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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.

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Background Programmed death ligand 1 (PD-L1) contributes to tumor immunosuppression and is upregulated in aggressive meningiomas. We performed a phase II study of nivolumab, a programmed death 1 (PD-1) blocking antibody among patients with grade ≥2 meningioma that recurred after surgery and radiation therapy. Methods Twenty-five patients received nivolumab (240 mg biweekly) until progression, voluntary withdrawal, unacceptable toxicity, or death. Tumor mutational burden (TMB) and quantification of tumor-infiltrating lymphocytes (TIL) were evaluated as potential immunocorrelative biomarkers. Change in neurologic function was prospectively assessed using the Neurologic Assessment in Neuro-Oncology (NANO) scale. Results Enrolled patients had multiple recurrences including ≥3 prior surgeries and ≥2 prior courses of radiation in 60% and 72%, respectively. Nivolumab was well tolerated with no unexpected adverse events. Six-month progression-free survival (PFS-6) rate was 42.4% (95% CI: 22.8, 60.7) and the median OS was 30.9 months (95% CI: 17.6, NA). One patient achieved radiographic response (ongoing at 4.5 years). TMB was >10/Mb in 2 of 15 profiled tumors (13.3%). Baseline TIL density was low but increased posttreatment in 3 patients including both patients with elevated TMB. Most patients who achieved PFS-6 maintained neurologic function prior to progression as assessed by NANO. Conclusion Nivolumab was well tolerated but failed to improve PFS-6, although a subset of patients appeared to derive benefit. Low levels of TMB and TIL density were typically observed. NANO assessment of neurologic function contributed to outcome assessment. Future studies may consider rationally designed combinatorial regimens.

Re-irradiation is therapeutically considered for select rGBM patients and may induce immunogenic cell death to stimulate anti-tumor immune responses. Our phase 2 study of re-irradiation with pembrolizumab among rGBM patients evaluated the efficacy and safety of this regimen. METHODS Adult rGBM patients with KPS ≥ 70, a maximum supratentorial tumor diameter of 6 cm who were on ≤ 2mg dexamethasone/day and were ≥ 6 months from initial conventional radiation therapy were eligible. Cohort A (bevacizumab [BEV]-naïve) had ≤ 2 prior progressions while cohort B (BEV-refractory) allowed unlimited progressions but only one on prior BEV. Re-irradiation included 35 Gy over 10 fractions to residual enhancing (cohort A) as well as enhancing + non-enhancing (cohort B) disease. Pembrolizumab was administered at 200 mg every three weeks beginning within one week of re-irradiation start. BEV was administered at 15 mg/kg every three weeks for cohort B only. RESULTS Sixty patients enrolled (n = 30 per cohort) with a median age of 61 years (range 20-76), 47% were female and 53% enrolled after 2 or more progressions. Grade 3 events deemed at least possibly related to study therapy in > one patient for cohort A included headache (n = 2) and for cohort B included elevated ALT (n = 2) and hypertension (n = 5). No grade 4 events occurred in more than single patients per cohort and no grade 5 events occurred. Median PFS and PFS-6 were 4.9 months (95% CI: 3.5, 5.6) and 26.0% (95% CI: 12.3%, 43.0%) for cohort A and 4.14 months (95% CI: 3.45, 5.42) and 16.9% (95% CI: 5.4, 33.7) for cohort B. Median survival for cohorts A and B were 11.5 months (95% CI: 9.6, 14.1) and 7.6 months (95% CI 5.5, 9.3), respectively. CONCLUSIONS Re-irradiation with pembrolizumab was overall well tolerated and achieved comparable efficacy to historical salvage therapy established with lomustine.

