bluuebunny/crossref_metadata_2025_split huggingface dataset:
AVID200, first-in-class TGF-beta 1 and 3 selective and potent inhibitor: Safety and biomarker results of a phase I monotherapy dose-escalation study in patients with advanced solid tumors.
Authors: Yap Timothy A , Lakhani Nehal J. , Araujo Daniel Vilarim , Rodon Ahnert Jordi , Chandana Sreenivasa R , Sharma Manish , Denis Jean-François , Gruosso Tina , Tremblay Gilles , O'Connor Maureen , Ghosh Ria , Sinclair Sandra , Wood Debra L. , Nadler Paul I. , Siu Lillian L. 
Published: May 2020

3587 Background: AVID200 is a rationally designed first-in-class, selective inhibitor of transforming growth factor-beta (TGF-beta) that neutralizes TGF-beta 1 & 3 with pM potency and 4,000 fold selectivity over TGF-beta 2. TGF-beta 1 & 3 signaling has been associated with immune checkpoint inhibitor resistance and immunosuppression in the tumor microenvironment while TGF-beta 2 is required for normal cardiac function and hematopoiesis. Methods: NCT03834662 (AVID200-03) is a multicenter Phase 1 study following a standard 3 + 3 dose escalation to evaluate safety and tolerability of AVID200 given IV every 3 weeks to patients (pts) with advanced solid tumors. Peripheral target engagement was assessed in blood by ELISA and a cell-based functional assay, and in skin biopsies by immunohistochemistry (IHC). Pharmacodynamic markers of TGF-beta signal modulation and immune activation were evaluated in serum using the InflammationMAP v 1.0 (Myriad RBM) and in paired tumor biopsies by IHC and Imaging Mass Cytometry. Results: Nineteen pts (ECOG 0-1, median age 63 [range 39-77], 52.6% male) received AVID200 at 3 planned dose levels of 180 (N = 7), 550 (N = 6), and 1100 mg/m2 (N = 6) (~5, 15, and 30 mg/kg). The maximum tolerated dose was not reached. Three Grade (G) 3 treatment-related adverse events (TRAEs) were reported in 2 pts (diarrhea and lipase elevation, anemia); no > G3 TRAEs were observed. Serum exposure was dose-proportional and AVID200 sequestered all active TGF-beta 1 & 3, but not beta 2, in blood across the entire dosing period at all dose levels, providing proof-of-mechanism of AVID200. SMAD2 phosphorylation in skin biopsies was detectably reduced on Day 4 at 15 and 30 mg/kg. Pro-inflammatory markers in serum were increased on Day 8 versus baseline in a dose-dependent manner. Tumor biopsies of pts treated at 15 mg/kg showed modulation of TGF-beta signaling and immune activation. A best response of RECIST stable disease > 12 weeks was observed in 2 pts: 1 with adenoid cystic carcinoma (5 mg/kg; 8.7 months); 1 with breast carcinoma (30 mg/kg; 3.1 months). Conclusions: AVID200 was safe and well tolerated at dose levels of 5-30 mg/kg, with peripheral target engagement across the entire dosing period. AVID200 led to TGF-beta target modulation and immune activation. These data provide proof-of-principle that AVID200-mediated selective and potent inhibition of TGF-beta 1 & 3 is feasible in the clinic. The AVID200 monotherapy data warrant exploration of rational combination with a PD-(L)1 inhibitor. Clinical trial information: NCT03834662 .
Selpercatinib (LOXO-292) in patients with RET-mutant medullary thyroid cancer.
Authors: Shah Manisha H. , Sherman Eric Jeffrey , Robinson Bruce , Solomon Benjamin J. , Kang Hyunseok , Lorch Jochen H. , Worden Francis P. , Brose Marcia S. , Leboulleux Sophie , Godbert Yann , Meurer Marie , Morris John C. , Owonikoko Taofeek Kunle , Tan Daniel Shao-Weng , Gautschi Oliver , Patel Jyoti D. , Yang Luxi , Kherani Jennifer , Cabanillas Maria E. , Wirth Lori J. 
