Adult Brain Tumor Consortium Research Articles

A multicenter, phase 1, Adult Brain Tumor Consortium trial of oral terameprocol for patients with recurrent high-grade glioma (GATOR)

Recurrent high-grade gliomas (rHGGs) have a dismal prognosis, where the maximum tolerated dose (MTD) of IV terameprocol (5days/month), a transcriptional inhibitor of specificity protein 1 (Sp1)-regulated proteins, is 1,700mg/day with median area under the plasma concentration-time curve (AUC) of 31.3μg∗h/mL. Given potentially increased efficacy with sustained systemic exposure and challenging logistics of daily IV therapy, here we investigate oral terameprocol for rHGGs in a multicenter, phase 1 trial (GATOR). Using a 3+ 3 dose-escalation design, we enroll 20 patients, with median age 60 years (range 31-80), 70% male, and median one relapse (range 1-3). Fasting patients tolerate 1,200mg/day (n= 3), 2,400mg/day (n= 6), 3,600mg/day (n= 3), and 6,000mg/day (n= 2) oral doses without major toxicities. However, increased dosage does not lead to increased systemic exposure, including in fed state (6,000mg/day, n= 4), with maximal AUC <5μg∗h/mL. These findings warrant trials investigating approaches that provide sustained systemic levels of transcription inhibitors to exploit their therapeutic potential. This study was registered at ClinicalTrials.gov (NCT02575794).

Evaluating the Base Excision Repair Inhibitor TRC102 and Temozolomide for Patients with Recurrent Glioblastoma in the Phase 2 Adult Brain Tumor Consortium Trial BERT.

Patients with glioblastoma (GBM) have a dismal prognosis. Although the DNA alkylating agent temozolomide (TMZ) is the mainstay of chemotherapy, therapeutic resistance rapidly develops in patients. Base excision repair inhibitor TRC102 (methoxyamine) reverses TMZ resistance in preclinical glioma models. We aimed to investigate the efficacy and safety of oral TRC102+TMZ in recurrent GBM (rGBM). A preregistered (NCT02395692), nonrandomized, multicenter, phase 2 clinical trial (BERT) was planned and conducted through the Adult Brain Tumor Consortium (ABTC-1402). Arm 1 included patients with bevacizumab-naïve GBM at the first recurrence, with the primary endpoint of response rates. If sufficient activity was identified, a second arm was planned for the bevacizumab-refractory patients. The secondary endpoints were overall survival (OS), progression-free survival (PFS), PFS at 6 months (PFS6), and toxicity. Arm 1 enrolled 19 patients with a median of two treatment cycles. Objective responses were not observed; hence, arm 2 did not open. The median OS was 11.1 months [95% confidence interval (CI), 8.2-17.9]. The median PFS was 1.9 months (95% CI, 1.8-3.7). The PFS6 was 10.5% (95% CI, 1.3%-33.1%). Most toxicities were grades 1 and 2, with two grade 3 lymphopenias and one grade 4 thrombocytopenia. Two patients with PFS ≥ 17 months and OS > 32 months were deemed "extended survivors." RNA sequencing of tumor tissue, obtained at diagnosis, demonstrated significantly enriched signatures of DNA damage response (DDR), chromosomal instability (CIN70, CIN25), and cellular proliferation (PCNA25) in "extended survivors." These findings confirm the safety and feasibility of TRC102+TMZ in patients with rGBM. They also warrant further evaluation of combination therapy in biomarker-enriched trials enrolling GBM patients with baseline hyperactivated DDR pathways.

Response Rate and Molecular Correlates to Encorafenib and Binimetinib in BRAF-V600E Mutant High-Grade Glioma.

Although fewer than 5% of high-grade gliomas (HGG) are BRAF-V600E mutated, these tumors are notable as BRAF-targeted therapy shows efficacy for some populations. The purpose of this study was to evaluate response to the combination of encorafenib with binimetinib in adults with recurrent BRAF-V600-mutated HGG. In this phase 2, open-label, Adult Brain Tumor Consortium (ABTC) trial (NCT03973918), encorafenib and binimetinib were administered at their FDA-approved doses continuously in 28-day cycles. Eligible patients were required to have HGG or glioblastoma with a BRAF-V600E alteration that was recurrent following at least one line of therapy, including radiotherapy. Five patients enrolled between January 2020 and administrative termination in November 2021 (due to closure of the ABTC). Enrolled patients received treatment for 2 to 40 months; currently one patient remains on treatment. Centrally determined radiographic response rate was 60%, with one complete response and two partial responses. Methylation profiling revealed that all tumors cluster most closely with anaplastic pleomorphic xanthoastrocytoma (PXA). Transcriptional profile for MAPK-response signature was similar across all tumors at baseline and did not correlate with response in this small population. Circulating tumor DNA measured in plasma samples before treatment, during response, and upon progression showed feasibility of detection for the BRAF-V600E alteration. No new safety signal was detected. Encorafenib and binimetinib exhibit positive tumor responses in patients with recurrent BRAF-V600E mutant HGG in this small series, warranting therapeutic consideration. Although toxicity remains a concern for BRAF-targeted therapies, no new safety signal was observed in these patients.

