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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.
PMCID:10940828
PMID: 38496907
ISSN: 2054-2577
CID: 5640092

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

ONC201 (Dordaviprone) in Recurrent H3 K27M-Mutant Diffuse Midline Glioma

Arrillaga-Romany, Isabel; Gardner, Sharon L; Odia, Yazmin; Aguilera, Dolly; Allen, Joshua E; Batchelor, Tracy; Butowski, Nicholas; Chen, Clark; Cloughesy, Timothy; Cluster, Andrew; de Groot, John; Dixit, Karan S; Graber, Jerome J; Haggiagi, Aya M; Harrison, Rebecca A; Kheradpour, Albert; Kilburn, Lindsay; Kurz, Sylvia C; Lu, Guangrong; MacDonald, Tobey J; Mehta, Minesh; Melemed, Allen S; Nghiemphu, Phioanh Leia; Ramage, Samuel C; Shonka, Nicole; Sumrall, Ashley; Tarapore, Rohinton; Taylor, Lynne; Umemura, Yoshie; Wen, Patrick Y
PURPOSE/OBJECTIVE:Histone 3 (H3) K27M-mutant diffuse midline glioma (DMG) has a dismal prognosis with no established effective therapy beyond radiation. This integrated analysis evaluated single-agent ONC201 (dordaviprone), a first-in-class imipridone, in recurrent H3 K27M-mutant DMG. METHODS:Fifty patients (pediatric, n = 4; adult, n = 46) with recurrent H3 K27M-mutant DMG who received oral ONC201 monotherapy in four clinical trials or one expanded access protocol were included. Eligible patients had measurable disease by Response Assessment in Neuro-Oncology (RANO) high-grade glioma (HGG) criteria and performance score (PS) ≥60 and were ≥90 days from radiation; pontine and spinal tumors were ineligible. The primary end point was overall response rate (ORR) by RANO-HGG criteria. Secondary end points included duration of response (DOR), time to response (TTR), corticosteroid response, PS response, and ORR by RANO low-grade glioma (LGG) criteria. Radiographic end points were assessed by dual-reader, blinded independent central review. RESULTS:The ORR (RANO-HGG) was 20.0% (95% CI, 10.0 to 33.7). The median TTR was 8.3 months (range, 1.9-15.9); the median DOR was 11.2 months (95% CI, 3.8 to not reached). The ORR by combined RANO-HGG/LGG criteria was 30.0% (95% CI, 17.9 to 44.6). A ≥50% corticosteroid dose reduction occurred in 7 of 15 evaluable patients (46.7% [95% CI, 21.3 to 73.4]); PS improvement occurred in 6 of 34 evaluable patients (20.6% [95% CI, 8.7 to 37.9]). Grade 3 treatment-related treatment-emergent adverse events (TR-TEAEs) occurred in 20.0% of patients; the most common was fatigue (n = 5; 10%); no grade 4 TR-TEAEs, deaths, or discontinuations occurred. CONCLUSION/CONCLUSIONS:ONC201 monotherapy was well tolerated and exhibited durable and clinically meaningful efficacy in recurrent H3 K27M-mutant DMG.
PMID: 38335473
ISSN: 1527-7755
CID: 5632032

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

Clinical Efficacy of ONC201 in H3K27M-Mutant Diffuse Midline Gliomas Is Driven by Disruption of Integrated Metabolic and Epigenetic Pathways

