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

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

Discussion

MBC‐11 is a conjugate of araC, linked through a phosphate group to an antiresorptive bisphosphonate, etidronate, designed to both target the conjugate to bone mineral and enable the concentration and release of drug to effectively kill cancer cells in bone lesions [1], [2]. In a subset of patients, MBC‐11 was associated with stabilized or reduced bone turnover, with a more pronounced effect on resorption biomarkers (TRAP5b, C‐telopeptide‐CTX, deoxypyridinoline‐DPD) than formation (bone‐specific alkaline phosphatase‐bALP, osteocalcine‐OC, and procollagen 1NH2‐terminal peptide‐P1NH); this was consistent with observations in the canine osteosarcoma study [8]. A modest effect on tumor biomarkers was noted in a subset of patients.

MBC‐11 is the first clinical demonstration of an araC delivery technology targeting bone and killing epithelial derived cancer cells. These observations indicate a significant fraction of MBC‐11 is binding bone and releasing active concentrations of araC in the bone compartment. The MBC‐11 MTD of 5 mg/kg results in a 1 μM systemic exposure to araC, notably 5–10‐fold below the exposure needed in patients with leukemia. Despite the lower molar dosing of MBC‐11 (at MTD) compared with araC regimens (2–20‐fold higher), similar myelosuppressive AEs were observed, suggesting a relative concentration of the active form of araC in the bone compartment provided by MBC‐11.

With PET Response Criteria in Solid Tumors (PERCIST) version 1.0 [3] criteria applied to 18F‐FDG‐PET/CT imaging performed at baseline with 14 of the 16 patients, three patients displayed partial metabolic response (PMR), three patients displayed stable metabolic disease (SMD), and eight displayed progressive metabolic disease (PMD). Patients diagnosed with PMD often displayed significant reduction or stabilization of bone lesions; however, the appearance of a new lesion, including nonosseous lesions, defines PMD. Of the five patients receiving four cycles of therapy, two patients remained with SMD, and three showed PMD.

A non‐PERCIST analysis of all measurable bone lesions with hypermetabolic cancer cell activity at baseline (Fig. 1) showed a significant reduction of 52% after cycle 2 and 64% after cycle 4. We observed both inter‐ and intrapatient variability, demonstrating that different lesions—even within the same patient—may regress below limits of detection, at a moderate level, or be unresponsive.

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: SUV

This study has demonstrated the dose‐limiting toxicity (DLT; 10 mg/kg) and MTD (5 mg/kg) levels are driven by myelosuppression, and at doses below this MBC‐11 is safe, well tolerated, and effective in treating CIBD lesions. Although reduction in bone lesion activity and antiresorptive activity occurs throughout the range of doses from 0.5 to 10 mg/kg, myelosuppression increases above 5 mg/kg. This is consistent with the wide therapeutic index of MBC‐11 observed in animal models of multiple myeloma and breast cancer‐induced bone disease [2]. The phase I clinical results of MBC‐11 safety and activity on bone lesions, tumor biomarkers, and bone resorption markers demonstrate the effects of MBC‐11 on treating cancer‐induced bone lesions and warrant further clinical investigation.

Trial Information

Breast cancer

Cervical cancer

Prostate cancer

Advanced cancer

Cancer‐induced bone disease

Metastatic/advanced

No designated number of regimens

Phase I

3 + 3

Safety

Tolerability

Maximum tolerated dose

Pharmacodynamics

Pharmacokinetics

Efficacy

Active and should be pursued further

Drug Information

MBC‐11

MBC‐11

Osteros Biomedica Ltd.

Small molecule

Bone‐targeting conjugate of antiresorptive and antimetabolite

0.5, 1.0, 2.5, 5.0, 10 milligrams (mg) per kilogram (kg)

IV

Treatment began with a single administration of MBC‐11, followed by 7‐day period of rest; treatment continued with a cycle of MBC‐11, defined as 5 consecutive days of dosing followed by a 23‐day period of rest (Fig. 1). Upon a cohort's completion of a cycle with acceptable safety and tolerability data, progression to the next dose was permitted. The progression from single to multiple administrations was applied to each successive cohort. Two cycles of MBC‐11 were planned per patient in the absence of unacceptable toxicity. Five patients choose to continue to cycle 3 and cycle 4 with investigator approval. The end of study visit was performed 23 days after the last dosing of MBC‐11.

Dose Escalation Table

Patient Characteristics

8

8

All patients presented with bone metastases: eight with <6 metastases, three with 6–20 metastases, and three with >20 metastases. Two patients received one cycle of MBC‐11, eight patients received two cycles of MBC‐11, and five received four cycles of MBC‐11

Median (range): 62 ± 13 years

Median (range): Not collected

0 — 3

1 — 11

2 — 2

3 — 0

Unknown —

Breast cancer — 7

Prostate cancer — 8

Cervical cancer — 1

Primary Assessment Method

18F‐FDG‐PET/CT Metabolic Response

16

16

14

Other (PERCIST 1.0)

n = 0 (0%)

n = 3 (21%)

n = 3 (21%)

n = 8 (57%)

Adverse Events

Serious Adverse Events

Dose‐Limiting Toxicities

Pharmacokinetics and Pharmacodynamics

Assessment, Analysis, and Discussion

Study completed

Active and should be pursued further

This is one of two bisphosphonate conjugates tested in clinical trials and the first to demonstrate efficacy (ClinicalTrials.gov identifiers: MBC‐11, NCT02673060; Osteodex, NCT01595087). Sixteen patients received at least one dose of MBC‐11. Fifteen patients completed at least one cycle of MBC‐11 (Fig. 2). The majority of adverse events were blood and lymphatic disorders and were consistent with the myelosuppressive effects known for the araC moiety of the conjugate.

