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2037 Background: Newly diagnosed glioblastoma (nGBM) routinely treated with surgery, radiation, and temozolomide (TMZ), still result in early progression and near-universal lethality within 5 years. Tumor associated “survivin” is expressed in >95% of nGBM and targetable by SurVaxM immunotherapy. Results from the recently completed multi-center phase 2a trial of SurVaxM in nGBM are presented. Methods: nGBM patients (pts) were enrolled at 5 trial sites. Eligibility criteria included: age ≥ 18, Karnofsky performance status ≥70, IHC confirmation of survivin expression, expression of HLA-A*02, A*03, A*11 or A*24 MHC-I alleles and residual contrast enhancement of ≤1 cm3 by MRI within 72h post-resection. Pts received standard TMZ chemoradiation followed by initiation of 4 priming doses of SurVaxM (500 mcg in emulsion with Montanide ISA 51, every 2 weeks) with 100 mcg sargramostim. Maintenance doses of SurVaxM-Montanide plus sargramostim were thereafter administered every 12 weeks. Adjuvant TMZ was administered for at least 6 cycles, after at least the first dose of SurVaxM and beginning no sooner than 28 days after completion of chemoradiation. Pts were monitored by MRI every 8 weeks, and progression was assessed using modified RANO criteria. The primary endpoint was 70% progression free survival (PFS) at 6 mos. Primary analyses of median PFS (mPFS) and median overall survival (OS) were measured from first immunization. Safety, tolerability, and immune responsiveness were also determined. Results: 63 pts with nGBM were enrolled, comprised of 38 males and 25 females with a median age of 60 years. The cohort was consistent with the 4 commonly observed primary molecular GBM subtypes (classical, mesenchymal, neural and proneural). SurVaxM was well tolerated, with no serious adverse events. A strong positive correlation, accounting for censoring, was observed between PFS and OS of all pts (r = 0.79; 95% CI (0.66,0.87)). SurVaxM was immunogenic and produced survivin-specific CD8+ T-cells and antibody (IgG) titers in both methylated and unmethylated MGMT pts and both groups showed clinical benefit. Conclusions: SurVaxM appeared to be safe and well-tolerated in pts with nGBM. SurVaxM was effective at stimulating survivin-specific immune responses and the primary endpoint was met. SurVaxM represents a promising therapy for nGBM, including for those pts with unmethylated MGMT genes. For pts treated with SurVaxM, PFS may be an acceptable surrogate for OS. Clinical trial information: NCT02455557. [Table: see text]

Background: Although familial susceptibility to glioma is known, the genetic basis for this susceptibility remains unidentified in the majority of glioma-specific families. An alternative approach to identifying such genes is to examine cancer pedigrees, which include glioma as one of several cancer phenotypes, to determine whether common chromosomal modifications might account for the familial aggregation of glioma and other cancers. Methods: Germline rearrangements in 146 glioma families (from the Gliogene Consortium; http://www.gliogene.org/) were examined using multiplex ligation-dependent probe amplification. These families all had at least 2 verified glioma cases and a third reported or verified glioma case in the same family or 2 glioma cases in the family with at least one family member affected with melanoma, colon, or breast cancer. The genomic areas covering TP53, CDKN2A, MLH1, and MSH2 were selected because these genes have been previously reported to be associated with cancer pedigrees known to include glioma. Results: We detected a single structural rearrangement, a deletion of exons 1-6 in MSH2, in the proband of one family with 3 cases with glioma and one relative with colon cancer. Conclusions: Large deletions and duplications are rare events in familial glioma cases, even in families with a strong family history of cancers that may be involved in known cancer syndromes. Meeting Abstract: P04.02 published in the same journal, Vol. 16, Suppl. 2.

2061 Background: Ruxolitinib is a novel, selective inhibitor of JAK1 (Janus kinase 1) and JAK2 and JAK3. JAK signaling involves recruitment of signal transducers and activators of transcription (STATs) to cytokine receptors, activation, and subsequent localization of STATs to the nucleus leading to modulation of gene expression. Dysregulation of the JAK/STAT pathway has been associated with several types of cancer and increased proliferation and survival of malignant cells. Preclinical evidence supports inhibition of JAJK STAT pathway arrogated glioma growth. Methods: Ruxolitinib is a novel, selective inhibitor of JAK1 (Janus kinase 1) and JAK2 and JAK3. JAK signaling involves recruitment of signal transducers and activators of transcription (STATs) to cytokine receptors, activation, and subsequent localization of STATs to the nucleus leading to modulation of gene expression. Dysregulation of the JAK/STAT pathway has been associated with several types of cancer and increased proliferation and survival of malignant cells. Preclinical evidence supports inhibition of JAJK STAT pathway arrogated glioma growth. Results: 60 patients were treated on the study and there were no dose limiting toxicity seen on the protocol. Survival data was calculated for GBM. The OS for arm 1 was 18.17 (10.15, NA) and was not reached for arm 2. The 1 year OS was 0.62 for arm 1 and 0.93 for arm 2. Patients that received ruxolitinib + radiation x 60 Gy + daily temozolomide at 75 mg/m2 for 6 weeks over 6 weeks (Arm 2) had significantly better PFS and OS than those that received ruxolitinib + radiation x 60 Gy alone. Conclusions: Dose of 20 mg twice daily of ruxolitinib is safe with radiation and temozolomide. Preliminary survival data appears promising compared to the historical benchmarks and randomized phase 2 trial is planned. Clinical trial information: NCT03514069. [Table: see text]