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Safety and pharmacokinetics of ONC201 (dordaviprone) administered two consecutive days per week in pediatric patients with H3K27M-mutant glioma

Odia, Yazmin; Koschmann, Carl; Vitanza, Nicholas A; de Blank, Peter; Aguilera, Dolly; Allen, Jeffrey; Daghistani, Doured; Hall, Matthew; Khatib, Ziad; Kline, Cassie; MacDonald, Tobey; Mueller, Sabine; Faison, Shamia L; Allen, Joshua E; Naderer, Odin J; Ramage, Samuel C; Tarapore, Rohinton S; McGovern, Susan Lynne; Khatua, Soumen; Zaky, Wafik; Gardner, Sharon L
BACKGROUND:This study evaluated the safety and pharmacokinetics (PK) of oral ONC201 administered twice-weekly on consecutive days (D1D2) in pediatric patients with newly diagnosed DIPG and/or recurrent/refractory H3 K27M glioma. METHODS:This phase 1 dose-escalation and expansion study included pediatric patients with H3 K27M-mutant glioma and/or DIPG following ≥1 line of therapy (NCT03416530). ONC201 was administered D1D2 at three dose levels (DLs; -1, 1, and 2). Actual administered dose within DLs was dependent on weight. Safety was assessed in all DLs; PK analysis was conducted in DL2. Patients receiving once-weekly ONC201 (D1) served as a PK comparator.1. RESULTS:Twelve patients received D1D2 ONC201 (DL-1, n=3; DL1, n=3; DL2, n=6); no dose-limiting toxicities or grade ≥3 treatment-related adverse events occurred. PK analyses at DL2 (D1-250mg, n=3; D1-625mg, n=3; D1D2-250mg, n=2; D1D2-625mg, n=2) demonstrated variability in Cmax, AUC0-24, and AUC0-48, with comparable exposures across weight groups. No accumulation occurred with D1D2 dosing; the majority of ONC201 cleared before administration of the second dose. Cmax was variable between groups but did not appear to increase with D1D2 dosing. AUC0-48 was greater with D1D2 than once-weekly. CONCLUSIONS:ONC201 given D1D2 was well-tolerated at all DLs and associated with greater AUC0-48.
PMID: 38400780
ISSN: 1523-5866
CID: 5634652

Final report of the phase II NEXT/CNS-GCT-4 trial: GemPOx followed by marrow-ablative chemotherapy for recurrent intracranial germ cell tumors

Shatara, Margaret; Blue, Megan; Stanek, Joseph; Liu, Yin A; Prevedello, Daniel M; Giglio, Pierre; Puduvalli, Vinay K; Gardner, Sharon L; Allen, Jeffrey C; Wong, Kenneth K; Nelson, Marvin D; Gilles, Floyd H; Adams, Roberta H; Pauly, Jasmine; O'Halloran, Katrina; Margol, Ashley S; Dhall, Girish; Finlay, Jonathan L
BACKGROUND/UNASSIGNED:Patients with relapsed intracranial germinoma can achieve durable remission with standard chemotherapy regimens and/or reirradiation; however, innovative therapies are required for patients with relapsed and/or refractory intracranial nongerminomatous germ cell tumors (NGGCTs) due to their poor prognosis. Improved outcomes have been reported using reinduction chemotherapy to achieve minimal residual disease, followed by marrow-ablative chemotherapy (HDCx) with autologous hematopoietic progenitor cell rescue (AuHPCR). We conducted a phase II trial evaluating the response and toxicity of a 3-drug combination developed for recurrent intracranial germ cell tumors consisting of gemcitabine, paclitaxel, and oxaliplatin (GemPOx). METHODS/UNASSIGNED:A total of 9 patients with confirmed relapsed or refractory intracranial GCT were enrolled after signing informed consent, and received at least 2 cycles of GemPOx, of which all but 1 had relapsed or refractory NGGCTs. One patient with progressive disease was found to have pathologically confirmed malignant transformation to pure embryonal rhabdomyosarcoma (without GCT elements), hence was ineligible and not included in the analysis. Patients who experienced sufficient responses proceeded to receive HDCx with AuHPCR. Treatment response was determined based on radiographic tumor assessments and tumor markers. RESULTS/UNASSIGNED:A total of 7 patients achieved sufficient response and proceeded with HDCx and AuHPCR, and 5 subsequently received additional radiotherapy. A total of 2 patients developed progressive disease while receiving GemPOx. Myelosuppression and transaminitis were the most common treatment-related adverse events. With a mean follow-up of 44 months, 4 patients (3 NGGCTs, 1 germinoma) are alive without evidence of disease. CONCLUSIONS/UNASSIGNED:GemPOx demonstrates efficacy in facilitating stem cell mobilization, thus facilitating the feasibility of both HDCx and radiotherapy.
PMID: 38496907
ISSN: 2054-2577
CID: 5640092

