bluuebunny/crossref_metadata_2025_split huggingface dataset:
RADT-08. A VOLUMETRIC ANALYSIS OF STEREOTACTIC RADIOSURGERY LOW DOSE VOLUMES IN PREVENTING FUTURE BRAIN METASTASES
Authors: Shumway John , Yoon Won Sup , Tan Xianming , Schreiber Eric , Yanagihara Ted , Jaikumar Sivakumar , Sasaki-Adams Deanna , Quinsey Carolyn , Ewend Matthew , Das Shiva , Marks Lawrence , Shen Colette 
Published: November 2021

Abstract

PURPOSE/OBJECTIVE(S)
Stereotactic radiosurgery (SRS), compared to whole brain radiotherapy is limited in its ability to prevent development of brain metastases in untreated areas. The purpose of this study is to assess whether low-dose volumes delivered to uninvolved regions of the brain during SRS can reduce the risk of developing brain metastases in those regions.

MATERIALS AND METHODS
Data were collected for 69 patients with brain metastases who were treated with SRS at least two occasions. The regions of uninvolved brain receiving a high, intermediate, and low dose of incidental radiotherapy were defined as the volume receiving at least 10, 5, and 2.5 Gy if the prescribed dose was &lt; 25 Gy (1-3 fraction plans) or the volume receiving at least 15, 7.5, and 5 Gy if the prescribed dose was ≥ 25 Gy (5 fraction plans). A second round metastasis was considered to occur within a given dose level if 20% or more of the tumor was found within that dose level. Probabilities were calculated based on the volume of each dose level as a percentage of total brain volume and were used to estimate the expected number of cases with at least one metastasis occurring in each dose level.

RESULTS
The average number of metastases treated in both rounds of SRS was two. The expected and observed number of cases with at least one second round metastasis were 0 and 2 for the high dose level (p=0.151), 7 and 3 for the intermediate dose level (p=0.018), and 17 and 11 for the low dose level (p=0.094).

CONCLUSION
We observed fewer than expected new metastases within prior SRS low dose levels based on volumetric probabilities, though this difference was only significant for the intermediate dose level. This suggests that low dose volumes from SRS may provide benefit in preventing future regional metastases.
RADT-09. ROLE OF RADIOTHERAPY IN MANAGEMENT OF PRIMARY SPINAL HIGH GRADE GLIOMA: A SINGLE INSTITUTION RETROSPECTIVE ANALYSIS
Authors: Upadhyay Rituraj , Khose Swapnil , Pokhylevych Halyna , Paulino Arnold dela Cruz , McAleer Mary Frances , Ghia Amol , Li Jing , Yeboa Debra Nana , Loghin Monica , Harrison Rebecca , O'Brien Barbara , Kamiya-Matsuoka Carlos , DeGroot John , Puduvalli Vinay , Tatsui Claudio , Prabhu Sujit , Zaky Wafik , Lin Frank , Weinberg Jeffrey , Rhines Laurence , Fuller Greg , Sandberg David , Johnson Jason Michael , McGovern Susan 
Published: November 2021

Abstract

BACKGROUND
Primary spinal high-grade gliomas(S-HGG) are rare, aggressive tumors and radiation therapy(RT) plays a dominant role in the management given their infiltrative nature. We conducted a single-institution retrospective review to study the clinicopathological features and management of S-HGGs.

METHODS
Patients with biopsy-proven S-HGG who received RT from 2001-2020 were analyzed for patient, tumor, and treatment characteristics. Kaplan-Meier estimate and Cox proportional hazard regression method were used for survival analyses.

RESULTS
Twenty-nine patients were identified with a median age of 25.9 years (range 1-74y). Four patients had gross total resection(GTR) while 25 underwent subtotal resection or biopsy. Nineteen patients had WHO grade 4 tumor. IDH1 mutation and MGMT promoter methylation were analyzed in 14 and four patients respectively; all were IDH wildtype and MGMT-promoter unmethylated. H3K27M mutation was present in five out of 10 patients tested. Twenty-two patients received photon-based radiation and 7 received proton therapy. Median RT dose was 50.4 Gy (range 39.6-54Gy) with 79% receiving &gt;45Gy. 65% patients received concurrent chemotherapy, most commonly temozolomide. Twenty-three (79%) patients had documented recurrence. Overall, 16 patients relapsed locally, 10 relapsed in the brain and 8 developed leptomeningeal disease; only 8(35%) had isolated local relapse. Median OS from diagnosis was 21.3 months and median PFS after RT was 9.7 months. On univariate analysis, age, sex, GTR, grade, RT modality, RT dose and concurrent chemotherapy did not predict for survival. Patients with H3K27M mutation had a poorer median PFS after RT compared to those without the mutation but the difference did not reach statistical significance (p = 0.26).

