Recurrent High Grade Research Articles

Advances in immunotherapeutic research for glioma therapy.

Gliomas are primary malignancies of the brain. Tumors are staged based on malignancy, nuclear atypia, and infiltration of the surrounding brain parenchyma. Tumors are often diagnosed once patients become symptomatic, at which time the lesion is sizable. Glioblastoma (grade IV glioma) is highly aggressive and difficult to treat. Most tumors are diagnosed de novo. The gold standard of therapy, implemented over a decade ago, consists of fractionated radiotherapy and temozolomide, but unfortunately, chemotherapeutic resistance arises. Recurrence is common after initial therapy. The tumor microenvironment plays a large role in cancer progression and its manipulation can repress progression. The advent and implementation of immunotherapy, via manipulation and activation of cytotoxic T cells, have had an outstanding impact on reducing morbidity and mortality associated with peripheral cancers under certain clinical circumstances. An arsenal of immunotherapeutics is currently under clinical investigation for safety and efficacy in the treatment of newly diagnosed and recurrent high grade gliomas. These immunotherapeutics encompass antibody-drug conjugates, autologous infusions of modified chimeric antigen receptor expressing T cells, peptide vaccines, autologous dendritic cell vaccines, immunostimulatory viruses, oncolytic viruses, checkpoint blockade inhibitors, and drugs which alter the behavior of innate immune cells. Effort is focusing on determining which patient populations will benefit the most from these treatments and why. Research addressing synergism between treatment options is gaining attention. While advances in the treatment of glioma stagnated in the past, we may see a considerable evolution in the management of the disease in the upcoming years.

Usefulness of apparent diffusion coefficient value and proton magnetic resonance spectroscopy as a noninvasive techniques in recurrent cerebral gliomas

ObjectiveConventional MRI does not provide sufficient information to differentiate post-radiotherapy necrosis from brain tumor recurrence, recent studies have investigated the use of more advanced imaging modalities that are able to differentiate between the two entities. Aim of the studyTo assess the usefulness of combined apparent diffusion coefficient (ADC) value and single voxel spectroscopy (SVS) in the differentiation between recurrent brain gliomas and post-radiotherapy necrosis. MethodsTwenty-two patients with suspected tumor recurrence after surgical resection and radiotherapy treatment were included in our study. MRI with contrast, diffusion weighted MRI with ADC value and MR spectroscopy were done to all patients. ResultsADC values were ≤1.150 × 10−3 mm2/sec for recurrent high grade gliomas, >1.150–≤1.370 × 10−3 mm2/sec for recurrent low grade gliomas and >1.370 × 10−3 mm2/sec for post radiation necrosis. NAA/Cr ratio could significantly differentiate between recurrent gliomas and post radiation necrosis (p value = .019), also Cho/Cr was significant p value = .006. Also NAA/Cr and Cho/Cr were statistically significant in differentiating recurrent high grade from low grade gliomas (p value < .001). ConclusionCombination of calculated ADC value and MR spectroscopy added more information and increase the accuracy of conventional MR imaging in the differentiation of patients with suspected recurrent brain glioma from post-radiotherapy necrosis.

Re-irradiation for recurrent glioma- the NCI experience in tumor control, OAR toxicity and proposal of a novel prognostic scoring system

Purpose/objectivesDespite mounting evidence for the use of re-irradiation (re-RT) in recurrent high grade glioma, optimal patient selection criteria for re-RT remain unknown. We present a novel scoring system based on radiobiology principles including target independent factors, the likelihood of target control, and the anticipated organ at risk (OAR) toxicity to allow for proper patient selection in the setting of recurrent glioma.Materials/methodsThirty one patients with recurrent glioma who received re-RT (2008–2016) at NCI – NIH were included in the analysis. A novel scoring system for overall survival (OS) and progression free survival (PFS) was designed to include:1) target independent factors (age, KPS (Karnofsky Performance Status), histology, presence of symptoms), 2) target control, and 3) OAR toxicity risk. Normal tissue complication probability (NTCP) calculations were performed using the Lyman model. Kaplan-Meier analysis was performed for overall survival (OS) and progression free survival (PFS) for comparison amongst variables.ResultsNo patient, including those who received dose to OAR above the published tolerance dose, experienced any treatment related grade 3–5 toxicity with a median PFS and OS from re-RT of 4 months (0.5–103) and 6 months (0.7–103) respectively. Based on cumulative maximum doses the average NTCP was 25% (0–99%) for the chiasm, 21% (0–99%) for the right optic nerve, 6% (0–92%) for the left optic nerve, and 59% (0–100%) for the brainstem. The independent factor and target control scores were each statistically significant for OS and the combination of independent factors plus target control was also significant for both OS (p = 0.02) and PFS (p = 0.006). The anticipated toxicity risk score was not statistically significant.ConclusionOur scoring system may represent a novel approach to patient selection for re-RT in recurrent high grade glioma. Further validation in larger patient cohorts including compilation of doses to tumor and OAR may help refine this further for inclusion into clinical trials and general practice.

