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Clinical Trial
. 2021 Nov 2;23(11):1949-1960.
doi: 10.1093/neuonc/noab087.

MEVITEM-a phase I/II trial of vismodegib + temozolomide vs temozolomide in patients with recurrent/refractory medulloblastoma with Sonic Hedgehog pathway activation

Didier Frappaz  1 , Marc Barritault  2 , Laure Montané  3 , Florence Laigle-Donadey  4 , Olivier Chinot  5 , Emilie Le Rhun  6   7   8   9   10 , Alice Bonneville-Levard  1 , Andreas F Hottinger  11 , David Meyronnet  2 , Anne-Sophie Bidaux  3 , Gwenaële Garin  3 , David Pérol  3
Affiliations
Clinical Trial

MEVITEM-a phase I/II trial of vismodegib + temozolomide vs temozolomide in patients with recurrent/refractory medulloblastoma with Sonic Hedgehog pathway activation

Didier Frappaz et al. Neuro Oncol. .

Abstract

Background: Vismodegib specifically inhibits Sonic Hedgehog (SHH). We report results of a phase I/II evaluating vismodegib + temozolomide (TMZ) in immunohistochemically defined SHH recurrent/refractory adult medulloblastoma.

Methods: TMZ-naïve patients were randomized 2:1 to receive vismodegib + TMZ (arm A) or TMZ (arm B). Patients previously treated with TMZ were enrolled in an exploratory cohort of vismodegib (arm C). If the safety run showed no excessive toxicity, a Simon's 2-stage phase II design was planned to explore the 6-month progression-free survival (PFS-6). Stage II was to proceed if arm A PFS-6 was ≥3/9 at the end of stage I.

Results: A total of 24 patients were included: arm A (10), arm B (5), and arm C (9). Safety analysis showed no excessive toxicity. At the end of stage I, the PFS-6 of arm A was 20% (2/10 patients, 95% unilateral lower confidence limit: 3.7%) and the study was prematurely terminated. The overall response rates (ORR) were 40% (95% CI, 12.2-73.8) and 20% (95% CI, 0.5-71.6) in arm A and B, respectively. In arm C, PFS-6 was 37.5% (95% CI, 8.8-75.5) and ORR was 22.2% (95% CI, 2.8-60.0). Among 11 patients with an expected sensitivity according to new generation sequencing (NGS), 3 had partial response (PR), 4 remained stable disease (SD) while out of 7 potentially resistant patients, 1 had PR and 1 SD.

Conclusion: The addition of vismodegib to TMZ did not add toxicity but failed to improve PFS-6 in SHH recurrent/refractory medulloblastoma. Prediction of sensitivity to vismodegib needs further refinements.

Keywords: SHH pathway; SMO inhibition; medulloblastoma.

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Figures

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Study scheme.
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Consort graph.
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Efficacy endpoints.
See this image and copyright information in PMC

Comment in

References

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