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ACTR-39. PAMIPARIB IN COMBINATION WITH RADIATION THERAPY (RT) AND/OR TEMOZOLOMIDE (TMZ) IN PATIENTS WITH NEWLY DIAGNOSED OR RECURRENT/REFRACTORY (R/R) GLIOBLASTOMA (GBM); PHASE 1B/2 STUDY UPDATE

ABSTRACT: Abstract Pamiparib, an investigational, selective PARP1/2 inhibitor that has demonstrated potent PARP trapping and ability to cross the blood-brain barrier, showed synergistic cytotoxicity with TMZ preclinically. We report updated safety and antitumor effects from a phase 1b/2 study of pamiparib + RT and/or TMZ in patients with newly diagnosed or R/R GBM (SNO 2018, ACTR-30). The dose-escalation/expansion study has 3 arms: Arm A, pamiparib (2, 4, or 6 weeks) + RT in newly diagnosed GBM patients with unmethylated MGMT promoter (unmethylated-GBM); Arm B, pamiparib (6 weeks) + RT and increasing TMZ dosed in weeks 1 and 5 of RT in newly diagnosed, unmethylated-GBM patients; and Arm C, pamiparib + increasing TMZ doses in methylated/unmethylated R/R-GBM patients. Arm A and B patients receive maintenance treatment post-RT rest period at the Arm C expansion dose/schedule. As of 10 April 2019, accrual was completed for Arms A and C dose-escalation (A: n=20; C: n=17) and continues in the dose expansion (A: n=28/40; C: n=28/30); accrual was completed in dose escalation for B (n=9). Recommended phase 2 doses were established for Arms A (pamiparib 60 mg BID×6 weeks + 6–7 weeks RT) and C (pamiparib 60 mg BID d1–28 + TMZ 60 mg d1–7/28-d cycle). One dose-limiting toxicity (grade 3 febrile neutropenia) was reported in Arm B. Treatment-related adverse events (?10%) were (overall/grade 3 [no grade 4/5]): Arm A, nausea (23%/2%); B, decreased WBC count (11%/11%); C (none). Of patients with tumor assessment post-RT: Arm A (n=17), 1 had cPR, 1 uPR, and 9 SD (disease control rate, 64.7% [95% CI, 38.3–85.8]); C (n=26), 1 had cPR (sustained 12 cycles), 1 uPR, and 5 SD (objective response rate, 7.7% [95% CI, 0.9–25.1]). Pamiparib 60 mg BID + RT/TMZ was generally well tolerated in patients with newly diagnosed or R/R GBM. Clinical trial ID: NCT03150862

SUBMITTER: Piotrowski A

PROVIDER: S-EPMC6847934 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Project description: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.

Project description:Abstract BACKGROUND Depatux-M is an antibody-drug-conjugate consisting of an antibody (ABT-806) specific to the activated conformation of EGFR bound to the toxin monomethylauristatin-F. In the primary analysis on EORTC 1410 we reported a trend (p = 0.06) towards improved overall survival (OS) in patients with EGFR-amplified (amp) recurrent glioblastoma treated with Depatux-M in combination with temozolomide. METHODS Eligible were patients with centrally confirmed EGFRamp glioblastoma at 1st recurrence after temozolomide chemo-irradiation. Patients were randomized to either a) Depatux-M 1.0 mg/kg every 2 weeks intravenously, or b) the same treatment combined with temozolomide 150–200 mg/m2 day 1–5 every 4 weeks, or c) either lomustine or temozolomide (TMZ/LOM) depending on the time of relapse. Primary endpoint was OS. Pharmacokinetic sampling was part of the study design, all samples were used to calculate the Depatux-M average concentration during course 1 (CavgC1). The level of EGFRamp was re-analysed using next generation sequencing. RESULTS In February 2018, an updated OS comparison performed after 220 observed deaths of Depatux-M in combination with TMZ versus TMZ/LOM using log-rank test and cox models stratified by stratification factors at randomization showed a HR of 0.68 (95%CI [0.48, 0.95]; p = 0.024) and 1-year OS rates of 40% versus 28%. In multivariate analysis CavgC1 was a significant predictor for OS (HR 0.96, 95% CI [0.93, 0.98], p = 0.0013). In Depatux-M treated patients, EGFR status (high vs low level amplification) did not correlate with OS. At the meeting the follow-up from Aug 2018 will be presented, obtained more than 24 months after the end of accrual. CONCLUSION: This updated OS analysis of Depatux-M in combination with temozolomide confirmed the OS improvement in EGFRamp recurrent glioblastoma. In Depatux-M treated patients, higher drug levels during course 1 were associated with improved OS, but high levels of EGFR amplification at first diagnosis were not.

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.

Dataset Information

ACTR-39. PAMIPARIB IN COMBINATION WITH RADIATION THERAPY (RT) AND/OR TEMOZOLOMIDE (TMZ) IN PATIENTS WITH NEWLY DIAGNOSED OR RECURRENT/REFRACTORY (R/R) GLIOBLASTOMA (GBM); PHASE 1B/2 STUDY UPDATE

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