurrent). Patients treated with ONC201 monotherapy following initial radiation, but prior to recurrence, demonstrated a median overall survival (OS) of 25.6 months from diagnosis and recurrent patients demonstrated a median OS of 16.2 months from recurrence, both of these more than doubling historical outcomes. Using a Cox model to correct for age, gender and tumor location, OS of ONC201-treated patients with H3K27M-mutant tumors remained significantly better than non-ONC201-treated historical controls (p = 0.0001). A survival and radiographic analysis based on tumor location, revealed stronger responses in thalamic patients. In patients with thalamic tumors treated after initial radiation (n = 16), median OS was not reached with median follow up of 22.1 months (historical control median OS of 12.5 months, n = 83, p = 0.0001). Significant correlations were found between baseline cerebral blood flow (CBF) on perfusion imaging and OS (Pearson's r = 0.75, p = 0.003) and between nrCBF and PFS (r = 0.77, p = 0.002). Baseline tumor sequencing from treated patients (n = 20) demonstrates EGFR mutation (n = 3) and high EGFR expression as a marker of resistance and improved response in tumors with MAPK-pathway alterations (n = 5). In conclusion, ONC201 demonstrates unprecedented clinical and radiographic efficacy in H3K27M-mutant DMG with outcomes enriched in patients with thalamic tumors, treatment prior to recurrence, MAPKpathway alterations, and patients with relatively high CBF
EMBASE:639939966
ISSN: 1523-5866
CID: 5513292

Nighttime supervision of internal medicine residents in the ICU: Perceptions of residency program directors from a national survey [Meeting Abstract]

Tuck, M; Bruti, C; Kisielewski, M; Harrison, R; Smith, D; Catalanotti, J; Burger, A
BACKGROUND: The ACGME requires programs to have the appropriate level of supervision in place for all residents. Hospitals have since changed staffing to provide greater nighttime presence of attendings. The aims of this study were to describe who provides nighttime supervision of residents in the ICU and the sufficiency of attending staffing at night as perceived by internal medicine (IM) program directors (PDs).
METHOD(S): The APDIM Annual Survey of Residency PDs studies issues critical to IM training. The 2017 survey was disseminated to PDs from all 379 APDIM member residency programs with ACGME accreditation. The Academic Hospitalist Commission of SGIM submitted 12 questions for inclusion in the survey addressing nighttime supervision and education of residents. Results from a subset of those questions is included in this study. Descriptive statistics included the reporting of frequencies and percentages. Group-based significance testing was conducted using the Adjusted Wald test for categorical variables and Welch's t-test to compare mean differences using continuous variables. Analyses were two-tailed (where applicable) with alpha set to 0.05.
RESULT(S): The survey response rate was 70%. There was no statistical association between respondents and non-respondents based on essential program and PD characteristics. Among those who reported onsite nighttime supervision was available in the ICU, the most common type of physician was a critical care attending (n = 144/207, 69.6%). The remainder used a variety of non- critical care physicians for supervision. However, 21.9% of PDs reported there was no nighttime resident supervision in the ICU. Compared to all other program types, university-based programs more commonly reported nighttime supervision by subspecialty fellows (p = 0.009) and less by tele- ICU (p = 0.036). Respondents reported at least sometimes having insufficient attending staffing overnight to ensure high-quality patient care (42.9%) and patient safety (40.1%) in the hospital. Compared to university- based programs, a higher percentage of respondents from all other program types reported never having insufficient attending staffing overnight to ensure high-quality patient care (40.4% and 53.7%, respectively, p = 0.024) and patient safety (43.0% and 56.8%, respectively, p = 0.027).
CONCLUSION(S): While the majority of PDs reported in-house supervision of residents in the ICU, a large number reported insufficient attending nighttime staffing to provide high-quality and safe patient care. This merits further exploration of optimal staffing models to assure resident supervision and high quality patient care. LEARNING OBJECTIVE #1: Describe who supervises internal medicine residents in the intensive care setting at night. (PBLI) LEARNING OBJECTIVE #2: Recognize program directors' perceptions about the adequacy of nighttime faculty staffing to provide high-quality and safe patient care. (SBP)
EMBASE:635796595
ISSN: 1525-1497
CID: 4984992

Clinical efficacy of ONC201 in thalamic H3 K27M-mutant glioma [Meeting Abstract]

Kawakibi, A R; Gardner, S; Chi, A; Kurz, S; Wen, P; Arrillaga-Romany, I; Batchelor, T; Butowski, N; Sumrall, A; Shonka, N; Harrison, R; DeGroot, J; Mehta, M; Odia, Y; Hall, M; Daghistani, D; Cloughesy, T; Ellingson, B; Umemura, Y; Schwartz, J; Yadav, V; Cartaxo, R; Miklja, Z; Bruzek, A; Siada, R; Mullan, B; Stallard, S; Muruganand, A; Wierzbicki, K; Paul, A; Wolfe, I; Kumar-Sinha, C; Marini, B; Leonard, M; Garton, H; Mody, R; Robertson, P; Merdinger, K; Tarapore, R; Oster, W; Allen, J; Koschmann, C
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
EMBASE:631168477
ISSN: 1523-5866
CID: 4388152

