Molecular Profiling Reveals Biologically Discrete Subsets and Pathways of Progression in Diffuse Glioma.

Therapy development for adult diffuse glioma is hindered by incomplete knowledge of somatic glioma driving alterations and suboptimal disease classification. We defined the complete set of genes associated with 1,122 diffuse grade II-III-IV gliomas from The Cancer Genome Atlas and used molecular profiles to improve disease classification, identify molecular correlations, and provide insights into the progression from low- to high-grade disease. Whole-genome sequencing data analysis determined that ATRX but not TERT promoter mutations are associated with increased telomere length. Recent advances in glioma classification based on IDH mutation and 1p/19q co-deletion status were recapitulated through analysis of DNA methylation profiles, which identified clinically relevant molecular subsets. A subtype of IDH mutant glioma was associated with DNA demethylation and poor outcome; a group of IDH-wild-type diffuse glioma showed molecular similarity to pilocytic astrocytoma and relatively favorable survival. Understanding of cohesive disease groups may aid improved clinical outcomes.

The somatic genomic landscape of glioblastoma.

We describe the landscape of somatic genomic alterations based on multidimensional and comprehensive characterization of more than 500 glioblastoma tumors (GBMs). We identify several novel mutated genes as well as complex rearrangements of signature receptors, including EGFR and PDGFRA. TERT promoter mutations are shown to correlate with elevated mRNA expression, supporting a role in telomerase reactivation. Correlative analyses confirm that the survival advantage of the proneural subtype is conferred by the G-CIMP phenotype, and MGMT DNA methylation may be a predictive biomarker for treatment response only in classical subtype GBM. Integrative analysis of genomic and proteomic profiles challenges the notion of therapeutic inhibition of a pathway as an alternative to inhibition of the target itself. These data will facilitate the discovery of therapeutic and diagnostic target candidates, the validation of research and clinical observations and the generation of unanticipated hypotheses that can advance our molecular understanding of this lethal cancer.

PKM2 phosphorylates histone H3 and promotes gene transcription and tumorigenesis.

Tumor-specific pyruvate kinase M2 (PKM2) is essential for the Warburg effect. In addition to its well-established role in aerobic glycolysis, PKM2 directly regulates gene transcription. However, the mechanism underlying this nonmetabolic function of PKM2 remains elusive. We show here that PKM2 directly binds to histone H3 and phosphorylates histone H3 at T11 upon EGF receptor activation. This phosphorylation is required for the dissociation of HDAC3 from the CCND1 and MYC promoter regions and subsequent acetylation of histone H3 at K9. PKM2-dependent histone H3 modifications are instrumental in EGF-induced expression of cyclin D1 and c-Myc, tumor cell proliferation, cell-cycle progression, and brain tumorigenesis. In addition, levels of histone H3 T11 phosphorylation correlate with nuclear PKM2 expression levels, glioma malignancy grades, and prognosis. These findings highlight the role of PKM2 as a protein kinase in its nonmetabolic functions of histone modification, which is essential for its epigenetic regulation of gene expression and tumorigenesis.

A survey of intragenic breakpoints in glioblastoma identifies a distinct subset associated with poor survival.

With the advent of high-throughput sequencing technologies, much progress has been made in the identification of somatic structural rearrangements in cancer genomes. However, characterization of the complex alterations and their associated mechanisms remains inadequate. Here, we report a comprehensive analysis of whole-genome sequencing and DNA copy number data sets from The Cancer Genome Atlas to relate chromosomal alterations to imbalances in DNA dosage and describe the landscape of intragenic breakpoints in glioblastoma multiforme (GBM). Gene length, guanine-cytosine (GC) content, and local presence of a copy number alteration were closely associated with breakpoint susceptibility. A dense pattern of repeated focal amplifications involving the murine double minute 2 (MDM2)/cyclin-dependent kinase 4 (CDK4) oncogenes and associated with poor survival was identified in 5% of GBMs. Gene fusions and rearrangements were detected concomitant within the breakpoint-enriched region. At the gene level, we noted recurrent breakpoints in genes such as apoptosis regulator FAF1. Structural alterations of the FAF1 gene disrupted expression and led to protein depletion. Restoration of the FAF1 protein in glioma cell lines significantly increased the FAS-mediated apoptosis response. Our study uncovered a previously underappreciated genomic mechanism of gene deregulation that can confer growth advantages on tumor cells and may generate cancer-specific vulnerabilities in subsets of GBM.

