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Background Responses to bevacizumab in glioblastoma (GBM) are not durable. Plasma levels of basic fibroblast growth factor (bFGF) increase at the time of tumor progression. By targeting vascular endothelial growth factor receptor (VEGFR), platelet‐derived growth factor receptor, Src, and FGF receptor pathways, ponatinib may potentially help to overcome some of the putative mechanisms of adaptive resistance. Methods We performed a phase II trial of ponatinib in patients with bevacizumab‐refractory GBM and variants. Adult patients with Karnofsky performance score (KPS) ≥60, measurable disease, and normal organ and marrow function received 45 mg ponatinib daily. No limit on the number of prior therapies but only one prior bevacizumab‐containing regimen was allowed. Primary endpoint was 3‐month progression‐free survival. Plasma biomarkers of angiogenesis and inflammation were evaluated before and after treatment. Results The study closed after the first stage. Fifteen patients enrolled: median age 61 [27‐74]; median KPS 80 [70‐90]; median number of prior relapses 2 [2‐4]. Three‐month progression‐free survival rate was 0, median overall survival was 98 days [95% CI 56, 257], and median PFS was 28 days [95% CI 27, 30]. No responses were seen. The most common grade ≥3 adverse events included fatigue (n = 3), hypertension (2), and lipase elevation (2). Ponatinib treatment significantly increased plasma VEGF, soluble (s)VEGFR1, sVEGFR2, sTIE2, interferon gamma (IFNγ), tumor necrosis factor alpha (TNF‐α), interleukin (IL)‐6, IL‐8, and IL‐10 and decreased sVEGFR2. Conclusions Ponatinib was associated with minimal activity in bevacizumab‐refractory GBM patients. Circulating biomarker data confirmed pharmacodynamic changes and suggested that resistance to ponatinib may be related to an increase in inflammatory cytokines., In this phase II trial, ponatinib was associated with minimal activity in bevacizumab‐refractory glioblastoma patients. Circulating biomarker data confirmed pharmacodynamic changes and suggested that resistance to ponatinib may be related to an increase in inflammatory cytokines.

BACKGROUND CC-115 is an oral, CNS-penetrant, selective inhibitor of mammalian target of rapamycin kinase (mTOR) and deoxyribonucleic acid-dependent protein kinase (DNA-PK). Both targets are important in glioblastoma; PI3K/Akt/mTOR signaling is hyperactive in most glioblastomas, and DNA-PK is integral to repair of radiotherapy-mediated DNA damage. To investigate CC-115 in newly diagnosed glioblastoma and explore potential genomic biomarker associations, CC-115 was evaluated in the Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT) trial, an adaptive platform trial designed to efficiently test experimental agents. METHODS Adults with newly diagnosed MGMT-unmethylated glioblastoma, with genomic data available, are eligible for this ongoing trial. Patients are adaptively randomized to one of several experimental arms or the control arm: standard radiotherapy with concurrent and adjuvant temozolomide. The primary endpoint is overall survival (OS). Patients randomized to CC-115 (10mg po BID) received it concurrently with radiotherapy and as adjuvant monotherapy. As the first in-human use of CC-115 with radiation, a safety lead-in 3 + 3 design was used. RESULTS Twelve patients were randomized to CC-115; seven patients had possible treatment-related CTCAE grade > 3 toxicity, including four pre-specified dose-limiting toxicities: liver function abnormality (n=1), hyperlipidemia (n=1), lipase elevation (n=1) and cerebral edema (n=1). There was no significant difference in progression-free survival (PFS, median 4.2 months [CC-115] vs. 5.2 months, p=0.9) or OS (median 10.1 months [CC-115] vs. 14.5 months, p=0.9) compared to the 50 patients randomized to the control arm. Based on early PFS results, randomization probability to CC-115 decreased from 25% to < 10% at time of the trial arm closure. CONCLUSION Concurrent and adjuvant CC-115 was associated with toxicity and failed to improve PFS or OS. The INSIGhT trial design allowed for more efficient testing of CC-115, decreasing patients and resources allocated to a therapy that was discontinued due to concerns about toxicity and unfavorable risk-to-benefit ratio.

