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Biomarker Study of the Antitumoral Activity of Denosumab in the Pre- Operative Setting of Early Breast Cancer (D-BIOMARK)

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ClinicalTrials.gov Identifier: NCT03691311
Recruitment Status : Recruiting
First Posted : October 1, 2018
Last Update Posted : October 1, 2018
Sponsor:
Collaborator:
Amgen
Information provided by (Responsible Party):
Institut Català d'Oncologia

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

Condition or disease Intervention/treatment Phase
Breast Neoplasm Female Stage I Breast Cancer Stage II Breast Cancer Hormone Receptor Negative Neoplasm Hormone Receptor Positive Tumor Drug: Denosumab 120 MG/1.7 ML Subcutaneous Solution [XGEVA] Early Phase 1

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 : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
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: None (Open Label)
Primary Purpose: Treatment
Official Title: An Open Label Biomarker Pilot Study of the Antitumoral Activity of Denosumab in the Pre- Operative Setting of Early Breast Cancer
Actual Study Start Date : July 5, 2018
Estimated Primary Completion Date : July 5, 2019
Estimated Study Completion Date : February 5, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer
Drug Information available for: Denosumab

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

No Intervention: Control
Control group



Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. 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].

  2. 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

  3. 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

  4. 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


Other Outcome Measures:
  1. Changes in overall expression profile determined by RNA expression microarrays [ Time Frame: From first biopsy until surgery intervention, which is around four weeks after enrolment ]
    Changes in rank/rankl normalized expression

  2. Validation of denosumab activity in clinical samples by Trap5b protein expression [ Time Frame: From first biopsy until surgery intervention, which is around four weeks after enrolment ]
    Results compared to preclinical activity



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03691311


Contacts
Contact: Eva González Suárez, PhD egsuarez@idibell.cat
Contact: Silvia Casellas + 34 93 451 52 50 s.casellas@anagram-esic.com

Locations
Spain
Institut Català d'Oncologia - L'Hospitalet Recruiting
L'Hospitalet De Llobregat, Barcelona, Spain, 08908
Contact: Catalina Falo Zamora, PhD    +34.93.260.77.44    contactfortrialsICOLH@iconcologia.net   
Sponsors and Collaborators
Institut Català d'Oncologia
Amgen

Responsible Party: Institut Català d'Oncologia
ClinicalTrials.gov Identifier: NCT03691311     History of Changes
Other Study ID Numbers: ICO 13-001
2016-002678-11 ( EudraCT Number )
20119112 ( Other Grant/Funding Number: Amgen reference )
First Posted: October 1, 2018    Key Record Dates
Last Update Posted: October 1, 2018
Last Verified: September 2018

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

Keywords provided by Institut Català d'Oncologia:
rank
rankl
denosumab

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms
Neoplasms by Site
Breast Diseases
Skin Diseases
Denosumab
Bone Density Conservation Agents
Physiological Effects of Drugs