bluuebunny/crossref_metadata_2025 huggingface dataset:
CTNI-02. PRECLINICAL DATA AND INITIAL CLINICAL EXPERIENCE IN THE PHASE 1/2A DOSE ESCALATION TRIAL OF RHENIUM-186 NANOLIPOSOME (186RNL) IN LEPTOMENINGEAL METASTASES [LM]: THE RESPECT-LM TRIAL
Authors: Brenner Andrew , Youssef Michael , LaFrance Norman , Hedrick Marc , Bao Ande , Phillips William , Patel Toral , Weinberg Jeffrey , Floyd John
Published: November 2022

INTRODUCTION

Leptomeningeal metastases (LM) is a clinical complication that occurs when cancer cells invade the leptomeninges and cerebrospinal fluid of patients with malignant tumors. Once diagnosed, limited treatment options exist, and survival is poor. Rhenium-186 Nanoliposome (186RNL) is a liposomal encapsulated beta emitter with a short path length of 1.8 mm, thereby allowing high specific activity brachytherapy with limited exposure to surrounding tissues.

METHODS

Preclinical efficacy was assessed using C6-Luc glioma cells in Wistar rats or MDA-MB-231 in Athymic Nude Rats via intraventricular injection. At 15 days post inoculation the animals were treated with 0.69 mCi of 186RNL. Absorbed doses were assessed with gamma camera imaging at 0h, 24h, and 48h post-treatment. Tumor growth was assessed by luciferase bioluminescence. A multicenter phase 1/2a dose (3 + 3 design) escalation trial was then initiated with 186RNL in LM patients to determine the maximum feasible dose, overall response rate (ORR) and overall survival distribution.

RESULTS

A significant difference in survival between the control and treatment groups (n = 8 each) was observed in the C6/Wistar model at 2 weeks post treatment, with 50% survival in the control group and 100% survival in the treatment group (p = 0.0087). Similar efficacy was observed in the MDA-MB-236/Athymic model. Thus far two patients have received 186RNL with 6.6 mCi in 5ml via Ommaya reservoir. Post treatment imaging shows full CSF distribution by 4 hours and persistence of activity through 7 days following administration. The dose was well-tolerated with no related AEs through day 56 following treatment. CSF cell count by BioCept analysis was reduced by > 90% with durability through day 28.

CONCLUSION

Intraventricular delivered 186RNL is promising for treatment of LM, with very early evidence of efficacy in patients. Enrollment is ongoing.
CTNI-03. A PHASE I/IIA, OPEN-LABEL STUDY OF THE BRAIN-PENETRANT PARP1-SELECTIVE INHIBITOR AZD9574 AS MONOTHERAPY AND IN COMBINATION IN PATIENTS WITH ADVANCED SOLID MALIGNANCIES (CERTIS1)
Authors: Mueller Nancy , Luen Stephen , Stupp Roger , Chalmers Anthony , Huang Baisong , Squatrito Massimo , Davies Barry , Hamerlik Petra , Yap Timothy
Published: November 2022

BACKGROUND

Currently approved Poly ADP-Ribose Polymerase (PARP) inhibitors (PARPi) selectively inhibit and trap both PARP1 and PARP2 (PARP1/2) at sites of single strand (ss) deoxyribonucleic acid (DNA) (ssDNA) damage, preventing ssDNA repair and leading to replication-dependent DNA double strand breaks. Recent data suggest that only inhibition of PARP1 is required for anti-proliferative effects, while PARP2 functions in the survival of haematopoietic stem and progenitor cells. These observations suggest that the inhibition and trapping of PARP 2 is not needed for anti-cancer effects, and may be a major driver of haematological toxicity observed. AZD9574 is a novel brain-penetrant PARPi that potently and selectively inhibits and traps PARP1, with the goal of delivering efficacious, less toxic, and more combinable PARPi. Furthermore, owing to its central nervous system penetration capability, AZD9574 may provide a new treatment option for patients with CNS malignancies or patients with brain metastases characterized by homologous recombination deficiency (HRD).

METHODS

This is a first-in-human modular study primarily designed to evaluate the safety and tolerability of AZD9574 as monotherapy and in combination with anti-cancer agents at increasing dose levels in patients with advanced solid malignancies, followed by expansion cohorts in specific indications. The study will also characterize the pharmacokinetics of AZD9574 and explore potential biological activity by assessing pharmacodynamic and exploratory biomarkers and anti-tumour activity. Module 1 will enrol patients with advanced breast, ovarian, pancreatic or prostate tumours harbouring homologous recombination deficiencies. Module 2 will enrol patients with isocitrate dehydrogenase (IDH)1/2 mutated glioma.
CTNI-20. RESULTS OF A PHASE 1/2 CLINICAL TRIAL OF BLOOD-BRAIN BARRIER (BBB) OPENING WITH THE SONOCLOUD-9 IMPLANTABLE ULTRASOUND DEVICE IN RECURRENT GLIOBLASTOMA PATIENTS RECEIVING IV CARBOPLATIN
Authors: Carpentier Alexandre , Sonabend Adam M , Stupp Roger , Chinot Olivier , Dufour Henry , Ducray François , Menei Philippe , de Groot John , Weinberg Jeffrey , Desseaux Carole , Canney Michael , Idbaih Ahmed
Published: November 2022