Purpose: VEGF is upregulated in glioblastoma and may contribute to immunosuppression. We performed a phase II study of pembrolizumab alone or with bevacizumab in recurrent glioblastoma. Patients and Methods: Eighty bevacizumab-naïve patients with recurrent glioblastoma were randomized to pembrolizumab with bevacizumab (cohort A, n = 50) or pembrolizumab monotherapy (cohort B, n = 30). The primary endpoint was 6-month progression-free survival (PFS-6). Assessed biomarkers included evaluation of tumor programmed death-ligand 1 expression, tumor-infiltrating lymphocyte density, immune activation gene expression signature, and plasma cytokines. The neurologic assessment in neuro-oncology (NANO) scale was used to prospectively assess neurologic function. Results: Pembrolizumab alone or with bevacizumab was well tolerated but of limited benefit. For cohort A, PFS-6 was 26.0% [95% confidence interval (CI), 16.3–41.5], median overall survival (OS) was 8.8 months (95% CI, 7.7–14.2), objective response rate (ORR) was 20%, and median duration of response was 48 weeks. For cohort B, PFS-6 was 6.7% (95% CI, 1.7–25.4), median OS was 10.3 months (95% CI, 8.5–12.5), and ORR was 0%. Tumor immune markers were not associated with OS, but worsened OS correlated with baseline dexamethasone use and increased posttherapy plasma VEGF (cohort A) and mutant IDH1, unmethylated MGMT, and increased baseline PlGF and sVEGFR1 levels (cohort B). The NANO scale contributed to overall outcome assessment. Conclusions: Pembrolizumab was ineffective as monotherapy and with bevacizumab for recurrent glioblastoma. The infrequent radiographic responses to combinatorial therapy were durable. Tumor immune biomarkers did not predict outcome. Baseline dexamethasone use and tumor MGMT warrant further study as potential biomarkers in glioblastoma immunotherapy trials.

Purpose: Although antiangiogenic therapy for high-grade glioma (HGG) is promising, responses are not durable. Correlative clinical studies suggest that the SDF-1α/CXCR4 axis may mediate resistance to VEGFR inhibition. Preclinical data have demonstrated that plerixafor (a reversible CXCR4 inhibitor) could inhibit glioma progression after anti-VEGF pathway inhibition. We conducted a phase I study to determine the safety of plerixafor and bevacizumab in recurrent HGG. Patients and Methods: Part 1 enrolled 23 patients with a 3 × 3 dose escalation design to a maximum planned dose of plerixafor 320 μg/kg subcutaneously on days 1 to 21 and bevacizumab 10 mg/kg intravenously on days 1 and 15 of each 28-day cycle. Cerebrospinal fluid (CSF) and plasma samples were obtained for pharmacokinetic analyses. Plasma and cellular biomarkers were evaluated before and after treatment. Part 2 enrolled 3 patients and was a surgical study to determine plerixafor's penetration in tumor tissue. Results: In Part 1, no dose-limiting toxicities were seen at the maximum planned dose of plerixafor + bevacizumab. Treatment was well tolerated. After plerixafor 320 μg/kg treatment, the average CSF drug concentration was 26.8 ± 19.6 ng/mL. Plerixafor concentration in resected tumor tissue from patients pretreated with plerixafor was 10 to 12 μg/g. Circulating biomarker data indicated that plerixafor + bevacizumab induces rapid and persistent increases in plasma SDF-1α and placental growth factor. Progression-free survival correlated with pretreatment plasma soluble mesenchymal–epithelial transition receptor and sVEGFR1, and overall survival with the change during treatment in CD34+ progenitor/stem cells and CD8 T cells. Conclusions: Plerixafor + bevacizumab was well tolerated in HGG patients. Plerixafor distributed to both the CSF and brain tumor tissue, and treatment was associated with biomarker changes consistent with VEGF and CXCR4 inhibition. Clin Cancer Res; 24(19); 4643–9. ©2018 AACR.

