Biomarker Study of the Antitumoral Activity of Denosumab in the Pre- Operative Setting of Early Breast Cancer

Sponsor:

Collaborators:

Information provided by (Responsible Party):

，

Tracking Information

First Submitted Date ^ICMJE

September 4, 2018

First Posted Date ^ICMJE

October 1, 2018

Last Update Posted Date

October 1, 2018

Actual Study Start Date ^ICMJE

July 5, 2018

Estimated Primary Completion Date

July 5, 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures ^ICMJE

Antiproliferative and/or pro-apoptotic activity of denosumab[ Time Frame: From first biopsy until surgery intervention, which is around four weeks after enrolment ]

Changes in the percentage of tumor cells expressing Ki67 and/or cleaved caspase 3 between Biopsy A and Biopsy B.

Original Primary Outcome Measures ^ICMJE

Same as current

Current Secondary Outcome Measures ^ICMJE

Correlation between antiproliferative activity of denosumab and Rank/RankL expression[ Time Frame: From first biopsy until surgery intervention, which is around four weeks after enrolment ]
Modified ratio of Rank/RankL: MR={log(RANK) -1.2} / log(RANKL) as described in Palafox et al [10].
Differential antiproliferative activity of denosumab among the different phenotypes of breast cancers.[ Time Frame: From first biopsy until surgery intervention, which is around four weeks after enrolment ]
Ki67 estimations for each phenotype
Differential antiproliferative activity of denosumab among pre and post menopausal patients[ Time Frame: From first biopsy until surgery intervention, which is around four weeks after enrolment ]
Ki67 estimations for each menopausal group
Safety of denosumab and biopsy procedures in terms of Frequency of adverse events (CTCAE V4.)[ Time Frame: From first biopsy until surgery intervention, which is around four weeks after enrolment ]
Frequency of adverse events derived from denosumab treatment and biopsy procedures

Descriptive Information

Brief Title ^ICMJE

Biomarker Study of the Antitumoral Activity of Denosumab in the Pre- Operative Setting of Early Breast Cancer

Official Title ^ICMJE

An Open Label Biomarker Pilot Study of the Antitumoral Activity of Denosumab in the Pre- Operative Setting of Early Breast Cancer

Brief Summary

This is a biomarker study designed to test the preclinically generated hypothesis of anti-tumoral activity of denosumab in patients with early breast cancer candidates a tumour excision

Detailed Description

This is a biomarker study designed to test in patients the preclinically generated hypothesis of anti-tumoral activity of denosumab.The main objective is to demonstrate the antiproliferative and/or pro-apoptotic activity of denosumab in early breast cancer. Other endpoints are to correlate denosumab activity with RANK and RANKL expressions through mRNA and protein; to characterize the differential antiproliferative activity of denosumab between different phenotypes of breast cancer; to identify biomarkers, to identify global changes in gene expression and validate the activity of RANKL antibody in clinical samples. A total of 60 patients with early breast cancer (Stages I and II) candidates to tumor excision as first therapeutic approach will be randomized 2:1, a treatment arm that will receive two doses of denosumab following diagnosis, and a control arm that will not receive treatment. At least 24 patients with hormone receptor negative breast cancer and 24 premenopausal patients will be included in the study.

Study Type ^ICMJE

Interventional

Study Phase

Early Phase 1

Study Design ^ICMJE

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: This is a parallel two arms trial randomized in 2:1 proportions to intervention group vs control group. . At least 24 patients with hormone receptor negative breast cancer and 24 premenopausal patients will be included in the study so allocation of patients without any of these two characteristics will be restricted depending on the overall characteristics of the included population
Masking: Interventional
Masking Description:
Primary Purpose: Treatment

Condition ^ICMJE

Intervention ^ICMJE

Drug: Denosumab 120 MG/1.7 ML Subcutaneous Solution [XGEVA]
Two injections on days 1 and 8 previous to surgery breast cancer excision

Study Arms

Experimental: Denosumab
Denosumab 120 MG/1.7 ML Subcutaneous Solution [XGEVA]
No Intervention: Control
Control group