A Phase Ib/II, open-label, multicenter study of INC280 (capmatinib) alone and in combination with buparlisib (BKM120) in adult patients with recurrent glioblastoma.

PURPOSE: To estimate the maximum tolerated dose (MTD) and/or identify the recommended Phase II dose (RP2D) for combined INC280 and buparlisib in patients with recurrent glioblastoma with homozygous phosphatase and tensin homolog (PTEN) deletion, mutation or protein loss. METHODS: This multicenter, open-label, Phase Ib/II study included adult patients with glioblastoma with mesenchymal-epithelial transcription factor (c-Met) amplification. In Phase Ib, patients received INC280 as capsules or tablets in combination with buparlisib. In Phase II, patients received INC280 only. Response was assessed centrally using Response Assessment in Neuro-Oncology response criteria for high-grade gliomas. All adverse events (AEs) were recorded and graded. RESULTS: 33 patients entered Phase Ib, 32 with altered PTEN. RP2D was not declared due to potential drug-drug interactions, which may have resulted in lack of efficacy; thus, Phase II, including 10 patients, was continued with INC280 monotherapy only. Best response was stable disease in 30% of patients. In the selected patient population, enrollment was halted due to limited activity with INC280 monotherapy. In Phase Ib, the most common treatment-related AEs were fatigue (36.4%), nausea (30.3%) and increased alanine aminotransferase (30.3%). MTD was identified at INC280 Tab 300 mg twice daily + buparlisib 80 mg once daily. In Phase II, the most common AEs were headache (40.0%), constipation (30.0%), fatigue (30.0%) and increased lipase (30.0%). CONCLUSION: The combination of INC280/buparlisib resulted in no clear activity in patients with recurrent PTEN-deficient glioblastoma. More stringent molecular selection strategies might produce better outcomes. TRIAL REGISTRATION: NCT01870726.

Molecular Mechanisms of Treatment Resistance in Glioblastoma.

Glioblastoma is the most common malignant primary brain tumor in adults and is almost invariably fatal. Despite our growing understanding of the various mechanisms underlying treatment failure, the standard-of-care therapy has not changed over the last two decades, signifying a great unmet need. The challenges of treating glioblastoma are many and include inadequate drug or agent delivery across the blood-brain barrier, abundant intra- and intertumoral heterogeneity, redundant signaling pathways, and an immunosuppressive microenvironment. Here, we review the innate and adaptive molecular mechanisms underlying glioblastoma's treatment resistance, emphasizing the intrinsic challenges therapeutic interventions must overcome-namely, the blood-brain barrier, tumoral heterogeneity, and microenvironment-and the mechanisms of resistance to conventional treatments, targeted therapy, and immunotherapy.

Phase 1 lead-in to a phase 2 factorial study of temozolomide plus memantine, mefloquine, and metformin as postradiation adjuvant therapy for newly diagnosed glioblastoma.

BACKGROUND: Repurposed memantine, mefloquine, and metformin have putative anticancer activity. The objective of this phase 1 study was to determine the maximum tolerated doses (MTDs) of combinations of these agents with temozolomide (TMZ). METHODS: Adults with newly diagnosed glioblastoma who completed chemoradiation were eligible. The patients were assigned to receive doublet, triplet, or quadruplet therapy with TMZ combined with mefloquine, memantine, and/or metformin. Dose-limiting toxicities (DLTs) were determined, using a 3 + 3 study design. RESULTS: Of 85 enrolled patients, 4 did not complete cycle 1 (the DLT observation period) for nontoxicity reasons, and 81 were evaluable for DLT. The MTDs for doublet therapy were memantine 20 mg twice daily, mefloquine 250 mg 3 times weekly, and metformin 850 mg twice daily. For triplet therapy, the MTDs were memantine 10 mg twice daily, mefloquine 250 mg 3 times weekly, and metformin 850 mg twice daily. For quadruplet therapy, the MTDs were memantine 10 mg twice daily, mefloquine 250 mg 3 times weekly, and metformin 500 mg twice daily. DLTs included dizziness (memantine) and gastrointestinal effects (metformin). Lymphopenia was the most common adverse event (66%). From study entry, the median survival was 21 months, and the 2-year survival rate was 43%. CONCLUSIONS: Memantine, mefloquine, and metformin can be combined safely with TMZ in patients with newly diagnosed glioblastoma.