BACKGROUND The Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT) is a phase II platform trial with Bayesian adaptive randomization and deep genomic profiling to more efficiently test experimental agents in newly diagnosed glioblastoma and to prioritize therapies for late-stage testing. METHODS In the ongoing INSIGhT trial, patients with newly diagnosed MGMT-unmethylated glioblastoma are randomized to the control arm or one of three experimental therapy arms (CC-115, abemaciclib, and neratinib). The control arm therapy is radiotherapy with concomitant and adjuvant temozolomide, and primary endpoint is overall survival. Randomization has been adapted based on Bayesian estimation of biomarker-specific probability of treatment impact on progression-free survival (PFS). All tumors undergo detailed molecular sequencing, and this is facilitated with the companion ALLELE protocol. To evaluate feasibility of this approach, we assessed the status of this ongoing trial. RESULTS Since INSIGhT was activated 4.3 years ago, it has expanded to include 12 sites across the United States. A total of 247 patients have been enrolled. Randomization probabilities have been repeatedly adjusted over time based upon early PFS results to alter the randomization ratio from standard 1:1:1:1 randomization. All three arms have completed accrual and efficacy estimates are available based upon comparison to the common control arm in context of relevant biomarkers. There are 87 patients alive and in follow-up, and there are ongoing plans to add additional arms to evaluate further treatments in the future. CONCLUSION The INSIGhT trial demonstrates that a multi-center Bayesian adaptive platform trial is a feasible and effective approach to help prioritize therapies and biomarkers for newly diagnosed GBM. The trial has maintained robust accrual, and the simultaneous testing of multiple agents, sharing a common control arm and adaptive randomization serve as features to increase trial efficiency relative to traditional clinical trial designs.

BACKGROUND The cyclin D-CDK4/6-Rb pathway is activated in most glioblastomas. Abemaciclib is a potent CDK4/6 inhibitor with good brain penetration approved for ER/PR/HER2- breast cancer. In order to efficiently evaluate the potential impact of abemaciclib on overall survival (OS) in newly diagnosed glioblastoma and to simultaneously develop information regarding potential genomic biomarker associations, abemaciclib was included as an arm on the Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT) trial. INSIGhT is a phase II platform trial using response adaptive randomization and deep genomic profiling to more efficiently test experimental agents in MGMT unmethylated glioblastoma and potentially accelerate identification of novel therapies for phase III testing. Initial randomization was equal between abemaciclib, control, and two other experimental arms but subsequent randomization was adapted based on efficacy as determined by progression-free survival (PFS). Ineffective arms were discontinued and new arms added by protocol amendment. We report preliminary results for the abemaciclib arm which has completed accrual. METHODS Patients with newly diagnosed MGMT-unmethylated glioblastoma were randomized to receive either radiotherapy with concomitant and adjuvant temozolomide at standard doses or standard radiochemotherapy followed by adjuvant abemaciclib (150–200 mg orally BID) without temozolomide. Treatment continued until progression or development of unacceptable toxicities. The primary endpoint was OS. Association between abemaciclib efficacy and cyclin D-CDK4/6-Rb pathway genomic alterations was also investigated. RESULTS There were 123 patients (50 control; 73 treated with abemaciclib). Abemaciclib was generally well-tolerated with no new toxicity signals identified. PFS was significantly longer (p=0.03, logrank test) with abemaciclib (median 6.31 months 95% CI [5.29, 8.18]) compared to the control arm (5.16 months 95% CI [4.37, 6.28]). 28/50 control and 36/73 abemaciclib patients remain alive. CONCLUSION Preliminary analysis suggests that abemaciclib increases PFS compared to control. Updated toxicity, PFS and survival data and potential genomic biomarker associations will be presented.

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 Vascular endothelial growth factor (VEGF) is upregulated in glioblastoma and may contribute to immunosuppression. We performed a phase 2 study of pembrolizumab, a programmed death-1 (PD-1) blocking antibody alone or with the anti-VEGF antibody bevacizumab in recurrent glioblastoma with detailed analyses of biomarkers and patient neurologic function. METHODS Eighty bevacizumab-naive, recurrent glioblastoma patients were randomized to receive pembrolizumab with bevacizumab (cohort A, n=50) or pembrolizumab monotherapy (cohort B, n=30). The primary endpoint was six-month progression-free survival (PFS-6). Exploratory endpoints included evaluation of tumor PD-L1 expression, TIL density, immune activation gene expression signature and plasma cytokines with outcome. Changes in neurologic function were prospectively assessed using the Neurologic Assessment in Neuro-Oncology (NANO) scale. RESULTS Pembrolizumab alone or with bevacizumab was well tolerated but of limited benefit. For cohort A, PFS-6 was 26.0% (95% CI: 16.3, 41.5), median OS was 8.8 months (95% CI: 7.7, 14.2), 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%. Factors associated with worsened OS included baseline dexamethasone use and increased post-therapy plasma VEGF (cohort A) and wild-type IDH1, unmethylated MGMT and increased baseline PlGF and sVEGFR1 levels (cohort B), but tumor immune markers were not informative. The NANO scale effectively predicted neurologic function. CONCLUSIONS Although well tolerated, pembrolizumab was ineffective both as monotherapy and with bevacizumab for recurrent glioblastoma. Nonetheless, radiographic responses to combinatorial therapy were durable. Baseline dexamethasone use and plasma cytokines but not tumor immunologic biomarkers were associated with outcome. Neurologic function evaluated by the NANO scale contributed to outcome assessment.