Low intensity pulsed ultrasound in combination with microbubbles can be used to temporarily disrupt the blood-brain barrier (BBB). A phase 1/2 clinical study (NCT03744026) was initiated to demonstrate the safety and efficacy of BBB disruption using an implantable ultrasound system (SonoCloud-9) in patients with recurrent glioblastoma receiving carboplatin chemotherapy. The SonoCloud-9 device, which contains nine, 1-MHz, 10-mm diameter ultrasound emitters (Carthera, Paris, France) was placed at the end of tumor resection and replaced the bone flap. The device was activated 9-14 days after surgery for a duration of 270 seconds every four weeks until progression or treatment completion, concomitantly with IV DEFINITY microbubbles (10 ml/kg, Lantheus, Billerica, US). The Phase 1 cohort consisted of an escalation of BBB disruption volume by activation of 3 (n = 3), 6 (n = 3), then 9 (n = 3) emitters of the device. Dose limiting toxicity (DLT) was assessed during the first two weeks after the 1st sonication. A subsequent expansion cohort consisted of patients treated with nine emitters in which the primary endpoint was assessment of BBB opening on MRI using gadolinium (< 1 hr after sonication). All patients received carboplatin either after (n = 21) or before (n = 12) device activation to disrupt the BBB. In addition, a sub-study was performed to investigate carboplatin concentration enhancement in the peritumoral region with sonication at time of device implantation. Study accrual is complete with 33 patients having been implanted and received at least one sonication. A total of 101 sonications were performed (range = 1-10 sonication sessions/patient). No DLTs were observed. Five serious adverse events (all resolved) were considered as possibly related to the study procedure. BBB disruption was confirmed by gadolinium enhancement after sonication. In three patients who underwent intraoperative sonication and carboplatin administration, a 7.58-fold increase in brain/plasma drug levels was demonstrated. Updated survival results will be presented.
CTNI-25. REGORAFENIB IN RECURRENT GLIOBLASTOMA PATIENTS: A MULTICENTRIC REAL-LIFE STUDY
Authors: Bruno Francesco , Pellerino Alessia , Pronello Edoardo , Palmiero Rosa , Polo Valentina , Vitaliani Roberta , Trincia Elena , Internò Valeria , Porta Camillo , Soffietti Riccardo , Rudà Roberta
Published: November 2022

BACKGROUND

In the phase 2 REGOMA trial, regorafenib improved overall survival, as compared to lomustine, for glioblastoma (GBM) patients at first progression after chemoradiation. Here, we present the results of a real-life multicentre study that analysed response to treatments, tolerability, and outcome of GBM patients treated with regorafenib at first tumour progression.

PATIENTS AND METHODS

Regorafenib was given following an escalation dose protocol (1st cycle: 80 mg/day for 2 weeks, then 120 mg/day for one week; 2nd cycle: 120 mg/day for 2 weeks, then 160 mg/day for one week; 160 mg/day from the 3rd cycle). Progression-free survival (PFS) and overall survival (OS) were defined as time from regorafenib initiation and disease progression or death.

RESULTS

From January 2020 to January 2022, 66 GBM patients were included. Median age was 60.0 years. MGMTp methylation was found in 30 patients (45.5%). Median dose was 120 mg/day 21q28 day, which was lower than that used in REGOMA trial (149 mg). Median PFS (mPFS) was 2.7 months and median OS (mOS) 7.1 months. RANO response to regorafenib was partial response (PR) in 10 (15.1%), stable disease in 14 (21.2%), and progressive disease in 42 (63.7%) patients. Forty-six (69.7%) patients presented adverse events of any grade, and 21 (31.8%) grade III-IV toxicity. Two patients only (3.0%) interrupted regorafenib due to toxicity. In a multivariable analysis, factors associated with disease progression were higher age (p = 0.035) and absence of MGMTp methylation (p = 0.024).

CONCLUSION

In our study, mPFS and mOS were similar to those of the 59 patients enrolled in the regorafenib arm of REGOMA trial (2.7 vs 2.0 months; 7.1 vs 7.4 months, respectively). However, we observed a higher rate of PRs (15% versus 3.0%). Moreover, we had a lower incidence of discontinuations due to toxicity, maybe because of the lower dose intensity.
CTNI-26. SURGICAL WINDOW OF OPPORTUNITY TRIAL OF NAVTEMADLIN (KRT 232; AMG232) IN PATIENTS WITH RECURRENT GLIOBLASTOMA
Authors: Lee Eudocia , Rudek Michelle , Rendo Veronica , Khuu Nicholas , Walbert Tobias , Holdhoff Matthias , Lieberman Frank , Desai Arati , Strowd Roy , Lapinskas Emily , Pelton Kristine , Pisano William , Desideri Serena , Danda Neeraja , Fisher Joy , Ye Xiaobu , Nabors L Burt , Grossman Stuart , Beroukhim Rameen , Alexander Brian , Ligon Keith , Wen Patrick Y
Published: November 2022

BACKGROUND

KRT232 is an orally bioavailable, selective small molecule inhibitor of MDM2 that blocks the protein-protein interaction between MDM2 and p53. We performed a surgical window of opportunity trial of KRT232 in patients with recurrent GBM.

METHODS

The primary endpoint was to determine the tumor tissue concentration of KRT232. Prior to surgery, patients received KRT232 at either 120mg (n = 10, minimal dose that is consistently associated with alterations in serum MIC-1) or 240mg (n = 10; recommended phase 2 dose as monotherapy) for two days prior to surgical resection. Surgery was performed 3-6 hours following the last administration of KRT232. Tissue was analyzed for KRT232 concentration by LC/MS and for correlative studies. Participants with TP53 wild-type tumors were eligible to continue KRT232 following recovery from surgery at the RP2D of 240mg QD x 7 days q3weeks.

RESULTS

Twenty-one patients were enrolled from July 2018 to April 2020. One patient was deemed ineligible after surgery due to non-GBM tumor. Study met the prespecified criteria of target intra-tumor drug concentration of ≥ 25nM in contrast enhancing tissue in more than 50% of the patients in the 120mg cohort (67.1 ± 42.7nM in 8/10 patients) and 240mg (328.7 ± 468.1nM in 10/10 patients) cohort. Serum MIC-1 fold-changes from baseline (FCB) approximately 24 hours after a single dose of KRT232 were higher in the 240mg cohort (9.1 ± 4.1-FCB) than the 120mg cohort (3.6 ± 2.0-FCB). CDKN1A (p21), a downstream marker of p53, was significantly upregulated in analyzed participants whose GBM was TP53 wildtype, but not in TP53 mutant GBM or control samples (GBM treated with standard of care).