Comprehensive, Integrative Genomic Analysis of Diffuse Lower-Grade Gliomas.

BACKGROUND: Diffuse low-grade and intermediate-grade gliomas (which together make up the lower-grade gliomas, World Health Organization grades II and III) have highly variable clinical behavior that is not adequately predicted on the basis of histologic class. Some are indolent; others quickly progress to glioblastoma. The uncertainty is compounded by interobserver variability in histologic diagnosis. Mutations in IDH, TP53, and ATRX and codeletion of chromosome arms 1p and 19q (1p/19q codeletion) have been implicated as clinically relevant markers of lower-grade gliomas. METHODS: We performed genomewide analyses of 293 lower-grade gliomas from adults, incorporating exome sequence, DNA copy number, DNA methylation, messenger RNA expression, microRNA expression, and targeted protein expression. These data were integrated and tested for correlation with clinical outcomes. RESULTS: Unsupervised clustering of mutations and data from RNA, DNA-copy-number, and DNA-methylation platforms uncovered concordant classification of three robust, nonoverlapping, prognostically significant subtypes of lower-grade glioma that were captured more accurately by IDH, 1p/19q, and TP53 status than by histologic class. Patients who had lower-grade gliomas with an IDH mutation and 1p/19q codeletion had the most favorable clinical outcomes. Their gliomas harbored mutations in CIC, FUBP1, NOTCH1, and the TERT promoter. Nearly all lower-grade gliomas with IDH mutations and no 1p/19q codeletion had mutations in TP53 (94%) and ATRX inactivation (86%). The large majority of lower-grade gliomas without an IDH mutation had genomic aberrations and clinical behavior strikingly similar to those found in primary glioblastoma. CONCLUSIONS: The integration of genomewide data from multiple platforms delineated three molecular classes of lower-grade gliomas that were more concordant with IDH, 1p/19q, and TP53 status than with histologic class. Lower-grade gliomas with an IDH mutation either had 1p/19q codeletion or carried a TP53 mutation. Most lower-grade gliomas without an IDH mutation were molecularly and clinically similar to glioblastoma. (Funded by the National Institutes of Health.).

NRG oncology RTOG 9006: a phase III randomized trial of hyperfractionated radiotherapy (RT) and BCNU versus standard RT and BCNU for malignant glioma patients.

From 1990 to 1994, patients with newly diagnosed malignant gliomas were enrolled and randomized between hyperfractionated radiation (HFX) of 72.0 Gy in 60 fractions given twice daily and 60.0 Gy in 30 fractions given once daily. All patients received 80 mg/m2 of 1,3 bis(2 chloroethyl)-1 nitrosourea on days 1-3 q8 weeks for 1 year. Patients were stratified by age, KPS, and histology. The primary endpoint was overall survival (OS), with secondary endpoints including progression-free survival (PFS) and toxicity. Out of the 712 patients accrued, 694 (97.5%) were analyzable cases (350 HFX, 344 standard arm). There was no significant difference between the arms on overall acute or late treatment-related toxicity. No statistically significant effect for HFX, as compared to standard therapy, was found on either OS, with a median survival time (MST) of 11.3 versus 13.1 months (p = 0.20) or PFS, with a median PFS time of 5.7 versus 6.9 months (p = 0.18). The treatment effect on OS remained insignificant based on the multivariate analysis (hazard ratio 1.16; p = 0.0682). When OS was analyzed by histology subgroup there was also no significant difference between the two arms for patients with glioblastoma multiforme (MST: 10.3 vs. 11.2 months; p = 0.34), anaplastic astrocytoma (MST: 69.8 vs. 50.0 months; p = 0.91) or anaplastic oligodendroglioma (MST: 92.1 vs. 66.5 months; p = 0.33). Though this trial provided many invaluable secondary analyses, there was no trend or indication of a benefit to HFX radiation to 72.0 Gy in any subset of malignant glioma patients.

Phase I study of sorafenib and tipifarnib for recurrent glioblastoma: NABTC 05-02.

Recurrent glioblastoma (GBM) has a very low 6-month progression free survival (PFS) with currently available treatments. Combination chemotherapy to target multiple cell signaling pathways is currently being investigated in order to improve prognosis for recurrent disease. The purpose of this phase I study was to determine the maximum tolerated dose (MTD) for the combination of tipifarnib and sorafenib for the treatment of recurrent GBM. Patients with pathologically proven WHO grade IV GBM and radiographically proven tumor recurrence were eligible for this study. Treatments included sorafenib at twice daily and escalating dosages of tipifarnib. Dose-limiting toxicity (DLT) was determined over the first 28-days of treatments, and the MTD was determined in a 3 + 3 study design. We enrolled 24 patients, and 21 patients completed the MTD period. The study was stopped early with no MTD determination for excessive toxicities. The last dose level reached was sorafenib at 200 mg twice a day and tipifarnib 100 mg twice a day on an alternating week schedule. The DLTs included diarrhea, lipase elevation, hypophosphatemia, and arthralgia. The combination of sorafenib and tipifarnib has excessive toxicities and full single agent dosages could not be achieved in combination.

Genomically amplified Akt3 activates DNA repair pathway and promotes glioma progression.

Akt is a robust oncogene that plays key roles in the development and progression of many cancers, including glioma. We evaluated the differential propensities of the Akt isoforms toward progression in the well-characterized RCAS/Ntv-a mouse model of PDGFB-driven low grade glioma. A constitutively active myristoylated form of Akt1 did not induce high-grade glioma (HGG). In stark contrast, Akt2 and Akt3 showed strong progression potential with 78% and 97% of tumors diagnosed as HGG, respectively. We further revealed that significant variations in polarity and hydropathy values among the Akt isoforms in both the pleckstrin homology domain (P domain) and regulatory domain (R domain) were critical in mediating glioma progression. Gene expression profiles from representative Akt-derived tumors indicated dominant and distinct roles for Akt3, consisting primarily of DNA repair pathways. TCGA data from human GBM closely reflected the DNA repair function, as Akt3 was significantly correlated with a 76-gene signature DNA repair panel. Consistently, compared with Akt1 and Akt2 overexpression models, Akt3-expressing human GBM cells had enhanced activation of DNA repair proteins, leading to increased DNA repair and subsequent resistance to radiation and temozolomide. Given the wide range of Akt3-amplified cancers, Akt3 may represent a key resistance factor.

A randomized phase II trial of standard dose bevacizumab versus low dose bevacizumab plus lomustine (CCNU) in adults with recurrent glioblastoma.