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 EGFR is amplified in over 50% of glioblastoma and 20-30% have EGFRvIII mutations. Neratinib is a potent inhibitor of EGFR/HER2 approved for metastatic HER2+ breast cancer. To efficiently evaluate the potential impact of neratinib on overall survival (OS) in newly-diagnosed glioblastoma and to simultaneously develop information regarding potential genomic biomarker associations, neratinib was included as an arm on the Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT) trial. INSIGhT is a phase II platform trial using response adaptive randomization and deep genomic profiling to more efficiently test experimental agents in MGMT unmethylated glioblastoma and accelerate identification of novel therapies for phase III testing. Initial randomization was equal between neratinib, control, and two other experimental arms but subsequent randomization was adapted based on efficacy as determined by progression-free survival (PFS). We report preliminary results for the neratinib arm. METHODS Patients with newly diagnosed MGMT-unmethylated glioblastoma were randomized to receive either radiotherapy with concomitant and adjuvant temozolomide or standard radiochemotherapy followed by adjuvant neratinib (240 mg daily). Treatment continued until progression or development of unacceptable toxicities. The primary endpoint was OS. Association between neratinib efficacy and EGFR amplification was also investigated. RESULTS There were 144 patients (70 control; 74 neratinib). Neratinib was reasonably well-tolerated with no new toxicity signals identified. PFS was compared (HR 0.84; p=0.38, logrank test – not significant) between the neratinib (median 6.05 months) and control (median 5.82 months) arms. For patients EGFR pathway activation the PFS HR was 0.53 (p-value=0.03 – significant, median PFS: neratinib, 6.21 months, control, 5.26 months). However, there was no significant improvement in OS in EGFR amplified/mutated patients (HR 1.05; p-value 0.87) between neratinib (median 14.2) compared to the control arm (median 14.6). CONCLUSION Neratinib prolonged PFS in the EGFR positive subpopulation but there was no overall PFS benefit, or any OS improvement.

The success of a facilitator-based model for advance care planning (ACP) in LaCrosse, Wisconsin, has inspired health systems to aim for widespread documentation of advance directives, but limited resources impair efforts to replicate this model. One promising strategy is the development of interactive, Internet-based tools that might increase access to individualized ACP at minimal cost. However, widespread adoption and implementation of Internet-based ACP efforts has yet to be described.We describe our early experiences in building a systematic, population-based ACP initiative focused on health system-wide deployment of an Internet-based tool as an adjunct to a facilitator-based model.With the sponsorship of our healthcare system's population health leadership, we engaged a diverse group of clinical stakeholders as champions to design an Internet-based ACP tool and facilitate local practice change. We describe how we simultaneously began to train clinicians in ACP conversations, engage patients and health system employees in thinking about ACP, redesign clinic workflows to accommodate ACP discussions, and integrate the Internet-based tool into the electronic medical record (EMR).Over 18 months, our project engaged two subspecialty clinics in a systematic ACP process and began work with a large primary care practice with a large Medicare Accountable Care Organization at-risk population. Overall, 807 people registered at the Internet site and 85% completed ACPs.We learned that changing culture and systems to promote ACP requires a comprehensive vision with simultaneous, interconnected strategies targeting patient education, clinician training, EMR documentation, and community awareness.

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.