CONCLUSION

KRT232 at both 120mg and 240mg achieves adequate tumor tissue penetration and affects downstream pathways in TP53 wildtype GBM. The study has moved to Alliance to complete a phase 1 study of radiation + KRT232 in patients with newly diagnosed MGMT unmethylated GBM.
CTNI-27. MULTI-CENTER, PHASE 2 STUDY EVALUATING THE PHARMACOKINETICS, SAFETY AND PRELIMINARY EFFICACY OF PAXALISIB IN NEWLY DIAGNOSED ADULT PATIENTS WITH UNMETHYLATED GLIOBLASTOMA (GBM)
Authors: Wen Patrick Y , de Groot John , Battiste James , Goldlust Samuel , Damek Denise , Ellingson Benjamin , Garner James , Friend John , Simpson Jeremy , Olivero Alan , Cloughesy Timothy
Published: November 2022

NCT03522298 was an open-label, multi-center, 2-stage trial designed to establish the maximum tolerated dose (MTD) for once-daily (QD) paxalisib dosing (Stage 1), then evaluate pharmacokinetics(PK) and safety and explore efficacy (Stage 2). Eligible patients had undergone surgical resection and chemoradiotherapy (EORTC 26981–22981/NCIC CE3), had a life expectancy of ³ 12 weeks and were progression free before starting adjuvant paxalisib. Stage 1 used a standard 3 + 3 dose-escalation design to determine the MTD. Stage 2 was a two-arm, open-label, expansion cohort with patients randomized 1:1 to receive paxalisib at the MTD under fed or fasted conditions. In both stages, treatment comprised daily paxalisib administered in continuous 28-day cycles, until disease progression or unacceptable toxicity. Patients (n = 30; 70.0% males, mean age 58.5 years, mean 3.75 months since diagnosis) received paxalisib for a mean duration of 99 (9-833) days. In Stage 1 (n = 9), an MTD of 60mg was established on the dose-limiting toxicities of hyperglycemia (n = 1) and stomatitis (n = 1) at 75mg. Paxalisib was well-tolerated with no unexpected safety signals. Adverse events (37%) or progressive disease (33%) were the primary reasons for treatment discontinuation. At the MTD, the PK profile was linear and dose-proportional with no differences in Tmax and elimination half-life under fed/fasted conditions. Ten patients underwent FDG-PET imaging, 8 (80%) had a decrease in FDG uptake on Day 3 and/or Day 7 in Cycle 1; 4 (40%) had a metabolic partial response. From date of diagnosis, progression free survival (mRANO, investigator review) was 8.6 months and overall survival was 15.7 months. Primary study outcomes (1) MTD of 60mg was established for QD dosing and (2) PK and safety were consistent with prior clinical experience. Preliminary efficacy signals were encouraging and further investigation of paxalisib 60mg QD in newly diagnosed and recurrent GBM is ongoing in a pivotal trial (GBM AGILE, NCT03970447).
CTNI-31. COG ACNS1721: PHASE 2 STUDY OF VELIPARIB AND LOCAL IRRADIATION, FOLLOWED BY MAINTENANCE VELIPARIB AND TEMOZOLOMIDE, IN PATIENTS WITH NEWLY DIAGNOSED HIGH-GRADE GLIOMA WITHOUT H3 K27M OR BRAF MUTATIONS
Authors: Karajannis Matthias , Thomas Arzu Onar , Baxter Patricia , Butingan Nina , Fuller Christine , Gajjar Amar , Haque Sofia , Jabado Nada , Lin Tong , Lucas John , MacDonald Shannon , Matsushima Celeste , Patel Namrata , Pierson Christopher , Springer Linda , Stark Eileen , Souweidane Mark , Walsh Michael , Zaky Wafik , Fouladi Maryam , Cohen Kenneth
Published: November 2022

BACKGROUND

The outcome for pediatric patients with high-grade glioma (HGG) remains poor. Veliparib, a potent oral PARP1/2 inhibitor, enhances the activity of radiotherapy and DNA-damaging chemotherapy. Preclinical data indicates that veliparib crosses the blood-brain-barrier and enhances the efficacy of radiotherapy and temozolomide in IDH mutant and wild-type HGG models. ACNS1721 was a single-arm, non-randomized phase 2 clinical trial designed to determine whether treatment with veliparib and radiotherapy, followed by the poly (ADP-ribose) polymerase (PARP) inhibitor veliparib and temozolomide, improves progression-free survival (PFS) in pediatric patients with newly diagnosed HGG without H3 K27M or BRAF mutations compared to patient level data from historical cohorts with closely matching clinical and molecular features.

METHODS

Following surgical resection, newly diagnosed children with non-metastatic HGG were screened by rapid central pathology review and molecular testing. Eligible patients without somatic H3 K27M or BRAF mutations were enrolled on Stratum 1 (IDH wild-type) or Stratum 2 (IDH mutant). Protocol radiochemotherapy consisted of involved field radiotherapy with concurrent veliparib at 65 mg/m2 twice daily. Adjuvant chemotherapy consisted of up to 10 cycles of veliparib 25 mg/m2 twice daily and temozolomide 135 mg/m2 once daily for 5 days every 4 weeks.

RESULTS

Both strata were closed to accrual for futility after planned interim analyses. Among the 23 eligible patients who enrolled on Stratum 1 and received protocol therapy, the 1-year progression-free survival (PFS) was 0.29 (SE = 0.09) and 1-year overall survival (OS) was 0.67 (SE = 0.10). Among the 14 eligible patients who enrolled on Stratum 2 and received protocol therapy, the 1-year PFS was 0.57 (SE = 0.15) and 1-year OS was 0.90 (SE = 0.09).

