Current standard-of-care for glioblastoma (GBM) includes surgery followed by concurrent therapy with radiation and temozolomide (TMZ) followed by adjuvant TMZ. Almost all GBM patients experience recurrent/progressive disease despite upfront standard-of-care treatment, with a median survival of 3-9 months after recurrence. Unmethylated promoter for O6-methylguanine-DNA-methyltransferase (MGMT) is a validated biomarker for TMZ-resistance and is correlated with poor patient prognosis. VAL-083 is a bi-functional DNA-targeting agent which rapidly induces interstrand DNA cross-links at N7-guanine inducing double-strand breaks causing cell death and acts independently of MGMT DNA repair. This trial is an open-label two-arm biomarker-driven phase 2 clinical trial in MGMT-unmethylated, bevacizumab-naïve GBM patients with either recurrent (Group 1) or newly diagnosed GBM requiring adjuvant therapy after chemo-irradiation with temozolomide (Group 2). Patients receive VAL-083 IV at 30 or 40 mg/m2/d on days 1, 2, and 3 of a 21-day cycle. The primary objective of this study is to determine the effect of VAL-083 on median overall survival (mOS) in MGMT-unmethylated recurrent GBM patients (Group 1); and progression-free survival (PFS) in newly diagnosed GBM patients requiring adjuvant therapy after chemo-irradiation with temozolomide (Group 2), compared to historical controls in both groups. Tumor response is assessed by MRI every 42 days, using RANO criteria. The initial starting dose in this study was 40 mg/m2/d on days 1, 2, and 3 of a 21-day cycle, which was subsequently reduced to 30 mg/m2/d to improve tolerance due to myelosuppression. As of May 2021, Group 1 (Recurrent GBM) is fully enrolled: 35 evaluable patients have received 40 mg/m2/d and 48 evaluable patients have received 30 mg/m2/d VAL-083. In the adjuvant setting (Group 2), 35 evaluable patients have been enrolled (30 mg/m2/day). Enrollment, safety data and efficacy updates will be presented at the meeting. Clinicaltrials.gov identifier: NCT02717962.
Ependymoma can occur anywhere in the central nervous system (CNS), but often occurs near the ventricle of the brain and central canal of the spinal cord. Ependymoma accounts for 5.7% of all childhood and 1.9% of all adult CNS tumors. RELA fusion-positive ependymoma is a subgroup associated with supratentorial location, higher WHO grade and worse prognosis. Diffuse Midline Glioma (DMG) is another relatively rare CNS tumor, originating in the midline locations of the brain (including thalamus, pons and spinal cord), accounting for 10% of all childhood and less than 4% of adult CNS tumors. For ependymoma standard treatment includes surgery and radiation therapy, with limited systemic options other than clinical trials for recurrent disease. For DMG, surgical intervention is restricted to biopsy, with radiation as standard therapy. Systemic options for both ependymoma and DMG are limited.VAL-083 is a bi-functional DNA-targeting agent which rapidly induces inter-strand DNA cross-links at N7-guanine inducing double-strand breaks causing cell death and acts independent of MGMT DNA repair and H3F3 K27M mutation status in high-grade gliomas. We report on 2 patients: one with ependymoma and one with DMG, treated with VAL-083 under an expanded access program. Both patients had recent disease progression and limited therapeutic options. Case #1: a 47-year-old male who was diagnosed with a left parietal high grade (3) anaplastic ependymoma and with IDHwt and unmethylated MGMT promoter status. Inter- and intragenic fusion analysis of tumor tissue revealed RELA fusion-positive ependymoma. He had undergone 2 resections and had received radiation and multiple systemic treatment regimens. Case #2: a 21-year-old male who was diagnosed with DMG of the brain stem, with IDHwt and unmethylated MGMT promoter status. He had undergone radiation therapy, and multiple treatment regimens. Both patients were not eligible to participate in any clinical trial and received VAL-083 under an expanded access program. They initiated treatment with VAL-083 (30 mg/m2 for 3 consecutive days every 21 days) and have completed 3 cycles. Both are neurological and radiological stable, they continue to receive VAL-083. No adverse events have been reported and no dose reductions have been required. These cases highlight that VAL-83 may be a treatment option for recurrent RELA fusion-positive ependymoma and DMG refractory to other treatment regimens. Additional safety and efficacy outcomes related to patient status will be presented at the meeting.Clinicaltrials.gov Identifier: NCT03138629. The treatment plans for this EAP patient were approved by MD Anderson Cancer Center IRB. Citation Format: Carlos Kamiya-Matsuoka, Stephanie Knight, Teresa Hanna, Timothy A. Gregory, John Langlands, Dennis Brown, Vinay K. Puduvalli. RELA fusion-positive ependymoma and diffuse midline glioma treated with VAL-083 under expanded access - case reports [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB126.
Ependymoma is a relatively rare central nervous system tumor accounting for 2-9 % of all neuroepithelial tumors. RELA fusion-positive ependymoma is a subgroup associated with supratentorial location, higher WHO grade and worse prognosis. In addition, there is no standard systemic chemotherapy treatment for adults with recurrent disease. VAL-083 is a bi-functional DNA-targeting agent which rapidly induces inter-strand DNA cross-links at N7-guanine inducing double-strand breaks causing cell death and acts independent of MGMT DNA-repair in high-grade gliomas. We report a 40-year-old male who was initially diagnosed with a right parieto-occipital high-grade glioma, with no somatic mutations including IDH1/2 genes, and with unmethylated MGMT promoter status. He initially underwent gross total resection, followed by chemoradiation with concurrent and adjuvant temozolomide for 12 cycles. Sixteen months later, he developed recurrent disease and had a second resection. Inter- and intragenic fusion analysis of tumor tissue revealed C11orf95-RELA fusion and the diagnosis of RELA fusion-positive ependymoma was established. The patient was not eligible to participate in any clinical trial and received VAL-083 under an expanded access program. He was then treated with VAL-083 (30 mg/m2 for 3 consecutive days every 21 days) and completed 12 cycles during a period of 9 months. No grade 3/4 adverse events such as thrombocytopenia, anemia, neutropenia, or lymphopenia were observed. His liver and renal functions were normal. No dose reduction was required. He also received levetiracetam, alprazolam and prochlorperazine, with no drug interactions. Steroid were not required. He has been under surveillance since completion of systemic treatment with VAL-083 and has remained radiologically stable, with no CSF dissemination, after 12 months. This case highlights that VAL-083 may be a treatment option for recurrent RELA fusion-positive ependymoma refractory to temozolomide-based regimens. Clinicaltrials.gov Identifier: NCT03138629. The treatment plans for this EAP patient were approved by MD Anderson Cancer Center IRB.
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