PURPOSE Phosphatidylinositol 3-kinase (PI3K) signaling is highly active in glioblastomas. We assessed pharmacokinetics, pharmacodynamics, and efficacy of the pan-PI3K inhibitor buparlisib in patients with recurrent glioblastoma with PI3K pathway activation. METHODS This study was a multicenter, open-label, multi-arm, phase II trial in patients with PI3K pathway–activated glioblastoma at first or second recurrence. In cohort 1, patients scheduled for re-operation after progression received buparlisib for 7 to 13 days before surgery to evaluate brain penetration and modulation of the PI3K pathway in resected tumor tissue. In cohort 2, patients not eligible for re-operation received buparlisib until progression or unacceptable toxicity. Once daily oral buparlisib 100 mg was administered on a continuous 28-day schedule. Primary end points were PI3K pathway inhibition in tumor tissue and buparlisib pharmacokinetics in cohort 1 and 6-month progression-free survival (PFS6) in cohort 2. RESULTS Sixty-five patients were treated (cohort 1, n = 15; cohort 2, n = 50). In cohort 1, reduction of phosphorylated AKTS473 immunohistochemistry score was achieved in six (42.8%) of 14 patients, but effects on phosphoribosomal protein S6S235/236 and proliferation were not significant. Tumor-to-plasma drug level was 1.0. In cohort 2, four (8%) of 50 patients reached 6-month PFS6, and the median PFS was 1.7 months (95% CI, 1.4 to 1.8 months). The most common grade 3 or greater adverse events related to treatment were lipase elevation (n = 7 [10.8%]), fatigue (n = 4 [6.2%]), hyperglycemia (n = 3 [4.6%]), and elevated ALT (n = 3 [4.6%]). CONCLUSION Buparlisib had minimal single-agent efficacy in patients with PI3K-activated recurrent glioblastoma. Although buparlisib achieved significant brain penetration, the lack of clinical efficacy was explained by incomplete blockade of the PI3K pathway in tumor tissue. Integrative results suggest that additional study of PI3K inhibitors that achieve more-complete pathway inhibition may still be warranted.

Purpose: Vandetanib, a tyrosine kinase inhibitor of KDR (VEGFR2), EGFR, and RET, may enhance sensitivity to chemotherapy and radiation. We conducted a randomized, noncomparative, phase II study of radiation (RT) and temozolomide with or without vandetanib in patients with newly diagnosed glioblastoma (GBM). Experimental Design: We planned to randomize a total of 114 newly diagnosed GBM patients in a ratio of 2:1 to standard RT and temozolomide with (76 patients) or without (38 patients) vandetanib 100 mg daily. Patients with age ≥ 18 years, Karnofsky performance status (KPS) ≥ 60, and not on enzyme-inducing antiepileptics were eligible. Primary endpoint was median overall survival (OS) from the date of randomization. Secondary endpoints included median progression-free survival (PFS), 12-month PFS, and safety. Correlative studies included pharmacokinetics as well as tissue and serum biomarker analysis. Results: The study was terminated early for futility based on the results of an interim analysis. We enrolled 106 patients (36 in the RT/temozolomide arm and 70 in the vandetanib/RT/temozolomide arm). Median OS was 15.9 months [95% confidence interval (CI), 11.0–22.5 months] in the RT/temozolomide arm and 16.6 months (95% CI, 14.9–20.1 months) in the vandetanib/RT/temozolomide (log-rank P = 0.75). Conclusions: The addition of vandetanib at a dose of 100 mg daily to standard chemoradiation in patients with newly diagnosed GBM or gliosarcoma was associated with potential pharmacodynamic biomarker changes and was reasonably well tolerated. However, the regimen did not significantly prolong OS compared with the parallel control arm, leading to early termination of the study. Clin Cancer Res; 21(16); 3610–8. ©2015 AACR.

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.

BACKGROUND: The impact of individualized neoepitope vaccination targeting neoantigens arising from tumor-specific mutations for GBM, a low mutation burden tumor with an immunologically cold tumor microenvironment, as well as that of concurrently administered dexamethasone (dex), are unknown. METHODS: Individualized vaccination of up to 20 synthetic, long neoepitope peptides with high predicted HLA binding affinity admixed with poly-ICLC, were administered subcutaneously using a prime-boost schedule after RT to newly diagnosed, MGMT unmethylated, at least partially resected, GBM patients without progression after radiation (RT) in our phase 1b study. RESULTS: 9 of 10 screened patients had sufficient (10) identified neoepitope peptides. 8 patients without progression after RT received vaccine consisting of a median of 12 peptides (range, 7–20) beginning a median of 19.9 wks (range 17.1–24.7) after surgery. Adverse events were limited to infrequent grade 1/2 local reactions and fatigue. Median PFS and OS were 7.5 mths (90% CI: 6.2, 9.7) and 16.8 mths (90% CI: 9.6, 21.3). Evaluation of neoepitope-specific immune responses and tumor immune infiltrate analyses were performed on five patients with pre- and post-vaccination samples. Three patients on dex for post-RT edema during vaccine had no immune responses and no change in tumor infiltrating effector cells. In contrast 2 patients not on dex had robust, de novo immune responses against multiple predicted personal neoantigens including polyfunctional neoantigen-specific CD4+ and CD8+ T cell responses that were enriched for memory and activated phenotypes as well as increased numbers of tumor-infiltrating CD4+ and CD8+ T cells. T cell receptor analysis from one patient identified identical clonotypes isolated from post-vaccination tumor tissue and peripheral blood including two clonotypes specific for ARHGAP35, a neoantigen targeted by vaccination. CONCLUSIONS: Individualized, multi-neoepitope vaccines are feasible, safe and capable of generating systemic and intra-tumoral immune responses in GBM patients that appear to be abrogated by dex.

