Clinical trial NCT01545648
Conditions: Early Stage Breast Cancer
Keywords: breast cancer early DTC disseminated tumor cells
Sponsor: Hope Rugo, MD
Start date: 2012-11-01; Completion date: 2016-06-09
Enrollment: 4 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to see whether taking denosumab for 12 months in women with a significant number of disseminated tumor cells in the bone marrow can reduce the number of these cells below a significant level.

Detailed description:
The presence of disseminated tumor cells (DTC) in the bone marrow in women with early stage breast cancer is an important prognostic factor associated with an increase in both recurrence and disease-associated death. In a pooled analysis of 4703 invasive breast cancer patients, detection of DTC in the bone marrow was associated with an increase in disease recurrence, distant metastases, and death from breast cancer over a median follow-up period of 5.2 years. Subsequent studies have demonstrated that the presence of DTC in the bone marrow of women with early breast cancer following completion of adjuvant therapy have an even greater impact on the risk of recurrence and death from breast cancer. Multivariate analysis demonstrated that the presence of marrow cells was an independent prognostic factor for reduced breast cancer specific survival with a relative risk of 6.3 (2.3-17.6, p\<0.0001). Clearly, the detection of DTC in women with early stage breast cancer is a marker for increased risk of relapse and death, and this could serve as a unique indicator to select higher risk patients for intervention with targeted therapeutics.

It has long been recognized that there is close relationship between bone and immune system, recent studies also suggests that in addition to monocytes/macrophage, T cells (especially Th17, a subset of T helper cells that produces IL-17), B cells and dendritic cells all play an important role in osteoclast formation. RANKL, in addition to its effect on osteoclasts, also induces local inflammation. Several recent studies have demonstrated that the presence of tumor associate macrophages (TAM) is associated with more aggressive disease, and a worse outcome. Preclinical data suggests that TAM plays an important role in promoting metastases and resistance to therapy. In addition to RANKL, there are other genes secreted by breast cancer cells, including TGF-β, TNF associated factor 6 (TRAF6), Hypoxia Induced Factor -1 (HIF-1) and Bone morphogenetic protein 2 (BMP2), also involve in bone-cancer "vicious cycle" and induce RANKL expression. Cytokines, such as IL-4, IL-6, IL-17, TNF-α and CSF-1, also play an important role in osteolysis and immune response in bone microenvironment by regulating TAM function (CSF-1, IL-4 and IL-17) and RANKL expression. Recently, CD47 and Signal Regulatory Protein α (SIRPA) were also shown to impair macrophage function, and associated with increased risk for recurrence in patients with breast cancer. The investigators hypothesize that patients with higher DTC may have higher expression of RANKL and chronic inflammatory cytokines. The investigators plan to evaluate the expression of RANK, RANKL, TRAF6, BMP2, CSF-1, CD47, IL-17 and SIRPA on isolated DTC and bone marrow hematopoietic cells, and correlate these results to the outcome of patients enrolled in the trial.

The investigators hypothesize that treatment with denosumab will decrease the number of DTC in women with early stage breast cancer who have completed adjuvant or neoadjuvant cytotoxic therapy possibly by preventing cancer cell migration, and by promoting cancer cell death by changing the bone into a "hostile" environment .

The investigators propose to conduct a non-randomized phase II trial testing this hypothesis in women with early stage breast cancer and persistent DTC following adjuvant systemic therapy. Patients with DTC will receive denosumab monthly for 6 months, then every 3 months for a total of one-year treatment, to mirror the schedule utilized in the ongoing randomized phase III denosumab versus placebo D-CARE trial. DTC will be monitored following 6 months and 12 months of therapy. The investigators anticipate that this treatment will reverse the "vicious cycle" between bone and cancer cells.

Arms: arm 1: Dosage: 120 mg, monthly for total of 6 months, then every 12 weeks for 2 doses, for a total treatment course of one year

Route of administration: subcutaneous injection
Interventions: intervention 1: Denosumab
Intervention descriptions: intervention 1: Formulation of Dosage forms

The vial presentations of denosumab contain 60 mg/mL denosumab, 17 mM sodium acetate, and 4.7% (w/v) sorbitol, at a pH of 5.2, filled to a target deliverable volume of 1.0 mL; or 70 mg/mL denosumab, 18 mM sodium acetate and 4.6% (w/v) sorbitol, at a pH of 5.2, filled to a target deliverable volume of 1.7 mL. The prefilled syringe (PFS) drug product contains denosumab at 60 mg/mL, 17 mM sodium acetate, 4.7% (w/v) sorbitol, and 0.01% (w/v) polysorbate 20, at a pH of 5.2, filled to a target deliverable volume of 1.0 mL.

Dosage: 120 mg, monthly for total of 6 months, then every 12 weeks for 2 doses, for a total treatment course of one year

Route of administration: subcutaneous injection

Protocol documents: