Abstract
BACKGROUND
Standard of care (SOC) and patient survival in glioblastoma have changed little in the past 17 years. We evaluated in a phase 3 trial whether adding an autologous tumor ...lysate-loaded dendritic cell vaccine (murcidencel) to SOC extends survival. Patients and
METHODS
Newly diagnosed glioblastoma patients were randomized 2:1 to either murcidencel or placebo. Under a crossover design, all patients could receive murcidencel following tumor recurrence. All parties remained blinded regarding treatments before recurrence. Patients thus received murcidencel at new diagnosis (nGBM) or at recurrence (rGBM) following crossover from placebo. The primary and secondary endpoints compare overall survival (OS) with contemporaneous, matched external controls. Four sets of analyses were conducted to ensure rigorous matching of the controls, reduce biases, and confirm the robustness of the results.
RESULTS
331 patients were enrolled. With the crossover, 89% received murcidencel. Median OS (mOS) for nGBM patients (n = 232) was 19.3 months from randomization (22.4 months from surgery) with murcidencel vs. 16.5 months from randomization in the controls (HR = 0.80, p = 0.002). Survival at 48 months from randomization was 15.7% vs. 9.9%, and at 60 months was 13% vs. 5.7%. For rGBM (n = 64), mOS was 13.2 months from relapse vs. 7.8 months in the controls (HR = 0.58, p < 0.001). Survival at 24 months post-recurrence was 20.7% vs. 9.6%, and at 30 months post-recurrence was 11.1% vs 5.1%. In nGBM patients with methylated MGMT (n = 90), mOS was 30.2 months from randomization (33 months from surgery) with murcidencel vs. 21.3 months from randomization in the controls (HR = 0.74, p = 0.027). The treatment was well tolerated, with only 5 serious adverse events deemed at least possibly related to the vaccine.
CONCLUSION
Clinically meaningful and statistically significant survival extension was seen in both nGBM and rGBM patients treated with murcidencel and SOC compared with contemporaneous, matched external controls who received SOC alone.
Abstract
BACKGROUND
Toca 511 (vocimagene amiretrorepvec) is a cancer-selective, retroviral replicating vector encoding a codon optimized, heat stabilized cytosine deaminase that converts Toca FC ...(extended-release 5-fluorocytosine, 5-FC) into the anticancer agent 5-fluorouracil. Three Ph1 studies in patients with recurrent high grade glioma have demonstrated a tolerable safety profile and encouraging efficacy.
METHODS
Toca 5 is a multi-national, randomized, open-label Ph3 trial (NCT02414165) of Toca 511 & Toca FC versus standard of care (SOC) options that comprises Investigator’s choice of single agent chemotherapy (lomustine, temozolomide) or bevacizumab in patients who have undergone resection for first or second recurrence of glioblastoma or anaplastic astrocytoma. 403 patients were randomized 1:1 to the Toca arm or the SOC arm and stratified by IDH1 status, KPS, and geographic region. Primary endpoint was overall survival (OS), and secondary endpoints were durable response rate, durable clinical benefit rate, duration of durable response, and 12-month survival rate. The study used group sequential design including 2 interim analyses and 1 final analysis, and the stratified log-rank test are used for the analysis.
RESULTS
271 events were observed for this analysis. Median follow-up was 22.8 months, and the Toca arm missed the primary endpoint (OS) compared to the SOC arm (11.1 months median compared to 12.2 months, HR=1.06, p=0.6154). All secondary endpoints showed no meaningful difference between the arms of the trial. The safety, tolerability and adverse event profile of Toca 511 and Toca FC was as expected for this patient population, with low incidences of Grade 3–4 adverse events. Pre-planned subgroup analyses showed compelling OS improvement in patients with secondary recurrence, and favorable trends in IDH1 mutant and AA population. Detailed data will be presented at the time of the conference.