Lisavanbulin (BAL101553), a novel, oral microtubule destabilizer plus radiation in patients with newly diagnosed, MGMT promoter unmethylated glioblastoma: A phase 1 Adult Brain Tumor Consortium study (ABTC1601).

2058 Background: Lisavanbulin (BAL101553, prodrug of BAL27862) is a novel, oral microtubule destabilizer that leads to cell death mediated by modulating the spindle assembly checkpoint. It has promising antitumoral activity in orthotopic glioblastoma (GBM) models in combination with radiation (RT) ± temozolomide (TMZ), including in MGMT promoter unmethylated (uMGMT) tumors. Lisavanbulin is a lipophilic and small molecule (MW 387), and data in rodents showed its ability to cross the blood-brain barrier (brain-plasma ratio 1:1). Methods: This multicenter phase 1 study was to determine the MTD of oral Lisavanbulin in combination with standard RT (60 Gy in 30 fractions) in patients with newly diagnosed uMGMT GBM. Dose escalation followed a modified 3+3 design. The safety evaluation period ended 4 weeks after completion of radiation, which was also the end of study. Patients were allowed to continue treatment with standard adjuvant TMZ as per treating physician’s recommendation. Results: Twenty-six patients with uMGMT GBM (median age 64y, 42.3% male, 61.5% with gross total resection, median KPS 80) were enrolled. Two GBM harbored an IDH1 mutation. Patients were treated at 5 different dose levels of Lisavanbulin administered once daily for 6 weeks concomitantly with RT: Lisavanbulin 4 mg (5 pts), 6 mg (5 pts), 8 mg (7 pts), 12 mg (5 pts), and 15 mg (4 pts). The initial starting dose was 8 mg. Due to Grade 4 aseptic meningoencephalitis in the first patient, the study was held and the dose decreased to 4 mg. Dose escalation resumed and continued to 15 mg with 1 DLT of Grade 2 confusion and memory impairment observed at 12 mg. A planned dose expansion was not conducted due to discontinuation of funding. Grade 3 AEs were hypertension (2), seizure (2), cognitive disturbance (1), cerebral edema (1), hyponatremia (1), and lymphopenia (1); no additional grade 4 AE was observed other than the 1 case of aseptic meningoencephalitis. Median OS was 12.8 months (95%CI: 9.1-18.3 months). At data cut-off, 8 subjects (30.8%) were still alive. 38.5% subjects had no information on disease progression and were censored during the estimation of PFS. The median PFS was 7.7 months (95%CI: 3.0-9.5 months). Conclusions: The maximum studied safe dose for Lisavanbulin in combination with RT in newly diagnosed uMGMT GBM was determined at 15 mg daily during radiation. Overall, the safety of this combination was acceptable. Next steps in developing Lisavanbulin in newly diagnosed GBM include safety studies in combination with TMZ and of TMZ+RT in MGMT promoter methylated GBM prior to formally studying efficacy in a prospective randomized trial. Clinical trial information: NCT03250299 .

CTNI-60. PRELIMINARY RESULTS OF BINIMETINIB AND ENCORAFENIB IN ADULTS WITH RECURRENT BRAF V600E-MUTATED HIGH-GRADE GLIOMA

Abstract BACKGROUND Although &amp;lt; 5% of high-grade gliomas (HGG) are BRAF-V600E mutated, these tumors are being identified more frequently as genetic testing increases in gliomas. Given the treatment-refractory nature HGG, RAF-targeted therapy is of special interest. The combination of encorafenib (BRAF inhibitor) with binimetinib (MEK inhibitor) was evaluated in adults with recurrent BRAFV600-mutated HGG. METHODS In this phase 2, open-label, Adult Brain Tumor Consortium trial(NCT03973918) encorafenib (450mg daily) and binimetinib (45mg twice daily) were administered continuously until disease progression, unacceptable toxicity, or death. Eligible patients had a histologically-confirmed HGG with BRAF-V600E mutation identified by PCR or next generation sequencing, and had progressed after radiation and any number of prior medical therapies. The primary endpoint was radiographic response rate by RANO criteria. Plasma was collected at baseline, on-study, and at progression for correlatives. RESULTS Five patients enrolled between January 2020 and November 2021. All patients had at least one prior recurrence (range 1-4) and received radiation one or more times. Median age was 27 years(range 22-77). Histopathologic diagnosis was glioblastoma(n = 2), anaplastic PXA(aPXA; n = 2), and anaplastic ganglioglioma(aGG; n = 1). Patients received treatment for 2-28months; currently 2/5 patients remain on treatment (8 and 30 months). Radiographic response rate was 60%(3/5): CR in two (glioblastoma, treated 10months; glioblastoma, 8months treatment ongoing), PR in one (aPXA, 28months treatment ongoing), SD in one (aGG, treated 3months), and PD in one (aPXA, treated 2months). Likely attributable adverse events (CTCAE grade ≥ 3) included cilioretinal artery occlusion (came off study) and asymptomatic elevated CPK. Analysis of paired plasma samples and correlation with response is ongoing. CONCLUSIONS Encorafenib and binimetinib demonstrate promising tumor responses in patients with recurrent BRAFV600E-mutated HGG with sustained responses in all GBM and 50% of aPXA in this small series, warranting careful consideration in this rare tumor subgroup. This Phase 2 study has closed due to enrollment issues

