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ATIM-18. A PHASE I TRIAL OF HYPOFRACTIONATED STEREOTACTIC IRRADIATION (HFSRT) WITH PEMBROLIZUMAB AND BEVACIZUMAB IN PATIENTS WITH RECURRENT HIGH GRADE GLIOMA (NCT02313272)

ABSTRACT: Abstract BACKGROUND There is strong pre-clinical evidence for the combination of PD-1 blockade with radiotherapy and anti-VEGF therapy. Herein, we present safety and efficacy data from a phase 1 study combining pembrolizumab, an anti-PD-1 monoclonal antibody, with hypofractionated stereotactic irradiation (HFSRT) and bevacizumab in recurrent high grade glioma. METHODS This phase I study (3 + 3 design) explored the safety, tolerability, recommended phase II dose (RP2D), and antitumor activity of pembrolizumab administered concurrently with HFSRT and bevacizumab. Adult patients with recurrent glioblastoma or anaplastic astrocytoma (maximum diameter of target lesion ? 3.5 cm) were eligible. Eligible patients received HFSRT to the recurrent tumor (30 Gy in 5 fractions) combined with bevacizumab (10 mg/kg, Q2W) and pembrolizumab (100 mg or 200 mg intravenously based on dose level, Q3W). Two dose levels of pembrolizumab were explored and 20 patients were treated at RPD2. Treatment continued until disease progression or unacceptable toxicity. RESULTS Twenty three patients with recurrent glioblastoma have been treated on this study (3 patients at 100 mg and 20 patients at 200 mg dose levels). Five patients had previous tumor progression on bevacizumab. Combination of HFSRT with pembrolizumab (200 mg every 3 weeks) and bevacizumab was generally well tolerated. The most common toxicities were grade 1 fatigue and grade 1 proteinuria. No treatment-related neurologic adverse events were observed. In 1 patient, study treatment was discontinued due to grade 3 elevation of liver transaminases. Durable objective responses (complete response + partial response ? 6 months) were observed in 53% of patients. The overall survival rate (at the time of abstract submission) at 6 and 12 months were 94% (16 out of 17 patients) and 64% (7 out of 11 patients), respectively. CONCLUSION Combination of HFSRT with pembrolizumab (200 mg every 3 weeks) and bevacizumab is safe. Clinical activity of this combination therapy is encouraging.

SUBMITTER: Sahebjam S

PROVIDER: S-EPMC5692068 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Project description:Abstract Toca 511 (vocimagene amiretrorepvec) is an investigational retroviral replicating vector that selectively infects dividing cancer cells, integrates into the genome and replicates due to immune defects in tumors. Toca 511 spreads through tumors and stably delivers the gene encoding an optimized yeast cytosine deaminase that converts the prodrug Toca FC (an investigational, extended-release formulation of 5-fluorocytosine) into 5-fluorouracil. 5-fluorouracil kills infected cancer cells and surrounding cancer cells, myeloid derived suppressor cells and tumor associated macrophages, thus enabling immune activity against the tumor. In this phase 1 trial (NCT01470794), ascending doses of Toca 511 were injected into the resection bed of patients with rHGG, followed by multiple courses of oral Toca FC. Additional cohorts included combination of the investigational therapy with bevacizumab or lomustine. Objective responses (ORs) are observed in patients with IDH1 wildtype and mutant tumors, including 3 complete responses (CRs) and 2 partial responses with the investigational therapy, and 1 CR with the investigational therapy and bevacizumab. The IDH1-mutant patients treated at 1st recurrence all had CRs and the fact that a CR in rHGG is rare suggests that the investigational treatment may be playing a role. ORs are observed 6–19 months after Toca 511 injection, consistent with an immunologic mechanism. Median time to initial response is 9.2 months; median duration of response (mDoR) is 25.2 months. Excluding combination cohorts, mDoR is 26.7 months. All responders are alive 21.2+ to 42.6+ months, suggesting a correlation of durable responses (ORs lasting > 24 weeks) with overall survival. In a 24-patient subgroup who received the recommended Ph2 Toca 511 dose, a durable response rate of 20.8% was observed. Across the Phase 1 program, the safety profile remains favorable. Updated clinical benefit, safety, immune activity, and molecular profiles will be reported.

Project description:PurposeBevacizumab is associated with decreased vascular permeability that allows for more aggressive radiotherapy schedules. We conducted a phase II trial in newly diagnosed glioblastoma utilizing a novel hypofractionated stereotactic radiotherapy (HFSRT) schedule combined with temozolomide and bevacizumab.Experimental designPatients with tumor volume ≤60 cc were treated with HFSRT (6 × 6 Gy to contrast enhancement and 6 × 4 Gy to FLAIR hyperintensity with dose painting) combined with concomitant/adjuvant temozolomide and bevacizumab at standard doses. Primary endpoint was 1-year overall survival (OS): promising = 70%; nonpromising = 50%; α = 0.1; β = 0.1.ResultsForty patients were enrolled (median age: 55 years; methylated MGMT promoter: 23%; unmethylated: 70%). The 1-year OS was 93% [95% confidence interval (CI), 84-100] and median OS was 19 months. The median PFS was 10 months, with no pseudo-progression observed. The objective response rate (ORR) was 57%. Analysis of The Cancer Genome Atlas glioblastoma transcriptional subclasses (Nanostring assay) suggested patients with a proneural phenotype (26%) fared worse (ORR = 14%, vs. 77% for other subclasses; P = 0.009). Dynamic susceptibility-contrast perfusion MRI showed marked decreases in relative cerebral blood volume over time (P < 0.0001) but had no prognostic value, whereas higher baseline apparent diffusion coefficient (ADC) ratios and persistent hypermetabolism at the 6-month FDG-PET predicted poor OS (P = 0.05 and 0.0001, respectively). Quality-of-life (FACT-BR-4) and neuropsychological test scores were stable over time, although some domains displayed transient decreases following HFSRT.ConclusionsThis aggressive radiotherapy schedule was safe and more convenient for patients, achieving an OS that is comparable with historical controls. Analysis of advanced neuroimaging parameters suggests ADC and FDG-PET as potentially useful biomarkers, whereas tissue correlatives uncovered the poor prognosis associated with the proneural signature in non-IDH-1-mutated glioblastoma.

Dataset Information

ATIM-18. A PHASE I TRIAL OF HYPOFRACTIONATED STEREOTACTIC IRRADIATION (HFSRT) WITH PEMBROLIZUMAB AND BEVACIZUMAB IN PATIENTS WITH RECURRENT HIGH GRADE GLIOMA (NCT02313272)

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