CONCLUSION

Rapid central pathology review and molecular testing was feasible. The protocol therapy was well tolerated but failed to improve outcome compared to clinically and molecularly matched historical control cohorts.
CTNI-32. PHASE 2 STUDY OF VAL-083 AND RADIOTHERAPY IN NEWLY DIAGNOSED MGMT-UNMETHYLATED GBM
Authors: Chen ZhongPing , Guo Chengcheng , Chen JianGen
Published: November 2022

VAL-083 is a novel bi-functional DNA targeting agent that induces inter-strand DNA cross-links at N7-guanine, leading to DNA double-strand breaks and cell death. In vitro and in vivo studies have demonstrated VAL-083 circumvents MGMT-mediated chemoresistance and differentiates it from other therapies used in the treatment of GBM, including temozolomide (TMZ). VAL-083 also acts as a radiosensitizer against GBM cancer stem cells in vitro. A Phase 2 study was conducted to evaluate the safety and tolerability of VAL-083 when administered concurrently with radiation therapy (RT) in newly diagnosed MGMT unmethylated GBM. Stage 1 was a dose-escalation phase to confirm the dose of VAL-083 in this setting. Patients received VAL-083 at 20, 30, or 40 mg/m2/day x 3 days every 21 days in combination with standard radiation treatment (RT) (2 Gy/day, 5 days/week for 6 weeks). Stage 2 was an expansion phase to enroll up to 20 additional patients at the 30 mg/m2/day of VAL-083 with RT. A total of 29 patients were enrolled in the study and completed treatment, with 25 patients receiving 30 mg/m2/day VAL-083. The median number of cycles completed by all patients was 9 (range 2-13). Consistent with our prior experience, myelosuppression was the most common adverse event. Pharmacokinetics (Cmax and AUC) of VAL-083 were broadly linear with respect to dose, and drug half-life was 0.8 hrs. In a sub-group of patients, levels of VAL-083 in CSF were found to be at least as high as those in plasma. The median progression free survival (PFS) for all patients enrolled was 9.3 (95%CI: 6.4-12.0) months. Eighteen (18/29; 62.1%) patients have died, and median overall survival for all patients enrolled was 19.6 (95%CI: 14.0-22.4) months. These results support the potential benefit of VAL-083 as a treatment alternative against GBM tumors with MGMT-mediated resistance to TMZ. Clinicaltrials.gov: NCT03050736.
CTNI-35. PHASE 0/1 TRIAL OF MYCOPHENOLATE MOFETIL COMBINED WITH CHEMORADIATION TO OVERCOME TREATMENT RESISTANCE IN NEWLY DIAGNOSED AND RECURRENT GLIOBLASTOMA BY TARGETING PURINE METABOLISM
Authors: Umemura Yoshie , Al-Holou Wajd , Marini Bernard , Leung Denise , Kim Michelle , Ferris Sean , Junck Larry , Sagher Oren , Heth Jason , Sun Yilun , Schipper Matthew , Lyssiotis Costas , Lawrence Theodore , Wahl Daniel
Published: November 2022

BACKGROUND

Purine metabolism promotes glioblastoma growth, stemness, invasiveness, and treatment resistance. The purine synthesis inhibitor, mycophenolate mofetil (MMF), improves radiation and temozolomide efficacy in preclinical glioblastoma models. This phase 0/1 trial (NCT04477200) aims to determine the maximum-tolerated dose of MMF combined with chemoradiation in glioblastoma. It also aims to quantify the levels of the active metabolite of MMF and the extent of purine synthesis inhibition in enhancing and non-enhancing tumor tissue.

METHODS

Key eligibility criteria are age ≥ 18 and KPS ≥ 60%. TITE-CRM dose-escalation is used for MMF dosing starting at 1000mg PO BID (range 500-2000mg BID). Thirty recurrent glioblastoma patients receive MMF one-week prior to and concurrently with re-irradiation (40.5 Gy in 15 fractions), with 28 days of dose-limiting toxicity (DLT) period. Thirty newly diagnosed glioblastoma patients receive MMF one-week prior to and concurrently with standard radiation with concurrent temozolomide and followed for 28 days for DLT1-period, then MMF is given days 0-5 of each adjuvant cyclic temozolomide using a separate dose-escalation with the first two cycles as the DLT2-period. In phase 0, eight recurrent glioblastoma patients receive MMF 500-2000mg PO BID one-week pre-operatively and tissues are analyzed using mass spectrometry.

RESULTS

Eighteen phase 1 subjects (11 recurrent, 7 new) have received study treatment with no DLT to date up to MMF 2000mg BID. Main toxicities are mild nausea, fatigue, and elevated liver enzymes. No notable study-related hematotoxicity nor opportunistic infection have been observed. The active metabolite of MMF accumulated to active concentrations in enhancing and non-enhancing tumor tissue and appeared to inhibit purine synthesis.

CONCLUSION

MMF combined with chemoradiation has been reasonably well tolerated in glioblastoma patients with preliminary evidence of intracranial target engagement of its active metabolite. This study will yield a recommended phase 2 dose and preliminary efficacy estimate for future randomized phase 2/3 trial.
CTNI-36. INITIATION OF A PHASE 1 DOSE-ESCALATING STUDY OF WEEKLY DIRECT-TO-BRAIN ADMINISTRATION OF SOLUBILISED FORMULATION OF PANOBINOSTAT (MTX110) IN PATIENTS WITH RECURRENT GLIOBLASTOMA (MAGIC-G1 STUDY)
Authors: Desjardins Annick , Conlon Kelly , Gunning Hannah , Davies Rhian , Komisarow Jordan , Cavaliere Robert , Zamoryakhin Dmitry
Published: November 2022

INTRODUCTION

Glioblastoma (GBM) is the most aggressive primary brain tumour in adults, leading to universal recurrence despite aggressive surgical and chemotherapeutic treatment. Post-recurrence, median overall survival is 6 to 10 months and treatment options are very limited. One of the biggest challenges in treating GBM is achieving high local drug concentration; systemic administration of cytotoxic agents has failed in the past due to this limitation. Convection enhanced delivery (CED) is a ‘direct-to-brain’ drug delivery method that previously demonstrated its usefulness in overcoming this challenge. MTX110 (Midatech Pharma Ltd) is a water-soluble form of panobinostat, that demonstrated cytotoxic activity in 4 GBM cell lines (U87MG, U251MG, U118MG and T98G) with an average IC50 value around 40nM which also translated into pre clinical in vivo efficacy, in combination with radiotherapy1. Delivery of MTX110 via an implanted pump and CED catheter system in patients with GBM appears to be an attractive treatment option, that allows for therapeutic doses of the drug to be delivered weekly directly to the tumour, thus avoiding systemic administration and therefore toxicity. This has previously been demonstrated in investigator-initiated studies of paediatric patients with diffuse intrinsic pontine glioma.