DDEL-11. DETERMINING THE DOSE OF REGADENOSON MOST LIKELY TO TRANSIENTLY ALTER THE INTEGRITY OF THE BLOOD-BRAIN BARRIER IN PATIENTS WITH GLIOMAS

Abstract BACKGROUND The blood brain barrier (BBB) is a major obstacle to the delivery of chemotherapy to the CNS. Regadenoson is an FDA approved adenosine A2 agonist used for cardiac stress tests. In murine models, it transiently increases BBB permeability to a 70KD dextran. This multi-institutional, NIH funded, Adult Brain Tumor Consortium trial was designed to discover a dose of regadenoson that substantially increases vascular permeability in normal appearing white matter (NAWM) where drug delivery is particularly challenging. METHODS Adults ages 18-45 with supratentorial gliomas at low-risk for regadenoson complications were recruited (n = 7). One patient was treated at each of seven dose levels (from 0.05 to 1.4 mg) that are known to be safe in humans. The primary outcome measure is change in vascular permeability via dynamic contrast enhanced (DCE) perfusion MRI estimates of Ktrans. The primary outcome measure was a 10-fold higher Ktrans in NAWM than reported in literature (Ktrans &amp;gt; 0.04 min-1). Contrast-enhanced T1 subtraction map estimates of change in contrast enhancement and other measurements in normal brain and non-enhancing tumor were quantified. RESULTS Ktrans measures in NAWM averaged 1.13x10-3 ± 0.44x10-3 (SEM) min-1, lower than the target of 0.04 min-1. Normalized, contrast enhanced T1-weighted MR signal intensity in NAWM increased an average of 74.0 ± 22.4% min-1 (SEM) min-1, which was significantly higher than zero (P = 0.0163). Data available from this limited sample failed to meet the target goal in Ktrans increase or change in contrast enhancing signal intensity. CONCLUSION Administration of regadenoson at seven different doses did not significantly elevate Ktrans for gadolinium in NAWM. This data suggests that single doses of regadenoson are unlikely to substantially increase the delivery of therapeutic agents in non-enhancing brain tissue. This trial design is appropriate for further human testing of other regadenoson schedules and other novel approaches aimed at transiently modifying BBB permeability.

CLRM-03. BGB-290 AND TEMOZOLOMIDE IN TREATING ISOCITRATE DEHYDROGENASE (IDH)1/2-MUTANT GRADE I-IV GLIOMAS – A NOVEL MODEL OF AYA TRIAL DEVELOPMENT AND DEPLOYMENT

DESCRIPTIONThe lack of enrollment of AYA patients on clinical trials is well documented and multivariant. Here we present the basic science, examination of its relevance to the AYA population specifically, and the parallel deployment of two international clinical trials via a pediatric neuro-oncology and adult brain tumor consortium.DISCUSSIONIn February of 2017, the laboratory of Ranjit Bindra, MD, PhD, published a manuscript describing the finding that tumors with IDH1/2 mutations induce a BRCAness state leading to PARP inhibitor (PARPi) sensitivity and synergistic interactions with temozolomide chemotherapy [2]. Despite IDH1/2 mutations being rare in the pediatric high-grade glioma population, three independent groups confirmed that the incidence is significantly increased to ~30% in the adolescent and young adult (AYA) population. Upon discovery of a high blood-brain-barrier penetrant, high potency PARPi by BeiGene Pharmaceuticals, an international trial was launched through the Pacific Pediatric Neuro-Oncology Consortium (PNOC) [3] to test this drug in an AYA specific trial recruiting patients ages 13 to 25, with a concurrent trial being run for patients older than 25 years of age through the Adult Brain Tumor Consortium (ABTC) [4].While most trials that enroll AYA patients are forced to assess them as a unique cohort in post-analysis, if at all, the PNOC trial mentioned above was designed from the ground up with the AYA population in mind. It has allowed us to base initial dosing, recruitment strategies, psychosocial assessments, and outcomes, specifically on the AYA population. Ultimately, we expect their distinctive biology to yield unique results when compared to the ABTC trial.We propose that this is a model that could potentially be replicated in other disease processes and early phase drugs with the buy-in of the pharmaceutical industry and early phase consortiums.Acknowledgements: BeiGene Pharmaceuticals, PNOC, ABTC, CureSearch, Gateway Foundation

The 1994 National Cancer Institute’s strategy to fund multi-institutional, multidisciplinary consortia to design and conduct early phase clinical trials in patients with high grade gliomas.