Impact of Rare and Multiple Concurrent Gene Fusions on Diagnostic DNA Methylation Classifier in Brain Tumors

Galbraith, Kristyn; Serrano, Jonathan; Shen, Guomiao; Tran, Ivy; Slocum, Cheyanne C; Ketchum, Courtney; Abdullaev, Zied; Turakulov, Rust; Bale, Tejus; Ladanyi, Marc; Sukhadia, Purvil; Zaidinski, Michael; Mullaney, Kerry; DiNapoli, Sara; Liechty, Benjamin L; Barbaro, Marissa; Allen, Jeffrey C; Gardner, Sharon L; Wisoff, Jeffrey; Harter, David; Hidalgo, Eveline Teresa; Golfinos, John G; Orringer, Daniel A; Aldape, Kenneth; Benhamida, Jamal; Wrzeszczynski, Kazimierz O; Jour, George; Snuderl, Matija
UNLABELLED:DNA methylation is an essential molecular assay for central nervous system (CNS) tumor diagnostics. While some fusions define specific brain tumors, others occur across many different diagnoses. We performed a retrospective analysis of 219 primary CNS tumors with whole genome DNA methylation and RNA next-generation sequencing. DNA methylation profiling results were compared with RNAseq detected gene fusions. We detected 105 rare fusions involving 31 driver genes, including 23 fusions previously not implicated in brain tumors. In addition, we identified 6 multi-fusion tumors. Rare fusions and multi-fusion events can impact the diagnostic accuracy of DNA methylation by decreasing confidence in the result, such as BRAF, RAF, or FGFR1 fusions, or result in a complete mismatch, such as NTRK, EWSR1, FGFR, and ALK fusions. IMPLICATIONS/UNASSIGNED:DNA methylation signatures need to be interpreted in the context of pathology and discordant results warrant testing for novel and rare gene fusions.
PMID: 37870438
ISSN: 1557-3125
CID: 5625782

Multicenter, prospective, phase II study of maintenance bevacizumab for children and adults with NF2-related schwannomatosis and progressive vestibular schwannoma

