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ACTR-19. A PHASE 2 STUDY OF TUMOR TREATING FIELDS AND BEVACIZUMAB IN RECURRENT OR PROGRESSIVE MENINGIOMA

ABSTRACT: Abstract Meningioma is the most common primary brain tumor with a prevalence of ~170,000 in the United States. For patients with WHO grade II meningioma, the two- and five-year overall survival was 93% and 73%, respectively. Patients with malignant meningioma (grade III) had significantly worse outcomes, with two-year and five-year overall survival rates of 57% and 42%. The recurrence rate remains high and for grade 3 meningioma overall survival is as low as 3 years after diagnosis. The current treatment for high grade and recurrent meningioma includes maximal safe surgical resection and radiation. Tumor treating fields (TTFields) and Bevacizumab (BEV) have been reported to show activity in recurrent and high-grade meningioma. This Phase 2 Simon two-staged, non-randomized, open-label, phase II, single arm clinical trial [NCT02847559] will investigate the combination of TTFields and BEV in recurrent or progressive meningioma. The primary endpoint is progression free survival (PFS) at 6 months (PFS-6). Secondary endpoints will include overall survival (OS); Tumor Response Rate (TRR), Objective Response Rate (ORR); and Quality of Life (QOL) using FACT-Br questionnaire. Patients (N=27) will receive BEV IV over 30–90 minutes on days 1 and 15 of courses 1–4. Beginning on day 1 of course 5, patients may choose to receive bevacizumab IV every 3 weeks or remain on the every 2-week schedule. Patients will receive TTFields 200KHZ daily via the Optune device for over 18 hours. This study is powered to detect a true PFS-6 rate of 20% with 80% probability (80% power) and to detect a true PFS-6 rate of 5% with 90% probability (alpha=0.10). We planned for 27 patients in total to have 24 evaluable patients. For patients who are unable to obtain commercial BEV, the study has been amended to include a monotherapy arm of TTFields alone to increase the pool of eligible patients.

SUBMITTER: Kumthekar P

PROVIDER: S-EPMC5692851 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Project description:Abstract BACKGROUND High-grade meningioma are aggressive intracranial tumors and currently only limited treatment options exist. Therefore, there is a need for further studies in search of new therapies. Tumor Treating TTFields (TTFields) therapy serves as an effective treatment against glioblastoma (GBM). Phase 3 clinical trials investigate the use of TTFields in other intracranial tumors, i.e. brain metastases of the non-small cell lung cancer. We here provide an overview of the currently available data regarding the use of TTFields in meningioma. MATERIALS AND METHODS We performed a literature search using the term “Tumor treating fields” “NovoTTF”, “TTFields” and “Optune” in combination with “Meningioma”. A brief overview of TTFields in meningioma is provided here. RESULTS In vitro studies using patient-derived anaplastic grade III meningioma cell lines showed that TTFields treatment at a frequency of 200 kHz causes a significant reduction of cell proliferation and clonogenicity as well as altering cell morphology. In a case report of a 44-year-old woman suffering from a right anterior temporal tumor as well as a distant right parietal extra-axial convexity meningioma TTFields and Temozolomide treatment was initiated. Brain MRI scans 8, 16 and 20 weeks later showed a reduction in the meningioma tumor size of 42%, 58% & 60%, respectively. Currently, two ongoing trials test the efficacy and safety of the use of TTFields in meningioma patients: a phase II single arm trial (n=27), investigating the combination of TTFields and Bevacizumab in recurrent or progressive meningioma (NCT02847559); and a pilot trial, investigating the effects of TTFields as monotherapy on recurrent atypical and anaplastic meningioma (NCT01892397). CONCLUSIONS First data indicate that TTFields might be an option in future high-grade meningioma treatment. Clinical trials need to show safety and efficacy for the TTFields treatment in meningioma patients.