2003 Background: : In the early 1990’s, the NCI suspended activities of the Brain Tumor Study Group seeking to shift clinical brain tumor research from phase III trials to innovative and correlative rich phase I/II studies. In 1994, NCI funded three early phase brain tumor consortia, later reduced to two consortia in 1999 and one in 2009. In 2020, the NCI announced it would discontinue funding the brain tumor consortium and emphasize pre-clinical glioblastoma drug development (RFA-CA-20-047). Methods: The activities of the New Approaches to Brain Tumor Therapy (NABTT: 1994-2009) and Adult Brain Tumor Consortium (ABTC: 2009-2021) were summarized using data from the Central Operations Office that served the consortia for 27 years. Results: From 1994-2020, 48 consortium meetings were held to discuss, develop, conduct, and evaluate early phase clinical trials. These involved multidisciplinary brain tumor experts (neuro-oncologists, neurosurgeons, radiation oncologists, neuropathologists, statisticians, pharmacologists, imaging experts, immunologists, etc) from 27 US academic centers and hospitals. 85 clinical trials were written, approved by NCI and the Brain Malignancy Steering Committee, and conducted. Most trials evaluated NCI-provided therapeutic agents. 34 trials were conducted in collaboration with 27 pharmaceutical companies eager to develop malignant brain tumor therapeutics; for 9 of these the consortia held the IND. 4870 patients were accrued: 3375 to therapeutic and 1495 to non-therapeutic studies. 49 grant proposals were submitted to fund consortium activities with a 46% approval rate. 91 peer reviewed manuscripts were published, with 174 presentations and abstracts. 18 pharmaceutical symposia were conducted to attract new agents toward early phase brain tumor research. Consortia sponsored 34 Guest Lectureships and multidisciplinary symposia to focus on relevant critical research areas. Additionally, the consortia provided unique opportunities for young faculty to lead multicenter NABTT/ABTC trials with appropriate support and mentorship. Conclusions: Therapeutic progress for high grade gliomas has been slow for many reasons (95% of systemically administered agents do not penetrate the blood-brain barrier, inherent treatment resistance, immunologically “cold” phenotype, etc). NABTT/ABTC focused multidisciplinary, multi-institutional experts on major challenges unique to brain tumor research. The consortia developed innovative early phase clinical studies rich in correlative endpoints, fostered research grants, hosted relevant topical symposia, and provided leadership roles for young investigators while bringing together the NCI, industry, and committed multidisciplinary academicians to explore novel therapeutic options for patients with primary brain tumors.

Baseline requirements for novel agents being considered for phase II/III brain cancer efficacy trials: conclusions from the Adult Brain Tumor Consortium’s first workshop on CNS drug delivery

Author(s): Grossman, Stuart A; Romo, Carlos G; Rudek, Michelle A; Supko, Jeffrey; Fisher, Joy; Nabors, L Burt; Wen, Patrick Y; Peereboom, David M; Ellingson, Benjamin M; Elmquist, William; Barker, Fred G; Kamson, David; Sarkaria, Jann N; Timmer, William; Bindra, Ranjit S; Ye, Xiaobu

Updated safety phase I trial of anti-LAG-3 alone and in combination with anti-PD-1 in patients with recurrent GBM.

2512 Background: Preclinical GBM data targeting the checkpoint molecule Lag-3 have shown promising anti-tumor immune response with resultant improved survival when combined with anti-PD-1. Here we report our experience from a multi-arm safety study in patients with recurrent GBM treated with anti-Lag-3 and in combination with anti-PD-1. Methods: A phase I, open label, multicenter, multi-arm dose-finding/safety study of anti-LAG-3 (BMS-986016) alone or in combination with anti-PD-1 in patients at first recurrence of GBM was carried out in The Adult Brain Tumor Consortium (ABTC) (1501). The primary objectives were safety and to define MTD (DLT rate &lt; 33%) for both the mono and combination arms. The major secondary objective was efficacy. The key inclusion criteria were: adults with first recurrence of GBM following RT+TMZ, TLC≥1000/ul, KPS≥ 60%, on a stable corticosteroid regimen, measurable disease, and written informed consent. Three pre specified dose levels of anti-Lag-3 at 80mg, 160mg, and 800mg were tested. Anti-PD-1was given at a flat dose of 240 mg in combination with anti-LAG-3 at 80 mg and 160 mg. Results: To date, the phase I portion of study completed its accrual and 33 patients were enrolled into the anti-LAG-3 alone or in combination with anti-PD-1 arms. The median age and KPS was 56 and 90 respectively. 39% tumors were MGMT methylated and the median treatment cycle was 3. The highest safe dose for Anti-LAG-3 alone is 800 mg without a DLT. Two DLT were observed in combination arms of Anti-LAG-3 +anti-PD-1 (80 mg/240mg), a grade 3 muscle weakness and a grade 4 edema. Three DLTs were observed in the higher Anti-LAG-3 + anti-PD-1 group (160 mg/240mg): grade 3 hypertension, syncope, and edema. 80% of the DLTs occurred after cycle 2 of the treatment. The estimated overall mOS was 8 months. Seven (44%) patients in the combination arm are still alive and 3 out of the 7 are living beyond 20 months suggesting a subset benefit. Conclusions: The phase I part of trial has completed enrollment. The MTD is 800mg for anti-LAG-3 as a monotherapy. For the combination arms, 160 mg of Anti-LAG-3 and 240 mg of anti-PD-1 was the MTD. DLTs were late onset events. Clinical trial information: NCT02658981 .