Plotkin, Scott R; Allen, Jeffrey; Dhall, Girish; Campian, Jian L; Clapp, D Wade; Fisher, Michael J; Jain, Rakesh K; Tonsgard, James; Ullrich, Nicole J; Thomas, Coretta; Edwards, Lloyd J; Korf, Bruce; Packer, Roger; Karajannis, Matthias A; Blakeley, Jaishri O
BACKGROUND:Prospective data on maintenance therapy with bevacizumab for persons with NF2-related schwannomatosis (NF2-SWN) is lacking. In this prospective multicenter phase II study, we evaluated the efficacy, safety, and tolerability of bevacizumab for maintenance therapy in children and adults with NF2-SWN and hearing loss due to vestibular schwannomas (VS). METHODS:Following induction therapy, participants received bevacizumab 5 mg/kg every 3 weeks for 18 months. Participants were monitored for changes in hearing, tumor size, and quality of life (QOL), and for adverse events. Hearing loss was defined as a statistically significant decline in word recognition score (WRS) or pure-tone average compared to the study baseline; tumor growth was defined as >20% increase in volume compared to baseline. RESULTS:Twenty participants with NF2-SWN (median age 23.5 years; range, 12.5-62.5 years) with hearing loss in the target ear (median WRS 70%, range 2%-94%) received maintenance bevacizumab. Freedom from hearing loss in the target ear was 95% after 48 weeks, 89% after 72 weeks, and 70% after 98 weeks. Freedom from tumor growth in the target VS was 94% after 48 weeks, 89% after 72 weeks, and 89% after 98 weeks. NF2-related QOL remained stable for 98 weeks whereas tinnitus-related distress decreased. Maintenance bevacizumab was well tolerated, with 3 participants (15%) discontinuing treatment due to adverse events. CONCLUSIONS:Maintenance bevacizumab (5 mg/kg every 3 weeks) is associated with high rates of hearing and tumor stability during 18 months of follow-up. No new unexpected adverse events related to bevacizumab were identified in this population.
PMID: 37010875
ISSN: 1523-5866
CID: 5592292

Clinical utility of whole-genome DNA methylation profiling as a primary molecular diagnostic assay for central nervous system tumors-A prospective study and guidelines for clinical testing

Galbraith, Kristyn; Vasudevaraja, Varshini; Serrano, Jonathan; Shen, Guomiao; Tran, Ivy; Abdallat, Nancy; Wen, Mandisa; Patel, Seema; Movahed-Ezazi, Misha; Faustin, Arline; Spino-Keeton, Marissa; Roberts, Leah Geiser; Maloku, Ekrem; Drexler, Steven A; Liechty, Benjamin L; Pisapia, David; Krasnozhen-Ratush, Olga; Rosenblum, Marc; Shroff, Seema; Boué, Daniel R; Davidson, Christian; Mao, Qinwen; Suchi, Mariko; North, Paula; Hopp, Amanda; Segura, Annette; Jarzembowski, Jason A; Parsons, Lauren; Johnson, Mahlon D; Mobley, Bret; Samore, Wesley; McGuone, Declan; Gopal, Pallavi P; Canoll, Peter D; Horbinski, Craig; Fullmer, Joseph M; Farooqui, Midhat S; Gokden, Murat; Wadhwani, Nitin R; Richardson, Timothy E; Umphlett, Melissa; Tsankova, Nadejda M; DeWitt, John C; Sen, Chandra; Placantonakis, Dimitris G; Pacione, Donato; Wisoff, Jeffrey H; Teresa Hidalgo, Eveline; Harter, David; William, Christopher M; Cordova, Christine; Kurz, Sylvia C; Barbaro, Marissa; Orringer, Daniel A; Karajannis, Matthias A; Sulman, Erik P; Gardner, Sharon L; Zagzag, David; Tsirigos, Aristotelis; Allen, Jeffrey C; Golfinos, John G; Snuderl, Matija
BACKGROUND/UNASSIGNED:Central nervous system (CNS) cancer is the 10th leading cause of cancer-associated deaths for adults, but the leading cause in pediatric patients and young adults. The variety and complexity of histologic subtypes can lead to diagnostic errors. DNA methylation is an epigenetic modification that provides a tumor type-specific signature that can be used for diagnosis. METHODS/UNASSIGNED:We performed a prospective study using DNA methylation analysis as a primary diagnostic method for 1921 brain tumors. All tumors received a pathology diagnosis and profiling by whole genome DNA methylation, followed by next-generation DNA and RNA sequencing. Results were stratified by concordance between DNA methylation and histopathology, establishing diagnostic utility. RESULTS/UNASSIGNED:Of the 1602 cases with a World Health Organization histologic diagnosis, DNA methylation identified a diagnostic mismatch in 225 cases (14%), 78 cases (5%) did not classify with any class, and in an additional 110 (7%) cases DNA methylation confirmed the diagnosis and provided prognostic information. Of 319 cases carrying 195 different descriptive histologic diagnoses, DNA methylation provided a definitive diagnosis in 273 (86%) cases, separated them into 55 methylation classes, and changed the grading in 58 (18%) cases. CONCLUSIONS/UNASSIGNED:DNA methylation analysis is a robust method to diagnose primary CNS tumors, improving diagnostic accuracy, decreasing diagnostic errors and inconclusive diagnoses, and providing prognostic subclassification. This study provides a framework for inclusion of DNA methylation profiling as a primary molecular diagnostic test into professional guidelines for CNS tumors. The benefits include increased diagnostic accuracy, improved patient management, and refinements in clinical trial design.
PMID: 37476329
ISSN: 2632-2498
CID: 5536102

