First-in-Human Phase I Study of MBC-11, a Novel Bone-Targeted Cytarabine-Etidronate Conjugate in Patients with Cancer-Induced Bone Disease

Abstract

Lessons learned: Results are consistent with MBC-11 targeting and treating cancer-induced bone lesions by concentrating cytarabine and etidronate at the site of disease.MBC-11 was well tolerated, with an maximum tolerated dose of 5 mg/kg per day and myelosuppression as the principal toxicity.Treatment significantly reduced cancer cell activity in over half of bone lesions detected at baseline.MBC-11 pharmacokinetic and pharmacodynamic parameters are consistent with the novel drug design goals, and encouraging results warrant further clinical development.

Background: MBC-11 is a first-in-class conjugate of the bone-targeting bisphosphonate etidronate covalently linked to the antimetabolite cytarabine (araC). This first-in-human phase I dose escalation study assessed safety, tolerability, maximum tolerated dose (MTD), plasma pharmacokinetics, bone turnover, tumor biomarkers, and bone lesion activity by fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) imaging.

Methods: Fifteen patients with advanced solid cancers and cancer-induced bone disease (CIBD) were treated with 0.5-10 mg/kg per day of MBC-11 administered daily for 5 days of every 4 weeks for up to four cycles.

Results: Grade 1-2 myelosuppression, involving all lineages, was the principal toxicity. Two of three patients treated with 10 mg/kg experienced dose-limiting grade 4 neutropenia and thrombocytopenia (adverse event [AE] duration ≤5 days); the MTD was 5 mg/kg. Four of five patients with pretreatment elevations of the bone resorption marker TRAP5b (tartrate resistant acid phosphatase-5b) had persistent decrements. Six of 13 patients who reported baseline pain noted a reduction after MBC-11. 18F-FDG-PET/CT imaging demonstrated partial metabolic responses in three patients and stable metabolic responses in three other patients. SUVmax (standard unit of emission normalized to total uptake) was reduced by at least 25% in 110 (52%) of 211 bone lesions. Significant activity was noted across all doses, and myelosuppression increased with dose.

Conclusion: At MBC-11 doses that were well tolerated, substantial reductions in metabolic activity of bone-associated cancer cells provide a foundation for further disease-directed efficacy studies.

Trial registration: ClinicalTrials.gov NCT02673060.

© AlphaMed Press; the data published online to support this summary are the property of the authors.

Figures

Figure 1.

Of 14 patients, 211 bone lesions were detected at baseline using fluorodeoxyglucose positron emission tomography/computed tomography imaging. The change in SUVmax after 2 months (two cycles of therapy) are shown with dark‐blue bars; −100% indicates reduction to below the limit of detection. Five patients continued on therapy for an additional 2 months (four cycles total); further changes from baseline are shown by light‐blue bars overlapping their respective bone lesion at the two‐cycle time point. Of the 211 lesions, 110 (52%) showed a reduction in SUVmax of ≥25% after two cycles of MBC‐11. Of the 133 bone lesions present at baseline in the five patients who received four cycles, 85 (64%) showed a reduction. Six patients with progressive disease developed new bone lesions (Table 3). Five patients requested two additional cycles of therapy; at the end of 4 months two of these patients had new bone lesions appear. A total of six patients persisted without new bone lesions. The underlying grey bars correspond to their respective blue bars and indicate the dose‐administered scale on right. Although not significant, it is interesting that the majority of responsive bone lesions correspond to the lower dosing.Abbreviation: SUVmax, standard unit of emission normalized to total uptake.

Figure 2.

MBC‐11 chemical structure and study design. (Top row): Chemical structures of active drug moieties, etidronate and araC, and MBC‐11. (Lower row): Screening: Confirmed metastatic bone cancer and consistency with exclusion/inclusion criteria. Treatment: MBC‐11 administered as a single 2‐hour infusion followed by 7 days without drug prior to first cycle; subsequently, MBC‐11 administered as 2‐hour infusions on the first 5 days of a 28‐day cycle. End of study defined as 1 week after the end of cycle 2, unless physician directed extension with cycles 3 and 4, defining end of study as 1 week after end of cycle 4.Abbreviations: /, single dose; BB, bone biomarkers; CB, cancer biomarkers (PSA or CA‐15‐3); Im, 18F‐FDG PET/CT.

Figure 3.

Plasma pharmacokinetics of MBC‐11. (A): MBC‐11 Metabolic breakdown pathway. MBC‐11 is hydrolyzed to etidronate and araCMP. Etidronate does not break down further. AraCMP is rapidly dephosphorylated to araC, which is deaminated to araU. (B): Time course of plasma exposure in patient 12 to MBC‐11 and its metabolites. (C): Single 5 mg/kg dose plasma PK parameters. The mean of the cohort dosed at 5 mg/kg is provided with standard deviation; calculations included the time points during the infusion.Abbreviations: AUC0‐00, Area under the concentration‐time curve from zero to infinity; AUC0–72, Area under the concentration‐time curve from zero to 72‐hours; AUMC, Area under the concentration‐time curve from the first moment to infinity; CL, clearance; Cmax, maximal concentration; Kel, elimination rate; MRT, mean residence time; PK, pharmacokinetics; T1/2, half‐life; Tmax, time for maximal concentration; Vd, volume of distribution.