Early Stage Breast CancerPhase 2NCT01545648
Pilot Study to Evaluate the Impact of Denosumab on Disseminated Tumor Cells (DTC) in Patients With Early Stage Breast Cancer
A Phase 2 study testing Denosumab in people with Early Stage Breast Cancer, run by Hope Rugo, MD at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Early Stage Breast Cancer
- What is being tested?
- Denosumab
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 4 participants
- Where
- 1 siteUnited States
- Study dates
- 1 Nov 2012to 9 Jun 2016
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Patients ≥18 years of age with histologically or cytologically confirmed stage I, II, or III breast cancer.
- ECOG Performance Status of 0 or 1
- Prior therapy:
- Prior adjuvant therapy is not required for participation in this study.
- If adjuvant or neoadjuvant treatment with chemotherapy is recommended, it must be completed before study start, and not more than 18 months prior to study start.
- If adjuvant or neoadjuvant treatment with trastuzumab (Herceptin®) is recommended, patients should have received at least 3 months of therapy before eligibility bone marrow is performed.
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- Patients who have had surgery following neoadjuvant chemotherapy or hormonal therapy are eligible
- Patients must have completed definitive surgery and have completely resected disease.
- Concomitant hormonal therapy is allowed.
- Concomitant adjuvant trastuzumab is permitted
- If adjuvant hormonal treatment is recommended, patients should have received at least 3 months of therapy before screening bone marrow is performed.
- Bone marrow aspirate positive by IE/FC assay within 12 weeks of study entry
- Definition of positive: >10 DTC/ml
- Timing of bone marrow aspiration to determine study eligibility
- i.If patient is to receive either no adjuvant therapy or hormonal therapy alone, the aspiration may be performed at diagnosis as part of the large micrometastasis study at UCSF, or following diagnosis if the patient received initial surgery elsewhere. This is also true for patients who have surgery following neoadjuvant therapy for breast cancer.
- ii.If the patient is to receive adjuvant chemotherapy, the aspiration will be performed at least three weeks after chemotherapy has been completed.
- iii.For trastuzumab and hormone therapy, see above.
- Laboratory studies
- Liver function tests within normal limits, including total bilirubin, alkaline phosphatase, and AST (elevation of total bilirubin due to Gilbert's disease is allowed).
- Gilbert's disease: a common hereditary cause of increased indirect bilirubin, but with normal direct bilirubin.
- Calculated creatinine clearance (calculated GFR) > 30 ml/min
- Ability to understand and sign informed consent
- Patients who have had surgery following neoadjuvant chemotherapy or hormonal therapy are eligible to participate in this trial.
Who cannot join
- Karnofsky performance status < 90%
- Patients participating in this study are not allowed to receive bisphosphonate therapy during the study period, either oral or intravenous.
- Patients who completed adjuvant or neoadjuvant therapy more than 18 months prior to study screening.
- A history of malignancy within the last 5 years except basal cell carcinoma of skin.
- A history of human immunodeficiency virus (HIV) infection.
- Severe, concurrent illness that would likely prevent the patient from being able to comply with the study protocol.
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- Pregnant or lactating women and women of child-bearing potential who are not using an effective method of birth control.
- Significant dental disease that requires major intervention during the study period, such as tooth extraction
- Significant coagulopathy that would prevent safe bone marrow aspiration
Trial locations and contacts
1 site in 1 country.
United States1 site
University of California San Francisco
San Francisco, California, 94143
About this study
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.
Read the 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.
- Conditions
- Early Stage Breast Cancer
- Being tested
- Denosumab
- Keywords
- breast, cancer, early, DTC, disseminated, tumor, cells
- Medical subject headings
- Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
DenosumabDrug
Also called AMG 162, XGEVA™, Prolia®
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
| Study group | Role | What they receive |
|---|---|---|
| denosumab | Experimental | 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 Receives: Drug: Denosumab |
What is being measured
The primary outcome is the main question the study is designed to answer.