ACTR-43. GENOMIC ANALYSIS OF RESPONDERS OF PHASE II TRIAL OF TEMOZOLOMIDE AND TRC-102 (BASE EXCISION REPAIR INHIBITOR) IN BEVACIZUMAB-NAÏVE GLIOBLASTOMA AT FIRST RECURRENCE

Abstract BACKGROUND Temozolomide forms O6-methylguanine (O6mG), 7-methylguanine (N7mG), and 3- methyladenine (N3mA) DNA adducts. The O6mG DNA adduct is repaired by MGMT. N7mG and N3mA DNA adducts are removed by the base excision repair (BER) pathway, initiated by N- methylpurine DNA glycosolase (MPG). TRC-102 is a BER inhibitor that binds to the apurinic site created through the action of MPG. METHODS A phase II study of adult glioblastoma in first recurrence was performed in the Adult Brain Tumor Consortium with temozolomide, 150 mg/ m2 and TRC-102, 150 mg (1–5/ 28 days). Primary objective included radiographic response rate. Secondary objectives included safety and PFS-6. Exploratory objectives included tumor expression of N-methylpurine DNA glycosylase (MPG). The study tested hypothesis that combination therapy will achieve 30% RR. To understand the context of vulnerability to TRC102 we performed RNA sequencing on treatment naïve tissue from 7 patients. RESULTS Nineteen patients were enrolled in first stage. Median age was 60 years (range: 48–76), 53% females, median KPS was 80 (range: 70–90). Median cycles of treatment was 2 (range: 1–12). No responses were observed. Median OS was 11.0 months (95% CI: 8–18 months), median PFS was 2.0 months (95% CI: 1.8–3.6 months). PFS-6 rate was 10.5 % (2/19). The combination was safe. MPG staining was negative in six, 1+ in five and 2+ in three patients. PFS of 11 + months in two patients (exceptional responders) was associated with MPG expression. Preliminary analysis on RNA sequencing revealed significant enrichment for DNA Damage Response pathways (MsigDB), chromosomal instability gene signature (CIN70 and CIN25), and proliferative gene signature (PCNA25) in these 2 patients. CONCLUSIONS TRC 102 with temozolomide has acceptable safety but did not meet the primary endpoint of response. Gene signature of MsigDB, CIN70, CIN25 and PCNA25 was seen in exceptional responders and biomarker driven study is planned.

THER-04. THE USE OF AN ADENOSINE A2 AGONIST TO IMPROVE THE PREVENTION AND TREATMENT OF BRAIN METASTASES

As systemic therapies for cancer become increasingly effective, there is generally a rise in the incidence of brain metastases as a site of first recurrence. This occurs because most antineoplastic agents do not reach the brain in therapeutic concentrations. Many approaches have been studied to improve drug distribution to the central nervous system (CNS) such as intra-arterial administration, osmotic blood-brain barrier (BBB) disruption, focused ultrasound, convection-enhanced delivery, development of CNS penetrant pro-drugs, and the use of vasoactive peptides to transiently disrupt the BBB. However, none of these has improved the prevention or treatment of CNS metastases. Regadenoson is an adenosine A2 agonist that is FDA approved for use in cardiac stress tests. In animals, it has been shown to transiently increase BBB permeability allowing high molecular weight dextran and chemotherapy to enter brain in higher concentrations. A clinical study designed to determine if regadenoson will perform similarly in humans has been CTEP approved and will soon be accruing patients through the Adult Brain Tumor Consortium. If the results are encouraging, future studies will focus on administering regadenoson concurrently with systemically administered chemotherapy in an effort to reduce the incidence of CNS metastases and to improve CNS drug delivery in patients with known brain metastases. This presentation will focus on the available pre-clinical and clinical data supporting this approach and the potential advantages and risks associated with transient BBB disruption in this setting.

Barriers to accrual and enrollment in brain tumor trials.

