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ACTR-40. A PHASE 1, MULTICENTER, OPEN-LABEL STUDY OF MARIZOMIB (MRZ) WITH TEMOZOLOMIDE (TMZ) AND RADIOTHERAPY (RT) IN NEWLY DIAGNOSED WHO GRADE IV MALIGNANT GLIOMA (GLIOBLASTOMA, ndGBM): FULL ENROLLMENT RESULTS

ABSTRACT: Abstract Proteasome inhibition sensitizes glioma cells to TMZ and RT, providing a novel therapeutic strategy for ndGBM. MRZ, an irreversible, brain-penetrant, pan-proteasome inhibitor with anti-glioma activity was combined with standard-of-care (SOC) concomitant TMZ/RT followed by adjuvant TMZ in ndGBM (NCT02903069), to determine the recommended dose (RD). Patients were enrolled in separate concomitant (TMZ/RT+MRZ, N=15) and adjuvant (TMZ+MRZ, N=18) cohorts in dose-escalation (3 + 3 design), followed by dose-expansion (N=20) at RD (0.8 mg/m2) in concomitant followed by adjuvant treatment. MRZ infused IV (10 min) at increasing dose levels (0.55, 0.7, 0.8, and 1.0 mg/m2): Concomitant days 1, 8, 15, 29, 36; Adjuvant days 1, 8, 15 (28-day cycle). RESULTS (as of 02May2018): Mean age 55 years, 68% male. Most common treatment-emergent adverse events (TEAEs, 20% patients, all grades): fatigue, nausea, vomiting, hallucination, ataxia, headache. Dose-limiting toxicities (DLTs): 1 (fatigue) at 0.7 mg/m2 adjuvant cohort, 3 (ataxia/diarrhea; ataxia/confusion; myocardial infarction) in concomitant and 2 (delirium/ataxia; ataxia/fatigue) in adjuvant cohorts at 1.0 mg/m2. Grade 3 TEAEs in 11 of 12 patients at 1.0 mg/m2 including one Grade 4 and one Grade 5 TEAE; at 0.8 mg/m2 MRZ, Grade 3 TEAEs in 9 of 21 patients. MRZ demonstrated a steep dose-response with TEAEs/DLTs predominately CNS AEs (ataxia, hallucinations) which were dose-related, short-lasting, reversible and ameliorated by early dose reductions, allowing patients to remain on treatment. Currently 8 dose-escalation patients remain active in Cycle 10–23. Median OS for dose-expansion not yet estimated; 7 patients remain active, 1 death, median follow-up 4.1 months. MRZ at the RD with adjuvant TMZ+Tumor Treating Fields (Optune) is currently enrolling. An international Phase 3 trial (EORTC #1709-BTG, NCT03345095) has been launched in 2018 to assess the overall survival benefit of MRZ added to SOC in ndGBM.