CONCLUSIONS
Although 86% of patients had gross disease at RT and received a lower median RT dose than typically used in cerebral high-grade gliomas, only 55% of patients failed locally. H3K27M mutation may portend worse survival; future studies to improve the therapeutic approach in these patients are warranted.
RADT-10. DEVELOPMENT AND INTERNAL VALIDATION OF A PREDICTIVE SCORE FOR VERTEBRAL COMPRESSION FRACTURE AFTER STEREOTACTIC BODY RADIATION THERAPY FOR SPINAL METASTASES
Authors: Kowalchuk Roman , Johnson-Tesch Benjamin , Marion Joseph , Mullikin Trey , Harmsen William , Rose Peter , Siontis Brittany , Kim Dong Kun , Costello Brian , Morris Jonathan , Gao Robert , Shiraishi Satomi , Lucido John , Trifiletti Daniel , Olivier Kenneth , Owen Dawn , Stish Bradley , Waddle Mark , Laack Nadia , Park Sean , Brown Paul , Merrell Kenneth 
Published: November 2021

Abstract

PURPOSE
Vertebral compression fracture (VCF) is a potential adverse effect following stereotactic body radiation therapy (SBRT) for spinal metastases. In this analysis, we developed and internally validated a risk stratification model for VCF.

METHODS
From an initial set of 680 treatments, we excluded those with proton therapy, prior surgical intervention, or missing data. The final dataset had 464 treatments in 313 patients. Delineations of VCF and all radiographic components of the spinal instability neoplastic score (SINS) were determined by a radiologist. Recursive partitioning analysis (RPA) was conducted using separate training (70%), internal validation (15%), and test (15%) sets. The log-rank test was used as the criterion for node splitting.

RESULTS
With a median follow-up of 21 months, we identified 84 VCF (18%), including 65 (77%) de novo and 19 (23%) progressive fractures. There was a median 9 months (IQR: 3 – 21) to VCF. From an initial set of 15 candidate variables, six were identified using the backwards selection method, feature importance testing, and a correlation heatmap. Four were then selected in the highest-fidelity RPA models: epidural tumor extension, lumbar location, gross tumor volume &gt; 10 cc, and SINS &gt; 6. One point was assigned to each variable, and the resulting multivariate Cox model had a concordance of 0.760. Each one point increase in score was associated with increasing rates of VCF. Low-risk lesions (score: 0-1, n=273) had 2-year freedom from VCF of 92%, compared to 80% for intermediate-risk (score: 2, n=99) and 56% (score: 3-4, n=92) for high-risk lesions (p &lt; 0.0001). Cumulative incidence curves with death as a competing risk showed increased VCF with higher scores via Gray’s test (p &lt; 0.001).

CONCLUSIONS
Our internally-validated model identifies a subgroup of patients with high risk for VCF who may benefit from prophylactic surgical stabilization or vertebroplasty.
RADT-17. FOCUSED ULTRASOUND MEDIATED BLOOD–BRAIN BARRIER OPENING IS SAFE AND FEASIBLE CONCURRENT WITH AND ADJUVANT TO A CLINICAL RADIATION SCHEME FOR BRAINSTEM DMG
Authors: Tazhibi Masih , McQuillan Nicholas , Wei Hong-Jian , Pouliopoulos Antonios , Bendau Ethan , Englander Zachary , Webster Andrea , Yoh Nina , Zacharoulis Stergios , Konofagou Elisa , Wu Cheng-Chia 
Published: November 2021