Single agent ONC201 in previously-treated, progressive adult H3 K27M-mutant glioma [Meeting Abstract]

Arrillaga-Romany, I; Kurz, S; Sumrall, A; Butowski, N; Harrison, R; DeGroot, J; Chi, A; Sulman, E; Shonka, N; Umemura, Y; Odia, Y; Mehta, M; Iwamoto, F; Nghiemphu, P L; Cloughesy, T; Tarapore, R; Merdinger, K; Oster, W; Allen, J; Batchelor, T; Lassman, A; Wen, P
H3 K27M-mutant gliomas often manifest as midline gliomas, have a dismal prognosis, and have no established or effective treatments at recurrence. ONC201 is the first clinical bitopic DRD2 antagonist/ClpP agonist and is under evaluation in Phase II trials for gliomas and other cancers. We previously reported in vitro studies suggesting dysregulated dopamine receptor expression and enhanced ONC201 sensitivity among H3 K27Mmutant gliomas. Following these observations, adults with midline H3 K27M-mutant glioma patients were enrolled to a dedicated Phase II clinical trial (NCT03295396), a multi-arm Phase II trial (NCT0252569), and expanded access protocols under the Sponsor's IND. An integrated radiographic analysis with an objective response rate primary endpoint in patients who received ONC201 monotherapy with confirmed H3 K27M-mutant glioma (not primarily in the pons or spinal cord and without leptomeningeal spread) that was progressive and measurable disease by RANO criteria, >90 days from completion of prior radiation, and had KPS >60. As of December 15, 2018, 15 patients have received single agent ONC201 who meet these criteria (n=9 NCT03295396; n=5 NCT0252569; n=1 expanded access). ONC201 was orally administered at 625 mg weekly, except for one patient dosed once every 3 weeks. As midline gliomas can exhibit a mixture of contrast-enhancing and non-contrast-enhancing disease, objective response was assessed by blinded independent central review using RANO-HGG and RANO-LGG criteria for each patient. Best response to date by RANO-HGG criteria is at least 27%: 1 CR, 3 PR, 7 SD, and 4 PD; by RANO-LGG is at least 36%: 1 CR, 1 PR, 3 minor response (MR), 4 SD, 5 PD, 1 unevaluable. By RANO-HGG, median onset of response is 2.6 months (range 1.3-3.4); median duration of response has not been reached with a median follow-up of 7.7 months (range 1.8-29.8). Updated radiographic response, pharmacodynamics, safety, and other clinical outcomes will be reported
EMBASE:631169109
ISSN: 1523-5866
CID: 4388032

Integrated clinical experience with ONC201 in previously-treated h3 K27M-mutant glioma patients [Meeting Abstract]

Chi, A; Arrillaga-Romany, I; Gardner, S; Wen, P; Batchelor, T; Hall, M; Odia, Y; Khatua, S; Zaky, W; McGovern, S; Harrison, R; De, Groot J; Sumrall, A; Shonka, N; Khatib, Z; Karajannis, M; Mueller, S; Tarapore, R; Merdinger, K; Schalop, L; Allen, J; Oster, W; Mehta, M P
BACKGROUND: H3 K27M-mutant gliomas have a dismal clinical prognosis and no proven curative therapy. We report the updated clinical experience with ONC201, the first cancer-specific DRD2 antagonist, in adult and pediatric H3 K27M-mutant gliomas.
METHOD(S): As of May 28, 2018, 26 patients with H3 K27M-mutant glioma have been treated with ONC201: 9 pediatric (<18 years old) and 17 adult patients (>18 years old). Twelve patients had recurrent disease and 14 had previously-treated stable disease prior to initiating ONC201. Patients had 1-4 prior lines of therapy and all received prior radiation. Ten adult patients were enrolled on clinical trials and the other 16 were on compassionate use. ONC201 was orally administered at 625 mg to adults and scaled by body weight for pediatric patients. All patients, except one, were dosed weekly.
RESULT(S): Fourteen of 26 patients (54%) remain progression-free on ONC201 with a median follow up of 3.6 (range 1.6-24.5) months. No dose modifications or discontinuation due to toxicity have occurred. Among the 12 adult patients with recurrent disease who received single agent ONC201, the estimated PFS6 is 36.5%. Seven patients have experienced radiographic and/or clinical benefit (neurological stabilization or improvement). Among the 5 adults with recurrent thalamic glioma, three have experienced durable complete regression of their thalamic tumors, including the first H3 K27M-mutant glioma patient treated with ONC201 who has experienced 96% regression of her recurrent disease and continues single agent ONC201 for >2 years. Two DIPG pediatric patients who initiated single agent ONC201 6-8 weeks after radiation have experienced radiographic and neurological improvements and exhibited PFS of >13 months from diagnosis.
CONCLUSION(S): Emerging clinical data suggest that ONC201 exhibits clinical activity for some patients with H3 K27M-mutant glioma
EMBASE:628633779
ISSN: 1523-5866
CID: 4021722

The UPDRS scale as a means of identifying extrapyramidal signs in patients suffering from dementia with Lewy bodies

Ballard, C; McKeith, I; Burn, D; Harrison, R; O'Brien, J; Lowery, K; Campbell, M; Perry, R; Ince, P
The study aimed to evaluate the merits of the Unified Parkinson's Disease Rating Scale (UPDRS) in the assessment of parkinsonism in patients suffering from Dementia with Lewy Bodies (DLB). Parkinsonian symptoms were assessed in 73 dementia patients using the UPDRS and staged using the Hoehn & Yahr system. A staging of 1 or greater was taken to indicate significant parkinsonism. DLB (n=42) was diagnosed using the McKeith et al. criteria, Alzheimer's disease (n=30) was diagnosed using the NINCDS ADRDA criteria. The inability of some patients to comply with some of the more complicated tasks meant that the full UPDRS assessment could only be completed in 35 (83%) of the DLB patients, 23 (66%) of whom had significant parkinsonism. Patients with parkinsonism were significantly younger than those without. A Principal Components Analysis derived a sub-scale including the items tremor at rest, action tremor, bradykinesia, facial expression and rigidity. These items had a specificity of 100% and a sensitivity of 85% for significant parkinsonism using a cut-off of 7/8. The brief scale had several advantages over the complete UPDRS. Unlike the full scale it was independent of the severity of cognitive impairment and the 5 key items could be assessed in 41 (98%) of the DLB patients. Autopsies have been completed on 31 patients, with a specificity of greater than 90% for the operationalized clinical diagnosis of DLB. It is suggested that a 5 item subscale of the UPDRS provides a reliable and generally applicable instrument for the assessment of parkinsonism in DLB patients.
PMID: 9449473
ISSN: 0001-6314
CID: 165514

Argon laser trabeculoplasty in pigmentary glaucoma

Ritch, R; Liebmann, J; Robin, A; Pollack, I P; Harrison, R; Levene, R Z; Hagadus, J
PURPOSE: To evaluate the long-term effect of argon laser trabeculoplasty (ALT) in pigmentary glaucoma. METHODS: The authors retrospectively analyzed results of ALT in 32 eyes of 32 patients with medically uncontrolled pigmentary glaucoma. Data were longitudinally adjusted to normalize the disparity in time of follow-up and evaluated by life-table analysis. RESULTS: Mean age (+/- standard deviation) was 45.1 +/- 13.1 years (range, 23-72 years) (males, 46.3 +/- 13.7 years; females, 42.9 +/- 12.2 years). Mean baseline intraocular pressure (IOP) was 27.8 +/- 5.3 mmHg. Mean follow-up time was 33.0 +/- 5.0 months (range, 1 week [immediate failures] to 96 months). Three eyes were lost to follow-up at 3 months. Eleven eyes required trabeculectomy between 1 week (2 eyes) and 37 months after laser treatment. Life-table analysis indicated a cumulative success for all eyes of 80% at 1 year, 62% at 2 years, and 45% at 6 years. Mean IOP was significantly reduced (P < 0.001; paired Student's t test) for male and female eyes at all intervals calculated. Age was a significant factor in determining time to failure. CONCLUSION: Argon laser trabeculoplasty is effective in pigmentary glaucoma. Younger patients had a greater chance of success than older patients at all intervals. This became highly significant (P < 0.001) after 3 years.
PMID: 8510905
ISSN: 0161-6420
CID: 266522

The role of subscleral Scheie procedure in glaucoma surgery

McGuigan LJ; Luntz MH; Freedman J; Harrison R
PMID: 3822383
ISSN: 0022-023x
CID: 24299

Clonidine. Effects of a topically administered solution on intraocular pressure and blood pressure in open-angle glaucoma

Harrison, R; Kaufmann, C S
A double-blind crossover study to determine the effects on intraocular pressure (IOP) and blood pressure of topically instilled 0.125% and 0.25% solutions of clonidine hydrochloride by comparison with a 2% pilocarpine hydrochloride solution and placebo was carried out in a total of 21 patients with open-angle glaucoma, each of whom received a single drop of each preparation in the same glaucomatous eye on separate days. Both clonidine solutions were effective in lowering the IOP; the 0.25% solution was more effective than the 0.125% solution, and the former was slightly less potent than pilocarpine. Pupil diameter was essentially unchanged in all but one of the patients after clonidine. Pilocarpine reduced pupil diameter in all patients. One eye treated with placebo also showed a reduction in pupil size. Both systolic and diastolic blood pressure showed a statistically significant reduction after clonidine, but the magnitude of the change was small. We do not regard the minor blood pressure changes as being a threat to the optic nerve but further studies in this aspect of topical clonidine therapy are required.
PMID: 889511
ISSN: 0003-9950
CID: 3639802