Venneti, Sriram; Kawakibi, Abed Rahman; Ji, Sunjong; Waszak, Sebastian M; Sweha, Stefan R; Mota, Mateus; Pun, Matthew; Deogharkar, Akash; Chung, Chan; Tarapore, Rohinton S; Ramage, Samuel; Chi, Andrew; Wen, Patrick Y; Arrillaga-Romany, Isabel; Batchelor, Tracy T; Butowski, Nicholas A; Sumrall, Ashley; Shonka, Nicole; Harrison, Rebecca A; de Groot, John; Mehta, Minesh; Hall, Matthew D; Daghistani, Doured; Cloughesy, Timothy F; Ellingson, Benjamin M; Beccaria, Kevin; Varlet, Pascale; Kim, Michelle M; Umemura, Yoshie; Garton, Hugh; Franson, Andrea; Schwartz, Jonathan; Jain, Rajan; Kachman, Maureen; Baum, Heidi; Burant, Charles F; Mottl, Sophie L; Cartaxo, Rodrigo T; John, Vishal; Messinger, Dana; Qin, Tingting; Peterson, Erik; Sajjakulnukit, Peter; Ravi, Karthik; Waugh, Alyssa; Walling, Dustin; Ding, Yujie; Xia, Ziyun; Schwendeman, Anna; Hawes, Debra; Yang, Fusheng; Judkins, Alexander R; Wahl, Daniel; Lyssiotis, Costas A; de la Nava, Daniel; Alonso, Marta M; Eze, Augustine; Spitzer, Jasper; Schmidt, Susanne V; Duchatel, Ryan J; Dun, Matthew D; Cain, Jason E; Jiang, Li; Stopka, Sylwia A; Baquer, Gerard; Regan, Michael S; Filbin, Mariella G; Agar, Nathalie Y R; Zhao, Lili; Kumar-Sinha, Chandan; Mody, Rajen; Chinnaiyan, Arul; Kurokawa, Ryo; Pratt, Drew; Yadav, Viveka N; Grill, Jacques; Kline, Cassie; Mueller, Sabine; Resnick, Adam; Nazarian, Javad; Allen, Joshua E; Odia, Yazmin; Gardner, Sharon L; Koschmann, Carl
UNLABELLED:Patients with H3K27M-mutant diffuse midline glioma (DMG) have no proven effective therapies. ONC201 has recently demonstrated efficacy in these patients, but the mechanism behind this finding remains unknown. We assessed clinical outcomes, tumor sequencing, and tissue/cerebrospinal fluid (CSF) correlate samples from patients treated in two completed multisite clinical studies. Patients treated with ONC201 following initial radiation but prior to recurrence demonstrated a median overall survival of 21.7 months, whereas those treated after recurrence had a median overall survival of 9.3 months. Radiographic response was associated with increased expression of key tricarboxylic acid cycle-related genes in baseline tumor sequencing. ONC201 treatment increased 2-hydroxyglutarate levels in cultured H3K27M-DMG cells and patient CSF samples. This corresponded with increases in repressive H3K27me3 in vitro and in human tumors accompanied by epigenetic downregulation of cell cycle regulation and neuroglial differentiation genes. Overall, ONC201 demonstrates efficacy in H3K27M-DMG by disrupting integrated metabolic and epigenetic pathways and reversing pathognomonic H3K27me3 reduction. SIGNIFICANCE:The clinical, radiographic, and molecular analyses included in this study demonstrate the efficacy of ONC201 in H3K27M-mutant DMG and support ONC201 as the first monotherapy to improve outcomes in H3K27M-mutant DMG beyond radiation. Mechanistically, ONC201 disrupts integrated metabolic and epigenetic pathways and reverses pathognomonic H3K27me3 reduction. This article is featured in Selected Articles from This Issue, p. 2293.
PMCID:10618742
PMID: 37584601
ISSN: 2159-8290
CID: 5626362

PTCy, Abatacept, and Short Course of Tacrolimus for GvHD Prevention Following Haploidentical Transplantation

Al-Homsi, A Samer; Cirrone, Frank; Wo, Stephanie; Cole, Kelli; Suarez-Londono, J Andres; Gardner, Sharon L; Hsu, Jingmei; Stocker, Kelsey; Bruno, Benedetto; Goldberg, Judith D; Levinson, Benjamin A; Abdul-Hay, Maher
Reducing the incidence of graft-versus host disease (GvHD) following haploidentical hematopoietic stem cell transplantation (HSCT) is warranted. Post-transplant cyclophosphamide (PTCy) is the main agent used for GvHD prevention in this setting. It remains unknown if costimulation blockade can be safely combined with PTCy and enhance its efficacy. We performed a phase Ib-II clinical trial to examine the combination of PTCy, abatacept and a short course of tacrolimus (CAST) following peripheral blood haploidentical HSCT. The primary end-point was the incidence of acute GvHD grades II-IV at day +120. The study enrolled 46 patients with a median age of 60 years (range: 18 to 74). The cumulative incidence of acute GvHD grades II-IV and III-IV was 17.4% (95% CI, 9.2% to 32.9%) and 4.4% (95% CI, 1.1% to 17.1%). With a median follow-up of 15.3 months, the cumulative incidence of one-year treatment-related mortality is 4.4% (95% CI, 1.1% to 17.1%). The estimated one-year chronic GvHD moderate to severe rate, relapse rate, progression-free survival, overall survival, and GvHD- and relapse-free survival were 15.9% (95% CI, 8% to 31.7%), 11.7% (95% CI, 5% to 27.2%), 84.1% (95% CI, 73.8% to 95.7%), 85.9% (95% CI, 75.9% to 97.2%) and 66.1% (95% CI, 53.4% to 81.8%), respectively. Toxicities were similar to those expected in patients receiving haploidentical HSCT. This clinical trial showed that CAST regimen is safe and effective in reducing the rate of grades II-IV acute GvHD following haploidentical peripheral blood HSCT (NCT04503616 at https://clinicaltrials.gov/ct2/show/NCT04503616).
PMID: 37163349
ISSN: 2473-9537
CID: 5509352