Background Angiopoietins contribute to tumor angiogenesis and may be upregulated as a compensatory factor after vascular endothelial growth factor (VEGF) blockade. The authors performed a phase 2 and biomarker study to evaluate trebananib, an angiopoietin 1 and angiopoietin 2 blocking peptibody, with and without bevacizumab in patients with recurrent glioblastoma. Methods Forty-eight patients who had bevacizumab-naive, recurrent glioblastoma were treated with trebananib (30 mg/kg weekly) as single agent (n = 11) or combined with bevacizumab (n = 37). The primary endpoint was 6-month progression-free survival rate as determined by investigator review. Circulating biomarker levels were assessed before and after study therapy. Results Trebananib was well tolerated as monotherapy and did not enhance bevacizumab-associated toxicity. Trebananib had no single-agent activity, and all treated patients exhibited progressive disease within 2 months. The 6-month progression-free survival rate for trebananib plus bevacizumab was 24.3% (95% confidence interval [CI], 12.1%-38.8%); whereas the median overall survival was 9.5 months (95% CI, 7.5-4.7 months), and the 12-month overall survival rate was 37.8% (95% CI, 22.6%-53.0%). Baseline and post-treatment changes in circulating vascular VEGF and interleukin-8 levels were correlated with survival among patients who received trebananib plus bevacizumab. Conclusions Angiopoietin 1 and angiopoietin 2 inhibition with trebananib was ineffective as monotherapy and did not enhance the ability of VEGF blockade with bevacizumab to improve the outcomes of patients with recurrent glioblastoma. Cancer 2018;124:1438-48. © 2017 American Cancer Society.

PURPOSE The neurologic assessment in neuro-oncology (NANO) scale was developed as a standardized metric to objectively measure neurologic function in brain tumor patients to complement radiographic assessment in defining overall outcome. A multicenter, phase 2 study of pembrolizumab with or without bevacizumab in patients with recurrent glioblastoma incorporated the NANO scale as an exploratory endpoint. METHODS Neurologic examination was evaluated at baseline and MRI assessments using the NANO scale until patients came off study. Statistical descriptive data analysis was performed using R (version 3.4.3). Correlation analysis utilized Fisher’s exact test. RESULTS NANO compliance rate was 94% in 80 patients accrued on the study. Of the 80 patients, 7 were missing NANO at baseline visit and were excluded from analysis for NANO response criteria. Fifteen patients did not have end of treatment NANO evaluation. Of 73 patients, 35 (48%) had a normal neurologic examination at baseline by NANO. Strength and language accounted for the majority of changes in neurologic function over the course of study treatment. Eighteen patients (25%) had neurologic progression by NANO, of whom 2 did not have concurrent radiographic progression. Three patients (pembrolizumab plus bevacizumab cohort) had a neurologic response associated with stable disease on MRI. NANO assessment prior to initiation of cycle 3 correlated with RANO response (p=0.011), change in KPS (p=0.002) and dexamethasone requirement (p=0.007) while those with NANO progression at this assessment had worse overall survival (291 vs 324 days), but this trend did not achieve statistical significance (p=0.2). CONCLUSIONS Evaluation of neurologic function by NANO scale was feasible in a multicenter prospective study in patients with GBM with a high compliance rate. The NANO scale objectively tracked stable neurologic function in most patients throughout the trial period and was associated with a trend for survival.

Objective: A subset of meningiomas recur after surgery and radiation therapy, but no medical therapy for recurrent meningioma has proven effective. Methods: Pasireotide LAR is a long-acting somatostatin analog that may inhibit meningioma growth. This was a phase II trial in patients with histologically confirmed recurrent or progressive meningioma designed to evaluate whether pasireotide LAR prolongs progression-free survival at 6 months (PFS6). Patients were stratified by histology (atypical [World Health Organization grade 2] and malignant [grade 3] meningiomas in cohort A and benign [grade 3] in cohort B). Results: Eighteen patients were accrued in cohort A and 16 in cohort B. Cohort A had median age 59 years, median Karnofsky performance status 80, 17 (94%) had previous radiation therapy, and 11 (61%) showed high octreotide uptake. Cohort B had median age 52 years, median Karnofsky performance status 90, 11 (69%) had previous radiation therapy, and 12 (75%) showed high octreotide uptake. There were no radiographic responses to pasireotide LAR therapy in either cohort. Twelve patients (67%) in cohort A and 13 (81%) in cohort B achieved stable disease. In cohort A, PFS6 was 17% and median PFS 15 weeks (95% confidence interval: 8–20). In cohort B, PFS6 was 50% and median PFS 26 weeks (12–43). Treatment was well tolerated. Octreotide uptake and insulin-like growth factor–1 levels did not predict outcome. Expression of somatostatin receptor 3 predicted favorable PFS and overall survival. Conclusions: Pasireotide LAR has limited activity in recurrent meningiomas. The finding that somatostatin receptor 3 is associated with favorable outcomes warrants further investigation. Classification of evidence: This study provides Class IV evidence that in patients with recurrent or progressive meningioma, pasireotide LAR does not significantly increase the proportion of patients with PFS at 6 months.