Clinical, Pathological, and Molecular Characteristics of Diffuse Spinal Cord Gliomas

Garcia, Mekka R; Feng, Yang; Vasudevaraja, Varshini; Galbraith, Kristyn; Serrano, Jonathan; Thomas, Cheddhi; Radmanesh, Alireza; Hidalgo, Eveline T; Harter, David H; Allen, Jeffrey C; Gardner, Sharon L; Osorio, Diana S; William, Christopher M; Zagzag, David; Boué, Daniel R; Snuderl, Matija
Diffuse spinal cord gliomas (SCGs) are rare tumors associated with a high morbidity and mortality that affect both pediatric and adult populations. In this retrospective study, we sought to characterize the clinical, pathological, and molecular features of diffuse SCG in 22 patients with histological and molecular analyses. The median age of our cohort was 23.64 years (range 1-82) and the overall median survival was 397 days. K27M mutation was significantly more prevalent in males compared to females. Gross total resection and chemotherapy were associated with improved survival, compared to biopsy and no chemotherapy. While there was no association between tumor grade, K27M status (p = 0.366) or radiation (p = 0.772), and survival, males showed a trend toward shorter survival. K27M mutant tumors showed increased chromosomal instability and a distinct DNA methylation signature.
PMID: 35997552
ISSN: 1554-6578
CID: 5338172

EANO, SNO and Euracan consensus review on the current management and future development of intracranial germ cell tumors in adolescents and young adults

Frappaz, Didier; Dhall, Girish; Murray, Matthew J; Goldman, Stuart; Faure Conter, Cecile; Allen, Jeffrey; Kortmann, Rolf Dieter; Haas-Kogen, Daphne; Morana, Giovanni; Finlay, Jonathan; Nicholson, James C; Bartels, Ute; Souweidane, Mark; Schönberger, Stefan; Vasiljevic, Alexandre; Robertson, Patricia; Albanese, Assunta; Alapetite, Claire; Czech, Thomas; Lau, Chin C; Wen, Patrick; Schiff, David; Shaw, Dennis; Calaminus, Gabriele; Bouffet, Eric
The incidence of intracranial germ cell tumors (iGCT) is much lower in European and North American (E&NA) than in Asian population. However, E&NA cooperative groups have simultaneously developed with success treatment strategies with specific attention paid to long-term sequelae. Neurological sequelae may be reduced by establishing a diagnosis with an endoscopic biopsy and/or cerebrospinal fluid (CSF) and/or serum analysis, deferring the need to perform a radical surgery. Depending on markers and/or histological characteristics, patients are treated as either germinoma or non-germinomatous germ cell tumors (NGGCT). Metastatic disease is defined by a positive CSF cytology and/or distant drops in craniospinal MRI. The combination of surgery and/or chemotherapy and radiation therapy is tailored according to grouping and staging. With more than 90% 5-year event-free survival (EFS), localized germinomas can be managed without aggressive surgery, and benefit from chemotherapy followed by whole ventricular irradiation with local boost. Bifocal germinomas are treated as non-metastatic entities. Metastatic germinomas may be cured with craniospinal irradiation. With a 5-year EFS over 70%, NGGCT benefit from chemotherapy followed by delayed surgery in case of residual disease, and some form of radiotherapy. Future strategies will aim at decreasing long-term side effects while preserving high cure rates.
PMID: 34724065
ISSN: 1523-5866
CID: 5219272