Abstract
Diffuse midline gliomas (DMG) are pediatric tumors with dismal prognosis. When these tumors emerge in the brainstem, there exists no feasible method of surgical resection or systemic intervention, making ionizing radiation the sole therapeutic avenue to date. However, radiotherapy (RT) provides only marginal survival benefit as the topographically diffuse and highly infiltrative tumors spread in areas in which the blood-brain barrier (BBB) is relatively intact. Focused ultrasound (FUS) with intravenous microbubbles provides a compelling solution, transiently and non-invasively opening the BBB to allow drug delivery across the cerebrovasculature. Nonetheless, it remains unclear whether FUS can be safely administered at the brainstem in patients receiving RT. Therefore, the goal of this study was to assess the safety and feasibility of FUS administered concurrent with and adjuvant to a clinical hypofractionated radiation scheme for brainstem DMG. Non-tumor bearing B6 albino mice were randomly assorted into control, RT, FUS, and RT+FUS groups. Mice designated RT+FUS received 39Gy/13fx (hypofractionated RT scheme) to the brainstem with two sessions of FUS approximately 1 week apart. A single-element, spherical-segment FUS transducer driven by a function generator through a power amplifier was used with concomitant microbubble injection to sonicate the brainstem. Magnetic resonance imaging (MRI) was used to confirm BBB opening and cardiopulmonary measures were recorded throughout sonication. Vitals were assessed daily, and all treatment animals underwent Kondziela inverted screen testing and sequential weight lifting to assess brainstem-related strength and motor coordination deficits. In both FUS and RT+FUS mice, MRI confirmed brainstem BBB opening and subsequent closure within 96 hours. Mouse weights were stable, with slight drops (mean=5.5%) following FUS that resolved within three days. No attenuation in cardiorespiratory, strength, and motor coordination measurements was observed from FUS. FUS is a safe and feasible technique for brainstem BBB opening concurrent with and adjuvant to clinical hypofractionated RT.
RADT-19. CLINICAL OUTCOMES OF RADIATION THERAPY FOR BRAIN STEM GLIOMA
Authors: Pyone Khin , Myint Lay , Hnin Tint , Khaing Aye 
Published: November 2021

Abstract

PURPOSE/OBJECTIVES
Brain stem gliomas are up to 20% of all brain tumor in children and unusual in adults. Radiotherapy is mainstay of treatment. Surgery for brain stem glioma is difficult because of anatomical location. This study was performed to evaluate the clinical outcomes of radiotherapy in brain stem glioma.

METHODS
Retrospective analysis of brain stem glioma patients treated with radiation therapy (54Gy/30 fractions of IMRT/ 3D CRT) with or without surgery or chemotherapy or other agents.

RESULTS
Twenty-four patients (median age 11.8 years) were treated between 2016 and 2020. Male to female ratio was 2:3. Surgical approach (biopsy and partial removal) was done in 16 patients. Histology revealed that anaplastic ependymoma in 2 patients, low grade astrocytoma in 2 patients, anaplastic astrocytoma in 8 patients, glioblastoma in 4 patients and remaining 8 patients had no histologic diagnosis. Radiotherapy (dose- 54Gy/ 30 fractions) was given with the technique of IMRT or 3D CRT. At the time of follow up, 8 patients had local recurrence, 10 patients died of due to disease and recurrence, 14 patients were alive. Among alive patients, 2 patients were treated with chemotherapy and 12 patients with temozolomide for 12 cycles. Patients who received temozolomide got improvement in performance status and reduced clinical symptoms; among them, 6 patients had more than 50% objective tumor response in radiological findings for follow-up 3-6 months after radiotherapy. The 2-years overall survival (OS) rate was 58.3% and 2-years Event-free Survival (EFS) rate was 50%. The median survival time was 14 months. There is no grade 3 or greater acute and late toxicities.

CONCLUSION
As the LMIC country with limited resources, our results of radiotherapy followed by temozolomide in brain stem glioma have optimal outcomes. However, prospective studies of this select group of patients with larger number and longer follow up is required.
RADT-33. LONG-TERM OUTCOMES, TREATMENT UTILIZATION, AND PROGNOSTIC FACTORS FOR PEDIATRIC CHORDOMA: AN NCDB ANALYSIS
Authors: Cantrell James , Acharya Pawan , Vesely Sara , Confer Michael , Algan Ozer , Gunter Tyler 
Published: November 2021

Abstract

BACKGROUND
Chordomas are rare tumors arising from the embryonal notochord presenting at the base of skull, spine, or sacrum. Pediatric chordomas (PC) comprise less than 5% of all chordomas and are more likely to be atypical or dedifferentiated. Evidence for management is limited to single institution series with 5-year overall survival (OS) between 60-100%.