Project description:Abstract Glioblastoma (GBM) is the most common and aggressive primary brain cancer. Current standard-of-care includes surgery followed by concurrent therapy with radiation and temozolomide (TMZ) and maintenance TMZ. Almost all GBM patients experience recurrent/progressive disease, and median survival after recurrence is 3–9 months. Effective therapies for recurrent GBM (rGBM) are lacking, representing a significant unmet medical need. Unmethylated promoter for O6-methylguanine-DNA-methyltransferase (MGMT) is a validated biomarker for TMZ-resistance and is correlated with a poor prognosis. Second-line treatment with the anti-angiogenic agent bevacizumab (BEV) has not improved survival, and 5-year survival is less than 3%. VAL-083 is a bi-functional DNA-targeting agent rapidly inducing interstrand cross-links at N7-guanine, leading to DNA double-strand breaks and cell-death. VAL-083s cytotoxicity is independent of MGMT status, and VAL-083 overcomes TMZ-resistance in GBM cell lines, GBM cancer stem cells, and in vivo GBM models. We completed a 3 + 3 dose-escalation trial of VAL-083 in TMZ- and BEV-refractory rGBM. 40mg/m2/day given on days 1,2,3 of a 21-day cycle was generally well-tolerated, and this dose was selected for further clinical evaluation in Phase 2 trials. The trial described here is an ongoing single-arm, biomarker-driven Phase 2 trial in MGMT-unmethylated BEV-naïve adult rGBM. In this trial, 48 patients will receive VAL-083 40mg/m2/day on days 1,2,3 of a 21-day cycle. Tumor response will be assessed by MRI approximately every 42 days, per RANO criteria. The primary objective of this study is to determine if VAL-083 improves median overall survival (mOS) for MGMT-unmethylated rGBM patients compared to a historical mOS of 7.1 months for such patients treated with lomustine (EORTC26101). Secondary efficacy endpoints include progression-free survival (PFS), overall response rate (ORR), duration of response (DOR), and quality-of-life (QOL) evaluation using the MD Anderson Symptom Inventory-Brain Tumor Module (MDASI-BT) self-reporting tool. Enrollment and safety data update will be provided at the meeting. Clinicaltrials.gov identifier: NCT02717962.

Project description:Abstract Prognosis of relapsed glioblastoma (GBM) is dismal and current treatment fails to provide prolonged survival. Small subsets of patients respond well to some novel therapeutics probably due to the genetic variations of tumors and patients. In the Phase 3 EF-11 recurrent GBM trial, a small subset of patients derived significant benefit from TTFields alone. This proof-of-concept trial [NCT01954576] will study adult patients with relapsed GBM treated with TTFields by genetic analysis of primary and recurrent tumors. Post-hoc correlations will be used between clinical response, mutational analyses and quantitative gene expression to define genomic signatures of response. Whole exome and RNA sequencing will be used to identify genomic signature of responders to TTFields. Fifteen patients with bevacizumab-naïve recurrent GBM and 15 patients with bevacizumab-refractory GBM will be treated with TTFields for 6 and 4 months respectively. Patients will undergo standard brain MRI scans without and with gadolinium contrast and perfusion imaging every 8 weeks. Tissue from the primary tumor at recurrence will be genetically analyzed. Genomic DNA (gDNA) will be extracted from patients tumor and blood samples. Purified gDNA fragments will be used for Illumina sequencing library construction. Certain germ-line variants may contribute to gliomagenesis and be associated with somatic mutations within the tumor and subtypes of GBM more or less sensitive to TTFields. Analyses will be conducted on all patients: bevacizumab-naïve and bevacizumab-refractory GBM separately, and patients with objective radiographic response (complete response + partial response (CR + PR) and stable disease (SD) separately. With 50% bevacizumab-refractory GBM patients, response rate will be significantly higher than the baseline rate of 14%. Using an Exact test with type I error of 0.05 and 80% power, the estimated sample sizes will detect a statistical difference on response rate in the TTFields group compared to historical controls. To-date 4 patients have been enrolled.

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ACTR-19. A PHASE 2 STUDY OF TUMOR TREATING FIELDS AND BEVACIZUMAB IN RECURRENT OR PROGRESSIVE MENINGIOMA

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