2006Background: Blockade of programmed-death 1 (PD-1) mediated immunosuppression has achieved meaningful benefit across many cancers. Vascular endothelial growth factor (VEGF), a highly upregulated...

2037Background: The neurologic assessment in neuro-oncology (NANO) scale was developed as a standardized metric to objectively measure neurologic function in patients (pts) with brain tumors to com...

2032Background: Responses to bevacizumab in recurrent glioblastoma (GBM) are not durable. Plasma levels of basic fibroblast growth factor (bFGF) increase at the time of tumor progression. By concom...

High-grade gliomas, which include glioblastomas (GBMs) and anaplastic gliomas (AGs), are the most common malignant primary brain tumors in adults1 and are associated with poor survival despite maximal surgery, radiation, and chemotherapy.2–4 Bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor (VEGF), is frequently used to treat recurrent high-grade glioma (HGG). Bevacizumab monotherapy received accelerated approval for recurrent GBM by the United States Food and Drug Administration in 2009 on the basis of phase II clinical trials demonstrating response rates of 20%–26%, 6-month progression-free survival (PFS6) rates of 29%–42.6%, and median overall survival (OS) of 7.1–9.2 months.5,6 Phase II studies in recurrent AG suggest that bevacizumab plus irinotecan also has activity in this patient population with response rates of 55%–66% and PFS6 rates of 56%–61%.7,8 However, responses to bevacizumab are not durable, and some patients fail to benefit.9 Panobinostat is a potent, small-molecule inhibitor of classes I, II, and IV histone deacetylases (HDACs) with greater potency than vorinostat.10 HDAC inhibitors, including panobinostat, may inhibit angiogenesis by reducing VEGF secretion and modulating the expression of other VEGF family members via inhibition of HIF-1α.11–14 In addition, the SDF-1α/CXCR4 pathway has been implicated in bevacizumab resistance,15–17 and panobinostat depletes CXCR4 levels and signaling.18 A phase I study of panobinostat in combination with bevacizumab for recurrent HGG suggested that oral panobinostat 30 mg 3 times per week, every other week, can be safely combined with bevacizumab 10 mg/kg every other week.19 We conducted a multicenter, phase II trial of panobinostat in combination with bevacizumab in patients with recurrent GBM. We also examined the same combination of agents in patients with recurrent AG as an exploratory arm.

Although anti‐angiogenic therapy for high-grade glioma (HGG) is promising, responses are not durable. The SDF-1/CXCR4 axis may help mediate resistance to VEGFR inhibition. Plerixafor is a reversible CXCR4 inhibitor that has demonstrated growth inhibition in glioblastoma xenografts. We conducted a Phase I study to determine the safety and tolerability of plerixafor in combination with bevacizumab in recurrent HGG. Part 1 of the study enrolled 23 patients and was a 3 x 3 dose escalation design to a maximum planned dose level of plerixafor 320 µg/kg on Days 1–21 and bevacizumab 10 mg/kg on Days 1 and 15 of each 28 day cycle. Dose-limiting toxicities (DLTs) were determined during the initial 4 weeks of therapy. CSF and concomitant plasma samples were obtained to determine pharmacokinetic (PK) data. Part 2 of the study enrolled 3 patients and was a surgical study to determine if plerixafor penetrates tumor tissue. Patients were pre-treated with plerixafor 320 µg/kg for 5–9 days before surgery. For all 26 patients enrolled on study, the median age is 59 (23–72), median KPS 90 (70–100), 11 women (42.3%). In Part 1, no DLTs were seen at the maximum planned dose level of plerixafor + bevacizumb. Treatment was well tolerated with one grade 3 hypophosphatemia and one grade 3 rectal fistula. Serum PK data on plerixafor in this study compares well with historical PK data. At a plerixafor dose of 320 µg/kg, the average CSF concentration was 26.8 ng/mL (SD +/- 19.6). Circulating biomarker data suggests that plerixafor + bevacizumab induces rapid and persistent increases in plasma SDF1 and PlGF. Plerixafor concentration in resected tumor tissue from patients pre-treated with plerixafor was 1000–1200 ng/mL. Combination treatment with bevacizumab and plerixafor was well tolerated in HGG patients. Plerixafor distributes to both the CSF and brain tumor tissue.