ATIM-18. A PHASE I TRIAL OF HYPOFRACTIONATED STEREOTACTIC IRRADIATION (HFSRT) WITH PEMBROLIZUMAB AND BEVACIZUMAB IN PATIENTS WITH RECURRENT HIGH GRADE GLIOMA (NCT02313272)

There is strong pre-clinical evidence for the combination of PD-1 blockade with radiotherapy and anti-VEGF therapy. Herein, we present safety and efficacy data from a phase 1 study combining pembrolizumab, an anti-PD-1 monoclonal antibody, with hypofractionated stereotactic irradiation (HFSRT) and bevacizumab in recurrent high grade glioma. This phase I study (3 + 3 design) explored the safety, tolerability, recommended phase II dose (RP2D), and antitumor activity of pembrolizumab administered concurrently with HFSRT and bevacizumab. Adult patients with recurrent glioblastoma or anaplastic astrocytoma (maximum diameter of target lesion ≤ 3.5 cm) were eligible. Eligible patients received HFSRT to the recurrent tumor (30 Gy in 5 fractions) combined with bevacizumab (10 mg/kg, Q2W) and pembrolizumab (100 mg or 200 mg intravenously based on dose level, Q3W). Two dose levels of pembrolizumab were explored and 20 patients were treated at RPD2. Treatment continued until disease progression or unacceptable toxicity. Twenty three patients with recurrent glioblastoma have been treated on this study (3 patients at 100 mg and 20 patients at 200 mg dose levels). Five patients had previous tumor progression on bevacizumab. Combination of HFSRT with pembrolizumab (200 mg every 3 weeks) and bevacizumab was generally well tolerated. The most common toxicities were grade 1 fatigue and grade 1 proteinuria. No treatment-related neurologic adverse events were observed. In 1 patient, study treatment was discontinued due to grade 3 elevation of liver transaminases. Durable objective responses (complete response + partial response ≥ 6 months) were observed in 53% of patients. The overall survival rate (at the time of abstract submission) at 6 and 12 months were 94% (16 out of 17 patients) and 64% (7 out of 11 patients), respectively. Combination of HFSRT with pembrolizumab (200 mg every 3 weeks) and bevacizumab is safe. Clinical activity of this combination therapy is encouraging.

ACTR-69. PHASE I TRIAL OF TG02 PLUS DOSE-DENSE OR METRONOMIC TEMOZOLOMIDE FOR ADULTS WITH RECURRENT ANAPLASTIC ASTROCYTOMA AND GLIOBLASTOMA

Most therapies for recurrent high grade gliomas have not been successful, largely due to the complexity of the disease. Our preclinical studies have demonstrated the anti-glioma effects of TG02 and the synergy with temozolomide (TMZ) through modulation of transcription and metabolism. We hypothesize that given the multiple mechanisms of TG02 and established efficacy of TMZ, combined treatment may be effective for malignant gliomas. We launched a phase I/II trial and herein report the phase I results. Adults with recurrent high-grade astrocytoma, KPS ≥ 60, normal organ function, no more than 2 prior relapses, and no prior bevacizumab were enrolled. A Bayesian Optimal Interval design was employed to determine the maximum tolerated dose (MTD) and the toxicity profile of the combination of TG02 (starting dose 200mg orally on days 1, 12, 15, and 26) and TMZ, either as a dose-dense (DD; 125mg/m2/d, 7on/7off) or metronomic (MN; 50mg/m2/d) dosing schedule on a 28-day cycle. A total of 15 patients have been enrolled; 80% are male, median age 50.6. Nine patients were enrolled in DD TMZ arm; 1/6 receiving TG02 at 200mg had grade 4 diarrhea, a dose-limiting toxicity (DLT); 1/3 patients receiving TG02 at 250mg in the DD arm had grade 4 neutropenia, a DLT. In MN TMZ arm, 0/3 patients receiving TG02 at 200mg had a DLT. 1/3 patients receiving TG02 at 250mg had a DLT of grade 4 lymphopenia. To date, although not a primary endpoint, 2 partial objective responses have been observed in ongoing patients receiving 200mg TG02 in combination with TMZ. The combination of TG02 at 200mg and DD/MN TMZ is well tolerated. Dose escalation continues in both DD/MN arms (currently at TG02 250mg) with determination of MTD anticipated soon. Additionally, objective responses have been observed suggesting activity for this regimen.