Personal vaccines directed at neoantigens arising from tumor mutations can induce neoepitope-specific T cell responses in patients with highly mutated tumors such as melanoma. It remains unknown if this approach can be successfully applied in tumors with low mutation frequency. We conducted a phase 1/1b study to determine the safety and feasibility of patient-specific neoantigen-targeting vaccination in patients with newly diagnosed, methylguanine methyltransferase (MGMT) unmethylated glioblastoma, administered following maximum surgical resection and conventional radiotherapy. Tumor-specific mutations were identified by whole-exome sequencing. Each vaccine, composed of up to 20 synthetic long peptides containing predicted tumor neoepitopes admixed with poly-ICLC, was administered subcutaneously on a prime-boost schedule. Among 8 treated patients, adverse events were limited to mild injection site reactions. Seven patients (88%) received a vaccine with ≥10 neoepitope peptides (median 12, range, 7-20), with median time to vaccine initiation of 18.6 weeks from surgery. All patients died from progressive disease. Median progression-free and overall survival was 7.5 months (95% CI: 6.2, 9.7) and 16.8 months (90% CI: 9.6, 21.3), respectively. 3 patients dropped out of the study due to disease progression. We analyzed vaccine responses on 5 patients that got at least one booster immunization. All 3 patients who required dexamethasone during vaccine priming failed to generate interferon-γ responses in peripheral blood mononuclear cells. In contrast, 2 patients who did not receive dexamethasone during vaccine priming, generated robust de novo immune responses against multiple personal neoantigens. Circulating vaccine-induced polyfunctional neoantigen-specific CD4+ and CD8+ T cell responses were enriched for memory and activated phenotypes, and increased numbers of tumor-infiltrating CD4+ and CD8+ T cells were detected in these 2 patients. T cell receptor analysis identified identical clonotypes isolated from post-vaccination glioblastoma tissue and peripheral blood including a clonotype specific for ARHGAP35, a neoantigen targeted by vaccination. To our knowledge we provide the first evidence that tumor specific T cells can traffic from the periphery into glioblastoma tumors and that neoantigen-targeting vaccines can favorably alter the tumor immune milieu of glioblastoma. In conclusion, individualized, multi-neoepitope vaccination is feasible, safe, and generates neoantigen-specific T cell responses in the periphery and intracranial tumors of patients with glioblastoma. Citation Format: Derin B. Keskin, Itay Tirosh, Annabelle Anandappa, Jing Sun, Nathan D. Mathewson, Sachet A. Shukla, Evisa Gjini, Shuqiang Li, Letitia Li, Anita Giobbie-Hurder, Phuong M. Le, Zhuting Hu, Wandi Zhang, Oriol Olive, Christine McCluskey, Heather Daley, Patrick Y. Wen, Antonio E. Chiocca, Maegan Harden, Niall Lennon, Stacey Gabriel, Gad Getz, Donna Neuberg, Jerome Ritz, Eric S. Lander, Aviv Regev, Kai Wucherpfennig, Mario Suva, Edward F. Fritsch, Rodig Scott, Keith L. Ligon, Kenneth J. Livak, Hacohen Nir, Patrick A. Ott, Catherine J. Wu, David A. Reardon. Personal neoantigen-targeting vaccination generates neoepitope-specific T cell responses in tumors of patients with glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5631.

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.

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.

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 ...

2027 Background: No medical therapy for recurrent meningioma has proven effective, yet a subset of these tumors recur after surgery and radiation. A pilot study of sustained-release somatostatin yi...

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.