Published: May 2020

3594 Background: Selpercatinib (LOXO-292) is a highly selective and potent small molecule RET kinase inhibitor. Here we report an update on the efficacy and safety of selpercatinib in RET-mutant medullary thyroid cancer (MTC). Methods: Patients with RET-mutant MTC were enrolled to the Phase 1/2 LIBRETTO-001 trial (NCT03157128), a global, multicenter trial (16 countries, 89 sites). Following the Phase 1 dose escalation portion of the trial, patients received the recommended dose of 160 mg orally twice daily. Each cycle was 28 days. The primary endpoint was objective response rate (ORR) per RECIST 1.1. Secondary endpoints included duration of response (DoR) and safety. Per health authority agreement, the primary analysis set was defined as the first 55 consecutively enrolled patients previously treated with multikinase inhibitors cabozantinib and/or vandetanib. Patients naïve to cabozantinib and vandetanib treatment were analyzed separately. All analyses were based on a 16-Dec-2019 data cutoff date. Results: In the primary analysis set of prior cabozantinib and/or vandetanib-treated patients with MTC (n = 55), the ORR by investigator assessment was 62% (95% CI 47.7–74.6, n = 34/55) and the median DoR was not reached (95% CI 18.4 months–not estimable) despite a median follow-up of 14.8 months. In cabozantinib/vandetanib treatment-naïve patients (n = 88), the ORR by investigator assessment was 69% (95% CI 58.6–78.7, n = 61/88, including 2 responses pending confirmation). Of the 59 confirmed responding patients, with a median follow-up of 8 months, responses were ongoing for 57 responders at the time of the analysis. In the safety analysis set consisting of all selpercatinib dosed patients (N = 702), the most common treatment-related adverse events (TRAEs) that occurred in ≥15% of patients were dry mouth (33.3%), increased AST (24.5%), increased ALT (23.8%), hypertension (23.2%), diarrhea (19.7%), and fatigue (16.8%). Only 2% (14 of 702) of patients discontinued selpercatinib for TRAEs. Conclusions: Selpercatinib use was associated with marked and durable antitumor activity in prior cabozantinib and/or vandetanib-treated patients and in cabozantinib/vandetanib-naïve patients with RET-mutant MTC, with the majority of responses ongoing in both cohorts. Selpercatinib was well tolerated. Efficacy data assessed by independent review committee based on the 16-Dec-2019 data cutoff date will be presented. Clinical trial information: NCT03157128 .
Prophylactic dihydropyrimidine dehydrogenase (DPYD), and reactive cytidine deaminase (CDA) testing is feasible and reduces severe toxicity in Irish patients receiving 5-fluorouracil (5-FU) based chemotherapy.