Diagnosis and treatment of recurrent high grade glioma

High grade glioma is a kind of malignant brain tumor with strong invasiveness, which progresses commonly after initial treatments and shows high mortality. Early diagnosis of tumor recurrence and highly-individualized systemic treatment mean significance to prolong survival. Multi-mode magnetic resonance imaging and molecular imaging play important roles in differential diagnosis and prognosis evaluation for recurrence. Therapeutic strategies like re-operation, re-irradiation, electric field technology, chemotherapy, targeted therapies and immunotherapeutic approaches are expected to bring survival benefits for patients with recurrent high grade glioma. Key words: Glioma; Recurrence; High-grade

Suspicious for recurrent low and high grade glioma and indeterminate MRI: the role of 18F-DOPA PET/CT

1691 Objectives: ACKGROUND. The aim of present study was to assess the role of 18F-FDOPA PET/CT in patients who had a suspicious forrecurrent low and high grade glioma but with an indeterminate MRI.MATERIALS AND METHODS . From a monocentric database, we retrospectively analyzed 21 patients (median age: 60 yrs;19-80) who underwent 18F- DOPA PET/CT for the restaging of low and high grade glioma. All PET/CT images werere-examined by two nuclear medicine physicians. Both visual and semiquantitative analysis was used for the interpretation ofimages. At visual analysis, PET/CT was defined as positive in case of a DOPA uptake in the lesion (identified by MRI) higherthan controlateral striatum uptake. For the semiquantitative analysis, the ratios between SUVmax of the lesion and SUVmax ofthe striatum (T/S)/normal brain tissue (T/B) equal to 1 and 2 respectively were used. Clinical reassessment consisted of standardevaluation including MRI and assessment of neurological symptoms. The agreement between visual and semiquantitativeanalysis was obtained by k statistical analysis. Diagnostic performance was calculated by standard methods.RESULTS. Six patients had a low grade glioma and 14 a high grade. At visual analysis, 15 (75%) patients had a positive PET/CTresult, in particular 4 with a low grade glioma and 11 with a high grade (67% and 79%, respectively). Based onsemiquantitative analysis, 14 (70%) and 14 (70%) patients had a positive PET/CT, respectively for T/S and T/B. The agreementbetween visual and semiquantitative analysis was 88% (p

Phase 1 Study of Alisertib With Concurrent Fractionated Stereotactic Radiation Treatment for Recurrent High Grade Gliomas

Phase 1 Study of Alisertib With Concurrent Fractionated Stereotactic Radiation Treatment for Recurrent High Grade Gliomas

A Comparison of Outcomes in Recurrent High Grade Gliomas Treated With Hypofractionated Stereotactic Radiation Therapy With or Without Programmed Cell Death Protein 1 (PD-1) Blockade

A Comparison of Outcomes in Recurrent High Grade Gliomas Treated With Hypofractionated Stereotactic Radiation Therapy With or Without Programmed Cell Death Protein 1 (PD-1) Blockade

Predictive biomarkers of resistance to hypofractionated radiotherapy in high grade glioma

BackgroundRadiotherapy plays a major role in the management of high grade glioma. However, the radioresistance of glioma cells limits its efficiency and drives recurrence inside the irradiated tumor volume leading to poor outcome for patients. Stereotactic hypofractionated radiotherapy is one option for recurrent high grade gliomas. Optimization of hypofractionated radiotherapy with new radiosensitizing agents requires the identification of robust druggable targets involved in radioresistance.MethodsWe generated 11 xenografted glioma models: 6 were derived from cell lines (1 WHO grade III and 5 grade IV) and 5 were patient derived xenografts (2 WHO grade III and 3 grade IV). Xenografts were treated by hypofractionated radiotherapy (6x5Gy). We searched for 89 biomarkers of radioresistance (39 total proteins, 26 phosphoproteins and 24 ratios of phosphoproteins on total proteins) using Reverse Phase Protein Array.ResultsBoth type of xenografted models showed equivalent spectrum of sensitivity and profile of response to hypofractionated radiotherapy. We report that Phospho-EGFR/EGFR, Phospho-Chk1/Chk1 and VCP were associated to resistance to hypofractionated radiotherapy.ConclusionsSeveral compounds targeting EGFR or CHK1 are already in clinical use and combining them with stereotactic hypofractionated radiotherapy for recurrent high grade gliomas might be of particular interest.

Abstract CT008: Phase I study of the alpha specific PI3-Kinase inhibitor BYL719 and the poly (ADP-Ribose) polymerase (PARP) inhibitor olaparib in recurrent ovarian and breast cancer: Analysis of the dose escalation and ovarian cancer expansion cohort