METHODS
Using the NCDB Participant User File, a retrospective observational cohort study was performed. The cohort was defined using the bone-soft-tissue, brain, and central nervous system databases selecting for cases with chordoma ICD-03 codes and age ≤ 25 years. Kaplan Meier method, log-rank test, and Cox proportional hazards regression were performed.

RESULTS
297 patients from 2004-2017 met inclusion criteria for descriptive analysis with 269 cases included for survival analysis. Mean age was 16.9 years, with 10% less than age 5. The cohort was 55% female, 8% Black, and 79% White. Primary sites included bones of the skull (70%), spine (22%), and pelvis (6%). Regarding treatment, 7% had no resection, 49% sub-total resection (STR), 33% gross-total resection (GTR), and 11% unspecified resection. 51% received radiation therapy with 46% of those receiving proton therapy. 7% received chemotherapy. The 1, 3, 5, and 10-year OS was 95%, 86%, 77%, and 72%. Selected prognostic factors from univariable OS model for OS analysis included: age &gt; 5 (HR 0.30 (95% CI 0.16-0.57) p = 0.0002), surgical resection [GTR (HR 0.28 (95% CI 0.12-0.63) p = 0.0023) and STR (HR 0.27 (95% CI 0.12-0.59) p = 0.0011)], and radiation dose ≥ 7200cGy (HR 0.40 (95% CI 0.16-0.99) p = 0.047).

CONCLUSION
In the largest cohort reported for PC, 3 and 10-year OS was 86% and 72%. Age, surgery, and radiation dose are important prognostic factors. Propensity score analysis to gauge effect of treatment, tumor, and patient characteristics on OS is forthcoming.
CTIM-09. PHASE I STUDY OF PD-L1 INHIBITION WITH AVELUMAB AND LASER INTERSTITIAL THERMAL THERAPY IN PATIENTS WITH RECURRENT GLIOBLASTOMA
Authors: Hormigo Adilia , Chiu Daniel , Hahn Mary , Qi Jingjing , Lee Brian , Mandeli John , Ghatan Saadi , Hadjipanayis Constantinos , Yong Raymund , Germano Isabelle , Gnjatic Sacha , Kim-Schulze Seunghee 
Published: November 2021

Abstract

BACKGROUND
The treatment of glioblastoma (GBM) poses many challenges. The use of immune checkpoint inhibition (ICI) has been disappointing as GBM is characterized by a low mutational burden and low infiltration by T cells. The combination of ICI with other treatment modalities may improve efficacy.

METHODS
Patients with recurrent GBM were treated with 800 mg avelumab, a human IgG1 antibody directed against PD-L1, either alone (in part A) or within a week after MRI-guided laser interstitial thermal therapy (LITT, in part B) and by-weekly thereafter (NCT03341806). To spare steroid use, bevacizumab was allowed to be combined with avelumab. The primary objective was to characterize the tolerability and safety of the regimen. The secondary objectives included overall survival, progression-free survival, and signature of plasma analytes.

RESULTS
A total of 12 patients (median age 64, range 37 - 73) enrolled from June 2018 to November 2019, 5 in part A and 7 in part B. Three serious adverse events (SAE) occurred in the same patient, not leading to death. There were 94 AEs reported, 5 grade 3, 28 grade 2, and 61 grade 1. The median PFS was 16.7 weeks (range 7.4-56.7) for patients in Part A and 30.9 weeks (range 8.5-77.7) for patients in Part B. The median survival for patients in part A was 11 months and 13.5 months for part B. The risk ratio of death by combining bevacizumab was 0.573 (p=0.258) with significantly decreased levels of peripheral blood plasma inflammatory markers such as EGF, CXCL5, VEGFA, LAP.TGβ1, ANGPT2 in women.

