S is a potent and selective oral inhibitor of Smo, a key component of the hedgehog (Hh) signaling pathway. Up-regulation of the Hh pathway is implicated in the genesis of a wide range of tumors including TN breast cancer. Here we report a phase I study exploring the combination of S with D in TN ABC pts to identify the Maximum Tolerated Dose (MTD) and Recommended Phase II Dose (RP2D) (ClinicalTrials.gov Identifier: NCT02027376).
Pts with ≤3 prior chemotherapy regimens for ABC were included. Treatment consisted of 21-day cycles (cy) of D 75mg/m2 on day 1, and increasing doses of S given once daily (QD). A standard 3 + 3 design was followed including 3 dose levels (DL) for S: DL1 400mg, DL2 600mg and DL3 800mg. The primary objective was to define the MTD and RP2D of the combination, based on dose-limiting toxicities (DLT) in the first 2 cy; secondary objectives included the evaluation of safety, changes on QTc, efficacy, and pharmacokinetics (PK).
12 pts were included (5 at DL1, 4 at DL2 and 3 at DL3); 3 pts were replaced due to early progressive disease (PD). Median age was 49.5 years (26–76). Pts received a median of 2 cy (2–4) at DL1, 2 cy (1–3) at DL2 and 8 cy (6–9) at DL3. No DLTs were observed in any DL. DL3 was the MTD, and toxicities grade (G) 3, none G4, in all cy included neutropenia (NP) 66.7%, CPK increase, leukopenia, and paresthesia 33.3% each; 1 event of NP and the event of CPK increase caused S dose reduction. 2 pts had G1 QTc prolongation. The mean relative dose intensity of S and D were 99.3% (94.1–100.8) and 100% (98.9-102.4), respectively. 11 pts discontinued study treatment due to PD and 1 pt by Investigator's criterion (on complete response at DL3). The objective response rate (n = 10) was 10% (95% CI 0.3-44.5). Median time to progression (n = 12) was 42.5 days (95% CI 29-155), being of 188 days at DL3. When co-administrated S and D, there was a trend to lower S trough concentrations, but could not be proved to be statistically significant and D clearance was similar on day 1 of Cycles 1 and 2.
S can be safely combined with D. Co-administration of S and D seems not to have PK interaction. S 800mg QD and D 75mg/m2 was declared as the RP2D.
Clinical trial identification
Nº EudraCT: 2013-001750-96
Legal entity responsible for the study
GEICAM (Spanish Breast Cancer Group)
Novartis Farmaceutica S.A.
All authors have declared no conflicts of interest.