Many factors contribute to the poor survival of malignant brain tumor patients, some of which are not easily remedied. However, one contributor to the lack of progress that may be modifiable is poor clinical trial accrual. Surveys of brain tumor patients and neuro-oncology providers suggest that clinicians do a poor job of discussing clinical trials with patients and referring patients for clinical trials. Yet, data from the Cancer Action Network of the American Cancer Society suggest that most eligible oncology patients asked to enroll on a clinical trial will agree to do so. To this end, the Society for Neuro-Oncology (SNO) in collaboration with the Response Assessment in Neuro-Oncology (RANO) Working Group, patient advocacy groups, clinical trial cooperative groups, including the Adult Brain Tumor Consortium (ABTC), and other partners are working together with the intent to double clinical trial accrual over the next 5 years. Here we describe the factors contributing to poor clinical trial accrual in neuro-oncology and offer possible solutions.

Updated phase I trial of anti-LAG-3 or anti-CD137 alone and in combination with anti-PD-1 in patients with recurrent GBM.

2017 Background: Preclinical GBM data targeting the checkpoint molecules Lag-3 and CD137 have shown promising anti-tumor immune response with resultant improved survival when combined with anti-PD-1. Here we report our experience from a multi-arm safety study in patients with recurrent GBM treated with anti-Lag-3 and anti-CD137. Methods: The Adult Brain Tumor Consortium (ABTC) 1501 trial is a phase I, open label, multicenter, multi-arm dose-finding/safety study of anti-LAG-3 (BMS-986016) or anti-CD137 (BMS-663513) alone and in combination with anti-PD-1 in patients at first recurrence of GBM. The primary objective is to define MTD for the mono and combinational treatment. The major secondary objective is to explore for a signal in efficacy. The key inclusion criteria are adults, first recurrence of GBM following RT+TMZ, TLC≥1000/ul, KPS≥ 60%, stable corticosteroid regimen, measurable disease, and written informed consent. Sequential allocation was used for the treatment assignment at starting dose of 80mg for anti-LAG-3 and 8mg for anti-CD137. Anti-PD-1was given at a flat dose of 240 mg in the combination treatment arms. The 3+3 design is used for the dose finding with a target DLT rate &lt; 33%. Results: to date 44 patients were enrolled into the trial with median age at 57, median KPS at 90. Median treatment cycle was 3 and 39% tumors were MGMT methylated. The highest safe dose for Anti-LAG-3 alone is 800 mg without a DLT. The safe dose for anti-CD137 alone arm is 8mg with 1 DLT, and 2 grade 3 elevated serum ALT at end of cycle 2. Combination arms of Anti-LAG-3 +anti-PD-1 (160 mg/240mg as the highest dose combination) had one DLT (hypertension) and no toxicities were seen in the combination arm of Anti-CD137+Anti-PD-1 (3 mg/240 mg). mOS was 14 months for anti-CD137 alone, 8 months for Anti-Lag-3, and 7 months for Anti-Lag-3 + Anti-PD-1. Correlative data will be discussed. Conclusions: The trial is ongoing. The RP2D is 800mg for anti-LAG-3 as a monotherapy and 8mg for anti-CD137. For the combination arms, 160 mg of Anti-LAG-3 and 240 mg of anti-PD-1 and 3 mg of anti-CD137 and 240 mg antiPD-1 were the RP2D. Clinical trial information: NCT02658981.

Safety and activity of a first-in-class oral HIF2-alpha inhibitor, PT2385, in patients with first recurrent glioblastoma (GBM).

2027 Background: Hypoxia inducible factor 2-alpha (HIF2a) mediates cellular responses to hypoxia and is overexpressed in GBM. PT2385 is an oral HIF2a inhibitor with in vivo activity against GBM. Methods: A two-stage single-arm open-label phase II study of adults with first recurrent GBM following chemoradiation with measurable disease was conducted through the Adult Brain Tumor Consortium. PT2385 was administered at the phase II dose (800 mg b.i.d.). The primary outcome was objective radiographic response (CR+PR); secondary outcomes were safety and survival. Exploratory objectives included PK (day 15 Cmin), PD, and pH-weighted amine-CEST MRI to quantify tumor acidity at baseline and explore associations with drug response. Stage 1 enrolled 24 patients with early stoppage for ≤1 response. Results: Of the 24 patients, mean age was 61±11 years, median KPS 80, MGMT promoter methylated in 46%. PT2385 was well tolerated. Grade ≥3 drug-related AEs were hypoxia (n = 2), anemia (1), hyperglycemia (1), hyponatremia (2) and lymphopenia (2). No objective radiographic responses were observed; median PFS was 1.8 months (95%CI 1.6-3.1). Drug exposure varied widely (Table) and did not differ by corticosteroid use (p = 0.12), antiepileptics (p = 0.09), or sex (p = 0.37). Patients with high systemic exposure had significantly longer PFS (6.7 vs 1.8 months, 0.009). Non-enhancing infiltrative disease with high acidity gave rise to recurrence. Baseline acidity correlated significantly with treatment duration (R2= 0.49, p = 0.017). Conclusions: Drug exposure to PT2385 was variable. Signals of activity were observed in GBM patients with high systemic exposure and acidic (e.g. hypoxic) lesions on baseline imaging. A second-generation HIF2a inhibitor is being studied. Clinical trial information: NCT03216499. [Table: see text]

Phase I study of AZD1775 with radiation therapy (RT) and temozolomide (TMZ) in patients with newly diagnosed glioblastoma (GBM) and evaluation of intratumoral drug distribution (IDD) in patients with recurrent GBM.