Antiangiogenic therapy can rapidly reduce vascular permeability and cerebral edema but high doses of bevacizumab may induce selective pressure to promote resistance. This trial evaluated the efficacy of low dose bevacizumab in combination with lomustine (CCNU) compared to standard dose bevacizumab in patients with recurrent glioblastoma. Patients (N = 71) with recurrent glioblastoma who previously received radiation and temozolomide were randomly assigned 1:1 to receive bevacizumab monotherapy (10 mg/kg) or low dose bevacizumab (5 mg/kg) in combination with lomustine (90 mg/m(2)). The primary end point was progression-free survival (PFS) based on a blinded, independent radiographic assessment of post-contrast T1-weighted and non-contrast T2/FLAIR weighted magnetic resonance imaging (MRI) using RANO criteria. For 69 evaluable patients, median PFS was not significantly longer in the low dose bevacizumab + lomustine arm (4.34 months, CI 2.96-8.34) compared to the bevacizumab alone arm (4.11 months, CI 2.69-5.55, p = 0.19). In patients with first recurrence, there was a trend towards longer median PFS time in the low dose bevacizumab + lomustine arm (4.96 months, CI 4.17-13.44) compared to the bevacizumab alone arm (3.22 months CI 2.5-6.01, p = 0.08). The combination of low dose bevacizumab plus lomustine was not superior to standard dose bevacizumab in patients with recurrent glioblastoma. Although the study was not designed to exclusively evaluate patients at first recurrence, a strong trend towards improved PFS was seen in that subgroup for the combination of low dose bevacizumab plus lomustine. Further studies are needed to better identify such subgroups that may most benefit from the combination treatment.

A phase II study of bevacizumab and erlotinib after radiation and temozolomide in MGMT unmethylated GBM patients.

Survival for glioblastoma (GBM) patients with an unmethyated MGMT promoter in their tumor is generally worse than methylated MGMT tumors, as temozolomide (TMZ) response is limited. How to better treat patients with unmethylated MGMT is unknown. We performed a trial combining erlotinib and bevacizumab in unmethylated GBM patients after completion of radiation (RT) and TMZ. GBM patients with an unmethylated MGMT promoter were trial eligible. Patient received standard RT (60 Gy) and TMZ (75 mg/m2 × 6 weeks) after surgical resection of their tumor. After completion of RT they started erlotinib 150 mg daily and bevacizumab 10 mg/kg every 2 weeks until progression. Imaging evaluations occurred every 8 weeks. The primary endpoint was overall survival. Of the 48 unmethylated patients enrolled, 46 were evaluable (29 men and 17 women); median age was 55.5 years (29-75) and median KPS was 90 (70-100). All patients completed RT with TMZ. The median number of cycles (1 cycle was 4 weeks) was 8 (2-47). Forty-one patients either progressed or died with a median progression free survival of 9.2 months. At a follow up of 33 months the median overall survival was 13.2 months. There were no unexpected toxicities and most observed toxicities were categorized as CTC grade 1 or 2. The combination of erlotinib and bevacizumab is tolerable but did not meet our primary endpoint of increasing survival. Importantly, more trials are needed to find better therapies for GBM patients with an unmethylated MGMT promoter.

Genetic, epigenetic, and molecular landscapes of multifocal and multicentric glioblastoma.

Ten to twenty percent of newly diagnosed glioblastoma (GBM) patients initially present with multiple lesions, termed multifocal or multicentric GBM (M-GBM). The prognosis of these patients is poorer than that of solitary GBM (S-GBM) patients. However, it is unknown whether multifocality has a genetic, epigenetic, or molecular basis. Here, we identified the genetic and epigenetic characteristics of M-GBM by performing a comprehensive analysis of multidimensional data, including imaging, genetic, epigenetic, and gene expression profiles, from 30 M-GBM cases in The Cancer Genome Atlas database and comparing the results with those of 173 S-GBM cases. We found that M-GBMs had no IDH1, ATRX, or PDGFRA mutations and were significantly associated with the mesenchymal subtype. We also identified the CYB5R2 gene to be hypo-methylated and overexpressed in M-GBMs. The expression level of CYB5R2 was significantly associated with patient survival in two major independent GBM cohorts, totaling 758 cases. The IDH1 mutation was markedly associated with CYB5R2 promoter methylation, but the survival influence of CYB5R2 was independent of IDH1 mutation status. CYB5R2 expression was significantly associated with collagen maturation and the catabolic process and immunoregulation pathways. These results reveal that M-GBMs have some underlying genetic and epigenetic characteristics that are associated with poor prognosis and that CYB5R2 is a new epigenetic marker for GBM prognosis.

A high Notch pathway activation predicts response to γ secretase inhibitors in proneural subtype of glioma tumor-initiating cells.