Abstract Background: In vivo synergy with concurrent PI3-Kinase inhibition and PARP inhibition has been observed in BRCA-deficient and BRCA-proficient preclinical models of triple negative breast cancer (TNBC) and ovarian cancer (OC). A phase I trial of the oral pan-class I PI3-Kinase inhibitor BKM120 and the PARP inhibitor olaparib demonstrated anti-cancer activity in TNBC and OC, both in patients with and without germline BRCA1 and BRCA2 (BRCA) mutations. However, CNS toxicity (depression) and liver function test abnormalities limited dose escalation of BKM120 prompting evaluation of the alpha specific PI3-Kinase inhibitor BYL719 (which has no CNS toxicity) in combination with olaparib. Methods: Olaparib was administered twice daily (tablet formulation) and BYL719 daily on a 28-day cycle, both orally. A 3 + 3 dose-escalation design was employed with primary objectives of defining the maximum tolerated dose (MTD) and recommended phase 2 dose of the combination of BYL719 and olaparib, and secondary objectives of defining toxicity, activity, and pharmacokinetic profiles of both agents. Eligibility included recurrent TNBC or high grade serous (HGS) OC, or any histology OC or breast cancer (BC) with presence of a known germline BRCA mutation, performance status of 0-1 and measurable/evaluable cancer. Patients with platinum sensitive or resistant or refractory OC were eligible and prior PARP inhibitor use was allowed. Dose-expansion cohorts at the MTD were enrolled for both BC and OC. Results: 46 patients (16 BC and 30 OC) have been enrolled in the study; 28 patients participated in the dose escalation portion of the study (4 BC and 24 OC). Two patients with OC did not receive study drugs because of ineligibility. MTD was defined as BYL719 200mg once daily and olaparib 200mg twice daily. Dose limiting toxicities included hyperglycemia, rash and fever with decreased neutrophil count. Four patients (3 OC and 1 BC) discontinued protocol therapy because of toxicity (2 for hyperglycemia, 1 for nausea and 1 for allergic reaction). Most common toxicities included nausea, hyperglycemia, fatigue, diarrhea and vomiting. At the MTD, 6 patients with OC and 12 patients with BC were enrolled into a dose expansion cohort. The OC expansion cohort has completed enrollment, while the BC cohort is still enrolling. Among patients with OC who received study drugs (28 patients, 26 (93%) with platinum resistant disease), objective response rate (ORR) by RECIST 1.1 was 36% (10/28 patients, all partial responses (PRs)). Median duration of response was 167 days (range 16-398 days); 5 of 10 patients with PR remain on treatment. ORR was 33% for patients with germline BRCA mutations and 31% for patients without germline BRCA mutations. Among patients without germline BRCA mutations with platinum resistant OC, ORR was 29%. Conclusions: Combined BYL719 and olaparib is feasible, and similar clinical benefit was observed in patients with and without germline BRCA mutations. The activity of this combination in OC patients without germline BRCA mutations and with platinum resistant disease was higher than expected from olaparib monotherapy and warrants further investigation. This work was funded in part by the Stand Up To Cancer Ovarian Dream Team. Clinical trial: NCT01623349. Citation Format: Panagiotis A. Konstantinopoulos, William T. Barry, Michael Birrer, Shannon N. Westin, Sarah Farooq, Karen Cadoo, Christin Whalen, Weixiu Luo, Hui Liu, Carol Aghajanian, David B. Solit, Gordon B. Mills, Barry S. Taylor, Helen Won, Michael F. Berger, Sangeetha Palakurthi, Joyce F. Liu, Lew Cantley, Scott H. Kaufmann, Elizabeth M. Swisher, Alan D. D'Andrea, Eric Winer, Gerburg M. Wulf, Ursula A. Matulonis. Phase I study of the alpha specific PI3-Kinase inhibitor BYL719 and the poly (ADP-Ribose) polymerase (PARP) inhibitor olaparib in recurrent ovarian and breast cancer: Analysis of the dose escalation and ovarian cancer expansion cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT008. doi:10.1158/1538-7445.AM2017-CT008

Abstract LB-301: PLK1 inhibitor targets mismatch repair-deficient temozolomide-resistant tumors

Abstract Background: Mismatch repair (MMR) deficiency through MSH6 alteration has been identified in approximately 30% of recurrent high grade gliomas, and represents a key molecular mechanism for the development of acquired resistance to the alkylating agent temozolomide (TMZ). Additionally, glioma progression post-TMZ treatment is frequently accompanied by distinct genomic alterations such as amplification of the MYC locus and resulting signaling activation. There is an urgent need to establish new treatment strategies that do not rely upon MMR to target MMR deficient, TMZ resistant glioma. Methods: We first screened 14 compounds that modulate DNA damage response for their ability to suppress viability of an MSH6 knockdown, TMZ resistant glioma cell line. Efficacy of PLK1 inhibitors and combination with TMZ were assessed in glioblastoma cells lines and patient-derived glioblastoma neurosphere lines engineered with MSH6 silencing, MYC overexpression and controls. Impacts of PLK1 blockade on cell cycle distribution, apoptosis, and DNA damage effects were examined. Results: The compound screening indentified PLK1 selective inhibitor, volasertib, as the most potent inhibitor of proliferation of both MMR intact and deficient glioblastoma cells. PLK1 inhibition induced G2/M cell cycle arrest, DNA damage and caspase-mediated apoptosis in glioblastoma cells, but no detectable toxicity in normal human astrocytes. Importantly, beneficial therapeutic effects of PLK1 inhibitors were not influenced by MMR deficiency due to MSH6 knockdown, whereas PLK1 inhibition had no additive or synergic effect when combined with TMZ. Furthermore, we found that MYC overexpression sensitized glioblastoma cells to PLK1 inhibitors. Conclusions: Selective PLK1 inhibitors are potently cytotoxic to glioblastoma and their action is independent of MMR status of the cells. Cells with deregulated MYC are vulnerable to PLK1 inhibition suggesting genomic MYC alteration as a biomarker for PLK inhibitor sensitivity. Thus PLK inhibitor represents a novel therapeutic option for MMR deficient TMZ resistant recurrent gliomas, particularly those driven by MYC. Citation Format: Fumi Higuchi, Daniel P. Cahill, Hiroaki Wakimoto. PLK1 inhibitor targets mismatch repair-deficient temozolomide-resistant tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-301. doi:10.1158/1538-7445.AM2017-LB-301

