815PD - A phase I/II trial of BNC105P with everolimus in metastatic renal cell carcinoma (mRCC): Results of the randomized phase II Disruptor-1 trial

Date 29 September 2014
Event ESMO 2014
Session Genitourinary tumours, non prostate
Topics Anti-Cancer Agents & Biologic Therapy
Renal Cell Cancer
Presenter Sumanta Pal
Citation Annals of Oncology (2014) 25 (suppl_4): iv280-iv304. 10.1093/annonc/mdu337
Authors S. Pal1, A. Azad2, S. Bhatia3, H. Drabkin4, B. Costello5, J. Sarantopolous6, R. Kanesvaran7, R. Lauer8, C. Sweeney9, N.M. Hahn10, G. Sonpavde11, S. Richey12, T. Breen13, G. Kremmidiotis14, E. Doolin14, D. Bibby15, J. Simpson14, J. Iglesias14, T. Hutson16
  • 1Medical Oncology And Experimental Therapuetics, City of Hope Cancer Center, 91010 - Duarte/US
  • 2Austin Health, Medical Oncology, Melbourne/AU
  • 3Medical Oncology, University of Washington, Seattle/US
  • 4Medical Oncology, Medical College of South Carolina, Charleston/US
  • 5Medical Oncology, Mayo Clinic, Rochester/US
  • 6Medical Oncology, University of Texas Health Sciences Center, San Antonio/US
  • 7Medical Oncology, National Cancer Center, SG-169610 - Singapore/SG
  • 8Medical Oncology, University of New Mexico Cancer Center, Albequerque/US
  • 9Lank Center For Genitourinary Oncology, Dana Farber Cancer Institute, 02115 - Boston/US
  • 10Medical Oncology, Johns Hopkins University, Baltimore/US
  • 11Medical Oncology, UAB (University of Alabama, Birmingham) Comprehensive Cancer Center, 35294 - Birmingham/US
  • 12Medical Oncology, Texas Oncology, Fort Worth/US
  • 13Biostatistics, Hoosier Oncology Group, Indianapolis/US
  • 14Medical Oncology, Bionomics, Thebarton/AU
  • 15Medical Oncology, bioCSL, Melbourne/AU
  • 16Gu Oncology Program, Baylor Sammons Cancer Center, Dallas/US

Abstract

Aim

BNC105P is an inhibitor of tubulin polymerization, and preclinical studies suggest possible synergy with everolimus (EVE). In the phase I component of the current study (ASCO 2013 [Abstr 4563]), full doses of BNCP105P (16 mg/m2 IV on days 1 & 8 of a 21-day cycle) with EVE (10 mg po daily) were well-tolerated with no PK interactions, thus constituting the recommend phase 2 dose (RP2D). Results of a randomized phase II study evaluating this regimen are reported herein.

Methods

Pts with clear cell mRCC and 1-2 prior therapies (including ≥1 VEGF-TKI) were randomized to BNC105P + EVE (Arm A) at the RP2D or EVE alone at 10 mg po daily (Arm B). Pts were stratified by MSKCC risk factors and number of prior VEGF-TKIs. Pts with progression or intolerable toxicity on EVE could subsequently receive BNC105P alone. The primary endpoint (EP) of the study was 6-mo progression-free survival (6MPFS), with 80% power to detect an improvement from 35% to 60% with the addition of BNC105P. Secondary EPs included overall response rate (ORR), PFS, overall survival (OS) and exploratory biomarker analyses.

Results

139 pts were randomized across 77 treatment centers (US: 63; non-US: 14), with 69 and 67 evaluable pts in Arms A and B, respectively. Baseline characteristics were balanced between treatment arms. 6MPFS was similar in the treatment arms (Arm A: 33% v Arm B: 29.8%, P = 0.66) and no difference in PFS was observed (Arm A: 4.7 mos v Arm B: 4.1 mos; P = 0.49). Unplanned subset analyses in patients with liver metastases (n = 26) showed a non-significant trend towards benefit with the addition of BNC105P (Arm A: 6.6 mos v Arm B: 2.8 mos). ORR in Arms A and B were 1.45% and 1.49%, respectively, with 1 complete response in Arm A. Most adverse events were consistent with EVE-related toxicity. Changes in several biomarkers were associated with clinical outcome with BNC105P and EVE (adiponectin [HR = 0.56, P = 0.0058], α-2-macroglobulin [HR = 0.01, P = 0.0001], ß-2-microglobulin [HR= 0.39, P = 0.0013], and TNF receptor-2 [HR = 0.86, P = 0.0016]).

Conclusions

Although the primary EP was not met in an unselected population, intriguing correlative studies suggest several potentially predictive biomarkers. Further prospective assessment of BNC105P in relevant biomarker-based subsets is warranted.

Disclosure

S. Pal: has previously served at an advisory meeting for Bionomics as a consultant; G. Kremmidiotis, J. Simpson and J. Iglesias: is employed by Bionomics; T. Hutson: has previously served at an advisory board meeting for Bionomics as a consultant. All other authors have declared no conflicts of interest.