A phase 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, has been shown to regulate metastasis of breast cancer in vivo. CR011-vcMMAE, a fully-human monoclonal anti-GPNMB antibody conjugated to the tubulin inhibitor monomethylauristatin E, is safe and active in pts with advanced melanoma. This is the first study of CR011-vcMMAE in 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 melanoma) using a standard 3+3 design. Immunohistochemistry (IHC) with goat polyclonal antibody to GPNMB was performed on pt biopsy specimens and on tissue microarrays containing normal breast, DCIS, breast tumor and lymph node metastases.

Results: 10 pts with MBC (median age 57, range 36 - 69) had a median of 7 prior regimens and were treated with CR011-vcMMAE for a median of 2 cycles (range 1–4). 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. Pts were treated at 1.0 mg/kg (n = 3), 1.34 mg/kg (n = 5), and 1.88 mg/kg (n = 2); enrollment at 1.88 mg/kg is continuing. Other adverse events (AEs) were grade 1/2 anorexia and pain in 4 pts; diarrhea, rash, fatigue, and neuropathy in 3 pts; and grade 3 rash in 1 pt. Evidence of antitumor activity has been observed. A response of 37% tumor shrinkage was seen in a pt after only 2 cycles and is ongoing. A second pt had a 51% reduction after 2 cycles, but had PD after 12 weeks. Breast tumor samples were more likely to stain positive for GPNMB than normal breast tissues.

Conclusions: CR011-vcMMAE 1.34 mg/kg IV q3w is well-tolerated in heavily pretreated pts with MBC. The 1.88 mg/kg q3w dose is being assessed and phase II expansion is planned at the MTD. IHC of pt tumor specimens is being evaluated.

Comments

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

Publication (Name of Journal)

Journal of Clinical Oncology

DOI

https://doi.org/10.1200/jco.2009.27.15_suppl.1067

Creative Commons License

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

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