Abstract AP01: HE4 IS A BIOMARKER FOR NEWLY DIAGNOSED AND RECURRENT HIGH–GRADE SEROUS OVARIAN CANCERS WITH NORMAL CA–125 VALUES

Abstract PURPOSE: CA125 is widely used for the diagnosis and monitoring of women with epithelial ovarian cancer. However, CA125 will not be elevated in ~20% of patients. Human epididymis protein 4 (HE4) was approved by the FDA in 2008 to monitor ovarian cancer. The objective of this study was to evaluate whether HE4 would serve as a useful biomarker in patients with a normal CA125 at either the time of diagnosis or at the time of recurrence. METHODS: Twenty–one patients with high–grade serous ovarian cancer and CA125 values &amp;lt;50U/ml at the time of diagnosis were identified from a bank of serum specimens collected between 2006–2012. Twenty patients with high–grade serous ovarian cancer and CA125 values &amp;gt;1000U/ml served as positive controls and 11 patients without disease served as negative controls. Fourteen patients with an elevated CA125 at diagnosis (&amp;gt;50 U/ml) and a normal CA125 at the time of recurrence were also identified. HE4 was measured using the Abbott Architect i2000 assay and validation was performed using the Fujirebio HE4 ELISA assay. Normal age–based HE4 values were obtained from the published literature (Urban N, et al.; PMID: 22962406). Data was compared between groups using standard two–sided statistical tests. RESULTS: At the time of diagnosis, the mean HE4 was 1082±437.9 in the positive control patients with elevated CA125, the mean HE4 was 50.96±11.43 in the patients without disease, and 214.4±236.9 in patients with a normal CA–125 (P = &amp;lt;.0001 compared to normal controls; Student's t–test). At the time of recurrence, the mean HE4 was 102.7±83.29 in patients with normal CA125 levels. For 12 of 14 (86%) patients, the HE4 value was greater than the expected normal age–based reference. CONCLUSIONS: These preliminary data suggest that HE4 values are elevated in newly diagnosed ovarian cancer patients with a normal CA125 value. HE4 also appears to be a potentially useful biomarker for detecting recurrent disease in patients with an elevated CA125 at the time of diagnosis who have a normal CA125 level at the time of recurrence. Citation Format: Katherine LaVigne, MD, Fanny Dao, MS, Nadeem Abu–Rustum, MD, Petar Jelinic, PhD, Lakshmi V. Ramanathan, PhD, Martin Fleisher, PhD, Douglas A. Levine, MD. HE4 IS A BIOMARKER FOR NEWLY DIAGNOSED AND RECURRENT HIGH–GRADE SEROUS OVARIAN CANCERS WITH NORMAL CA–125 VALUES [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr AP01.

A multicenter phase II study of the efficacy and safety of quisinostat (an HDAC inhibitor) in combination with paclitaxel and carboplatin chemotherapy (CT) in patients (pts) with recurrent platinum resistant high grade serous epithelial ovarian, primarily peritoneal or fallopian tube carcinoma cancer (OC).

5541 Background: Quisinostat is an orally bioavailable potent pan-histone deacetylase inhibitor. Combinations of HDAC inhibitors with paclitaxel or cisplatin demonstrate promising results in preclinical models with cisplatin and paclitaxel resistant OC. In phase Ib study the dosage of Quisinostat in combination of paclitaxel and carboplatin recommended for the phase II study was 12 mg. We report results of the phase II study of Quisinostat in combination with paclitaxel and carboplatin in pts with recurrent platinum resistantOC. Methods: the main inclusion criteria was tumor progression observed not less than 1 month and no more than 6 months after completion of the planned number of cycles of 1st line platinum/paclitaxel based CT. Quisinostat was administered at dose 12 mg p.o. each 3 week cycle on Days 1, 3, 5, 7, 9, 11 with of paclitaxel (175 mg/m2) and carboplatin (AUC5) on Day 7 of each cycle, for 2ndline. Pts received up to 6 cycles. The primary efficacy endpoint is the objective response rate (ORR) verified by the ICR. The secondary endpoints include safety, progression free survival (PFS) and overall survival. The study design implies the use of the two-stage Simon model: 29 patients who underwent treatment would provide 80% power for hypothesis testing in order to frequency of the ORR 30% (α = 0.05). Results: 31 pts were enrolled (30 pts evaluated). Median age was 57 years. Twenty one pts (67.7%) received all 6 cycles of therapy. ORR was 50.0% (15 pts). Median duration of response was 5 months (4.2-5.7). Median PFS - 6 months (95%CI 4.4-7.6). Any SAE were seen in 16.1% pts, AE of grade 3 and 4 – in 71% and 48.4% pts temporarily discontinued therapy due to AE. Dose reduction of CT due to AE was performed in 22.6% pts. The most common adverse events were neutropenia – 67,7%, nausea – 61.3%, weakness – 29%, thrombocytopenia – 22.6%, neuropathy – 19.4%, vomiting – 19.4%. Conclusions: Quisinostat in combination with paclitaxel and carboplatin in pts with recurrent platinum resistant ovarian cancer showed high efficacy and good tolerability Clinical trial information: NCT02948075.