METHOD

MAGIC-G1 study is a Phase 1 two-cohort dose-escalating study that will assess safety and feasibility of intermittent intratumoral administration of MTX110 by CED to rGBM patients; either as a single agent (Cohort 1) or in combination with lomustine (Cohort 2). Eligible patients will have a catheter system and an abdominal refillable pump implanted in an aseptic manner, with the tip of the catheter positioned stereotactically at the centre of the tumour. 48-hour infusions will be administered weekly until disease progression and doses of 30, 60 and 90 mM will be investigated. Cohort 1 recruitment will be completed before Cohort 2 starts dosing. Study results are expected in 2023.
CTNI-40. PHASE I TRIAL OF SULFASALAZINE COMBINED WITH STEREOTACTIC RADIOSURGERY FOR RECURRENT GLIOBLASTOMA: STUDY PROTOCOL FOR NCT04205357
Authors: Skeie Bente Sandvei , Bragstad Sidsel , Sarowar Shahin , Behbahani Maziar , Filippi Christopher , Knisely Jonathan , Schulder Michael , Goplen Dorota , Eide Geir Egil , Heggdal Jan Ingemann , Gruner Renate , Enger Per Øyvind
Published: November 2022

Glioblastoma (GBM) is one of the most aggressive, radioresistant types of cancer with a dismal prognosis. Sulfasalazine (SAS) has shown tumor selective radiosensitizing properties in preclinical studies. The antioxidant glutathione (GSH) produced at high levels in glioma cells normally protects against radiation injury by scavenging reactive oxygen species produced during radiation therapy (RT). SAS blocks cysteine uptake through the xCT-channel, a rate-limiting step for GSH production. We have previously shown slowing of tumor growth and prolonged survival when SAS was combined with stereotactic radiosurgery (SRS) in vivo compared to either treatment alone. Our hypothesis is that SAS potentiates the efficacy of SRS for recurrent GBM with a low risk of adverse events (AE). The primary end-point is to establish the recommended dose for efficacy testing in phase II/III trials. This phase 1 dose-escalation trial utilizes a standard 3 + 3 design with 3-6 patients per cohort. Patients will be treated with oral SAS (1.5, 3.0, 4.5 or 6.0 g/day) 3 days prior to single session SRS. The SAS-dose will be escalated depending on the absence/presence of toxicity in the previous cohort of treated patients. If more than 1 of 3-6 patients ( ≥ 33 %) is experiencing grade 3 or higher toxicity levels, the study will be terminated. The dose below will be the recommended dose. Toxicity is graded using the Common Toxicity Criteria for Adverse Events (CTCAE) v5.0 recorded the first 30 days. Secondary end-points are assessments of 1) intratumoral GSH production (GSH-spectroscopy), 2) late AE utilizing 11C-MET-MRI-PET 3) changes in KPS/quality of life (FACT-Br), 4) need for steroidal treatment, 5) progression free and overall survival. Novel treatment modalities are urgently needed. This trial will establish the recommended dose for SAS repurposed as a radiosensitizer for a future phase 2/3 trial and may ultimately lead to improvement of current GBM treatment.
CTNI-43. COMBINATION OF TROFOSFAMIDE PLUS ETOPOSIDE IN RECURRENT ADULT-TYPE DIFFUSE GLIOMAS
Authors: Schmidt Teresa , Agkatsev Sarina , Feldheim Jonas , Oster Christoph , Blau Tobias , Sure Ulrich , Keyvani Kathy , Kleinschnitz Christoph , Stuschke Martin , Hermann Ken , Deuschl Cornelius , Scheffler Björn , Kebir Sied , Glas Martin , Lazaridis Lazaros
Published: November 2022

Disease relapse almost inevitably occurs in patients with adult-type diffuse glioma. Standard of care treatment options at tumor relapse are still not well defined. Few studies indicate that the combination of trofosfamide plus etoposide (T/E) may be feasible in pediatric glioblastoma patients. We collected clinicopathological data from adult patients with adult-type diffuse glioma treated with the combination of Trofosfamide (100mg/m2/day) and Etoposide (25mg/m2/day) for a minimum of four weeks at the Division of Clinical Neurooncology at the University Hospital Essen. T/E was administered orally in a “one week on, one week off” scheme. A cohort of patients receiving empiric treatment at the investigators’ discretion balanced for tumor entity and canonical prognostic factors served as control. We collected toxicity data as it pertained to CTCAE (Common Terminology Criteria for Adverse Events, version 5.0) and survival data to explore putative efficacy.A total of 33 patients were eligible for this analysis. In the IDH wild-type glioblastoma (n = 18) subgroup, median progression-free survival (3.8 months versus 2.9 months, HR: 2.09, 95% CI: 1.010-4.312, p = 0.0227; PFS-6: 39% versus 6%) and median overall survival (10.4 months versus 5.7 months, HR: 3.05, 95% CI: 1.393-6.655, p = 0.0008) were significantly prolonged as compared to the control cohort. In a multivariable Cox regression analysis, treatment with T/E emerged as statistically significant prognostic marker regarding progression-free survival and overall survival. We observed high-grade adverse events (CTCAE grade III or higher) in 21 (64%) of all recurrent glioma patients with hematotoxicity comprising most adverse events (n = 18, 86%; Lymphopenia: n=13, 62%). This study provides first indication that the combination of T/E is safe in patients with adult-type diffuse gliomas and may be associated with prolonged survival in adult patients with recurrent IDH wildtype glioblastoma. Our data provide a reasonable rationale for follow-up of a larger cohort in a prospective controlled trial.
CTNI-45. CLINICORADIOLOGICAL AND HISTOPATHOLOGICAL CHARACTERISTICS AND TREATMENT OUTCOMES OF CEREBRAL ASTROBLASTOMA IN CHILDREN: A SINGLE-INSTITUTION EXPERIENCE
Authors: Choi Jung Won , Jeon Chiman
Published: November 2022

OBJECTIVE

Astroblastoma (AB) is a rare glial tumor. The optimal treatment and prognosis of this tumor remain unclear. The authors retrospectively analyzed the clinical characteristics, neuroimaging findings, histopathological results, and treatment outcomes of 7 patients with AB.

METHODS

The study comprised 7 patients with pathologically proven AB who were surgically treated at Samsung Medical Center from November 1994 to January 2019. Clinicoradiological, histopathological, and surgical records were reviewed.