Authors: Murphy Jake 
Published: May 2020

3600 Background: 5-Fluorouracil (5-FU) steady state concentrations can vary up to fourfold among cancer patients. 5-FU intolerance and toxicity is associated with reduced activity of the key metabolic enzyme dihydropyrimidine dehydrogenase (DPD) due to polymorphisms of the DPYD gene, as well as mutations in cytidine deaminase (CDA). Since 2012, Bon Secours Hospital, Cork has implemented prophylactic DPYD screening to reduce toxicity. Methods: In this retrospective cohort study, 742 adult cancer patients who underwent reactive or prophylactic DPYD testing in our center between 2012 and 2019 were included. Reactively tested patients were screened prior to 2012. 5-FU related toxicities were graded according to Common Terminology Criteria for Adverse Events (CTCAE) and analysed. Frequencies of polymorphisms in DPYD, affecting 5-FU metabolism in patients who experienced severe toxicity are described, in both patients who were retrospectively tested, and in our larger prophylactic patient cohort. Mutations of genes encoding CDA were also analysed. Analysis of type and severity of toxicity, and survival analysis will be presented at the Annual Meeting. Results: 742 patients were tested for DYPD in our centre, of which 704 were prophylactic tests. 11.4% of the patients tested prophylactically were found to have polymorphisms in the DYPD gene. Expectedly, a higher proportion of patients tested reactively were found to have polymorphisms in DYPD (21.9%). 21 out of 34 patients who had severe toxicity had CDA mutations present on testing. Further data involving classification and severity of toxicities, along with survival analysis will be presented at the Annual Meeting. Conclusions: The prevalence of DPYD mutations in Ireland is estimated to be 7-10%, and is putatively responsible for approximately 20% of all severe 5-FU toxicities suffered by cancer patients. Implementing prophylactic DPYD screening is beneficial in reducing toxicities in this setting. Future work will focus on phenotypic measurements of uracil metabolism and pharmacokinetic 5-FU monitoring to further reduce toxicity in patients who do not have DPYD mutations.
A phase I, first-in-human, open-label, dose-escalation, safety, pharmacokinetic, and pharmacodynamic study of oral TP-1287 administered daily to patients with advanced solid tumors.
Authors: George Ben , Richards Donald A. , Edenfield William Jeffery , Warner Steven L , Mouritsen Lars , Bishop Reyna , Anthony Stephen Patrick , Bearss David , Vogelzang Nicholas J. , Whatcott Clifford 
Published: May 2020

3611 Background: TP-1287 is a an orally bioavailable phosphate prodrug of alvocidib, a cyclin dependent kinase 9 (CDK9) inhibitor. TP-1287 exhibits potent inhibition of intracellular kinases including CDK9. Inhibition of CDK9 leads to downregulation of the BCL-2 family member, MCL-1, which in turn inhibits tumor growth in preclinical animal models of prostate, breast, and lung carcinomas. Methods: This is a multicenter, Phase 1, dose escalation study using a standard 3+3 design with a modified Fibonacci scheme to examine the safety and clinical activity of TP-1287 in patients with advanced solid tumors. Patients will be added at the maximum tolerated dose (i.e. expansion cohort) to test TP-1287 as a single agent in patients with castrate resistant prostate cancer. Results: Twenty-two patients who were enrolled between December 2018 and January 2020 received a range of doses from 1 mg QD to 11 mg BID over 7 cohorts. Data are available for 20 patients as of the data cutoff date. TP-1287 plasma PK Cmax and AUC increased in near linear fashion over cohorts 1 thru 6, reaching 80 ng/mL and 499.3 ng*h/mL in cohort 6 for Cmax and AUC, respectively. TP-1287 treatment resulted in dose-dependent reductions of phospho-RNA Pol II, consistent with CDK9 inhibition, as measured by a flow cytometric assay assessing pharmacodynamic changes in phosphorylation state in PBMCs. The most frequently observed Grade 3 AE was unrelated anemia in 2 patients. All other events of Grade 3 (9 events/7 patients) and Grade 4 (1 event/seizure with new CNS mets) were unlikely related or unrelated. Clinical benefit was seen in one sarcoma patient with PR (15+cycles), one RCC patient with SD (7+cycles) and 2 bladder cancer patients with SD (6 and 8 cycles). Conclusions: These findings suggest that TP-1287 is tolerated as a monotherapy in patients with heavily pretreated, relapsed, refractory solid tumors and further clinical development in selected indications is warranted. Clinical trial information: NCT03298984 .
Single-agent ONC201 in recurrent H3 K27M-mutant diffuse midline glioma.
