A Phase I/II Trial of BNC105P with Everolimus in Metastatic Renal Cell Carcinoma

Abstract

Purpose: BNC105P inhibits tubulin polymerization, and preclinical studies suggest possible synergy with everolimus. In this phase I/II study, efficacy and safety of the combination were explored in patients with metastatic renal cell carcinoma (mRCC).

Experimental design: A phase I study in patients with clear cell mRCC and any prior number of therapies was conducted using a classical 3 + 3 design to evaluate standard doses of everolimus with increasing doses of BNC105P. At the recommended phase II dose (RP2D), patients with clear cell mRCC and one to two prior therapies (including ≥ 1 VEGF-TKI) were randomized to BNC105P with everolimus (arm A) or everolimus alone (arm B). The primary endpoint of the study was 6-month progression-free survival (6MPFS). Secondary endpoints included response rate, PFS, overall survival, and exploratory biomarker analyses.

Results: In the phase I study (N = 15), a dose of BNC105P at 16 mg/m(2) with everolimus at 10 mg daily was identified as the RP2D. In the phase II study, 139 patients were randomized, with 69 and 67 evaluable patients in arms A and B, respectively. 6MPFS was similar in the treatment arms (arm A: 33.82% vs. arm B: 30.30%, P = 0.66) and no difference in median PFS was observed (arm A: 4.7 mos vs. arm B: 4.1 mos; P = 0.49). Changes in matrix metalloproteinase-9, stem cell factor, sex hormone-binding globulin, and serum amyloid A protein were associated with clinical outcome with BNC105P.

Conclusions: Although the primary endpoint was not met in an unselected population, correlative studies suggest several biomarkers that warrant further prospective evaluation.

Figure 1

CONSORT diagram outlining overall study accrual. (Note: A CONSORT diagram reflecting patients receiving BNC105P monotherapy after progression on everolimus monotherapy is included in Supplementary Figure 2.) * Two patients remain on therapy in Arm A, and one patient remains on therapy in Arm B.

Figure 2

PFS with the combination of everolimus with BNC105P (Arm A) and everolimus monotherapy (Arm B).

Figure 3

PFS with the combination of everolimus with BNC105P (Arm A) and everolimus monotherapy (Arm B) in an exploratory analysis of patients with liver metastasis.

Figure 4

PFS in patients treated with everolimus with BNC105P stratified by change in serum biomarkers above or below median values. Serum biomarkers include MMP-9 (a), SCF (b), SHGB (c) and SAP (d).