Percentage of Change in Reduction of Disseminated Tumor Cells (DTC)/Mililitre (ml)
Reduction of disseminated tumor cells (DTC)/ mililitre (ml) from >10DTC/ml to ≤ 10DTC/ml. DTC measured by IE/FC in patients with early stage
Measured: Up to 12 months
Disseminated Tumor Cell Counts
Changes from baseline in disseminated tumor cell counts
Measured: Up to 12 months
Secondary outcomes (1)
Correlation of Local Recurrence With DTC
Correlate breast cancer recurrence risk with individual values for DTC at each time point
Measured: Up to 12 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted7 Mar 2012 (estimated)
- Study start1 Nov 2012
- Primary completion9 Jun 2015
- Study completion9 Jun 2016
Why it stopped: Low Accrual
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Early Stage Breast CancerStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 4 participants (actual)
Sponsor and investigators
- Lead sponsor
- Hope Rugo, MD
- Sponsor type
- University, hospital or other
- Collaborators
- University of California, San Francisco, Amgen
- Responsible party
- Sponsor-investigator, Hope Rugo, MD, University of California, San Francisco
- Investigators
- Hope Rugo, MD, Principal investigator, University of California, San Francisco
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01545648
- Sponsor's protocol ID
- 117527
- Other IDs
- NCI-2012-02802
- Status last verified
- Dec 2019
- First submitted
- 27 Feb 2012
- Last updated
- 2 Jan 2020
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Stefanovic S, Diel I, Sinn P, Englert S, Hennigs A, Mayer C, Schott S, Wallwiener M, Blumenstein M, Golatta M, Heil J, Rom J, Sohn C, Schneeweiss A, Schuetz F, Domschke C. Disseminated Tumor Cells in the Bone Marrow of Patients with Operable Primary Breast Cancer: Prognostic Impact in Immunophenotypic Subgroups and Clinical Implication for Bisphosphonate Treatment. Ann Surg Oncol. 2016 Mar;23(3):757-66. doi: 10.1245/s10434-015-4895-3. Epub 2015 Oct 14.
PubMed 26467455
Study at a glance
From the registry record, last updated by the sponsor on 2 Jan 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Pilot Study to Evaluate the Impact of Denosumab on Disseminated Tumor Cells (DTC) in Patients With Early Stage Breast Cancer
- ClinicalTrials.gov ID
- NCT01545648
- Acronym / sponsor ID
- 117527
- Conditions
- Early Stage Breast Cancer
- Keywords
- breast, cancer, early, DTC, disseminated, tumor, cells
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Low Accrual
- Enrolment
- 4 participants (actual)
- Lead sponsor
- Hope Rugo, MDUniversity, hospital or other
- Collaborators
- University of California, San Francisco, Amgen
- Study start
- 1 Nov 2012 (actual)
- Primary completion
- 9 Jun 2015 (actual)
- Study completion
- 9 Jun 2016 (actual)
- First posted
- 7 Mar 2012 (estimated)
- Results
- Posted 2 Jan 2020
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| denosumab | Experimental | Drug: DenosumabDosage: 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 |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (23 listed)
- Patients ≥18 years of age with histologically or cytologically confirmed stage I, II, or III breast cancer.
- ECOG Performance Status of 0 or 1
- Prior therapy:
- Bone marrow aspirate positive by IE/FC assay within 12 weeks of study entry
- i.If patient is to receive either no adjuvant therapy or hormonal therapy alone, the aspiration may be performed at diagnosis as part of the large micrometastasis study at UCSF, or following diagnosis if the patient received initial surgery elsewhere. This is also true for patients who have surgery following neoadjuvant therapy for breast cancer.
Key exclusion criteria (9 listed)
- Karnofsky performance status < 90%
- Patients participating in this study are not allowed to receive bisphosphonate therapy during the study period, either oral or intravenous.
- Patients who completed adjuvant or neoadjuvant therapy more than 18 months prior to study screening.
- A history of malignancy within the last 5 years except basal cell carcinoma of skin.
- A history of human immunodeficiency virus (HIV) infection.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| DenosumabAlso: AMG 162, XGEVA™, Prolia®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 | Drug | denosumab |
Primary outcome
Percentage of Change in Reduction of Disseminated Tumor Cells (DTC)/Mililitre (ml)
Time frame: Up to 12 months
Reduction of disseminated tumor cells (DTC)/ mililitre (ml) from >10DTC/ml to ≤ 10DTC/ml. DTC measured by IE/FC in patients with early stage
Disseminated Tumor Cell Counts
Time frame: Up to 12 months
Changes from baseline in disseminated tumor cell counts
1 secondary outcome
Correlation of Local Recurrence With DTC
Time frame: Up to 12 months
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 2 Jan 2020.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 26467455Stefanovic S, Diel I, Sinn P, Englert S, Hennigs A, Mayer C, Schott S, Wallwiener M, Blumenstein M, Golatta M, Heil J, Rom J, Sohn C, Schneeweiss A, Schuetz F, Domschke C. Disseminated Tumor Cells in the Bone Marrow of Patients with Operable Primary Breast Cancer: Prognostic Impact in Immunophenotypic Subgroups and Clinical Implication for Bisphosphonate Treatment. Ann Surg Oncol. 2016 Mar;23(3):757-66. doi: 10.1245/s10434-015-4895-3. Epub 2015 Oct 14.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Hope Rugo, MD principal investigator
University of California, San Francisco
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Denosumab in people with Early Stage Breast Cancer, run by Hope Rugo, MD at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 23 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 2 Jan 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 2 Jan 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Percentage of Change in Reduction of Disseminated Tumor Cells (DTC)/Mililitre (ml) (time frame: Up to 12 months). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01545648, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 2 Jan 2020.