Authors: Arrillaga-Romany Isabel , Kurz Sylvia Christine , Tarapore Rohinton , Sumrall Ashley , Butowski Nicholas A. , Harrison Rebecca A. , De Groot John Frederick , Chi Andrew S. , Shonka Nicole A. , Umemura Yoshie , Odia Yazmin , Mehta Minesh P. , Nghiemphu Phioanh Leia , Cloughesy Timothy Francis , Lu Guangrong , Oster Wolfgang , Allen Joshua E. , Batchelor Tracy , Lassman Andrew B. , Wen Patrick Y. 
Published: May 2020

3615 Background: Recurrent H3 K27M-mutant diffuse midline glioma is a lethal brain tumor that predominantly affects children and young adults and has no effective therapy. ONC201 is a first-in-class orally administered, anti-cancer small molecule that selectively antagonizes the dopamine receptors DRD2/DRD3 and agonizes ClpP, a mitochondrial protease. Prior studies have indicated dysregulated dopamine receptor expression and enhanced ONC201 sensitivity among H3 K27M-mutant gliomas. Methods: Adults with midline H3 K27M-mutant glioma patients were enrolled to a dedicated Phase II clinical trial (NCT03295396), a multi-arm Phase II clinical trial (NCT02525692), and expanded access protocols under the Sponsor’s IND. Results were pooled among patients treated with ONC201 monotherapy through any of these trial with H3 K27M confirmed glioma, progressive and measurable disease by RANO, > 90 days from completion of prior radiation, no evidence of leptomeningeal dissemination, midline location other than primarily pons or spinal cord, and baseline KPS > 60. Using an enrollment cutoff of February 15, 2019 and data cutoff of July 31, 2019, there were 20 patients (NCT03295396, 12; NCT02525692, 7; expanded access, 1). Dosage was 625 mg weekly in 19 and once every 3 weeks in 1. Results: No DLTs or treatment discontinuations due to toxicity occurred. Midline gliomas can exhibit minimal contrast enhancement or exhibit a mixture of contrast-enhancing and non-contrast enhancing regions in the tumor. As a result, blinded independent central review (BICR) of tumor response by MRI was assessed by RANO-HGG and RANO-LGG for each patient to capture contrast-enhancing lesions by T1 post-contrast and non-contrast-enhancing assessments by T2/FLAIR, respectively, in the object response rate. The best response by RANO-HGG or RANO-LGG is 30% (95% CI, 11.9-54.3%). Duration of response by RANO-HGG is median 52.7 weeks (range 15.9-138.3). One patient with stable disease as of this data cutoff has continued on treatment beyond 12 months and recently underwent an investigator-reported PR by RANO-HGG that is pending confirmation. Conclusions: Single agent ONC201 is well tolerated and clinically active in recurrent H3 K27M-mutant diffuse midline glioma patients. Clinical trial information: NCT03295396, NCT02525692 .
The next-generation RET inhibitor TPX-0046 is active in drug-resistant and naïve RET-driven cancer models.
