Safety and Efficacy of BIND-014, a Docetaxel Nanoparticle Targeting Prostate-Specific Membrane Antigen for Patients With Metastatic Castration-Resistant Prostate Cancer: A Phase 2 Clinical Trial

Abstract

Importance: Preferential delivery of docetaxel to tumors by prostate-specific membrane antigen (PSMA)-targeted nanoparticles is clinically effective, and the selective reduction of PSMA-positive circulating tumor cells (CTCs) after treatment has implications for patient selection and disease monitoring.

Objective: To determine the safety and efficacy of BIND-014, a PSMA-directed docetaxel-containing nanoparticle, in patients with metastatic castration-resistant prostate cancer (mCRPC).

Design, setting, and participants: A multicenter open-label, phase 2 clinical trial of 42 chemotherapy-naive patients with progressing mCRPC after treatment with abiraterone acetate and/or enzalutamide was conducted from June 24, 2013, to June 10, 2016.

Intervention: Treatment with BIND-014 at a dosage of 60 mg/m2 was given intravenously on day 1 of 21-day cycles in combination with prednisone until disease progression or unacceptable toxic effects occurred.

Main outcomes and measures: The primary end point was radiographic progression-free survival according to Prostate Cancer Working Group 2 recommendations and Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary end points included prostate-specific antigen (PSA) response (≥50% reduction from baseline) and changes in CTC number (from ≥5 to <5 cells per 7.5 mL of blood) (CellSearch). Changes in CTC number based on PSMA expression levels on CTCs were also evaluated (Epic Sciences).

Results: Among the 42 patients (81% white), the median age was 66 (range, 50-85) years, and median number of doses received was 6 (range, 1-21). A PSA response was observed in 12 of 40 patients (30%; 95% CI, 18%-45%), measurable disease response in 6 of 19 (32% [95% CI, 15%-54%]), and CTC conversions in 13 of 26 (50%; 95% CI, 32%-68%). Median radiographic progression-free survival was 9.9 (95% CI, 7.1-12.6) months. With use of the Epic Sciences non-EPCAM-based CTC detection platform, CTCs were detected in 16 of 18 patients (89%); 11 of 18 (61%) had CTCs with PSMA expression above the analytical threshold level (PSMA positive) at baseline (range, 0.4-72.4 CTCs/mL). After treatment, PSMA-positive CTCs were preferentially reduced. Treatment-related adverse events included grade 1 or 2 fatigue (29 of 42 patients [69%]), nausea (23 [55%]), neuropathy (14 [33%]), and neutropenic fever (1 [2%]).

Conclusions and relevance: These findings suggest that treatment with BIND-014 is active and well tolerated in patients with chemotherapy-naive mCRPC. Antitumor activity may be related to PSMA expression levels on CTCs, which suggests that patients who are likely to benefit from this treatment can be identified before treatment is initiated.

Trial registration: ClinicalTrials.gov Identifier: NCT01812746.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Dreicer reported consulting for EMD Serono, Pfizer, Orion, Astra Zeneca, Astellas, Bristol-Myers Squibb, and Incyte. Dr Hart reported being on the speakers bureau for Pfizer and Lilly. Dr Milowsky reported receiving research funding from Acerta Pharma; Agensys, Inc; Bristol-Myers Squibb; Incyte; Merck; Pfizer; and Roche/Genentech. Dr Graf and Mr Dittamore reported being employees of EPIC Sciences, Inc. Mr Summa and Dr Youssoufian reported being employees of BIND Therapeutics, Inc. Dr Morris reported being an uncompensated consultant for Bayer and Endocyte, a compensated consultant for Blue Earth Diagnostics and Tolmar Pharmaceuticals, and having received research support via institutional contracts from Endocyte, Bayer, Corcept, Sanofi, and Progenics. Dr Scher reported being a paid consultant for BIND Therapeutics, Inc; Astellas; Clovis Oncology; Ferring Pharmaceuticals; Janssen Research & Development, LLC; Merck; Sanofi Aventis; and WCG Oncology. Dr Scher also reported being a member of the board of directors for Asterias Biotherapeutics and participating in an unpaid industry collaboration with EPIC Sciences, Inc.

Figures

Figure 1.. Molecular Circulating Tumor Cell (CTC) Characterization Sample Testing CONSORT Diagram

CONSORT diagram for samples tested for prostate-specific membrane antigen (PSMA) expression on CTCs. There were 18 patients in the PSMA CTC analysis subcohort, and samples were collected at 4 time points, giving 72 potential samples.

Figure 2.. Prostate-Specific Membrane Antigen (PSMA) Expression on Circulating Tumor Cells (CTCs) in Individual Patients Before Therapy

Heterogeneity of PSMA expression on CTCs in individual patients. A, Plot of all patient CTCs detected across 2 slides tested (approximately 1 mL of blood), with the x-axis indicating the PSMA signal to noise ratio detected per CTC. The vertical dotted line indicates the analytical threshold for PSMA signal positivity. B, The intrasample composition by PSMA status, transformed per milliliter.

Figure 3.. Changes in Prostate-Specific Membrane Antigen (PSMA) Expression on Circulating Tumor Cells (CTCs) With BIND-014 Treatment

The PSMA-expressing CTCs are reduced during therapy. A, Plot of all patient CTCs detected across 2 slides tested (approximately 1 mL of blood), with the x-axis indicating the PSMA signal to noise ratio detected per CTC. The vertical dotted line indicates the analytical threshold for PSMA signal positivity. B, Density plot (area under the curve = 1 for both) comparing the distributions of PSMA expression on CTCs from baseline (BL) to week 9 (WK9). The vertical dotted line indicates the analytical threshold of the assay.