Final report of a phase I study of 2-hydroxyoleic acid (2OHOA) a novel sphingomyelin synthase activator in patients (pt) with advanced solid tumors (AST) including recurrent high grade gliomas (rHGG).

2554 Background: 2OHOA is an orally bioavailable, first-in-class synthetic hydroxylated fatty acid, that activates SGMS1 and modulates the lipid content of cancer cell membranes. This regulates the localization of key signaling proteins, including Ras and PKC at the plasma membrane, leading to inactivation of Ras/MAPK, PI3K/Akt and PKC/cyclin/CDK signaling pathways. A dose escalation (DE) and partial expansion cohorts (EC) results of the phase 1 study have previously been reported. We now present the final results of the study. Methods: 2OHOA was evaluated in a 3+3 DE design (7 cohorts from 500mg/d to 16000mg/d) and 2 EC at 4000mg TID in 21 days cycles. PK profiles were determined after single dose (fasted [D-7] or fed [D1]) and multiple doses (fed [D21]) during DE phase and only on D1 throughout EC.Safety assessments were based on CTCAEv4.Tumor response was measured by RECIST and RANO every 6 weeks. Results: Overall 54 pt (DE: 32 pt; 21AST/11rHGG; EC: 22 pt; 12 AST/10 rHGG) were treated (median age 60, range 19-78 years). During the EC the most common treatment related G1-G2 toxicities were diarrhea (n = 13;11pt),nausea (n = 7;6pt), ALT increase (n = 6;4pt), pruritus in throat (4pt), fatigue (4pt) and vomiting (3pt). No G3-G4 toxicities or DLTs were reported confirming the MTD from the DE at 4g TID. Food intake did not alter oral 2OHOA bioavailability. Steady state was already achieved at D8. Power model showed dose proportionality in terms of AUC and Cmax, after single and multiple BID dosing. Average t1/2 ranged from1-2h to 8-12h with delayed Tmax and longer half-lives at higher doses. One glioblastoma (GBM) pt had sustained partial response ( &gt; 2,5 years) and 4rHGG pt (3 GBM) achieved stable disease for at least 6 months. They had previously received 2 lines of treatment without bevacizumab. Tumor markers were measured and will be presented. Conclusions: 2OHOA is well tolerated at the P2RD of 4000mg TID PO daily. The preliminary antitumor activity including a sustained PR in heavy pretreated rHGG pt warrants further investigation in a Ph2 study Clinical trial information: NCT01792310.

PD-L1 expression of high grade glial tumors at diagnosis and change of expression status at recurrence.

2035 Background: PD-L1 expression status is the main predictive factor for response to immune checkpoint inhibitors. PD-L1 status may change over time with the impact of therapies. The aim of this study is to determine if PD-L1 expression status changes in recurrent gliomas after chemoradiotherapy. Methods: Thirty eight patients with recurrent high grade gliomas who had surgical excision at least two times were included in this retrospective cross-sectional study. Nine patients were excluded because of the lack of appropriate pathology slides for pathologic evaluation. PD-L1 expression of 29 patients was evaluated by an expert pathologist with immunohistochemical methods. PD-L1 positivity was defined as expression in ≥1% of tumor cells. Change in PD-L1 expression status was defined as an absolute 5% difference between two resections. Results: Of the 29 patients, 15 patients (51.7%) had PD-L1 expression in ≥1% of tumor cells and 7 patients (24.1%) had PD-L1 expression in ≥10% of tumor cells. Tumor PD-L1 expression (defined as expression in ≥1% of tumor cells) was positive in 15 (51.7%) of 29 patients at diagnosis and at the time of recurrence. The PD-L1 status did not change in 17 patients (58.6%). 8 patients had PD-L1 negative tumors both at diagnosis and at recurrence, while 9 patients had PD-L1 positive tumors both at diagnosis and at recurrence. In 6 patients (20.7%) a negative-to-positive switch and in 6 patients (20.7%) a positive to negative switch were seen. Tumor PD-L1 expression increased in 7 of 29 patients (24.1%) and decreased in 9 of 29 patients (31.1%). PD-L1 expression remained stable in 13 of 29 patients (34.4%). The change in PD-L1 status over time was not statistically significant. Conclusions: More than 50% of high grade glial tumors express PD-L1 at diagnosis, so these tumors are good candidates for immune checkpoint inhibitors. The expression status changes in more than 40% of high grade glial tumors at recurrence, so immune responsiveness of glial tumors can be modified by treatments like chemotherapy and radiotherapy.