RESULTS

The patients included 5 girls (71.4%) and 2 boys (28.6%), with a median age of 13 years. All patients showed contrast enhancement on preoperative MRI: 5 ABs (71.4%) showed a concomitant solid and cystic appearance, and 2 (28.6%) demonstrated a solid appearance. ABs in 6 patients (85.7%) showed a well-circumscribed, characteristic "bubbly" appearance on T2-weighted MRI. Gross-total resection (GTR) was achieved in all cases (100%). Six patients (85.7%) were diagnosed with high-grade AB and 1 (14.3%) with low-grade AB. Six (85.7%) of the 7 patients received adjuvant treatment after resection, including 5 (83.3%) with AB who received chemotherapy and radiotherapy and 1 (16.7%) who received proton therapy alone. The median clinical follow-up duration was 96 months (range 48-189 months). Two patients experienced recurrence, and all patients in this series were alive at the last follow-up.

CONCLUSIONS

In this study, the clinicoradiological and histopathological features of AB were described. Based on the authors' limited experience with 7 cases, resection with the goal of GTR is currently the mainstream treatment for AB, and adjuvant radiation treatment should be considered after surgery.
CTNI-49. EARLY SIGNAL OF ACTIVITY FROM A PHASE 2 STUDY OF ST101, A FIRST-IN-CLASS PEPTIDE ANTAGONIST OF CCAAT/ENHANCER-BINDING PROTEIN Β (C/EBPΒ), IN RECURRENT GLIOBLASTOMA (GBM)
Authors: Iwamoto Fabio , Gondi Vinai , Butowski Nicholas , Falchook Gerald , Williams Anja , Peters Katherine B , Evans Jeff , Lakhani Nehal , McKean Meredith , Symeonides Stefan , Ellingson Benjamin , Rotolo Jim , Capiaux Gina , Wiegert Erol , Michel Rob , Kaesshaefer Steve , Bexon Alice
Published: November 2022

BACKGROUND

C/EBPβ is a transcription factor that is active during embryofetal development but held in an inactive state in most mature cells (Zahnow 2009). C/EBPβ activates a proliferation/survival gene signature in multiple cancers, where it inversely correlates with disease prognosis and survival. ST101 is a cell-penetrating peptide antagonist of C/EBPβ. ST101 exposure leads to selective tumor cell death in multiple human cancer cell lines, including GBM, without impacting normal cell viability. In vivo, ST101 displays rapid uptake into multiple organs, the ability to cross the blood-brain barrier, and a long plasma half-life due to its resistance to degradation. It has potent anti-tumor activity in multiple GBM models, as a single agent or in combination, which supported moving into clinical development. TRIAL DESIGN: This phase 2 study is enrolling adult patients with GBM that has recurred or progressed after one standard treatment regimen (surgery, radiotherapy +/-temozolomide). Patients require measurable disease at baseline and at least 3 months from prior radiotherapy. Subjects receive the recommended phase 2 dose of ST101 (500mg IV weekly). Recruitment in the phase 2 portion of this trial began in January, 2022.

RESULTS

As of June 1, 2022, 14 GBM patients were enrolled. One patient has a confirmed mRANO partial response (PR) after 18 weeks of therapy, seven patients have not reached the first on-study assessment and six patients progressed. The median duration of therapy was 5 weeks. ST101 has a favorable safety profile with minor infusion related reactions being the most common adverse event. Based on the confirmed PR, the GBM cohort will be expanded.

CONCLUSION

This first-in-class C/EBPβ inhibitor, ST101, showed an early signal of activity in recurrent GBM. More extensive follow-up and clinical experience will be presented as this trial expands and matures.
CTNI-50. A RANDOMIZED PHASE 2 TRIAL OF CEDIRANIB/OLAPARIB VERSUS BEVACIZUMAB IN PATIENTS WITH RECURRENT GLIOBLASTOMA: UPDATED RESULTS
Authors: Hsieh Annie , Gerstner Elizabeth , Sahebjam Solmaz , Piccioni David , Campian Jian , Drappatz Jan , Aiken Robert , Lee Eudocia , Welch Mary , Becker Kevin , Williams Mickey , Karlovich Christopher , Muzikansky Alona , Giglio Pierre , Ivy Percy , Batchelor Tracy , Arrillaga-Romany Isabel
Published: November 2022

PURPOSE

Hypoxia from inhibition of angiogenesis reduces DNA repair capacity. Targeting homologous recombination pathway also has anti-angiogenic effects. To examine the synergistic effects of disrupting DNA repair pathways and angiogenesis in glioblastoma, we combine cediranib (ced), a pan vascular endothelial growth factor (VEGF) receptor inhibitor with olaparib (ola), a poly-ADP ribose polymerase (PARP) inhibitor compared with bevacizumab (bev), a VEGF-A inhibitor alone. To identify potential biomarkers predicting response to treatments, we also perform whole exome sequencing on archival tissues.

METHODS

Bevacizumab-naïve adult patients with first or second recurrence of glioblastoma after radiation and temozolomide were randomly assigned to cediranib (30mg PO daily)/olaparib (200mg PO twice daily) or bevacizumab (10mg/kg IV every 2 weeks). The primary end point was progression-free survival (PFS) at 6 months. The secondary end points included safety and overall survival (OS). Whole exome sequencing of formalin-fixed paraffin embedded archival tissue from 23 patients was performed.

RESULTS

We are presenting the final data from this trial. Between December 2017 and November 2018, a total 70 adult patients with recurrent glioblastoma were randomly assigned to receive ced/ola (n = 35) or bev (n = 35). With a data cut off on 5/30/2022, median PFS was 118 days and 92 days in ced/ola and bev groups, respectively (hazard ratio, 1.099, 95% CI 0.6-2, p = 0.76). Median overall survival was 269.5 days and 192 days in ced/ola and bev groups, respectively (hazard ratio, 0.6892, 95% CI 0.39-1.2, p = 0.2). Whole exome sequencing was performed in total 23 patients (24 samples), 14 patients in the ced/ola group and 9 patients in the bev group.

