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CTNI-76. PHASE 2 CLINICAL TRIAL OF VAL-083 IN NEWLY DIAGNOSED MGMT-UNMETHYLATED GBM

ABSTRACT: Abstract Approximately 60% of glioblastoma multiforme (GBM) patients possess an unmethylated methylguanine DNA-methyltransferase (MGMT) promoter region, which confers a limited response to standard-of-care treatment with temozolomide (TMZ), resulting in shorter median survival when compared to patients with methylated MGMT promoter. VAL-083 is a novel bi-functional DNA targeting agent that induces inter-strand cross-links at N7-guanine, leading to DNA double-strand breaks and ultimately cell death. VAL-083 circumvents MGMT-mediated TMZ resistance in vitro and in vivo. A Phase 2 study has been initiated for VAL-083 in newly diagnosed MGMT unmethylated GBM. The study has 2 stages: Stage 1 is a dose-escalation safety and tolerability phase to confirm the phase 2 dose of VAL-083 when administered concurrently with radiation therapy (RT). Patients received VAL-083 at 20, 30, or 40 mg/m2/day x 3 days every 21 days along with standard radiation treatment (RT) (2 Gy/day, 5 days/week). The dose escalation stage is complete, and 30 mg/m2/day of VAL-083 in combination with RT was generally safe and well-tolerated. Stage 2 comprises an expansion phase to enroll up to 20 additional patients at the 30 mg/m2/day of VAL-083 in combination with RT. As of June 2, 2020, all patients have been enrolled, with a total of 29 patients in the study, and 25 patients receiving 30 mg/m2/day VAL-083. Of the 29 patients enrolled, 27 have completed their prospectively planned MRI scans and had their initial assessment for tumor response. Two additional patients died prior to their post-cycle 3 MRI. Consistent with our prior experience, myelosuppression was the most common adverse event. Three patients have experienced dose-limiting toxicities - one (1/3; 33%) at the 40 mg/m2/day and two (2/25; 8%) at the 30 mg/m2/day dose. Further safety and efficacy updates will be presented at the meeting. Clinicaltrials.gov identifier: NCT03050736.

SUBMITTER: Chen Z

PROVIDER: S-EPMC7651087 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Abstract Glioblastoma (GBM) is the most common and aggressive primary brain cancer. Current standard-of-care includes surgery followed by chemo-radiation and temozolomide. An unmethylated promoter for O6-methylguanine-DNA-methyltransferase (MGMT) is a validated biomarker for temozolomide-resistance and is strongly correlated with poor outcomes. Unmethylated MGMT represents the majority of newly diagnosed GBM tumors. VAL-083 is a first-in-class bi-functional DNA-targeting agent that has shown activity against GBM in NCI-sponsored clinical trials both as single agent and in combination with radiotherapy. VAL-083 induces interstrand cross-links at N7-guanine, leading to DNA double-strand breaks and cell-death. VAL-083s unique mechanism-of-action circumvents MGMT-mediated chemoresistance, and it has demonstrated cytotoxicity in MGMT-unmethylated GBM cell-lines, cancer stem cells (CSCs) and in vivo models. Furthermore, VAL-083 acts as a radiosensitizer in GBM CSCs and non-CSCs. We completed a dose-escalation trial of VAL-083 in recurrent GBM, and a generally well-tolerated dosing regimen was selected for further clinical development. The present trial is an ongoing open-label, biomarker-driven, Phase 1/2 study to evaluate the tolerability and efficacy of VAL-083 in combination with radiotherapy in newly diagnosed MGMT-unmethylated GBM patients. A treatment regimen, consisting of a 6-week induction period of VAL-083 and concurrent radiation (2 Gy daily, 5 days/week) followed by up to 24 weeks of maintenance therapy with single-agent VAL-083, is being evaluated. The study is being conducted in two parts: 1) a dose-escalation part (20, 30, and 40mg/m2/day IV infusion on days 1,2,3 of a 21-day cycle) in up to 10 patients; 2) an expansion part in up to 20 additional patients at the determined well-tolerated dose. Tumor response will be assessed by MRI, according to RANO criteria. Efficacy endpoints include progression-free survival (PFS) and overall survival (OS). Additional endpoints include safety evaluations and pharmacokinetic assessments of plasma and CSF samples. Enrollment and safety data update will be provided at the meeting. Clinicaltrials.gov identifier: NCT03050736.