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.

Pharmacokinetic parameters and a representative time course of plasma exposure to MBC‐11 and its metabolites are presented in Figure 3 for the patients dosed at 5 mg/kg. During the 2‐hour infusion period of MBC‐11, araCMP (direct hydrolysis product), araC (metabolite of araCMP), and araU (metabolite of araC) remained at an approximate concentrations of 1 μM, whereas etidronate (direct hydrolysis product of MBC‐11) increased up to 10 μM by the end of infusion and continued to increase another 40% over the next 30–60 minutes (as shown in Fig. 3’s graph of patient 12). At the end of infusion of MBC‐11, araCMP and araC were eliminated rapidly (T1/2 < 30 minutes). Etidronate elimination after infusion was consistent with reported elimination half‐life of 1–6 hours [4], [5]. During and after the infusion, the appearance of araU lagged behind that of etidronate (Tmax 3.25 and 2.75 hours, respectively). The rapid conversion of araC into araU and the slow elimination of araU are consistent with published reports [6], [7].

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: AUC

In a subset of patients, MBC‐11 was associated with stabilized or reduced bone turnover, with a more pronounced effect on resorption (TRAP5b, CTX, DPD) than formation (bALP, OC, P1NH); this was consistent with observations in the canine osteosarcoma study [8].

The changes in the breast cancer marker, CA15‐3 antigen, are presented in Table 1. CA15‐3 antigen serum level was decreased or unchanged in three of six patients at the end of cycle 2.

Table 1.

CA15.3 antigen in patients with breast cancer

Bolded values indicate values within the normal reference range ≤25 U/mL.

Abbreviation: —, data was not collected for patients that completed study after 2‐cycles of treatment.

The changes in the prostate cancer markers, total prostate‐specific antigen (PSA) and the ratio of free PSA to total PSA, are presented in Table 2. Four patients demonstrated a trend in stabilization, and one patient demonstrated an improvement in PSA status.

Table 2.

Prostate‐specific antigen in prostate cancer subgroup

Bolded values indicate values within the normal reference.

Abbreviation: —, data was not collected for patients that completed study after 2‐cycles of treatment.

All patients from cohorts 1–5 had median Eastern Cooperative Oncology Group (ECOG) performance status of 1 at baseline and end of cycle 2. ECOG worsened in four patients; two went from 0 to 1, and two went from 1 to 3 ECOG status by the end of cycle 2. All other patients and the five patients treated through four cycles remained unchanged at ECOG status of 1.

Six of 13 patients reported a reduction in pain (Numerical Rating Scale) at the end of the first week of dosing that remained below baseline in four patients at the end of cycle 2; of five patients who continued through four cycles of treatment, two remained below baseline reports; this suggests a trend toward pain reduction in a subset of patients.

Skeletal related events were not observed throughout the duration of the study and are consistent with the overall stabilization or reduction in bone lesion activity observed by imaging.

Fluorodeoxyglucose positron emission tomography/computed tomography (18F‐FDG‐PET/CT) imaging demonstrated a significant reduction in cancer cell metabolic activity in many bone lesions. Table 3 shows the results of 14 of the 16 patients who had 18F‐FDG‐PET/CT performed at baseline and at the end of two cycles of treatment; five patients continued therapy and were imaged after completion of four cycles of therapy. PET Response Criteria in Solid Tumors (PERCIST) version 1.0 [3] criteria limited analysis to one or two target bone lesions and a total of seven lesions—including nonosseous lesions—per patient. After two cycles of MBC‐11, three patients displayed partial metabolic response (requiring ≥30% reduction in a target lesion SULmax [standard unit of emission normalized to lean body mass] and the absence of new lesions or increase of any lesions by ≥30% SULmax), three patients displayed stable metabolic disease (SMD), and eight displayed progressive metabolic disease (PMD). It is important to note that patients diagnosed with PMD often displayed significant reduction or stabilization of bone lesions; however, the appearance of a new lesion, including nonosseous lesions, is defined as PMD by PERCIST. Of the five patients receiving four cycles of therapy, two patients remained with SMD, and three showed PMD.

Table 3.

Results of 18F‐FDG‐PET/CT image analysis using PERCIST criteria and independent assessment of all measurable bone lesions

Patient number and original primary cancer.

PERCIST criteria define the following: PMR, ≥30% reduction in SULmax (standard unit of fluorescence normalized to lean body mass) in up to two target lesions; SMD, ≤30 increase in SULmax in any measurable lesion; PMD, if ≥30 increase in SULmax in any measurable lesion or appearance of any new lesion.