TPS2079 Background: Patient with glioblastoma (GBM) with unmethylated MGMT promoters derive limited benefit from temozolomide (TMZ) and have dismal outcome. Prioritizing the numerous available therapies and biomarkers for late stage testing requires an efficient clinical testing platform. INSIGhT (NCT02977780) is a biomarker-based, Bayesian adaptively randomized, multi-arm phase II platform screening trial for patients with newly diagnosed GBM and unmethylated MGMT promoters. Methods: INSIGhT compares experimental arms to a common control of standard concurrent TMZ and radiation therapy (RT) followed by adjuvant TMZ. The primary endpoint is overall survival (OS). Patients with newly diagnosed, unmethylated GBM that are IDH R132H mutation negative, and with genomic data available or who consent to whole exome sequencing through the ALLELE companion study for biomarker grouping are eligible. Two experimental arms consist of concurrent RT/TMZ followed by adjuvant neratinib (EGFR, HER2, and HER4 inhibitor) or abemaciclib CDK 4/6 inhibitor), respectively, in place of TMZ. The other experimental arm is CC-115 (TORC1/2 and DNA PK inhibitor), which replaces TMZ in both the concurrent and adjuvant phases. Biomarker groups include: EGFR + patients with EGFR amplification/mutation; PI3K + patients with PIK3CA mutation/amplification, PIK3R1 mutation, AKT3amplification, PIK3C2B > 1 copy gain, or PTEN dual loss; CDK: + patients with wild-type RB1 and CDK4 amplification, CDK6 amplification, or CDKN2A > 1 copy loss. Given the lack of pretrial biomarker data and the anticipated overlap of the groups, randomization will initially be equal. As the trial progresses, randomization probabilities will be adapted based on the Bayesian estimation of the probability of treatment impact on progression-free survival (PFS). These randomization probabilities can vary among the biomarker groups so predictive biomarkers will be identified and utilized if present. Treatment arms may drop due to low probability of treatment impact on OS, and new arms may be added. Experimental arms are compared only with control and should be thought of as discrete experimental questions, with INSIGhT being open to new investigators with proposed therapeutic hypotheses. Clinical trial information: NCT02977780.

Although anti-angiogenic therapy for high-grade glioma is promising, responses are not durable. The SDF-1/CXCR4 axis may help mediate resistance to VEGFR inhibition. Plerixafor is a reversible CXCR4 inhibitor that has demonstrated growth inhibition in glioblastoma xenografts. We conducted a Phase I study to determine the safety and tolerability of plerixafor in combination with bevacizumab in patients with recurrent HGG. A 3 x 3 dose escalation design to a maximum planned dose level of plerixafor 320 µg/kg on Days 1-21 and bevacizumab 10 mg/kg on Days 1 and 15 of each 28 day cycle was used. DLTs were determined during the initial 4 weeks of therapy and included drug-related Grade ≥ 3 non-hematologic toxicities and Grade ≥ 4 hematologic toxicities. Part 1 of the study has been completed with a total of 23 patients enrolled with the following characteristics: median age 58 (23-72), median KPS 90 (70-100), 11 women (47.8%). One DLT (grade 3 rectal fistula) was seen at a dose level of plerixafor 240 µg/kg + bevacizumab and the cohort was expanded. Because no further DLTs were seen at the 240 µg/kg dose level, the maximum planned dose level of plerixafor 320 µg/kg + bevacizumb opened and a total of 12 patients were treated with no DLTs. Treatment was well tolerated with one grade 3 hypophosphatemia and one grade 3 rectal fistula. Preliminary pharmacokinetic data on plerixafor from the first two cohorts compares well with historical PK data. Combination treatment with bevacizumab and plerixafor was well tolerated in the studied HGG patients. No DLTs were encountered at the maximum planned dose level. The study will now expand to a surgical cohort to examine tumor tissue penetration as well as a separate non-surgical cohort with patients treated with continuous daily dosing of plerixafor 320 µg/kg and bevacizumab. Updated results will be presented.