[S.l.] : Tandem Meetings, Transplantation & Cellular Therapy Meetings of ASTCT and CIBMTR, 2023

Phase Ib-II Study of Post-Transplant Cyclophosphamide, Abatacept and Short Course of Tacrolimus (CAST) for Graft-Versus-Host Disease Prevention Following Haploidentical Peripheral Blood Stem Cell Transplantation

Al-Homsi, A Samer; Cirrone, Frank; Cole, Kelli; Londono, J Andres-Suarez; Gardner, Sharon; Hsu, Jingmei; Wo, Stephanie; Stocker, Kelsey; Goldberg, Judith; Levinson, Benjamin; Abdul-Hay, Maher
(Website)
CID: 5515802

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.
PMCID:10355794
PMID: 37476329
ISSN: 2632-2498
CID: 5536102

The children's brain tumor network (CBTN) - Accelerating research in pediatric central nervous system tumors through collaboration and open science

Lilly, Jena V; Rokita, Jo Lynne; Mason, Jennifer L; Patton, Tatiana; Stefankiewiz, Stephanie; Higgins, David; Trooskin, Gerri; Larouci, Carina A; Arya, Kamnaa; Appert, Elizabeth; Heath, Allison P; Zhu, Yuankun; Brown, Miguel A; Zhang, Bo; Farrow, Bailey K; Robins, Shannon; Morgan, Allison M; Nguyen, Thinh Q; Frenkel, Elizabeth; Lehmann, Kaitlin; Drake, Emily; Sullivan, Catherine; Plisiewicz, Alexa; Coleman, Noel; Patterson, Luke; Koptyra, Mateusz; Helili, Zeinab; Van Kuren, Nicholas; Young, Nathan; Kim, Meen Chul; Friedman, Christopher; Lubneuski, Alex; Blackden, Christopher; Williams, Marti; Baubet, Valerie; Tauhid, Lamiya; Galanaugh, Jamie; Boucher, Katie; Ijaz, Heba; Cole, Kristina A; Choudhari, Namrata; Santi, Mariarita; Moulder, Robert W; Waller, Jonathan; Rife, Whitney; Diskin, Sharon J; Mateos, Marion; Parsons, Donald W; Pollack, Ian F; Goldman, Stewart; Leary, Sarah; Caporalini, Chiara; Buccoliero, Anna Maria; Scagnet, Mirko; Haussler, David; Hanson, Derek; Firestein, Ron; Cain, Jason; Phillips, Joanna J; Gupta, Nalin; Mueller, Sabine; Grant, Gerald; Monje-Deisseroth, Michelle; Partap, Sonia; Greenfield, Jeffrey P; Hashizume, Rintaro; Smith, Amy; Zhu, Shida; Johnston, James M; Fangusaro, Jason R; Miller, Matthew; Wood, Matthew D; Gardner, Sharon; Carter, Claire L; Prolo, Laura M; Pisapia, Jared; Pehlivan, Katherine; Franson, Andrea; Niazi, Toba; Rubin, Josh; Abdelbaki, Mohamed; Ziegler, David S; Lindsay, Holly B; Stucklin, Ana Guerreiro; Gerber, Nicolas; Vaske, Olena M; Quinsey, Carolyn; Rood, Brian R; Nazarian, Javad; Raabe, Eric; Jackson, Eric M; Stapleton, Stacie; Lober, Robert M; Kram, David E; Koschmann, Carl; Storm, Phillip B; Lulla, Rishi R; Prados, Michael; Resnick, Adam C; Waanders, Angela J
Pediatric brain tumors are the leading cause of cancer-related death in children in the United States and contribute a disproportionate number of potential years of life lost compared to adult cancers. Moreover, survivors frequently suffer long-term side effects, including secondary cancers. The Children's Brain Tumor Network (CBTN) is a multi-institutional international clinical research consortium created to advance therapeutic development through the collection and rapid distribution of biospecimens and data via open-science research platforms for real-time access and use by the global research community. The CBTN's 32 member institutions utilize a shared regulatory governance architecture at the Children's Hospital of Philadelphia to accelerate and maximize the use of biospecimens and data. As of August 2022, CBTN has enrolled over 4700 subjects, over 1500 parents, and collected over 65,000 biospecimen aliquots for research. Additionally, over 80 preclinical models have been developed from collected tumors. Multi-omic data for over 1000 tumors and germline material are currently available with data generation for > 5000 samples underway. To our knowledge, CBTN provides the largest open-access pediatric brain tumor multi-omic dataset annotated with longitudinal clinical and outcome data, imaging, associated biospecimens, child-parent genomic pedigrees, and in vivo and in vitro preclinical models. Empowered by NIH-supported platforms such as the Kids First Data Resource and the Childhood Cancer Data Initiative, the CBTN continues to expand the resources needed for scientists to accelerate translational impact for improved outcomes and quality of life for children with brain and spinal cord tumors.
PMCID:9641002
PMID: 36335802
ISSN: 1476-5586
CID: 5356872