Genomic, transcriptional, and proteomic analyses of brain tumors reveal subtypes that differ in pathway activity, progression, and response to therapy. However, a number of small molecule inhibitors under development vary in strength of subset and pathway-specificity, with molecularly targeted experimental agents tending toward stronger specificity. The Notch signaling pathway is an evolutionarily conserved pathway that plays an important role in multiple cellular and developmental processes. We investigated the effects of Notch pathway inhibition in glioma tumor-initiating cell (GIC, hereafter GIC) populations using γ secretase inhibitors. Drug cytotoxicity testing of 16 GICs showed differential growth responses to the inhibitors, stratifying GICs into responders and nonresponders. Responder GICs had an enriched proneural gene signature in comparison to nonresponders. Also gene set enrichment analysis revealed 17 genes set representing active Notch signaling components NOTCH1, NOTCH3, HES1, MAML1, DLL-3, JAG2, and so on, enriched in responder group. Analysis of The Cancer Genome Atlas expression dataset identified a group (43.9%) of tumors with proneural signature showing high Notch pathway activation suggesting γ secretase inhibitors might be of potential value to treat that particular group of proneural glioblastoma (GBM). Inhibition of Notch pathway by γ secretase inhibitor treatment attenuated proliferation and self-renewal of responder GICs and induces both neuronal and astrocytic differentiation. In vivo evaluation demonstrated prolongation of median survival in an intracranial mouse model. Our results suggest that proneural GBM characterized by high Notch pathway activation may exhibit greater sensitivity to γ secretase inhibitor treatment, holding a promise to improve the efficiency of current glioma therapy.

Survival outcome of early versus delayed bevacizumab treatment in patients with recurrent glioblastoma.

Bevacizumab (BEV) is widely used for treatment of patients with recurrent glioblastoma. It is not known if there are differences in outcome between early versus delayed BEV treatment of recurrent glioblastoma. We examined the relationship between the time of starting BEV treatment and outcomes in patients with recurrent glioblastoma. In this retrospective chart review, we identified patients with recurrent glioblastoma diagnosed between 2005 and 2011 who were treated with BEV alone or BEV-containing regimens. Data was analyzed to determine overall survival (OS) from time of diagnosis and progression free survival (PFS) from time of starting BEV. A total of 298 patients were identified, 112 patients received early BEV, 133 patients received delayed BEV, and 53 patients were excluded because they either progressed within 3 months of radiation or received BEV at the time of diagnosis. There was no significant difference in PFS between patients that received early BEV and those that received delayed BEV (5.2 vs. 4.3 months, p = 0.2). Patients treated with delayed BEV had longer OS when compared to those treated with early BEV (25.9 vs. 20.8 months, p = 0.005). In patients with recurrent glioblastoma, there was no significant difference in PFS from the time of starting BEV between early and delayed BEV. Although patients treated with delayed BEV seemed to have longer OS, a conclusion regarding OS outcome requires further prospective trials. These results may indicate that delaying treatment with BEV is not detrimental for survival of patients with recurrent glioblastoma.

Social obstetrics: non-local expectant mothers admitted through accident and emergency department in a public hospital in Hong Kong.

OBJECTIVES: To review the pregnancy outcomes of non-booked, non-local pregnant women delivering in Kwong Wah Hospital via admission to the Accident and Emergency Department 1 year after the announcement by the Hospital Authority to stop antenatal booking for non-eligible persons; and to perform a literature review of local studies about non-eligible person deliveries over the last decade. DESIGN: Case series. SETTING: A public hospital in Hong Kong. PARTICIPANTS: All women who held the People's Republic of China passport or the two-way permit and those non-eligible persons whose spouses were Hong Kong Identity Card holders, who delivered in Kwong Wah Hospital from 1 April 2011 to 31 March 2012. RESULTS: Overall, 219 women who were non-eligible persons delivered 221 live births during the study period. Compared with the annual statistics of Kwong Wah Hospital in 2011, non-local mothers were of higher parity; more likely to have hypertensive disease (including pre-eclamptic toxaemia), preterm deliveries (ie at <37 weeks), babies needing admission to the special care baby unit, and macrosomic babies (ie weighing >4.0 kg). The rates of induction of labour and caesarean section were lower in this group. There was no significant difference in the maternal and neonatal outcomes between women who had no booking and those who had a booking in another Hospital Authority or private hospital. There were many incidents of near-miss obstetric complications or suboptimally managed obstetric conditions due to lack of well-structured and continuous antenatal care in this group of non-eligible persons. CONCLUSION: Non-eligible person delivering babies in Hong Kong has become a social obstetrics phenomenon. Despite the introduction of policies, reduction in the number of deliveries (quantity) did not improve the obstetric outcomes (quality). Health care professionals should continue to be prepared for managing the potential near-miss clinical complications in this group of 'travelling mothers'.