CONCLUSIONS
Avelumab was generally well-tolerated, and the combination with LITT had a manageable safety profile and increased survival in a subset of patients. The addition of bevacizumab may increase survival by lowering cytokine expression in a gender-dependent manner. These results warrant further investigation in the next phase study.
CTIM-17. INTRA-CRANIAL ADMINISTRATION OF CTLA-4 AND PD-1 IMMUNE CHECKPOINT-INHIBITING MONOCLONAL ANTIBODIES IN RECURRENT GLIOBLASTOMA PATIENTS: A MULTI-COHORT ADAPTIVE PHASE I CLINICAL TRIAL
Authors: Duerinck Johnny , Geens Wietse , Schwarze Julia Katharina , Bertels Cleo , Tijtgat Jens , Awada Gil , Vaeyens Freya , cras Louise , Nijland Lynn , Vanbinst Anne-Marie , Everaert Hendrik , Michotte Alex , Janssens Toon , Caljon Ben , Cauwenbergh Tom , Bruneau Michaël , Forsyth Ramses , Tuyaerts Sandra , Neyns Bart 
Published: November 2021

Abstract
BACKGROUND: Intracerebral (iCE) administration of nivolumab (NIVO) and ipilimumab (IPI) after resection of recurrent glioblastoma (rGB), followed by repeated intravenous(IV) NIVO was recently shown to be feasible, safe and associated with encouraging survival. Subsequent cohorts were defined to investigate the addition of biweekly intracavitary (iCA) or intrathecal (iTH) NIVO +/- IPI administrations. METHODS Four groups were defined according to rGB resectability and postoperative treatment schedule. Group A and D underwent biopsy, B and C maximal safe resection. All patients received iCE injections of 10 mg/1ml NIVO + 5 mg/1ml IPI at the end of surgery, after which an Ommaya catheter was implanted iCA (A, B and C) or iTH (D). Following surgery, all patients received biweekly IV low-dose NIVO(10mg) combined with iCA/iTH 10 mg NIVO (A and B) + 1, 5 or 10 mg IPI (C and D) for up to 24 weeks. NIVO/IPI concentrations were dosed in the cerebrospinal fluid (CSF). Gene sequencing and RNA gene expression profiling were performed on all tissue samples RESULTS 39pts(27 male; 16 in A, 16 in B, 4 in C, 3 in D; recruitment ongoing in C+D) were enrolled. All patients received the predefined dose of iCE IPI/NIVO. Most frequent AEs were fatigue (n=30), headache (n=19), confusion (n=14), dysphasia (n=13), and fever (n=10). Ommaya infection occurred in 5patients, subacute neurological deterioration requiring corticosteroids in 6patients. There were no G5 AEs. irAEs were infrequent and mild. Median PFS and OS were 5w(95% CI 1-8) and 23w(95% CI 0-53) in A and 13w(95% CI 7-19) and 42w(95% CI 30-54) in B, respectively. &gt;90% of CSF samples had elevated protein levels and lymphocytic pleocytosis. There was no evidence for accumulation of NIVO/IPI in the CSF. CONCLUSION Repeated intracavitary or intrathecal administration of NIVO +/- IPI in rGB is feasible and safe. Favourable survival outcome is seen in patients amenable to surgical resection.
CTIM-20. FINAL RESULTS OF CONTROLLED IL-12 MONOTHERAPY AND IN COMBINATION WITH PD-1 INHIBITOR IN ADULT SUBJECTS WITH RECURRENT GLIOBLASTOMA
Authors: Lukas Rimas , Oberheim-Bush Nancy Ann , Cavaliere Robert , Landolfi Joseph , Yu John S , Chen Clark , Cordova Christine , Amidei Christina , Buck Jill Y , Hadar Nira , Demars Nate , Miao John , Loewy John , Estupinan Taylor , Chadha Kamal , Cooper Laurence J N , Chiocca E Antonio 
Published: November 2021