Project description:Abstract 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 after recurrence of 3–9 months. 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 inter-strand cross-links at N7-guanine inducing double-strand breaks causing cell death and acts independent 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-radiation 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 will be 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 June 2-2020, 35 patients with recurrent GBM (Group 1) have received 40 mg/m2/d and 39 patients have received 30 mg/m2/d VAL-083. In the adjuvant setting (Group 2), 25 patients have been enrolled (30 mg/m2/day). Enrollment, safety data and study updates will be presented at the meeting. Clinicaltrials.gov identifier: NCT02717962.

Project description:Abstract Glioblastoma (GBM) is the most common and aggressive primary brain cancer. Current standard-of-care includes surgery, radiation and treatment with temozolomide (TMZ), however nearly all tumors recur and the prognosis for recurrent GBM is dismal. Resistance to TMZ is correlated with expression of the DNA repair enzyme O6-methylguanine-DNA-methyltransferase (MGMT), which is highly expressed in a majority of GBM tumors. Dianhydrogalactitol (VAL-083) is a first-in-class bi-functional DNA-targeting agent that exhibited activity against GBM in NCI-sponsored clinical trials both as a single agent and in combination with radiotherapy. VAL-083 readily crosses the blood-brain barrier and accumulates in brain tumor tissue. We have demonstrated that VAL-083 targets N7-Guanine and rapidly induces interstrand DNA cross-links, leading to DNA double-strand breaks, S/G2 cell-cycle arrest and cell death in GBM cell lines and GBM cancer stem cells (CSCs) in vitro. This unique N7-guanine targeting mechanism not only circumvents MGMT-mediated chemo-resistance but also maintains cytotoxic activity in cancer cells deficient in mismatch repair (MMR). These data suggest VAL-083 may offer a superior chemotherapeutic alternative in the treatment of MGMT-unmethylated or MMR deficient GBM. Here, we provide an update of ongoing clinical trials with VAL-083 in MGMT-unmethylated GBM: i) a single-arm, biomarker-driven, Phase II study to determine if VAL-083 treatment of MGMT-unmethylated adult GBM patients at first recurrence/progression, prior to bevacizumab improves survival compared to historical lomustine control (clinicaltrials.gov identifier: NCT02717962); ii) a single-arm, biomarker-driven, Phase II study to confirm the tolerability and efficacy of VAL-083 in combination with radiotherapy in newly diagnosed MGMT-unmethylated GBM patients (clinicaltrials.gov identifier: NCT03050736). The results of these studies may support a new treatment paradigm in for the treatment of MGMT-unmethylated GBM.

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 Current standard-of-care for glioblastoma (GBM) includes surgery followed by concurrent therapy with radiation and temozolomide (TMZ) followed by adjuvant TMZ (days 1–5 every 28 days. Almost all GBM patients experience recurrent/progressive disease, with a median survival after recurrence of 3–9 months. Second-line treatment for recurrent GBM with bevacizumab (BEV) has not improved survival, and effective therapies for GBM are lacking. 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, induces double-strand breaks and acts independent of MGMT DNA repair. The current ongoing trial is a biomarker-driven Phase 2 study in MGMT-unmethylated BEV-naïve adult GBM. The primary objective of this study is to determine the effect of VAL-083 on median overall survival (mOS) for MGMT-unmethylated GBM patients compared to historical control. Secondary efficacy endpoints include progression-free survival (PFS), overall response rate (ORR), duration of response (DOR), and quality-of-life. Thirty-five (35) subjects with recurrent GBM have received 40 mg/m2/day VAL-083 on days 1, 2, 3 of a 21-day cycle as the starting dose. Myelosuppression is the most common adverse event and a higher potential for this toxicity correlated with those patients who received a higher number of cycles of prior TMZ maintenance therapy, (>5 cycles vs. ≤5 cycles, p< 0.05). To minimize the potential for hematological toxicity in rGBM, subsequent subjects initiated treatment at 30 mg/m2/d VAL-083 x 3 consecutive days every 21 days. In addition, since TMZ is of limited value in the MGMT-unmethylated setting, a second arm in newly diagnosed GBM has been included to explore whether substituting TMZ with VAL-083 offers clinical benefit and extends the time to recurrence. Enrollment, safety data and study updates will be presented at the meeting. Clinicaltrials.gov identifier: NCT02717962.

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CTNI-76. PHASE 2 CLINICAL TRIAL OF VAL-083 IN NEWLY DIAGNOSED MGMT-UNMETHYLATED GBM

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