2005 Background: The standard of care treatment for newly diagnosed GBM is maximal safe surgical resection followed by two DNA damaging agents, RT and TMZ. Cellular response to DNA damage involves checkpoints that halt the cell cycle to allow DNA repair. AZD1775 is an oral small molecular inhibitor of a nuclear tyrosine kinase Wee1, a key regulator of the G2/M checkpoint. Abrogation of the G2/M checkpoint prevents repair and pushes cells into mitosis with unrepaired DNA damage. AZD1775 was shown to enhance TMZ and RT effects in preclinical models. Methods: The Adult Brain Tumor Consortium 1202 trial (NCT01849146) is a phase I, open label, multicenter dose-finding study of AZD1775 in combination with standard RT and TMZ followed by an IDD study for patients undergoing surgery for recurrent GBM. The dose finding portion is comprised of two arms, one with AZD1775 given Monday through Friday during concurrent RT/TMZ and a second arm given with adjuvant TMZ qd x 5d/28d cycle. Each arm had standard 3+3 design. A combination cohort with both concurrent and adjuvant AZD1775 at MTD and analysis of PK/PD and IDD at MTD in patients undergoing surgery for recurrent GBM followed. Results: 51 patients enrolled in the dose finding arms. For the concurrent arm, the MTD was 200 mg. At 275 mg one patient had grade 3 fatigue and another had grade 4 thrombocytopenia and neutropenia. Two of 6 total patients enrolled at 200 mg experienced DLTs (grade 4 neutropenia and grade 3 ALT elevation). The MTD for the adjuvant arm was 425 mg as 1 of 6 patients had DLT (grade 4 decrease in ANC). At 500 mg, 2 of 3 patients experienced intolerable diarrhea despite prophylaxis. Enrollment in the combination cohort is completed and evaluation of safety is underway. The drug concentration in contrast enhancing and non-enhancing brain tumor was 4-8 x and 0.5-2.6 x greater than plasma, respectively for patients on IDD portion. Conclusions: The MTD for AZD1775 in combination with RT/TMZ is 200 mg qd M-F with concurrent RT/TMZ and 425 mg qd x 5d/28d cycle in combination with adjuvant TMZ. IDD and PK/PD analysis is ongoing to inform the decision to proceed to phase II testing. Clinical trial information: NCT01849146.

The role of tumor board conferences in neuro-oncology: a nationwide provider survey.

The tumor board or multidisciplinary cancer meeting (MCM) is the foundation of high value multidisciplinary oncology care, coordinating teams of specialists. Little is known on how these meetings are implemented in Neuro-oncology. Benefits of MCMs include coordination, direction for complicated cases, education, and a forum for communication, emerging technology, and clinical trials. This study identifies participation and utilization of neuro-oncology MCMs. A cross-sectional descriptive survey was dispersed through an internet questionnaire. The Society of Neuro-Oncology and the American Brain Tumor Association provided a list of dedicated neuro-oncology centers. All National Cancer Institute designated centers, and participants in the Adult Brain Tumor Consortium or the Brain Tumor Trials Collaborative were included, identifying 85 centers. Discussion included primary brain tumors (100%), challenging cases (98%), recurrent disease (96%), neoplastic spine disease (93%), metastatic brain lesions (89%), pre-surgical cases (82%), pathology (76%), and paraneoplastic disease (40%). MCMs were composed of neuro-oncologists, neurosurgeons, and radiation oncologists (100%), radiologists (98%), pathologists (96%), and clinical trial participants (64%). Individual preparation ranged from 15 to 300min. MCMs were valued for clinical decision making (94%), education (89%), and access to clinical trials (69%). 13% documented MCMs in the medical record. 38% of centers used a molecular tumor board; however, many commented with uncertainty as to how this is defined. Neuro-oncology MCMs at leading U.S. institutions demonstrate congruity of core disciplines, cases discussed, and perceived value. We identified variability in preparation time and implementation of MCM recommendations. There is high uncertainty as to the definition and application of a molecular tumor board.

