Phase II propensity-matched controlled trial evaluating metformin as an adjunct to neo-adjuvant, concomitant, and adjuvant temozolomide and hypofractionated-accelerated radiotherapy (M-HART) in glioblastoma patients (NCT02780024).

2064 Background: Phase II, propensity-matched trial, to assess feasibility and toxicity of adding Metformin (MTF) to neo-adjuvant, concomitant and adjuvant Temozolomide (TMZ) and hypofractionated accelerated radiotherapy (M-HART), for patients with Glioblastoma (GBM). We compared median survival time (MST), and progression-free-survival (PFS) of M-HART versus a contemporaneous cohort of propensity-score matched controls (PSMC) who received standard of care (SOC). Methods: Eligible patients were ≥ 18 years with newly diagnosed GBM, ECOG score ≤ 2, with known MGMT status, gross total or partial resection, and residual surgical cavity > 15 mm from brainstem, or optic apparatus. Four weeks from surgery, M-HART patients started 2 weeks of neo-adjuvant MTF/TMZ followed by concomitant MTF/TMZ + HART 60 Gy/20 daily fractions, and 6 cycles of adjuvant MTF/TMZ. The PSMC patients received Stupp’s regimen. We used a nearest neighbor matching with a caliper width of 0.2 SD and compared patients’ characteristics using chi-square test (Table). Propensity scores were estimated using logistic regression model, with probability of M-HART treatment as dependent variable. Results: From April 2015 to November 2020, 50 patients participated in the M-HART trial and matched with 50 PSMC cohort treated during the same period, with a median follow up of 24.1 (M-HART) vs 17.6 months PSMC, respectively. M-HART patients had significantly longer MST of 24.1 (95% CI, 15.2- 30.3) vs. 17.7 months for PSMC patients (95% CI, 12-20) (HR, 0.62 [95% CI, 0.40-0.93]; P = 0.02), and significantly longer PFS of 13.7 (95% CI, 11.7 to 18.8) vs. 11.0 months (95% CI, 9-12) (HR, 0.63 [95% CI, 0.42-0.95]; P = 0.02). M-HART treatment was an independent predictor of survival. M-HART patients with methylated-MGMT and gross total resection had significant longer MST of 41.9 vs. 17.8 months for PSMC (95% CI, 15.1-20.5 months) (HR 0.21 [95% CI, 0.09-0.49]; P = 0.001). Conclusions: M-HART protocol is novel, feasible, and well-tolerated approach with significantly longer MST and PFS as compared to propensity-matched SOC controls. These results add to growing evidence for the use of Metformin as an adjunct to HART and TMZ especially in M-MGMT GBM. Clinical trial information: NCT02780024 . Characteristics of M-HART versus propensity-matched standard of care control patients. M-HART N=50 (%) CONTROLS N=50 (%) P-value Age (years)≤ 60> 60 34 (68)16 (32) 27 (54)23 (46) 0.218 SexMaleFemale 22 (44)28 (56) 30 (60)20 (40) 0.161 ECOG-score0-12 43 (84)7 (14) 47 (94)3 (6) 0.318 Surgery Gross Total Subtotal 41 (82)9 (18) 39 (78)11 (22) 0.803 MGMT statusUnmethylatedMethylated 34 (68)16 (32) 29 (58)21 (42) 0.015 Re-operationYesNo 24 (84)26 (52) 18 (36)32 (64) 0.077 Chemotherapy at recurrenceYesNo 14 (28)36 (74) 27 (54)23 (46) <0.001