SUBMITTER: Bota D

PROVIDER: S-EPMC6216380 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Project description:Abstract BACKGROUND The original 3-arm CODEL design included a radiotherapy (RT)-alone control arm, an RT plus temozolomide (TMZ) arm, and an exploratory TMZ-alone arm. We report the analysis involving patients treated per the initial design. METHODS Adults (18+ years) with newly-diagnosed 1p/19q codeleted WHO grade III oligodendroglioma were randomized to RT (5940 cGy) alone (Arm A); RT with concomitant and adjuvant TMZ (Arm B); or TMZ alone (Arm C). Primary endpoint was OS, Arm A vs. B. Secondary comparisons were performed for OS and PFS, comparing pooled RT arms with the TMZ-alone arm. RESULTS 36 patients were randomized equally to the three arms. At median follow-up of 7.5 years, 83.3% (10/12) TMZ-alone patients had progressed, versus 37.5% (9/24) patients on the RT arms. PFS was shorter in TMZ-alone patients compared to RT-treated patients (HR=3.12; 95% CI: 1.26, 7.69; p=0.014). Death from disease progression occurred in 3/12 (25%) of TMZ-alone patients and 4/24 (16.7%) of RT-treated patients. OS did not statistically differ between arms, although this comparison was underpowered. After adjustment for IDH status (mutated vs. wildtype) in a Cox regression model, with IDH status and RT treatment status as co-variables (Arm C vs pooled A and B), PFS remained shorter for patients not receiving RT (HR= 3.33; 95% CI: 1.31, 8.45; p=0.011), and OS differences remained non-significant ((HR = 2.78; 95% CI 0.58, 13.22, p=0.20). Grade 3+ adverse events occurred in 25%, 42% and 33% patients (Arms A, B and C, respectively). Neurocognitive assessments, comparing baseline and 3 month timepoints, showed no significant differences between arms. CONCLUSIONS TMZ-alone treated patients experienced significantly shorter PFS than patients treated on the pooled RT arms, which remained significant when adjusting for IDH status. CODEL has been redesigned to compare the efficacy and toxicity of RT+PCV versus RT+TMZ. Clinicaltrials.gov Identifier: NCT00887146. Support: U10CA180821, U10CA180882, https://acknowledgments.alliancefound.org.

Project description:BackgroundThe impact of prolonging temozolomide (TMZ) maintenance beyond six cycles in newly diagnosed glioblastoma (GBM) remains a topic of discussion. We investigated the effects of prolonged TMZ maintenance on progression-free survival (PFS) and overall survival (OS).Patients and methodsIn this retrospective single-center cohort study, we included patients with GBM who were treated with radiation therapy with concomitant and adjuvant TMZ. For analysis, patients were considered who either completed six TMZ maintenance cycles (group B), continued with TMZ therapy beyond six cycles (group C), or stopped TMZ maintenance therapy within the first six cycles (group A). Patients with progression during the first six TMZ maintenance cycles were excluded.ResultsClinical data from 107 patients were included for Kaplan-Meier analyses and 102 for Cox regressions. Median PFS times were 8.1 months (95% confidence interval [CI] 6.1-12.4) in group A, 13.7 months (95% CI 10.6-17.5) in group B, and 20.9 months (95% CI 15.2-43.5) in group C. At first progression, response rates of TMZ/lomustine rechallenge were 47% in group B and 13% in group C. Median OS times were 12.7 months (95% CI 10.3-16.8) in group A, 25.2 months (95% CI 17.7-55.5) in group B, and 28.6 months (95% CI 24.4-open) in group C. Nevertheless, multivariate Cox regression for patients in group C compared with group B that accounted for imbalances of other risk factors showed no different relative risk (RR) for OS (RR 0.77, p = .46).ConclusionOur data do not support a general extension of TMZ maintenance therapy beyond six cycles. The Oncologist 2017;22:570-575 IMPLICATIONS FOR PRACTICE: Radiation therapy with concomitant and adjuvant temozolomide (TMZ) maintenance therapy is still the standard of care in patients below the age of 65 years in newly diagnosed glioblastoma. However, in clinical practice, many centers continue TMZ maintenance therapy beyond six cycles. The impact of this continuation is controversial and has not yet been addressed in prospective randomized clinical trials. We compared the effect of more than six cycles of TMZ in comparison with exactly six cycles on overall survival (OS) and progression-free survival (PFS) by multivariate analysis and found a benefit in PFS but not OS. Thus, our data do not suggest prolonging TMZ maintenance therapy beyond six cycles, which should be considered in neurooncological practice.

Dataset Information

ACTR-40. A PHASE 1, MULTICENTER, OPEN-LABEL STUDY OF MARIZOMIB (MRZ) WITH TEMOZOLOMIDE (TMZ) AND RADIOTHERAPY (RT) IN NEWLY DIAGNOSED WHO GRADE IV MALIGNANT GLIOMA (GLIOBLASTOMA, ndGBM): FULL ENROLLMENT RESULTS

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