Abstract
Ad-RTS-hIL-12(Ad) is a gene therapy candidate conditionally expressing IL-12 under the transcriptional control of veledimex(V) acting via the RheoSwitch Therapeutic System® gene switch. Veledimex plasma and tumor PK demonstrated a dose-response relationship and crossing the BBB. PD-1+ T-cells were increased in tumor biopsy samples after treatment with Controlled-IL-12 in a phase-l study. This finding was the rationale for conducting 2 trials of Controlled-IL-12 in combination with PD-1-inhibitor to enhance T-cell-mediated anti-tumor effects. Data from two completed phase-I studies (presented in SNO2020), and an ongoing phase-II study of Controlled-IL-12 with cemiplimab study for the treatment of recurrent glioblastoma (rGBM) will be discussed. Ziopharm has conducted 3 phase-I (NCT02026271/NCT03679754 (monotherapy), NCT03636477 (combination with nivolumab)) and one phase-ll (NCT04006119) multicenter, open-label, single-arm trial in subjects with rGBM is evaluating Ad (single intratumoral injection, 2 x 1011-viral-particles, Day0) with oral V dosing (20mg, Days 0-14) with cemiplimab infusions (350 mg IV) on Days -7, 15, then Q3W. Systemic biomarkers (serum cytokines, and immune-activation-markers), local effects (tumor cytokines, T-cell immunobiology, pathology), neoepitope, and imaging will be assessed. Subject characteristics (Controlled IL-12 monotherapy (n=75); combination (Controlled IL-12 with anti-PD-1s) (n=61) were consistent across all 3 studies. Safety profiles were comparable between monotherapy and in combination with anti-PD-1s. Adverse reactions (ARs) after nivolumab or cemiplimab were consistent with labeling of anti-PD-1s. ARs related to Controlled IL-12 were all manageable and reversible with no synergistic toxicities in combination with anti-PD-1s. Increases in serum cytokine levels and pathology findings consistent with immune-mediated anti-tumor effect were observed in subjects who received Controlled-IL-12 monotherapy and in combination with anti-PD-1s. Final survival data and results from neoepitope analysis will be presented. Further investigation is warranted to understand the impact of monotherapy vs. combination, concurrent steroids use and unifocal vs. multifocal disease on overall survival in subjects with rGBM receiving Controlled-IL-12.
CTIM-33. PHASE II TRIAL OF VACCINE IMMUNOTHERAPY IN PRIMARY GLIOBLASTOMA: ADJUNCTIVE AUTOLOGOUS DENDRITIC CELLS PULSED WITH LYSATE FROM IRRADIATED SELF-RENEWING AUTOLOGOUS TUMOR CELLS (AV-GBM-1)
Authors: Bota Daniela A , Piccioni David E , Duma Christopher M , LaRocca Renato V , Kesari Santosh , Abedi Mehrdad , Carrillo Jose A , Aiken Robert D , Hsu Frank , Kong Xiao-Tang , Taylor Thomas H , Hsieh Candace , Nistor Gabriel , Dillman Robert 
Published: November 2021

Abstract
In primary glioblastoma (GBM), overall survival (OS) is poor despite standard aggressive therapy. Adjunctive AV-GBM-1 vaccine immunotherapy may improve OS. In this multi-institutional phase II trial, key eligibility criteria for intent-to-treat (ITT) enrollment were: (1) primary GBM, (2) age &lt; 70 years when GBM was resected, (3) successful GBM cell culture, (4) successful monocyte collection by leukapheresis, (5) KPS &gt; 70 post-surgery, and (6) plan to treat with concurrent RT/TMZ. Dendritic cells (DC) were differentiated from monocytes by culturing in IL-4 and granulocyte-macrophage colony stimulating factor (GM-CSF). AV-GBM-1 consisted of autologous DC incubated with autologous tumor antigens contained in the lysate of irradiated cultured GBM cells. After recovery from RT/TMZ, doses were admixed with 500 mcg GM-CSF; up to 8 doses were injected subcutaneously over 6 months. Patients were not excluded by apparent progression or pseudo-progression post RT/TMZ. OS and progression-free-survival (PFS) were calculated from ITT enrollment. The success rate was 97% for both GBM cell cultures and collection of monocytes; 60/60 vaccines were successfully manufactured. Median age was 59 years. 57 patients received 392 injections. After two weekly injections there were significant increases in plasma lipocalin-2 and angiopoietin-1, and decreases in thrombospondin-5, angiotensinogen, and beta-fibroblast growth factor. The most common adverse events attributed to AV-GBM-1 were local injection site reactions (16%) and flu-like symptoms (10%). With follow up from 15.2 to 32 months, median PFS and OS were 10.3 (8.5,11.6 95% CI) and 16.0 (13.0,21.3 95% CI) months respectively. OS was better in the 25 patients who had methylguanine-methyltransferase (MGMT) methylation and/or isocitrate dehydrogenase (IDH) mutation. Age was not independently correlated with survival. From date of first injection, OS was not increased in 14 patients who were treated with alternating electrical tumor-treating fields. CONCLUSION: feasibility, safety, and PFS were encouraging. A phase III trial is in development.
Clinicaltrials.gov NCT03400917.