Presurgical Trial of Denosumab in Breast Cancer

Pre-surgical Evaluation of Denosumab in Patients With Operable Invasive Breast Cancer

The purpose of this study is to determine whether one dose of denosumab can lead to changes in the tumor, which may decrease the ability of tumor to spread.

Study Overview

• Status: Completed
• Conditions: Breast Cancer
• Intervention / Treatment: Biological: denosumab; Procedure: Surgery

Detailed Description

Breast cancer is the most common cancer among women, affecting one in eight women, and is the second leading cause of mortality from cancer. Bone metastases are a frequent complication of breast cancer, and the mechanism of breast cancer metastases to bone is an ongoing area of research.. Receptor activator of NF-kB (RANK) and its ligand (RANKL) have been identified and characterized for its role in bone remodeling. RANKL is a member of the tumor necrosis factor (TNF) family of cytokines that binds to its receptor RANK to control osteoclast differentiation, activation, and survival. RANK protein expression is not only found on osteoclasts and dendritic cells but also on T cells and mammary epithelial cells. RANK and RANKL is important for lymph node and thymus formation as well as lactating mammary gland development during pregnancy. Furthermore, the RANK/RANKL axis has been linked to progestin driven breast carcinomas and bone metastases.

RANK is expressed in 6-57% of invasive human breast cancers (depending upon the parameters for defining positivity and antibodies utilized for immunohistochemistry (IHC)), and RANKL driven hormone (progesterone -dependent proliferation, survival, and nonproliferative expansion of mammary stem cells may contribute to breast cancer initiation, progression, and recurrence.

We hypothesize that denosumab can inhibit RANKL signaling in early breast tumors which express RANK, inhibiting pro-metastatic mechanisms and reducing immunosuppression in the tumor microenvironment. This will be tested in a pre-surgical clinical trial (Phase 0) to evaluate and select the pharmacodynamics markers of RANKL inhibition in breast cancer.

• Study Type: Interventional
• Enrollment (Actual): 44
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • New York
    • New York, New York, United States, 10016
      • NYU Perlmutter Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Patients must have histologically confirmed invasive breast cancer (stages I-III) who have undergone core needle biopsy (clinically or radiographically at least T1c to allow adequate residual cancer tissue at surgery) and will be scheduled for surgical resection (i.e. segmental excision or mastectomy).
• Archival tissue freshly cut from core biopsy must be available; patients who had a diagnostic core biopsy at an outside institution are eligible as long as it is confirmed that tumor specimens in paraffin blocks (preferred) or ≥ 25 unstained slides, with an associated pathology report, are available.
• Female, Age ≥18 years (pre or postmenopausal).
• Signed informed consent
• Serum calcium or albumin-adjusted serum calcium ≥2.0mmol/L (8.0mg/dL) and ≤ 2.9 mmol/L (11.5mg/dL)
• Patients 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 5 months after study duration. Subjects who are surgically sterile (eg, history of bilateral tubal ligation, hysterectomy) or whose sexual partner is sterile (eg, history of vasectomy) are not required to use additional contraceptive measures.

Exclusion Criteria:

• Consideration for neoadjuvant therapy
• Serious infections including a history of active Hepatitis B, Hepatitis C or HIV
• 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 5 months after the end of treatment
• Patients have prior history or current evidence of osteonecrosis or osteomyelitis of the jaw, evidence of untreated local gum or oral infection, or non-healed dental or oral surgery
• Patients with active dental or jaw conditions which require oral surgery/dental procedures, including tooth extraction for the course of the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Denosumab & surgery; denosumab: 120 mg subcutaneous injection Surgery: 2-4 weeks after denosumab	Biological: denosumab; denosumab: 120 mg subcutaneous injection; Other Names: Xgeva; Procedure: Surgery; Surgery: approximately 2-4 weeks after dosing of denosumab

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacodynamic markers of RANKL inhibition determination	Immunohistochemical analyses (IHC) of RANK and RANKL protein expression will be performed by Clarient Diagnostics Services Inc., Aliso Viejo, CA using prototype assays developed and optimized by Dako on their automated staining platform	Change from baseline RANKL inhibition determination at one month

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Frequency of RANK and RANKL protein expression (by IHC) in operable breast cancer using Immunohistochemical analyses (IHC)	Immunohistochemical analyses (IHC) of RANK and RANKL protein expression will be performed by Clarient Diagnostics Services Inc., Aliso Viejo, CA using prototype assays developed and optimized by Dako on their automated staining platform	Change from baseline frequency of RANK and RANKL protein expression at one month

Collaborators and Investigators

• Sponsor: NYU Langone Health
• Investigators: Principal Investigator: Sylvia Adams, MD, NYU Perlmutter Cancer Center

Study record dates

Study Major Dates

• Study Start: October 1, 2016
• Primary Completion (Actual): December 3, 2019
• Study Completion (Actual): January 3, 2020

Study Registration Dates

• First Submitted: August 29, 2016
• First Submitted That Met QC Criteria: September 8, 2016
• First Posted (Estimate): September 14, 2016

Study Record Updates

• Last Update Posted (Actual): August 21, 2020
• Last Update Submitted That Met QC Criteria: August 19, 2020
• Last Verified: August 1, 2020

More Information

Terms related to this study

• Keywords: RANKL; RANK
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Physiological Effects of Drugs; Bone Density Conservation Agents; Denosumab
• Other Study ID Numbers: s14-01311

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No