Measurable bone lesions were not restricted to the target lesions defined by PERCIST but included all measurable detected bone lesions; the change in SUVmax was grouped into Responsive (reduction of ≥25%, including lesions no longer detectable [BD]), Stable (no ± change >25%), and Progressive (increase of ≥25% or the appearance of a new bone lesion [NL]).

Abbreviations: —, data was not collected for patients that completed study after 2‐cycles of treatment; B, breast cancer; BD, below the limit of detection; C, cervical cancer; NL, new lesion; P, prostate cancer; PERCIST, Positron Emission Tomography Response Criteria in Solid Tumors; PMD, progressive metabolic disease; PMR, partial metabolic response; SMD, stable metabolic disease.

Within PERCIST analysis, five patients had 14 sites of nonosseous cancer followed over the course of therapy. SULmax for three nonosseous sites increased by >30%; the remaining 11 nonosseous sites remained stable or decreased—including three below the limits of detection after two cycles of therapy (see Table 5).

To further understand the impact of MBC‐11 upon bone lesions, a non‐PERCIST analysis included all measurable bone lesions, identifying a total of 211 bone lesions with hypermetabolic cancer cell activity at baseline. Of the 211 lesions, 110 (52%) showed a reduction in SUVmax (standard unit of emission normalized to total uptake) of ≥25% after two cycles of MBC‐11 compared with baseline. Of the 133 bone lesions present at baseline in the five patients who received four cycles of treatment, 85 (64%) showed a reduction in SUVmax of ≥25%.

We observed both inter‐ and intrapatient variability, demonstrating that different lesions—even within the same patient—may regress below limits of detection, at a moderate level, or be unresponsive. Although the bone lesions of patient 02 were stabilized, significantly reduced, or reduced below the limits of detection (Table 3), the increase of ≥30% in activity in a prostate lesion defines PMD by PERCIST (Table 4) [3]. This example highlights the need in the case of bone‐targeted drugs to analyze bone tissue specifically while separately applying PERCIST criteria to understand the impact across all tissues. It is interesting to note that significant benefit was observed in a subset of patients across all cohorts, and thus no dose response was observed with regard to efficacy, whereas dose response was obvious in regard to myelosuppression.

Table 4.

Nonosseous sites of cancer and metastases

Imaging results provided as SULmax; zero indicates below limit of detection, blank cell indicates data was not collected at that time point.

Abbreviations: B, breast cancer; P, prostate cancer; SULmax, standard unit of fluorescence normalized to lean body mass.

The phase I clinical results of MBC‐11 safety and activity on bone lesions, tumor biomarkers, and bone resorption markers demonstrate the effects of MBC‐11 on treating cancer‐induced bone lesions and warrant further clinical investigation; an additional six patients at the maximum tolerated dose would be included if this study were to be repeated.

In summary, the pharmacokinetic results are consistent with a large fraction of MBC‐11 being hydrolyzed in the blood, while a smaller but significant fraction—accounting for efficacy—binds the bone mineral and is subsequently hydrolyzed on the bone surface or presumably within osteoclasts to release araC for uptake by bone‐localized cancer cells—as was the intent of the drug design. MBC‐11 was discovered and preclinically developed by MBC Pharma Inc (Aurora, CO) and subsequently licensed to Osteros Biomedica Ltd. (Moscow, Russia) for clinical development. MBC‐11 active pharmaceutical ingredient was manufactured by Johnson Matthey Pharma Services (Devens, MS). Phase II work is planned for in a multisite open label study in Russia; with success, continued international development will be pursued.

The phase II study will investigate the effects of MBC‐11 in patients with bone metastases as the dominant site of disease due to castration‐resistant prostate cancer or breast cancer.

Worst‐grade toxicity recorded in all patients, across all cycles.

Abbreviation: NC/NA, no change from baseline/no adverse event.

Of all adverse events, 14 were severe, including seven SAEs (two grade 4, and one grade 3 thrombocytopenia; two grade 4, and one grade 3 neutropenia one; one hematuria). The hematuria was listed as a urinary bladder hemorrhage and occurred 7 days after a single injection, and the patient did not complete a full cycle or proceed in the study. The SAE resolved after 54 days and was not considered a DLT. Four of the seven SAEs listed as blood disorders were considered DLT: two patients with breast cancer receiving 10 mg/kg MBC‐11 each developed a grade 4 thrombocytopenia and a grade 4 neutropenia; all resolved within 7 days.

Abbreviation: SAE, serious adverse event.

Single 5 mg/kg dose plasma pharmacokinetic parameters derived from the four patients of cohort 4. The mean of the cohort dosed at 5 mg/kg is provided with standard deviation; calculations included the time points during the infusion. Note the Tmax for MBC‐11 and the two rapidly cleared metabolites (araCMP and araC) occurred during the infusion.Abbreviations: AUC0–72, area under the concentration‐time curve from 0 to 72 hours; CI F, total plasma clearance; Cmax, maximal concentration; T1/2, half‐life; Tmax, time for maximal concentration; Vd, volume of distribution.