Bevacizumab is frequently used to treat recurrent high-grade gliomas, but responses are generally not durable. Panobinostat is a histone deacetylase inhibitor with anti-neoplastic and anti-angiogenic effects in glioma models and may work synergistically with bevacizumab. We conducted a multicenter phase II trial of panobinostat in combination with bevacizumab. Two cohorts were enrolled: one with recurrent glioblastoma (GBM) as the primary study and one with recurrent anaplastic glioma (AG) as the exploratory study. Patients received oral panobinostat 30 mg 3 x per week, every other week, in combination with bevacizumab 10 mg/kg every other week. The primary endpoint was PFS6 in the GBM cohort and the study was powered to discriminate between a 35% and 55% PFS6 rate (85% power at an alpha level of 0.07). At planned interim analysis, 13 of the first 21 patients accrued to the GBM cohort had progressed within 6 months of initiating study treatment. The GBM cohort did not meet criteria for continued accrual and was closed early. In the GBM cohort, PFS6 rate was 30.4%, median PFS 5 months, median OS 9 months. Accrual in the AG cohort continued to completion and a total of 15 patients were enrolled. In the AG cohort, PFS6 rate was 46.7%, median PFS 7 months, median OS 17 months. The most common grade 3 or 4 toxicities in the GBM arm were hypophosphatemia (12.5%), thrombocytopenia (12.5%), lymphopenia (8.3%), neutropenia (8.3%), and ALT elevation (8.3%). In the AG arm, the most common toxicities were thrombocytopenia (20.0%) and hypophosphatemia (13.3%). Although reasonably well-tolerated, this phase II study of panobinostat and bevacizumab in recurrent GBM did not meet criteria for continued accrual and the GBM cohort of the study was closed. In the recurrent AG cohort, the PFS6 rate was similar to historical controls. Updated data will be presented.

Bevacizumab is FDA-approved for patients with recurrent GBM. However, the median duration of response is only 4 months. Potential mechanisms of resistance include upregulated FGF signaling and increased PDGF-mediated pericyte coverage. Nintedanib is an oral, small-molecule tyrosine kinase inhibitor of PDGFR α/β, FGFR 1-3, and VEGFR 1-3 that may overcome resistance to anti-VEGF therapy. This was a two-stage phase II trial in adults with first or second recurrence of GBM, stratified by prior bevacizumab therapy (ClinicalTrials.gov number NCT01380782; 1199.94). The primary endpoint was PFS6 in the bevacizumab-naive arm (Arm A) and PFS3 in the post-bevacizumab arm (Arm B). Up to 10 anaplastic glioma (AG) patients were accrued to each arm in exploratory cohorts. Twenty-two patients enrolled in Arm A and 14 in Arm B. Arm A included 12 GBMs (55 %), 13 patients with one prior regimen (59 %), and median age 54 years (range 28-75). Arm B included 10 GBMs (71 %), one patient with one prior regimen (7 %), and median age 52 years (range 32-70). Median KPS overall was 90 (range 60-100). There were no responses. In Arm A (GBM only), PFS6 was 0 %, median PFS 28 days (95 % CI 27-83), and median OS 6.9 months (3.7-8.1). In Arm B (GBM only), PFS3 was 0 %, median PFS 28 days (22-28), and median OS 2.6 months (1.0-6.9). Among AG patients in each arm, PFS6 was 0 %. Treatment was well tolerated. In conclusion, nintedanib is not active against recurrent high-grade glioma, regardless of prior bevacizumab therapy.

2010Background: Inhibition of vascular endothelial growth factor (VEGF) may enhance immunotherapies and decrease cerebral edema among GBM patients (pts). This multicenter, randomized phase 2 study determined safety and anti-tumor activity of pembrolizumab (P), a PD-1 blocking monoclonal antibody (Mab) with and without bevacizumab (Bev), a humanized anti-VEGF Mab among rGBM pts. Herein, we report the safety lead-in of this study. Methods: Pts in dose level 1 received P 200 mg Q3W and Bev 10 mg/kg Q2W. Dose de-escalation levels -1 and -2 increased the P interval to 4 and 6 weeks, respectively if dose level 1 exceeded maximum tolerated dose (MTD) based on standard 3+3 criteria. Eligible pts were ≥ 18 years, had 1or 2 recurrences, no prior anti-VEGF treatment, and KPS ≥ 70. The primary endpoint was MTD/recommended phase 2 dose (RP2D) determination based on dose limiting toxicity (DLT) during cycle 1. MRI scans were obtained after each 6-week cycle. Results: 6 pts were treated (4 male, 2 female) at1st (n = 2) ...