EPID-04. TUMOR BOARD CONFERENCES IN NEURO-ONCOLOGY: A NATIONWIDE PROVIDER SURVEY

Tumor board or multidisciplinary cancer meetings (MCM) are the centerpiece of coordinated specialized neuro-oncology care. Little is known on how these meetings are implemented. Benefits of MCM include coordination, direction for complicated cases, education, and a forum for communication, emerging technology, and clinical trials. This study identifies participation and utilization of neuro-oncology MCM with the goal of improving practice patterns and establishing models for high value care. A cross-sectional descriptive internet survey was used. 85 neuro-oncology centers were identified by the Society for Neuro-Oncology and the American Brain Tumor Association. In addition, NCI designated cancer centers, participants in the Adult Brain Tumor Consortium, or the Brain Tumor Trials Collaborative were asked to participate. 46 centers completed the survey. All centers reviewed primary brain tumors, 93% discussed neoplastic spine disease, 89% metastatic brain lesions, 40% paraneoplastic disease. 98% discuss “challenging cases”, 96% recurrent disease, 82% undiagnosed or pre-surgical cases, 89% utilize radiology review. 100% of MCM included Neuro-Oncologists, Neurosurgery, and Radiation Oncology; Radiologist 98%, Pathologist 96%, and clinical trials 64%. Geneticist, Behavioral Health, and Social Work less than 15%. 76% reviewed Pathology. 80% meet weekly, and 36% include satellite centers. Individual preparation time varied 15-300 minutes. 94% value MCM for clinical decision-making, access to clinical trials 69%, and education 89%. Only 13% document MCM in the medical record. 38% of centers use a molecular tumor board, however many commented with uncertainty as to how this is defined. Neuro-oncology MCMs at leading U.S. institutions show high congruity of core disciplines, cases discussed, and perceived value. There is strong agreement on the role of clinical decision making and education, but the implementation of recommendations varies widely. We identified marked variability in preparation time, documentation, and high uncertainty as to the definition and application of a molecular tumor board.

Repeatability of 18F-FLT PET in a Multicenter Study of Patients with High-Grade Glioma.

Quantitative 3'-deoxy-3'-18F-fluorothymidine (18F-FLT) PET has potential as a noninvasive tumor biomarker for the objective assessment of response to treatment. To guide interpretation of these quantitative data, we evaluated the repeatability of 18F-FLT PET as part of a multicenter trial involving patients with high-grade glioma. Methods:18F-FLT PET was performed on 10 patients with recurrent high-grade glioma at 5 different institutions within the Adult Brain Tumor Consortium trial ABTC1101. Data were acquired according to a double baseline protocol in which PET examinations were repeated within 2 d of each other with no intervening treatment. On each of the 2 imaging days, dedicated brain PET was performed at 2 time points, 1 and 3 h after 18F-FLT administration. Tumor SUVs and related parameters were measured at a central laboratory using various volumes of interest: isocontour at 30% of the maximum pixel (SUVmean_30%), gradient-based segmentation (SUVmean_gradient), the maximum pixel (SUVmax), and a 1-mL sphere at the region of highest uptake (SUVpeak). Repeatability coefficients (RCs) were calculated from the relative differences between corresponding SUV measurements obtained on the 2 d. Results: RCs for tumor SUVs were 22.5% (SUVmean_30%), 23.8% (SUVmean_gradient), 23.2% (SUVmax), and 18.5% (SUVpeak) at 1 h after injection. Corresponding data at 3 h were 22.4%, 25.0%, 27.3%, and 23.6%. Normalizing the tumor SUV data with reference to a background region improved repeatability, and the most stable parameter was the tumor-to-background ratio derived using SUVpeak (RC, 16.5%). Conclusion: SUV quantification of 18F-FLT uptake in glioma had an RC in the range of 18%-24% when imaging began 1 h after 18F-FLT administration. The volume-of-interest methodology had a small but not negligible influence on repeatability, with the best performance obtained using SUVpeak Although changes in 18F-FLT SUV after treatment cannot be directly interpreted as a change in tumor proliferation, we have established ranges beyond which SUV differences are likely due to legitimate biologic effects.

Repurposing and Rescuing of Mibefradil, an Antihypertensive, for Cancer: A Case Study

The expanding "valley of death" in drug development is leaving potentially life-saving new chemical entities and molecular targets fallow. This situation is forcing early-stage companies to think creatively about moving their technologies forward, especially as institutional investors show more interest in later stages of development. Drug repurposing, a strategy to examine existing drugs for therapeutic value against different diseases, is an emerging method to bring an off-market drug back onto the market. Tau Therapeutics LLC identified the role of T-type calcium channel blockers (Cav3) in cancer proliferation, but the company was unable to attract funding while having both a nonvalidated drug target and new chemical entities. To change the risk profile of the company, Tau set out to repurpose the known Cav3 drug mibefradil as a proof of concept for the treatment of cancer. Mibefradil was launched for hypertension in the 1990s but withdrawn because of drug-drug interactions. A new sequential combination treatment, termed Interlaced Therapy™, uses short-term administration of mibefradil to enhance the overall therapeutic potential of conventional anticancer agents. Mibefradil is currently in a phase Ib clinical trial with the National Cancer Institute (NCI) Adult Brain Tumor Consortium. Mibefradil has been repurposed from an abandoned antihypertensive to a targeted solid tumor treatment, and it has been rescued from drug-drug interactions by using short-term dose exposure. Tau is using the early success of mibefradil as a proof of concept to build a platform technology of Cav3 blockers for broad antitumor applications in combination with new targeted cancer therapies, well-established chemotherapies, and radiation.