FIREFLY-1 (PNOC026): PHASE 2 STUDY OF PAN-RAF INHIBITOR TOVORAFENIB IN PEDIATRIC AND YOUNG ADULT PATIENTS WITH RAF-ALTERED RECURRENT OR PROGRESSIVE LOW-GRADE GLIOMA OR ADVANCED SOLID TUMORS [Meeting Abstract]

Kilburn, L; Landi, D; Leary, S; Ziegler, D; Baxter, P; Franson, A; McCowage, G; Waanders, A; Van, der Lugt J; Yalon, Oren M; Gerber, N; Gottardo, N; Khuong-Quang, D -A; Nysom, K; Bailey, S; Driever, P H; Perreault, S; Witt, O; Hahn, S; Hargrave, D; Hassall, T; Jabado, N; Kang, H J; Larouche, V; Toledano, H; Kline, C; Abdelbaki, M; Chi, S; Gardner, S; Whipple, N; Mueller, S; Blackman, S; Zhao, X; Da, Costa D; Cox, M; Packer, R; Hansford, J
BACKGROUND: RAF alterations are oncogenic drivers found in most pediatric low-grade gliomas (LGGs). Tovorafenib is an investigational, oral, selective, CNS-penetrant, small molecule, type II pan-RAF inhibitor.
METHOD(S): FIREFLY-1 (NCT04775485) is a multicenter phase 2 study evaluating the safety and efficacy of tovorafenib monotherapy. Registrational arm 1 enrolled patients with recurrent/progressive LGG harboring an activating BRAF alteration. Patients aged 6 months-25 years who progressed following >= 1 prior line of systemic therapy were eligible. Tovorafenib 420 mg/m2 (<= 600 mg) was administered weekly (tablet or liquid suspension formulation) until progression or for >= 26, 28-day cycles. The primary endpoint (arm 1) was overall response rate, as defined by RANO criteria, per independent review.
RESULT(S): As of April 14, 2022, 25 patients were enrolled to arm 1 and had >= 6 months of follow-up. Median age at enrollment was 8 years (range 3-18). Most patients had astrocytomas (92%), 48% with optic pathway involvement. Patients were heavily pretreated (56% with >= 3 prior lines of therapy), and 72% previously received MAPK pathwaytargeted agents. Tumors harbored BRAF fusions (84%) or BRAF V600E mutations (16%). Per independent assessment, partial responses (1 unconfirmed) were seen in 14 (64%) of 22 evaluable patients, with 6 additional patients having stable disease, and a clinical benefit rate of 91%. Responses were achieved in tumors with BRAF fusions and V600E mutations. Most treatment-emergent adverse events (AEs) were grade 1 or 2 (96%). The most common grade >= 3 AEs were anemia (12%), vomiting, increased blood creatinine phosphokinase and maculopapular rash (8% each). Seven patients (28%) required dose modification for treatment-related AEs; no patients discontinued tovorafenib due to AEs. Updated results, including efficacy per RAPNO assessments will be presented.
CONCLUSION(S): Tovorafenib was generally well tolerated and showed encouraging evidence of antitumor activity in children with pretreated BRAF-altered LGG
EMBASE:639940150
ISSN: 1523-5866
CID: 5513272