A phase 2 study of temozolomide in patients affected by pretreated metastatic colorectal cancer with MGMT promoter methylation.
2017; Lippincott Williams & Wilkins; Volume: 35; Issue: 4_suppl Linguagem: Inglês
10.1200/jco.2017.35.4_suppl.629
ISSN1527-7755
AutoresMaria Alessandra Calegari, Santa Monterisi, Alessandro Inno, Armando Orlandi, Michele A. Basso, Alessandra Cassano, Daniele Santini, Maurizio Martini, Tonia Cenci, Ivana De Pascalis, Brunella Barbaro, Floriana Camarda, Cesare Colosimo, Luigi Maria Larocca, Giuseppe Tonini, Stefania Gori, Carlo Barone,
Tópico(s)Epigenetics and DNA Methylation
Resumo629 Background: Presently few options are available for pts with mCRC who failed standard treatments and prognosis remains grim. MGMT promoter methylation is a frequent and early event in CRC tumorigenesis. This epigenetic silencing is a predictor of response to the alkylating drug TMZ in glioblastoma. Preclinical evidences and a couple of clinical cases showed TMZ activity in pts affected by mCRC with MGMT silencing. We designed a study to evaluate the efficacy and safety of TMZ in pts with refractory mCRC harboring MGMT promoter methylation. While the trial was ongoing three analogous studies, reporting discordant results, were published. Methods: This was a 3-institutional, single arm, phase 2 trial, planned according to a 2-stage Simon’s optimal design. The primary endpoint was ORR. Secondary outcomes included DCR, OS, PFS and safety. A first cohort of 21 pts was accrued: if more than 1 response was observed a second cohort of 20 pts would be enrolled; if 4 or fewer responses were observed by the end of stage two, then no further investigation would be warranted. MGMT promoter methylation was assessed on archival tissue samples by MS-PCR. Patients affected by MGMT methylated mCRC, who failed 2 or more prior treatments, received TMZ, provided by TEVA Pharmaceutical Industries, at a dose of 150-200 mg/mq/day once a day on days 1-5 every 28 days. Results: From July 2012 to June 2016, 225 pts were screened and 80 showed MGMT promoter methylation, among those 42 met the inclusion and exclusion criteria and were enrolled. ORR was 10% with no CR and 4 (10%) PR. SD was achieved in 9 (22%) pts, accounting for a DCR of 32%. At a median FU of 9 months all pts experienced PD and 88% died. Median PFS and OS were 2.6 months (95% CI 2.1-3.2) and 7.1 months (95% CI 5.1-9.2) respectively. Overall, any-grades AEs were reported in 75.6% pts, most of them were G1-2 (84%). The most frequent AE were nausea (56%) and platelet count decreased (39%). 4 pts discontinued study treatment due to AE. No SAE neither toxic death was recorded. Conclusions: The study did not meet its primary endpoint, however an interesting DCR (32%) and 4 PR were achieved. The role of TMZ in mCRC treatment remains still controversial and might warrant further analysis. Clinical trial information: 2012-002766-13.
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