A phase 2 study to determine the efficacy and safety of TVB-2640 in combination with bevacizumab in patients with first relapse of high grade astrocytoma.

TPS2080 Background: The mainstay of treatment for Glioblastoma Multiforme (GBM) remains surgical removal followed by combined chemotherapy with temozolomide and radiation therapy. Second line Bevacizumab (Bev) is indicated upon progression, but unfortunately the responses are not very long lasting, and there are no therapeutic options available at that point. We have learned that antiangiogenic resistance in GBM is promoted by hypoxia; moreover, metabolomic profile of GBM under such conditions reveals an increased presence of long chain fatty acids. On second hand, tumor cells compared to normal cells depend more on palmitate, and is Fatty Acid Synthase (FASN) the enzyme capable of catalyzing its biosynthesis. Further studies have shown how GBM overexpress FASN and how its inhibition selectively inhibits growth and viability of tumor cells by inducing tumor cell apoptosis. TVB-2640 emerges as a novel agent that selectively inhibits FASN. This study represents a phase 2 clinical investigation of TVB-2640, which is to be conducted in patients with Recurrent High Grade Astrocytoma. Methods: This is a prospective, randomized, phase 2 study of TVB-2640 in combination with Bev or Bev alone in patients with GBM in first relapse. Primary end point is progression free survival (PFS). Patients 18 years or older, with ECOG 0 to 2 and GBM progression following standard combined modality treatment will qualify for the study. Patients will be randomized into 2 separate arms. Patients in arm number one will receive Bev every 2 weeks in combination with TVB-2640 while patients in arm number two will receive Bev alone every 2 weeks. MR-Spectroscopy will be obtained on all patients at day 1 and 28 of first cycle. Starting on cycle 2 day 1, all patients will converge to a single arm and will continue to receive Bev in combination with TVB-2640. A total sample size of 24 patients will provide 90% power to detect a 4 months difference in PFS (3 months for Bev alone (historic controls) versus 7 months for TVB-2640 in combination with Bev, i.e., a hazard ratio of 0.43) using a one-sided log-rank test with alpha = 0.1. The trial is open and enrollment will begin in Feb 2017. Clinical trial information: NCT03032484.

Durable complete responses observed in IDH1 mutated high grade glioma at first recurrence undergoing treatment with Toca 511 and Toca FC.

e13504 Background: Toca 511 (vocimagene amiretrorepvec) is an investigational, conditionally lytic, retroviral replicating vector (RRV). RRVs selectively infect cancer cells due to cell division requirements for virus integration into the genome and defects in innate and adaptive immune responses found in cancers that support virus replication. Toca 511 spreads through cancer cells and stably delivers the gene for an optimized yeast cytosine deaminase that converts the prodrug Toca FC (an investigational, extended-release formulation of 5-fluorocytosine) into 5-fluorouracil (5-FU). 5-FU kills infected cancer cells that are dividing, diffuses and kills surrounding cancer cells as well as myeloid derived suppressor cells and tumor associated macrophages, thus reestablishing immunity to tumor. Methods: In this phase 1 trial (NCT01470794), ascending doses of Toca 511 were injected into the resection bed of patients with recurrent high grade glioma undergoing resection, followed by oral administration of courses of Toca FC 5-7 weeks after Toca 511 injection. Additional cohorts included combination of Toca 511 &amp; Toca FC with bevacizumab or lomustine. Results: Objective responses (ORs) are observed in IDH1 wildtype (wt) and mutant (mt) phenotypes, including 3 complete responses (CRs) (2 IDH1 mt and 1 IDH1 wt) and 2 partial responses (2 IDH1 wt) for patients treated with Toca 511 &amp; Toca FC, and 1 CR (1 IDH1 mt) for a patient treated with Toca 511 &amp; Toca FC and bevacizumab. ORs are observed 6-19 months after Toca 511 injection and are consistent with an immunologic mechanism. Median time to initial response is 9.2 months; median duration of response (mDOR) is 25.2 months. Excluding the combination cohorts, mDOR is 26.7 months. All responders are alive 21.2+ to 42.6+ months, suggesting a correlation of OR and OS. An additional radiologic CR is observed in 1 IDH1 mt patient at 1st recurrence who received intravenous Toca 511 plus injection into the resection bed. All 4 IDH1 mt patients treated at 1st recurrence had CRs. Conclusions: There may be an association between ORs and IDH1 mutation with Toca 511 &amp; Toca FC treatment. Updated clinical benefit, molecular profiles and tumor mutational load are reported. Clinical trial information: NCT01470794.