PURPOSE: To perform a phase I study to evaluate the safety, and tolerability of panobinostat, an HDAC inhibitor, when combined with fractionated stereotactic re-irradiation therapy (FSRT) for ...recurrent gliomas. METHODS: Patients with recurrent gliomas (WHO grade II-IV) were eligible for this trial. FSRT was prescribed to 30-35 Gy delivered in 10 daily fractions. Panobinostat was administrated orally once daily every Monday, Wednesday, and Friday concurrently with radiation treatment. The panobinostat dose was escalated from 10 to 30 mg using a 3 + 3 trial design. RESULTS: A total of 16 patients were enrolled on the trial. Four patients were excluded. There were no treatment related grade 3 or higher toxicities in the 10 mg or 20 mg cohort. In the 30 mg panobinostat cohort, one patient developed grade 3 leukopenia and grade 4 neutropenia which was possibly related to the treatment. The minimum follow up of the living patients is 8.5 m. The 4-m progression survival (PFS) of all the evaluable patients is 87%, and 6-m PFS of 56%. The medial overall survival is 9.5 m. There is a suggestion of dose response to the panobinostat. The 4-m PFS is 100%, 100%, and 67% for 30 mg, 20 mg, and 10 mg cohort respectively. The 6-m PFS is 83%, 33%, and 67% for 30 mg, 20 mg, and 10 mg cohort respectively. The overall survival for the 30 mg cohort is not reached with a median follow up of 11.5 m. CONCLUSIONS: Panobinostat administrated with FSRT is well tolerated at a 30 mg dose. There is a suggestion of a dose response with panobinostat. The median overall survival is not reached with a median follow up of 11.5 m for the 30 mg cohort. A phase II trial is warranted to confirm the efficacy of combining panobinostat with FSRT for recurrent gliomas.
Abstract Background Context Large cell neuroendocrine carcinoma of the lung is an aggressive tumor with unique histopathological features. It is not known to metastasize to the spine. Purpose To ...report a metastatic case of this rare tumor to the cauda equina. Study Design Case report. Methods Retrospective case review and review of the literature. Results The authors report a rare case of a large cell neuroendocrine lung metastasis to the lumbar spine, causing right foot drop. Magnetic resonance imaging revealed a heterogeneously enhancing intradural extramedullary mass at L2/L3 level compressing the surrounding nerve roots. During surgery, the identified nerve roots were encased by the tumor, and the dissection was tedious. Postoperatively, the patient reported significantly improved back pain and he had severe foot weakness. The functional outcome was poor because the patient lost entirely his foot function; however, his back pain improved significantly after surgery. Conclusions This is the first published study in which the authors described a metastasis of a rather uncommon lung cancer to the cauda equina. When a lesion of the cauda equina presents with a rapid progressive neurological deficit, leptomeningeal metastasis should be in the differential diagnosis.
PURPOSE: To perform a phase I study to evaluate the safety, and tolerability of panobinostat, an HDAC inhibitor, when combined with fractionated stereotactic re-irradiation therapy (FSRT) for ...recurrent gliomas. METHODS: Patients with recurrent gliomas (WHO grade II-IV) were eligible for this trial. FSRT was prescribed to 30-35 Gy delivered in 10 daily fractions. Panobinostat was administrated orally once daily every Monday, Wednesday, and Friday concurrently with radiation treatment. The panobinostat dose was escalated from 10 to 30 mg using a 3 + 3 trial design. RESULTS: A total of 16 patients were enrolled on the trial. Four patients were excluded. There were no treatment related grade 3 or higher toxicities in the 10 mg or 20 mg cohort. In the 30 mg panobinostat cohort, one patient developed grade 3 leukopenia and grade 4 neutropenia which was possibly related to the treatment. The minimum follow up of the living patients is 8.5 m. The 4-m progression survival (PFS) of all the evaluable patients is 87%, and 6-m PFS of 56%. The medial overall survival is 9.5 m. There is a suggestion of dose response to the panobinostat. The 4-m PFS is 100%, 100%, and 67% for 30 mg, 20 mg, and 10 mg cohort respectively. The 6-m PFS is 83%, 33%, and 67% for 30 mg, 20 mg, and 10 mg cohort respectively. The overall survival for the 30 mg cohort is not reached with a median follow up of 11.5 m. CONCLUSIONS: Panobinostat administrated with FSRT is well tolerated at a 30 mg dose. There is a suggestion of a dose response with panobinostat. The median overall survival is not reached with a median follow up of 11.5 m for the 30 mg cohort. A phase II trial is warranted to confirm the efficacy of combining panobinostat with FSRT for recurrent gliomas.
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