Objective: We conducted a randomized phase II study of vandetanib in patients with newly-diagnosed GBM in combination with radiation (RT) and temozolomide (TMZ). Background EGFR and VEGFR signaling have been implicated in the development and growth of GBM. In addition, angiogenesis inhibitors may enhance radiation sensitivity. Vandetanib is an inhibitor of VEGFR-2 and EGFR tyrosine kinase activities. Design/Methods: We planned to randomize a total of 114 newly-diagnosed GBM patients in a ratio of 1:2 to Arm A: RT/TMZ or Arm B: vandetanib 100 mg daily + RT/TMZ. All pts received RT (60 Gy) and concurrent TMZ 75 mg/m 2 daily, followed by adjuvant TMZ for up to 12 cycles (150-200 mg/m 2 on days 1-5 of each 28 day cycle). Pts with age ≥ 18, Karnofsky performance status (KPS) ≥ 60, and not on enzyme-inducing antiepileptics were eligible. Primary endpoint was overall survival (OS) from the date of randomization. Secondary endpoints included median progression-free survival (PFS) and safety. Results: We enrolled 106 pts (36 in Arm A, 70 in Arm B) with median age 59 yrs (range: 23-83) and median KPS 90 (range: 60-100). Most frequent Gr ≥ 3 AEs in the vandetanib arm were lymphopenia (20%), thrombosis (12.5%), transaminitis (8%) and leukopenia (5%). Preliminary median OS is 487 days with 95% CI (350, NR) in Arm A and 503 days with 95% CI (451, 634) in Arm B. Median PFS is 141 days with 95% CI (104. 252) in Arm A and 127 days with 95% CI (93. 165) in Arm B. Due to an unplanned interim analysis demonstrating no survival difference, enrollment was terminated early and the study was closed. Conclusions: Although reasonably well-tolerated, the addition of vandetanib to standard chemoradiation in newly-diagnosed GBM may not significantly prolong OS compared to the parallel control arm. Updated efficacy and toxicity data will be presented. Supported by: AstraZeneca. Disclosure: Dr. Lee has received personal compensation for activities with Norvartis and Genentech as an advisory board member.Dr. Lee has received personal compensation in an editorial capacity for UpToDate, Inc. Dr. Batchelor has received personal compensation for activities with Roche Diagnostics Corporation, Genentech, Inc., Merck & Co. Inc., and Millennium. Dr. Batchelor has received personal compensation in an editorial capacity for UpToDate Inc. Dr. Batchelor has received research support from Pfizer Inc, AstraZeneca Pharmaceuticals and Millennium. Dr. Kaley has nothing to disclose. Dr. Schiff has received personal compensation for activities with Novocure and Genentech. Dr. Schiff has received research support from Exelixis. Dr. Lassman has received personal compensation for activities with Schering-Plough Corp., ImClone Systems, Genentech, Inc., Eisai Inc., Cephalon, Inc., Physicians Education Resource, The Robert Michael Educational Institute, and Medical Communications Media.Dr. Lassman has received research support from Keryx Biopharmaceuticals, Genentech, and Schering Plough Corp. Dr. Wong has received research support from AstraZeneca Pharmaceuticals, Exelixis, Novartis and NovoCure as a researcher. Dr. Mikkelsen has received personal compensation for activities with Merck and Roche. Dr. Purow has nothing to disclose. Dr. Drappatz has nothing to disclose. Dr. Norden has nothing to disclose. Dr. Beroukhim has received personal compensation for activities with Novartis as a consultant. Dr. Beroukhim holds stock and/or stock options in AstraZeneca, which sponsored research in which Dr. Beroukhim was involved as an investigator. Dr. Beroukhim holds stock and/or stock options in Baxter, CareFusion, Edwards Lifesciences, and Cardinal Health. Dr. Beroukhim has received research support from Novartis. Dr. Weiss has received personal compensation for activities with a consulting firm as RT expert. Dr. Weiss has received research support from Aposence. Dr. Alexander has nothing to disclose. Dr. McCluskey has nothing to disclose. Dr. Gerard has nothing to disclose. Dr. Teulings has nothing to disclose. Dr. Smith has nothing to disclose. Dr. Muzikansky has nothing to disclose. Dr. Wen has received personal compensation for activities with Merck & Co., and Novartis as consutant and/or speaker. Dr. Wen has received personal compensation in an editorial capacity for UptoDate. Dr. Wen has received research support from Amgen Inc, AstraZeneca Pharmaceuticals, Eisai Inc, Exelixis, Genentech, Inc., Medimmune, Merck & Co., Novartis, Sanofi-Aventis Pharmaceuticals and Vascular Biogenics.