Authors: Drilon Alexander E. , Zhai Dayong , Rogers Evan , Deng Wei , Zhang Xin , Ung Jane , Lee Dong , Rodon Laura , Graber Armin , Zimmerman Zachary Franklin , Murray Brion W , Subbiah Vivek 
Published: May 2020

3616 Background: RET fusions/mutations drive oncogenesis in lung and thyroid cancers, and several other malignancies. Selective RET inhibitors (selpercatinib/pralsetinib) are active in patients with these cancers; unfortunately, resistance often occurs. On-target resistance includes the acquisition of solvent front mutations (SFMs i.e. RET G810 substitutions). TPX-0046 is a structurally differentiated RET inhibitor that is potent against a range of RET fusions and mutations including SFMs. Methods: The rationally-designed, compact, macrocyclic RET/SRC inhibitor TPX-0046 was characterized in RET-driven in vitro and in vivo tumor models. Results: In enzymatic assays, TPX-0046 showed low nanomolar potency against wild-type RET and 18 RET mutations/fusions. It was potent against SRC and spared VEGFR2/KDR. TPX-0046 inhibited RET phosphorylation (IC50 < 10 nM) in tumor cell lines (LC2/ad, CCDC6-RET; TT, RET C634W) and Ba/F3 engineered RET models (WT, G810R). In cell proliferation assays, TPX-0046 inhibited KIF5B-RET Ba/F3, LC2/ad, and TT cells with IC50 values ~1 nM. Ba/F3 RET engineered cells with SFMs (e.g. G810C/R/S) were potently inhibited by TPX-0046 (mean proliferation IC50 1–17 nM). TPX-0046 demonstrated marked in vivo anti-tumor efficacy in RET-driven cell-derived and patient-derived xenograft tumor models. In a Ba/F3 KIF5B-RET xenograft model, a single dose of 5 mg/kg TPX-0046 inhibited > 80% of RET phosphorylation (corresponding mean free plasma concentration: 51 nM). At 5 mg/kg BID, tumor regression was observed in RET-dependent xenograft models, including those that harbor RET SFMs: TT, CTG-0838 PDX (NSCLC, KIF5B-RET), CR1520 PDX (CRC, NCOA4-RET), Ba/F3 KIF5B-RET, and Ba/F3 KIF5B-RET G810R. Conclusions: TPX-0046 is a unique next-generation RET inhibitor that possesses potent in vitro and in vivo activity against a diverse range of RET alterations, including SFM-mediated resistance. A phase 1/2 trial for RET inhibitor-resistant and naïve RET-driven cancers is on-going (NCT04161391).
Clinical efficacy of ONC201 in thalamic H3 K27M-mutant glioma.
Authors: Kawakibi Abed Rahman , Tarapore Rohinton , Gardner Sharon L. , Kurz Sylvia Christine , Wen Patrick Y. , Arrillaga-Romany Isabel , Batchelor Tracy , Butowski Nicholas A. , Sumrall Ashley Love , Shonka Nicole A. , Harrison Rebecca A. , De Groot John Frederick , Mehta Minesh P. , Odia Yazmin , Hall Matthew David , Cloughesy Timothy Francis , Ellingson Benjamin M. , Umemura Yoshie , Allen Joshua E. , Koschmann Carl Johannes ,   Koschmann Lab, Oncoceutics Team
Published: May 2020

3617 Background: Diffuse midline gliomas, H3 K27M-mutant are associated with a poor prognosis compared to H3 wild-type gliomas and have no effective therapy following first-line radiation. ONC201 is a bitopic DRD2 antagonist and allosteric ClpP agonist that has shown encouraging single agent efficacy in recurrent H3 K27M-mutant gliomas located in various midline structures of the brain. In addition to tumor and immune cells, the pharmacodynamics of ONC201 extend to stromal cells that can mediate a bystander antitumor response in preclinical models. Given this observation and that the thalamus has the highest extrastriatal expression of DRD2, we report the clinical experience of ONC201 in a subgroup of H3 K27M-mutant glioma patients with primary tumors located in the thalamus. Methods: We analyzed 29 thalamic H3 K27M-mutant glioma patients treated with ONC201 in clinical trials enrolled as of 5/22/19. Nineteen enrolled with recurrent disease whereas 10 enrolled following radiation prior to recurrence. Twelve patients enrolled on NCT03295396, 10 NCT03416530, 4 NCT02525692, and 3 expanded access. Median age was 22 years old (range: 5-70) and baseline KPS was 80 (range: 60-90). Median time from radiation to start of ONC201 was 1.8 months (range: 0.2-8.7) for non-recurrent patients and 7.2 months (range: 1.4-102.0) for recurrent patients. Results: As of 12/18/2019, PFS6 and OS12 measured relative to initiation of ONC201 are 26.3% and 36.8%, respectively, in the recurrent group. For patients initiating ONC201 post-radiation prior to recurrence, median PFS or OS have not been reached with a median follow up of 21.9 months (8.6-26.6) from diagnosis, which surpass historical OS of 13.5 months. Best response for evaluable recurrent patients by RANO: 1 CR, 3 PR, 4 SD, 8 PD, 3 not reported; for non-recurrent patients: 2 PR, 4 SD, 1 PD, 3 not reported. Median duration of response for recurrent patients is 14.0 months (2.0-33.1). ONC201 was well tolerated and no dose-limiting toxicities or treatment discontinuations due to toxicity occurred. Furthermore, H3 K27M cell-free tumor DNA in plasma and CSF correlated with MRI response. Conclusions: In summary, single agent ONC201 administered at recurrence or following radiation, demonstrates promising clinical efficacy in thalamic H3 K27M-mutant glioma patients. Investigations are ongoing to assess whether micro-environmental DRD2 expression correlates with responses of thalamic H3 K27M-mutant glioma to ONC201. Clinical trial information: NCT03295396, NCT03416530, NCT02525692 .