CONCLUSION

No significant survival benefit was observed in patients with recurrent glioblastoma treated with ced/ola compared to patients treated with bev monotherapy. Potential biomarkers predicting response to treatment identified from the whole exome sequencing on archival tissues will be presented.
CTNI-51. FEASIBILITY AND SAFETY OF NEUROSURGICAL RESECTION AND INTRA-OPERATIVE RADIATION THERAPY USING THE XOFT AXXENT ELECTRONIC BRACHYTHERAPY SYSTEM AND BEVACIZUMAB IN RECURRENT GLIOBLASTOMA
Authors: Wagle Naveed , Barkhoudarian Garni , Chaiken Lisa , Wollman Robert , Sharma Akanksha , Carrillo Jose , Nguyen Minh , Truong Judy , Chow Jared , Chacon Emma , Kesari Santosh
Published: November 2022

Glioblastoma (GBM) is the most common and aggressive primary brain tumor. External beam radiation therapy (EBRT) is widely recognized as an effective treatment for primary GBM. EBRT applied after GBM resection is associated with an increase in overall survival. Beyond upfront therapy with radiation and temozolomide chemotherapy, there is no standard therapy that has been proven effective. Re-irradiation with ERBT is minimally effective and with significant comorbidities. Our study uses IORT at the time of re-resection in patients who have recurrent, operable GBM after failure of who received primary EBRT and temozolamide in their first course of treatment. IORT allows the delivery of a large effective radiation dose applied directly to the tumor bed at the time of resection. This affords direct radiation to be delivered to the micro- and macroscopic tumor remnants in the vicinity of the resection cavity immediately following gross resection. In contrast, the more distant, surrounding brain tissue does not receive high radiation exposure. This Phase II study continues to accrue subjects with the primary endpoint of overall survival and several secondary endpoints that includes progression free survival, quality of life, and adverse events/safety. To date, five patients have been treated on this protocol. The technical feasibility and safety of administering intraoperative radiation with the Xoft System has been established in this cohort. Preliminary GLIOX Trial findings demonstrate the safety and feasibility of using the Xoft Axxent® Electronic Brachytherapy System to administer intracranial radiation during resection of recurrent glioblastomas. We will report new and expansive study results to include these early findings.
CTNI-52. A RANDOMIZED CONTROLLED TRIAL OF BERUBICIN, A DOXORUBICIN ANALOG THAT EFFECTIVELY CROSSES THE BLOOD-BRAIN BARRIER (BBB), AFTER FIRST-LINE THERAPY FOR GLIOBLASTOMA MULTIFORME (GBM): PRELIMINARY RESULTS
Authors: Silberman Sandra , Hsu Sigmund , Picker Don , Muzyczenko Zena , Priebe Waldemar
Published: November 2022

Berubicin is a doxorubicin (Dox) analog that crosses the BBB with significant central nervous system (CNS) uptake. Berubicin prolongs survival in orthotopic mouse intracranial models with greater infiltration of the tumor compared to normal tissue. A Phase 1 dose-escalation study showed myelosuppression as the dose-limiting toxicity, with 1 complete response (14+ years), 1 partial response durable for 12 weeks, and 9 patients with stable disease for a clinical benefit rate of 44%.A trial of Berubicin vs Lomustine in patients with recurrent GBM after first-line therapy in the US and EU is enrolling patients in a 2:1 randomization design of Berubicin:Lomustine. Patients will be stratified by MGMT methylation status. The primary endpoint is overall survival (OS) and secondary endpoints include progression-free survival and overall response rates. Advanced imaging technology is being utilized for consistency in the evaluation of MRI scans. An interim futility analysis to explore the relative efficacy of these drugs will be conducted after up to half of the patients enrolled have reached 6 months of therapy. Currently, 31 patients are enrolled with 21 in the Berubicin arm and 10 in the Lomustine arm. At present these patients show comparable demographics, with an unmethylated MGMT population of ~60% in both arms. Patients with all grades of adverse events were 57% and 60% on the Berubicin and Lomustine arms, respectively. Grade 3-4 events were 43% (Berubicin arm) and 30% (Lomustine arm). Less than 10% of patients discontinued the study due to adverse events.The available data to date shows that Berubicin and Lomustine arms are presently balanced with relatively comparable safety profiles. This study is continuing to evaluate the efficacy of this novel drug with the goal of providing therapeutic options for patients after first-line therapy. An updated patient population profile, safety, and initial efficacy will be presented.
CTNI-54. A PHASE 0/1 ‘TRIGGER’ TRIAL OF RIBOCICLIB PLUS EVEROLIMUS IN RECURRENT HIGH-GRADE GLIOMA
Authors: Sanai Nader , Tien An-Chi , Jiang Jun , Chang Yu-Wei , Montgomery Chelsea , DeSantis Anita , Fujita Yoko , Kim Seongho , Mehta Shwetal
Published: November 2022

BACKGROUND

The RB-CDK4/6 and mTOR signaling pathways are deregulated in high-grade glioma (HGG) and mTOR activation is a potential mechanism of resistance to CDK4/6 inhibition. This study evaluates the tumor pharmacokinetics (PK) and pharmacodynamics (PD) of combined CDK4/6 and mTOR inhibition in recurrent HGG patients.

METHODS

Eligible patients had recurrent HGG with (1) RB+, (2) CDKN2A/B deletion or CDK4/6 amplification, and (3) PTEN loss or PIK3CA mutations. Six patients received five days of ribociclib (400mg QD) plus everolimus (2.5mg QD) and underwent tumor resection at 2, 8 or 24 hours following the last dose. Six dose-escalation cohorts (n = 3 each) reached a dose-level of ribociclib (600mg QD) plus everolimus (70mg QW). Tumor tissue, CSF, and plasma were collected. Total and unbound drug concentrations were determined using validated LC-MS/MS methods. Tumor PD effects were compared to matched archival tissue. A PK ‘trigger’ (i.e., unbound concentration > 5-fold biochemical IC50) and a PD ‘trigger’ ( >30% decrease in both pRB and pS6) in Gd-nonenhancing tissue were set to qualify patients for expansion.