Kanakamedala, Siri; Gardner, Sharon; Allen, Jeffrey; Nicolaides, Theodore; Pudel, Miriam; Roman, Elizabeth
ISSN: 1545-5009
CID: 5243872

Clinical value of DNA methylation in practice: A prospective molecular neuropathology study [Meeting Abstract]

Galbraith, Kristyn; Shen, Guomiao; Serrano, Jonathan; Vasudevaraja, Varshini; Tran, Ivy; Movahed-Ezazi, Misha; Harter, David; Hidalgo, Eveline; Wisoff, Jeffrey; Orringer, Daniel; Placantonakis, Dimitris; Gardner, Sharon; William, Christopher; Zagzag, David; Allen, Jeffrey; Sulman, Erik; Golfinos, John; Snuderl, Matija
ISSN: 0022-3069
CID: 5244322

Phase I dose escalation and expansion trial of single agent ONC201 in pediatric diffuse midline gliomas following radiotherapy

Gardner, Sharon L; Tarapore, Rohinton S; Allen, Jeffrey; McGovern, Susan L; Zaky, Wafik; Odia, Yazmin; Daghistani, Doured; Diaz, Zuanel; Hall, Matthew D; Khatib, Ziad; Koschmann, Carl; Cantor, Evan; Kurokawa, Ryo; MacDonald, Tobey J; Aguilera, Dolly; Vitanza, Nicholas A; Mueller, Sabine; Kline, Cassie; Lu, Guangrong; Allen, Joshua E; Khatua, Soumen
BACKGROUND/UNASSIGNED:ONC201, a dopamine receptor D2 (DRD2) antagonist and caseinolytic protease P (ClpP) agonist, has induced durable tumor regressions in adults with recurrent H3 K27M-mutant glioma. We report results from the first phase I pediatric clinical trial of ONC201. METHODS/UNASSIGNED:This open-label, multi-center clinical trial (NCT03416530) of ONC201 for pediatric H3 K27M-mutant diffuse midline glioma (DMG) or diffuse intrinsic pontine glioma (DIPG) employed a dose-escalation and dose-expansion design. The primary endpoint was the recommended phase II dose (RP2D). A standard 3 + 3 dose escalation design was implemented. The target dose was the previously established adult RP2D (625 mg), scaled by body weight. Twenty-two pediatric patients with DMG/DIPG were treated following radiation; prior lines of systemic therapy in addition to radiation were permitted providing sufficient time had elapsed prior to study treatment. RESULTS/UNASSIGNED:The RP2D of orally administered ONC201 in this pediatric population was determined to be the adult RP2D (625 mg), scaled by body weight; no dose-limiting toxicities (DLT) occurred. The most frequent treatment-emergent Grade 1-2 AEs were headache, nausea, vomiting, dizziness and increase in alanine aminotransferase. Pharmacokinetics were determined following the first dose: <i>T</i> <sub>1/2</sub>, 8.4 h; <i>T</i> <sub>max</sub>, 2.1 h; <i>C</i> <sub>max</sub>, 2.3 µg/mL; AUC<sub>0-tlast</sub>, 16.4 hµg/mL. Median duration of treatment was 20.6 weeks (range 5.1-129). Five (22.7%) patients, all of whom initiated ONC201 following radiation and prior to recurrence, were alive at 2 years from diagnosis. CONCLUSIONS/UNASSIGNED:The adult 625 mg weekly RP2D of ONC201 scaled by body weight was well tolerated. Further investigation of ONC201 for DMG/DIPG is warranted.
PMID: 36382108
ISSN: 2632-2498
CID: 5384822