Phase 1/1b study of lonafarnib and temozolomide in patients with recurrent or temozolomide refractory glioblastoma.

BACKGROUND: Lonafarnib is an oral selective farnesyltransferase inhibitor, a class of drugs which have shown activity in preclinical glioma models. Temozolomide (TMZ) is an alkylating agent that is the first-line chemotherapy for glioblastoma. METHODS: The current study combined the cytotoxic agent TMZ with the cytostatic agent lonafarnib for patients with recurrent glioblastoma to establish a maximum tolerated dose (MTD) of the combination and its preliminary efficacy. Three dose cohorts of lonafarnib were studied in the phase 1 component of the trial (100 mg twice daily [bid], 150 mg bid, and 200 bid) with dose-dense schedule of TMZ (150 mg/m² daily) administered in an alternating weekly schedule. After establishing the MTD of lonafarnib, a subsequent expansion phase 1b was undertaken to evaluate efficacy, primarily measured by 6-month progression-free survival (PFS-6). RESULTS: Fifteen patients were enrolled into the phase 1 component and 20 patients into the phase 1b component. The MTD of lonafarnib in combination with TMZ was 200 mg bid. Among the patients enrolled into the study, 34 were eligible for 6-month progression evaluation and 35 patients were evaluable for time-to-progression analysis. The PFS-6 rate was 38% (95% confidence interval [CI] = 22%, 56%) and the median PFS was 3.9 months (95% CI = 2.5, 8.4). The median disease-specific survival was 13.7 months (95% CI = 8.9, 22.1). Hematologic toxicities, particularly lymphopenia, were the most common grade 3 and 4 adverse events. There were no treatment-related deaths. CONCLUSIONS: These results demonstrate that TMZ can be safely combined with a farnesyltransferase inhibitor and that this regimen is active, although the current study cannot determine the relative contributions of the 2 agents or the contribution of the novel administration schedule.

A phase II study of conventional radiation therapy and thalidomide for supratentorial, newly-diagnosed glioblastoma (RTOG 9806).

The Radiation Therapy Oncology Group (RTOG) initiated the single-arm, phase II study 9806 to determine the safety and efficacy of daily thalidomide with radiation therapy in patients with newly diagnosed glioblastoma. Patients were treated with thalidomide (200 mg daily) from day one of radiation therapy, increasing by 100-200 to 1,200 mg every 1-2 weeks until tumor progression or unacceptable toxicity. The median survival time (MST) of all 89 evaluable patients was 10 months. When compared with the historical database stratified by recursive partitioning analysis (RPA) class, this end point was not different [hazard ratio (HR) = 1.18; 95 % CI: 0.95-1.46; P = 0.93]. The MST of RPA class III and IV patients was 13.9 versus 12.5 months in controls (HR = 0.99; 95 % CI: 0.73-1.36; P = 0.48), and 4.3 versus 8.6 months in RPA class V controls (HR = 1.63, 95 % CI: 1.17-2.27; P = 0.99). In all, 34 % of patients discontinued thalidomide because of adverse events or refusal. The most common grade 3-4 toxicities were venous thrombosis, fatigue, skin reactions, encephalopathy, and neuropathy. In conclusion, thalidomide given simultaneously with radiation therapy was safe, but did not improve survival in patients with newly diagnosed glioblastoma.