ABTC-0904: targeting glioma stem cells in GBM: a phase 0/II study of hedgehog pathway inhibitor GDC-0449

Abstract

Purpose: Gliomagenesis and resistance of glioblastoma (GBM) are believed to be mediated by glioma stem cells (GSC). Evidence suggests that SHH signaling promotes GSC proliferation and self-renewal.

Methods: ABTC-0904 was a two-arm, multicenter phase 0/II study of GDC-0449, an oral inhibitor of Smoothened (SMO) in patients undergoing resection for recurrent GBM. All patients (Arms I and II) had surgery and received drug post-operatively. Only patients in Arm I received drug prior to surgery. The primary objective was to determine 6-month progression free survival (PFS-6). Secondary endpoints include median PFS (mPFS) and overall survival (mOS), response rate, and toxicity. Correlative studies included bioanalysis of GDC-0449, and inhibition of SHH signaling, GSC proliferation and self-renewal.

Results: Forty-one patients were enrolled. Pharmacokinetics of GDC-0449 in plasma demonstrated levels within expected therapeutic range in 75% of patients. The proportion of tumorcells producing CD133⁺ neurospheres, neurosphere proliferation, self-renewal, and expression of the SHh downstream signaling was significantly decreased in Arm I following GDC-0449 treatment (p < 0.005; p < 0.001 respectively) compared to Arm II (no drug pre-op). Treatment was well tolerated. There were no objective responders in either arm. Overall PFS-6 was 2.4% (95% CI 0.9-11.1%). Median PFS was 2.3 months (95% CI 1.9-2.6) and mOS was 7.8 months (95% CI 5.4-10.1).

Conclusions: GDC-0449 was well tolerated, reached tumor, and inhibited CD133⁺ neurosphere formation, but had little clinical efficacy as a single agent in rGBM. This suggests growth and maintenance of rGBM is not solely dependent on the SHH pathway thus targeting SMO may require combined approaches.

Keywords: GDC-0449; Glioblastoma; Glioma stem cells (GSC); Hedgehog (SHH) signaling pathway; Phase 0/II Clinical Trial.

Fig. 1

Clinical trial schema

Fig. 2

Progression Free & Overall Survival from Time to Registration by Arm. APFS; B OS. There was no statistical difference in survival by arm (p = 0.98 and p = 0.37 respectively)

Fig. 3

Representative Array comparative genomic hybridization (cGH) from patient derived NS and neural stem cells (NSC). Array cGH of tissue from neurospheres of representative patients in Arm I (3 and 9) as well as Arm II (5) are illustrated along with cells from neurospheres derived from NSC control as per methods. All three tumors demonstrated Gain of Chromosome 7 and LOH of chromosome 10 typical of many GBM. In contrast, no chromosomal abberations were noted in the neurospheres derived NSC