Recruitment Information

Recruitment Status ^ICMJE

Recruiting

Estimated Enrollment ^ICMJE

Original Estimated Enrollment ^ICMJE

Same as current

Estimated Study Completion Date

February 5, 2020

Estimated Primary Completion Date

July 5, 2019 (Final data collection date for primary outcome measure)

Eligibility Criteria ^ICMJE

Inclusion Criteria: - Understand and sign Informed Consent for this study. - Women ≥ than 18 years, (the inclusion process will be modified to recruit at least 24 premenopausal patients). - Capable, under investigator judgment, to understand the non-therapeutic nature of the study. - Diagnosed with invasive breast cancer in early, curable, stage (I or II) candidate to radical surgery as first therapeutic approach. - Her2 negative receptor status. - Any estrogen, progesterone status (the inclusion process will be modified to recruit at least 24 patients with TNBC tumors). - No previous systemic treatment for any malignancy. - No ongoing treatment with denosumab or bisphosphonates. - Tumour amenable for baseline Biopsy and punch-Biopsy after excision. - Adequate Serum calcium or albumin-adjusted serum calcium ≥ 2.0 mmol/L (8.0 mg/dL) and ≤ 2.9 mmol/L (11.5 mg/dL) - No prior history or current evidence of osteonecrosis of the jaw - No Active dental or jaw condition which requires oral surgery, including tooth extraction. Noplanned invasive dental procedures. - General Laboratory test within normality or with non-relevant deviations of normality as per investigator judgment. - Patients must have a normal organ and bone marrow function as defined local standards: Leukocytes, Absolute neutrophil count, Platelets, Total bilirubin, AST/ALT/GOT/GPT, Creatinine, Creatinine clearance, Magnesium, Phosphorus. - Subject with reproductive potential must be willing to use, in combination with her partner, 2 acceptable methods of effective contraception or practice sexual abstinence throughout the study and continue for 6 months after study duration. Subjects who are surgically sterile (e.g. history of bilateral tubal ligation, hysterectomy) or whose sexual partner is sterile (e.g. history of vasectomy) are not required to use additional contraceptive measures". Exclusion Criteria: - Invasive breast cancer non-amenable to surgical excision as first therapeutic approach. - HER2-positive Breast Cancer - Metastatic breast cancer or other condition that recommends other treatment than surgery as the primary therapeutic approach. - Prior systemic treatment for any malignancy. - Treatment with denosumab contraindicated. - Bleeding diathesis or other concomitant condition that contraindicate inclusion in the study as per investigator judgment. - High risk of ONJ or hypocalcemia: - Inadequate Serum calcium or albumin-adjusted serum calcium < 2.0 mmol/L (8.0 mg/dL) or > 2.9 mmol/L (11.5 mg/dL). - Prior history or current evidence of osteonecrosis of the jaw - Active dental or jaw condition which requires oral surgery, including tooth extraction. Planned invasive dental procedures. - Subject has known sensitivity to any of the products to be administered during the study (e.g., mammalian derived products, calcium, or vitamin D). - Subject is pregnant or breast feeding or planning to become pregnant / breastfeed while on study through 6 months after the end of treatment. - Subject is of child bearing potential and is not willing to use, in combination with her partner, two highly effective methods of contraception or abstinence during treatment and for 5 months after the end oftreatment. - Patients have prior history or current evidence of osteonecrosis or osteomyelitis of the jaw. - Patients have active dental or jaw condition which requires oral surgery, including tooth extraction. - Patients have non-healed dental or oral surgery, including tooth extraction. - Patients with planned invasive dental procedures for the course of the study. - Ongoing treatment with denosumab or bisphosphonates

Sex/Gender

Sexes Eligible for Study:

Female

Ages

18 Years and older (Adult, Older Adult)

Accepts Healthy Volunteers

Listed Location Countries ^ICMJE

Spain

Removed Location Countries

Administrative Information

Has Data Monitoring Committee

U.S. FDA-regulated Product

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

Plan to Share IPD:

Responsible Party

，

Study Sponsor ^ICMJE

Institut Català d'Oncologia

Collaborators ^ICMJE

Investigators ^ICMJE

PRS Account

Verification Date

September 2018

^ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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