2013Background: The P13K/Akt/mTOR signaling axis plays a central role in cell growth and survival in a variety of cancers. MLN0128 is an oral TORC1/2 inhibitor. Bevacizumab is a monoclonal antibody targeting VEGF with activity in some cancers, including glioblastoma (GBM). Methods: This ongoing Cancer Therapeutic Evaluation Program (CTEP)-sponsored phase I trial uses a 3+3 dose escalation design to determine the maximum tolerated dose (MTD/recommended phase 2 dose (RP2D) of MLN0128 when administered daily with bevacizumab (10 mg/kg every 2 weeks) and includes a dose expansion at the MTD/RP2D for recurrent GBM (n=10) and recurrent endometrial/ovarian cancer (n=30) patients (pts). Eligibility includes histologically confirmed recurrent GBM or other advanced solid tumors, >18 years old, KPS> 60, adequate bone marrow and organ function. The starting dose of MLN0128 was 3 mg daily. Results: Thirty-six pts have enrolled (12 in dose escalation and 24 in dose expansion). The median age and KPS were 56 (range: 25-...

BACKGROUND: The P13K/Akt/mTOR signaling axis plays a central role in cell growth and survival in a variety of cancers. MLN0128 is an oral inhibitor of TORC1/2 complexes. Bevacizumab is a monoclonal antibody targeting VEGF with activity in some cancers. METHODS: We are conducting NCI 9552, a Cancer Therapeutic Evaluation Program (CTEP)-sponsored phase I trial of MLN0128 and bevacizumab. Eligibility criteria include histologically confirmed recurrent glioblastoma (GBM) and advanced solid tumors, >18 years old, KPS> 60, adequate bone marrow reserve and organ function. The study has 2 stages; dose escalation using a 3 + 3 design to estimate MTD/RP2D defined as the highest dose at which

TPS2080 Background: Although anti-angiogenic therapy for high-grade glioma is promising, responses are not durable. The SDF-1/CXCR4 axis may help mediate resistance to VEGFR inhibition. Plerixafor ...

2020 Background: Bevacizumab is frequently used to treat recurrent high-grade gliomas, but responses are generally not durable. Panobinostat is a histone deacetylase inhibitor with anti-neoplastic ...

2053 Background: Bevacizumab is FDA-approved for patients with recurrent GBM. However, the median duration of response is only 4 months. Potential mechanisms of resistance include upregulated FGF s...

2013 Background: Bevacizumab is frequently used to treat recurrent GBM, but responses are generally not durable. Panobinostat is a histone deacetylase inhibitor with anti-neoplastic and anti-angiogenic effects in GBM and may work synergistically with bevacizumab. We conducted a multicenter phase I/II trial of panobinostat in combination with bevacizumab in patients with recurrent GBM. Methods: In the phase II trial, patients with recurrent GBM were treated with oral panobinostat 30 mg three times per week, every other week, in combination with bevacizumab 10 mg/kg every other week. The primary endpoint was 6-month progression-free survival (PFS6) and the study was powered to discriminate between a 35% and 55% PFS6 rate (85% power at an alpha level of 0.07). A planned interim analysis specified suspension of accrual and careful data review if 12 or more of the first 21 patients accrued to the study progress within 6 months of initiating treatment. Patients with recurrent GBM enrolled in the phase I study at the maximum tolerated dose (which is the phase II dose) were eligible for inclusion in the interim analysis. Results: Thirteen of the first 21 patients accrued to the GBM arm of the study had progressed within 6 months of initiating study treatment. The study was closed to further accrual and a planned interim analysis was performed. Median age was 53 (range 22-66) and median KPS was 80% (60%-100%). PFS6 rate was 33.9% [95% CI 12.8, 56.5), median was PFS 5 months [95% CI 3 months, NR], and median OS was 342 days [95% CI 203 days, NR]. Five patients (23.8%) achieved partial responses. Conclusions: Although reasonably well-tolerated, this phase I/II study of panobinostat and bevacizumab in recurrent GBM did not meet criteria for continued accrual and the study was closed. Updated outcome and safety data will be presented at the meeting. Study Supported by: Novartis and Genentech Clinical trial information: NCT00859222.