Nivolumab combined with hypofractionated stereotactic irradiation (HFSRT) for patients with recurrent high grade gliomas: A phase I trial (NCT02829931).

TPS2084 Background: Nivolumab is an IgG4 monoclonal antibody that targets the PD-1 immune checkpoint pathway and prevents binding of PD-1 with PD-L1 and PD-L2. Expression of PD-1 and PD-L1 is found in the microenvironment of high grade gliomas and correlates with worse outcome providing a rationale for investigating nivolumab in this group of patients (pts) with very limited treatment options. Nivolumab monotherapy is well tolerated in recurrent glioblastoma pts. Preclinical studies have demonstrated that radiotherapy synergizes with anti PD-1/PD-L1 blockade and produces tumor regression and long-term survival in orthotopic murine models of glioma. This report describes an ongoing phase I trial of nivolumab in combination with HFSRT in pts with recurrent WHO grade III or IV gliomas. Methods: This phase I study includes a safety cohort of 6 pts followed by dose expansion cohort of 20 pts (NCT02829931). Pts with bevacizumab naïve recurrent WHO grade III or IV gliomas (maximum diameter of enhancing brain lesion ≤ 4 cm) are eligible. An interval of at least 6 months after the end of prior radiation therapy is required unless there is a new recurrence outside of the previous radiotherapy treatment field. Eligible patients will be treated with HFSRT to the recurrent tumor (30 Gy delivered in 5 fractions). Nivolumab will be started 5 days after HFSRT. It will be administered intravenously every 2 weeks (at 240 mg flat dose) for 4 months. After 4 months, nivolumab will be administered every 4 weeks at 480 mg flat dose. The primary study objectives are to determine safety and tolerability of nivolumab administered in combination with HFSRT to recurrent high grade gliomas. Secondary endpoints include determination of the preliminary antitumor activity (response rate, 6-months survival and 9-months survival rates), and exploring tissue and imaging biomarkers. Study Progress: At deadline for abstract submission, 5 patients have been treated on this study. Clinical trial information: NCT02829931.

Phase I study of olaparib (O), in combination with oral cyclophosphamide (C), in patients (pts) with metastatic triple negative breast cancer (TNBC) and recurrent high grade serous ovarian cancer (OVCA).

1104 Background: Poly (ADP-ribose) polymerase (PARP) inhibitors can potentiate chemotherapy induced DNA damage, through synthetic lethality, leading to increased tumor death. We hypothesized that O+C would increase antitumor activity of O through increased DNA damage induced by C. This study ( ANZCTR N12613000924752) evaluated the safety and activity of O+C. Methods: Eligible patient (pts) had performance status 0-2, with ≤3 lines of therapy (including platinum for OVCA and anthracycline and taxane for BC). Pts received O+C with a dose escalations strategy using a 3+3 design with cohort expansions once maximal tolerated dose (MTD) was determined. Dose level 1 (DL1); O, 300 mg bid continuously, C, 50mg on days 1,3 and 5 weekly, 21 day cycle. Dose level 2 (DL2); O, 300 mg bid continuously, C, 50mg days 1-5 weekly 21 day cycle. Dose limiting toxicity was evaluated during 1st two cycles. Safety was assessed by CTCAEv4.0 and efficacy with RECISTv1.1 and GCIC criteria. Results: Of the 32 pts (median age 56, 9 had BC ( BRCA1 22%, BRCA2 44%) and 23 had HGSOC ( BRCA1 39%, BRCA2 26%). 4 pts were treated at DL1 and 28 pts at DL2. DL2 was the MTD. At the time of analysis, 16 of 29 pts had 8 cycles of O+C, with 14 of 16 pts continued with O beyond the 8th cycle. One pt stopped because of adverse events (AEs) and the remaining 12 stopped due to disease progression. The median treatment duration of O+C was 4.3 months (0.7-23.5). Common AEs were nausea (Grade (Gr) 1/2: 88%, Gr 3: 3%), fatigue (Gr 1/2: 81%), constipation (Gr 1/2: 38%, Gr 3: 3%), and vomiting (Gr 1/2: 38%, Gr 3: 3 %). There were no grade (Gr) 4 or 5 AE. 50% required blood transfusion for anemia. Unconfirmed disease control rate (DCR) was 73% (N = 30; CR = 1, PR = 9, SD = 12). DCR for BC and HGSOC were 56% and 81% respectively. In the BRCA cohort (N = 19), DCR was 79%. GCIG CA125 response rates were 70% and 92% for all HGSOC and BRCA cohort respectively. Conclusions: In HGSOC and BC pts, the recommended phase II dose (O 300 mg bid continuously, C 50mg on days 1-5 weekly) is tolerable and active, particularly in those with germline BRCA mutation, supporting our hypothesis. A randomised phase II study in BRCA mutant HGSOC is planned. Clinical trial information: ACTRN12613000924752.