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ATIM-02. TUMOR TREATING FIELDS IN COMBINATION WITH BEVACIZUMAB IN RECURRENT OR PROGRESSIVE MENINGIOMA IN A PHASE 2 STUDY

ABSTRACT: Abstract For patients with WHO grade II meningioma, the two-year and five-year overall survival is 93% and 73%, respectively. Patients with malignant meningioma (grade III) have significantly worse outcomes, with five-year overall survival rates of 42%. The recurrence rate remains high with 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 potentially show activity in recurrent and high-grade meningioma. The combination of TTFields and BEV may provide a viable treatment option for patients with 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 include overall survival (OS); Tumor Response Rate (TRR), Objective Response Rate (ORR); and Quality of Life (QOL) using FACT-Br questionnaire. Patients (N=27), including those who have failed prior BEV therapy, will receive BEV IV 10 mg/kg 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 15 mg/kg every 3 weeks or remain on the every 2-week schedule. Patients will receive TTFields 200 KHz (1–3 V/cm) daily for at least 18 hours/day. This study is powered to detect a true PFS-6 rate of 20% with 80% probability (80% power) and a true PFS-6 rate of 5% with 90% probability (alpha=0.10). 27 patients were planned to have 24 evaluable patients. To-date 4 patients have been enrolled at the principal site and at least two additional sites are planned to open this year.

SUBMITTER: Kumthekar P

PROVIDER: S-EPMC6216118 | biostudies-literature | 2018 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 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.

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.

Dataset Information

ATIM-02. TUMOR TREATING FIELDS IN COMBINATION WITH BEVACIZUMAB IN RECURRENT OR PROGRESSIVE MENINGIOMA IN A PHASE 2 STUDY

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