ONC201 in previously irradiated pediatric H3 K27M-mutant glioma or newly diagnosed DIPG.
Authors: Gardner Sharon L. , Koschmann Carl Johannes , Tarapore Rohinton , Allen Jeffrey C. , Zaky Wafik Tharwat , Odia Yazmin , Hall Matthew , Daghistani Doured , Khatib Ziad , Aguilera Dolly , MacDonald Tobey J. , Fouladi Maryam , McGovern Susan Lynne , Kline Cassie , Vitanza Nicholas A , Lu Guangrong , Oster Wolfgang , Allen Joshua E. , Khatua Soumen 
Published: May 2020

3619 Background: ONC201 is a first-in-class DRD2 antagonist and ClpP agonist that has demonstrated promising activity in high-grade glioma preclinical models and radiographic regressions with single agent ONC201 in recurrent H3 K27M-mutant glioma patients . The recommended phase 2 dose (RP2D) of 625mg ONC201 orally once a week has been established in adult patients as well tolerated and biologically active. ONC201 efficacy has been shown in high-grade glioma preclinical models and radiographic regressions with single agent ONC201 have been reported in adult recurrent H3 K27M-mutant glioma patients. We report results from the first Phase I pediatric clinical trial of ONC201. Methods: This open-label, multi-center trial for pediatric H3 K27M-mutant glioma or non-biopsied DIPG employed a 3+3 dose-escalation and dose-expansion design with 6 arms. Arms A and E, which have completed accrual, determined the RP2D of ONC201 using oral capsule and liquid formulations in post-radiation pediatric H3 K27M-mutant glioma patients ONC201, respectively. Arm B aims to determine the RP2D for ONC201 in combination with radiotherapy in patients with newly diagnosed DIPG. Arms C and D aim to measure intratumoral ONC201 concentrations in midline glioma patients and the impact of ONC201 on H3 K27M DNA levels in CSF, respectively. Arm F was recently opened to study ONC201 as a single agent in patients with progressive H3 K27M-mutant tumors (excluding DIPG and spinal cord tumors) following radiotherapy. After determining the RP2D, a dose-expansion cohort will evaluate the safety, radiographic response, and activity of ONC201. Results: An RP2D of weekly 625mg ONC201 scaled by body weight as a capsule or in liquid formulation was established in the primary endpoints of arms A, B and E alone or in combination with radiation, without incidence of dose-limiting toxicity (DLT). Pharmacokinetic profiles were similar to those observed in adults (T1/2: 8.4h; Tmax: 2.1h; Cmax: 2.3ug/mL; AUC0-tlast: 16.4ug/mL), with similar exposure across body weights. Conclusions: ONC201 was well tolerated without DLTs at the same adult RP2D scaled by body weight as monotherapy or in combination with radiotherapy in pediatric H3 K27M-mutant glioma patients. Further investigation of ONC201 to treat H3 K27M-mutant glioma and DIPG is warranted. Clinical trial information: NCT03416530 .