Phase 1 study of the bone-targeting cytotoxic conjugate, etidronate-cytosine arabinoside (MBC-11), in cancer patients with bone metastases

Autor: Shawn Zinnen, Larisa Plekhova, Alexander Karpeisky, Marina Roudas, Alexander Alexandrov, Eric K. Rowinsky
Rok vydání: 2017
Předmět:
Zdroj: Journal of Clinical Oncology. 35:2589-2589
ISSN: 1527-7755
0732-183X
DOI: 10.1200/jco.2017.35.15_suppl.2589
Popis: 2589 Background: MBC-11 is a first-in-class therapeutic conjugate of the bone targeting bisphosphonate etidronate covalently linked to the antimetabolite cytosine arabinoside (Ara-C). In preclinical studies, MBC-11 localizes at the site of cancer-induced bone disease (CIBD) where it demonstrates both antiresorptive and antitumor activities following local release of Ara-C. Robust efficacy was observed in several rodent models of CIBD, as well as in spontaneous osteosarcoma in dogs. Herein, the results of the first-in-human study of MBC-11 are reported. Methods: Patients with advanced solid cancers and CIBD were treated with escalating doses (0.5-10 mg/kg/day) of MBC-11 administered as an intravenous infusion daily for 5 days every 4 weeks for up to 4 cycles. Fifteen patients (prostate cancer [PC; 7], breast cancer [BC; 7], cervical cancer [1]) received 38 total cycles. The study sought to characterize the safety, pharmacokinetics, and the effects of MBC-11 on bone turnover, and tumor response by 18F-FDG-PET/CT imaging and tumor biomarkers. Results: Myelosuppression was generally grade 1-2, involved all lineages, and was the principal toxicity of MBC-11. Two of three patients treated at the 10 mg/kg dose level had dose-limiting toxicity (DLT), each with both grade 4 neutropenia and thrombocytopenia, the maximum tolerated dose (MTD) was 5 mg/kg. Four of 5 patients with pretreatment elevations of the bone resorption marker Trap5b had persistent decrements. 18F-FDG-PET/CT imaging demonstrated partial metabolic responses in 3 patients; one BC patient treated at the 0.5 mg/kg and two CRPC patients treated at 1.0 mg/kg dose levels. An additional 3 patients had stable metabolic responses according to PERSIST. SUV values were reduced by at least 25% in 111 (53.8%) of 206 measurable bone lesions; significant activity was noted at all doses. Conclusions: At doses that were well tolerated and even much lower than the MTD, MBC-11 treatment resulted in substantial reductions in metabolic activity in CIBD patients, providing a foundation for further disease-directed studies to further assess efficacy. Clinical trial information: NCT02673060.
Databáze: OpenAIRE
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