A phase (Ph) I/II study of CR011-VcMMAE, an antibody-drug conjugate, in patients (Pts) with locally advanced or metastatic breast cancer (MBC).

Document Type

Article

Department

Haematology and Oncology, East Africa

Abstract

Background: Glycoprotein NMB (GPNMB), also known as osteoactivin, is expressed in 25-40% of breast cancers and is associated with an increased risk of recurrence. This is the first study of CR011-vcMMAE, a fully-human monoclonal anti-GPNMB antibody conjugated to the tubulin inhibitor monomethylauristatin E (MMAE), in pts with breast cancer.Methods: Eligible pts with MBC had 2 prior chemotherapy regimens, including a taxane, an anthracycline, and capecitabine; and ECOG PS ≤ 2. Doses were escalated to 1.88 mg/kg IV q3w (the maximum tolerated dose [MTD] in a previous study of patients with melanoma) using a standard 3+3 design followed by a Ph II expansion at the MTD. Pts received CR011-vcMMAE until disease progression (PD) or intolerable toxicity. The primary endpoint of the Ph II study was 12-week progression free rate, defined as the proportion of patients who were alive and free of progressive disease 12 weeks from the first dose of CR011-vcMMAE. A Simon two-stage minimax design was used (p0=0.1; p1=0.3, α=β=0.1) with 16 patients in the first stage and a total of 25 pts. Secondary endpoints included objective response rate and duration of response. IHC with a goat polyclonal antibody to GPNMB was performed on pt biopsy specimens.

Results: In Ph I, 14 pts were treated with CR011-vcMMAE at 1.0 mg/kg (n=3), 1.34 mg/kg (n=5), and 1.88 mg/kg (n=6). In the first 2 pts at 1.34 mg/kg, dose limiting toxicity of worsening peripheral sensory neuropathy was observed. Pts with baseline neuropathy worse than grade 1 were subsequently excluded. There were 3 partial responses, one confirmed, and 1.88 mg/kg q3w was selected for Ph II. In Ph II, 14 pts with MBC (median age 57 years, range 34 - 76) had a median of 5 prior regimens; median follow up was 6 weeks; 12 pts are ongoing (median duration 6 weeks, range 1 - 14 weeks). Two pts were progression-free at 12 weeks, therefore the study has met the criteria for advancement to the second stage. The most common AEs were rash (61%), fatigue (50%) and alopecia (50%). The most common grade 3/4 AEs were neutropenia (17%) and neuropathy (11%). IHC staining of 5 patient biopsies revealed 2 with positive GPNMB expression, including one of the patients with PR.Conclusions: CR011-vcMMAE is active and well-tolerated in heavily pretreated pts with advanced breast cancer. The Phase II study has met the criteria for advancement into the second stage, and enrollment is ongoing.

Comments

This work was published before the author joined Aga Khan University.

Publication (Name of Journal)

Cancer Research

DOI

https://doi.org/10.1158/0008-5472.SABCS-09-6096

Creative Commons License

Creative Commons Attribution 4.0 International License
This work is licensed under a Creative Commons Attribution 4.0 International License.

Link to Full Text

Share

COinS