RESULTS

24 patients with WHO Grade III (n = 2) and Grade IV (n = 22) gliomas were enrolled. No dose-limiting toxicities were observed. Following presurgical drug, all patients demonstrated marked decrease in Gd-enhancement on preoperative MRI. In Gd-nonenhancing tumor regions, the median unbound concentration of ribociclib was 561 nM whereas no unbound everolimus concentrations were detected. Across all dose-levels, 57% (13/23) and 43% (10/23) of tumors demonstrated RB and S6 phosphorylation decrease, respectively.

CONCLUSION

In adult HGG, ribociclib achieves pharmacologically-relevant concentrations in Gd-nonenhancing tumor. Everolimus exhibits limited penetration into human glioma tissue. Our study supports further development of ribociclib, but not everolimus, for the treatment of glioma patients.
CTNI-57. RADIONUCLIDE THERAPY WITH 177LU-DOTATATE (LUTATHERA) IN ADULTS WITH ADVANCED INTRACRANIAL MENINGIOMA - INTERIM ANALYSIS RESULTS OF A SINGLE-ARM, OPEN-LABEL, MULTICENTER PHASE II STUDY
Authors: Kurz Sylvia , Zan Elcin , Cordova Christine , Barbaro Marissa , Troxel Andrea , Silverman Joshua , Snuderl Matija , Zagzag David , Golfinos John , Kondziolka David , Sulman Erik
Published: November 2022

BACKGROUND

While most meningiomas are considered benign tumors, a subset of these tumors are characterized by a more aggressive clinical course and require multimodal treatment. Beyond surgical and radiotherapeutic options, there are no effective medical treatments available. Somatostatin receptor 2 (SSTR2) is expressed by the majority of meningiomas. 177Lu-DOTATATE is a SSTR2-targeting radionuclide that has been successful in neuroendocrine tumors. Here we report the results of the interim analysis of an ongoing clinical trial (NCT03971461) that is evaluating the effect of 177Lu-DOTATATE in treating progressive intracranial meningiomas.

METHODS

In this Simon two-stage design phase II study, adults with advanced intracranial meningiomas received 177Lu-DOTATATE 7.4 GBq (200 mCi) every eight weeks for four doses. 68Ga-DOTATATE PET-MRI was performed before and at the end of treatment. The primary endpoint was progression-free survival at 6 months (PFS-6). Correlative studies evaluated the association of PFS-6, objective response rate, progression-free survival, overall survival with radiographic tumor measurements, 68Ga-DOTATATE uptake on PET-MRI, SSTR2 expression in tumor, and meningioma methylation subclass.

RESULTS

Fourteen patients (F = 11, M = 3) with progressive meningiomas (WHO I = 3, II = 10, III = 1) have been enrolled. Median age was 63.1 (range 49-78) years. All patients previously underwent tumor resection and at least one course of radiation. Treatment with 177Lu-DOTATATE was well tolerated, no treatment-limiting toxicities were observed. Six of 14 patients (42%) achieved PFS-6. Radiographically, all six patients had achieved Stable Disease. A functional alteration of tumoral SSTR2 expression by 68Ga-DOTATATE PET-MR imaging was observed in three patients.

CONCLUSIONS

Treatment with SSTR2-targeting 177Lu-DOTATATE is well tolerated. In this interim analysis, six of 14 patients achieved PFS-6. This exceeds the predefined threshold to continue to stage two of this study. This clinical trial is now open to patient enrollment at two study sites in the US.
CTNI-58. IMPROVING TRIAL ACCESS FOR PEOPLE WITH RARE CNS TUMORS: AN NCI-CONNECT PHASE I/II TRIAL OF PLX038 IN TUMORS WITH MYC/MYCN AMPLIFICATIONS INCORPORATING CORRELATIVE STUDIES AND PATIENT REPORTED OUTCOMES
Authors: Penas-Prado Marta , Wooley Joseph , Jung Jinkyu , Yuan Ying , Zhang Meili , Baranello Laura , Briceno Nicole , Levens David , Mendoza Tito , Pommier Yves , Thomas Craig , Vera Elizabeth , Santi Daniel , Armstrong Terri , Gilbert Mark
Published: November 2022

MYC genes encode transcription factors that regulate expression of genes involved in cell division. Supraphysiologic levels of MYC drive oncogenesis in many human cancers and induce the formation of topoisome complexes, essential to managing the torsional strain that would otherwise oppose transcription and replication. MYC/MYCN amplifications are seen in multiple primary CNS tumors including 30% of relapsed medulloblastomas (MB) and a subtype of ependymoma (EPN) where MYCN amplification defines the tumor. PLX038 is a PEGylated macromolecule containing the topoisomerase I inhibitor SN-38. PEGylations lead to longer half-life, tumor accumulation and decreased toxicity. We hypothesize that PLX038 will be efficacious in primary CNS tumors driven by MYC/MYCN amplifications by targeting the MYC-induced topoisome (Das, S.K. 2022 DOI10.1016/j.molcel.2021.11.016).

METHODS

Trial in development. Design/Objectives: Phase I (N = 12) – determine the maximum tolerated dose and recommended phase 2 dose of PLX038 in recurrent primary CNS tumors using TITE-BOIN design. Phase II - 3 independent cohorts, N = 30 for each group with interim analysis after 10 each: 2A - MYC-N amplified EPN post resection and radiotherapy (PFS); 2B - Recurrent MYCN amplified EPN or MYC/MYCN amplified MB (disease control rate, DCR); 2C - Other recurrent primary CNS tumors with MYC/MYCN amplifications (DCR). Additional measures: PROs from the Office of Patient-Centered Outcomes Research (OpCORe) web-based early phase trial endpoints; biomarkers of PLX038 distribution and response/resistance in peripheral blood, tumor tissue, hair follicles, and abdominal wall fat pad tissue.

CONCLUSIONS

NCI-CONNECT’s commitment to innovative designs can mitigate some of the barriers to access experimental therapy for people with rare CNS tumors. This basket trial will enroll participants with unifying molecular features and potential susceptibility to PLX038 despite different histological diagnoses. Furthermore, incorporation of comprehensive PROs will help identify clinical benefit and tolerability while correlative studies in tumor and other tissues will help identify biomarkers of response or resistance.