Denosumab in Treating Patients With ER and/or PR Positive, HER2 Negative Metastatic Breast Cancer With Bone Metastases and Detectable Circulating Tumor Cells

• Sponsor: Northwestern University (Other)
• Overall Status: Terminated
• CT.gov ID: NCT03070002
• Collaborator: Amgen (Industry), National Cancer Institute (NCI) (NIH)
• Enrollment: 1
• Locations: 2
• Arm: 1
• Actual Duration (Months): 6.1
• Patients Per Site: 0.5
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this study is to look at the amount of cancer cells in the blood of participants who are being treated with denosumab. The other purpose is to look at how long it takes for cancer to get worse when participants are being treated with denosumab. Circulating tumor cells (CTCs) in the blood of patients with metastatic breast cancer (MBC) have been associated with shorter survival than when CTCs are absent, especially in patients whose cancer has spread to their bones. In this study, we want it see if denosumab (the study drug) will decrease the number of CTCs measured in patients with MBC and cancer that has spread to their bones. We also plan to get blood from participants to study other research markers of interest.

Condition or Disease	Intervention/Treatment	Phase
Breast Carcinoma Metastatic in the Bone; Circulating Tumor Cell Count; Estrogen Receptor Positive; HER2/Neu Negative; Progesterone Receptor Positive; Stage IV Breast Cancer	Biological: Denosumab; Other: Laboratory Biomarker Analysis	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To assess the effect of denosumab in Her2/neu negative ER+ and/or PR+ metastatic breast cancer patients who are in partial response (PR) or stable disease (SD) after starting systemic therapy with bone metastases and >= 5 circulating tumor cells (CTCs) by measuring the fraction of patients with reduction in CTCs after 3 cycles of denosumab.

SECONDARY OBJECTIVES:

1. To assess the effect of denosumab on CTCs enumeration considered as a continuous variable (percent change from baseline) in this population.

2. To evaluate median progression-free survival (m-PFS).

TERTIARY OBJECTIVES:

1. CTC enumeration after enrichment. II. To assess the effect on CTC profiling and characterization of stem cell phenotype (CTC-EMT).

2. To evaluate the type of progressive disease (new site versus [vs.] progression of lesions in previous sites).

3. To analyze the expression of RANKL.

OUTLINE:

Patients receive denosumab subcutaneously (SC) on day 1. Treatment repeats every 28 days for up to 3 courses in the absence of disease progression, unexpected toxicity, or patient withdrawal or death.

After completion of study treatment, patients are followed up every 12 weeks for up to 2 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 1 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II, Open Label Study to Evaluate Denosumab in Patients With ER and/or PR-Positive, HER2-Negative Metastatic Breast Cancer (MBC) With Bone Metastases and Detectable Circulating Tumor Cells (CTCs)
• Actual Study Start Date: Oct 19, 2017
• Actual Primary Completion Date: Mar 6, 2018
• Actual Study Completion Date: Apr 24, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (denosumab) Patients receive denosumab SC on day 1. Treatment repeats every 28 days for up to 3 courses in the absence of disease progression, unexpected toxicity, or patient withdrawal or death.	Biological: Denosumab; Given SC; Other Names: AMG 162 AMG-162 Prolia Xgeva ; Other: Laboratory Biomarker Analysis; Correlative studies

Outcome Measures

Primary Outcome Measures

1. Fraction of Patients With Reduction in CTCs [Up to 3 months]

   Assess the effect of denosumab in Her2/neu negative ER+ and/ or PR+ metastatic breast cancer patients who are in Partial Response (PR) or Stable Disease (SD) after starting systemic therapy with bone metastases and ≥ 5 CTCs by measuring the fraction of patients with reduction in CTCs.

Secondary Outcome Measures

1. Percent Change in CTCs [Baseline up to 3 months]

   Evaluate the effect of denosumab on CTCs enumeration by assessing the percent change from baseline.

2. Median Progression Free Survival [Up to 2 years]

   Assess median progression free survival (m-PFS) using statistical analysis evaluating the relationship between longitudinal CTC counts and PFS. PRS will be measured from the time of treatment up until progressive disease.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Patients must have histologically or cytologically confirmed ER and/or PR positive, HER-2/neu negative metastatic breast cancer; they can be enrolled in any line of therapy without investigational agents and should have stable disease or a partial response (which can be determined clinically) on current systemic treatment; patients must also have pathologic OR radiographic evidence of bone metastases and >= 5 CTCs; (Note: the pathology report that is used by the physician to determine diagnosis, will be used to determine patient eligibility; ER and PR status should be available at the time of registration)

• Patients may have either measurable or non-measurable within 30 of days of registration; (lesions treated with radiation therapy must not be used as a target lesion); (Note: per Response Evaluation Criteria in Solid Tumors [RECIST] criteria version [v.] 1.1, measurable disease is defined as at least one lesion that can be accurately measured in at least one dimension; non-measurable disease is defined as all other lesions, including small lesions [longest diameter < 10 mm or pathological lymph nodes with P10 to < 15 mm short axis] as well as truly non-measurable lesions; lesions considered truly nonmeasurable include: leptomeningeal disease, ascites, pleural or pericardial effusion, and inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal masses/abdominal organomegaly identified by physical exam that is not measurable by reproducible imaging techniques)

• Patients may be enrolled in any line of standard treatment (without investigational agents); the start date of current treatment should be at least two 2 weeks or more prior to registration; (Note: patients will continue to receive the planned active treatment with chemotherapy or endocrine therapy [standard of care] and initiate denosumab at the recommended dose for this protocol)

• Eastern Cooperative Oncology Group (ECOG) performance status 0-2

• Leukocytes >= 3,000/mcL (without growth factor)

• Platelets >= 100,000/mcL (with or without transfusion)

• Hemoglobin >= 8 (with or without transfusion)

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) (serum glutamic-oxaloacetic transaminase [SGOT] and serum glutamate pyruvate transaminase [SGPT]) =< 2.5 times institutional upper limit of normal (for patients with liver metastasis up to =< 5 times of upper limit of normal [ULN] is allowed)

• Bilirubin =< 1.5 ULN (for patients with liver metastasis up to =< 5 times of ULN is allowed)

• Serum creatinine =< 1.5 ULN

• Creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal (creatinine clearance should be calculated per institutional standard)

• Patients must have a serum calcium of >= 2.0 mmol/L (8.0 mg/dL) or albumin-adjusted serum calcium =< 2.9 mmol/L (11.5 mg/dL) within 30 days of registration; (Note: if patients are undergoing treatment for hypocalcemia and the serum calcium value at screening is > 8.0 mg/dl, then the patient will be eligible for this study)

• Females of child-bearing potential (FOCBP) and males with his or her partner must agree to use two acceptable methods of effective contraception, at study entry, for the duration of study participation, and for 5 months following completion of therapy; 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; should a female patient become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately; likewise, if a male patient impregnates his female partner, he should inform the treating physician immediately; NOTE: a FOCBP is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria:

• Has not undergone a hysterectomy or bilateral oophorectomy

• Has had menses at any time in the preceding 12 consecutive months (and therefore has not been naturally postmenopausal for > 12 months)

• FOCBP must have a negative serum OR urine pregnancy test =< 7 days prior to registration

• Ability to understand and willingness to sign a written informed consent and Health Insurance Portability and Accountability Act (HIPAA) consent document prior to registration

• Willingness and ability of subject to comply to study requirements

Exclusion Criteria:

• Patients may not be receiving any other investigational agents; a 2 week washout period for investigational agents is required before registration

• Patients with clinically symptomatic brain metastases or who required treatment for brain metastases within 4 weeks of registration (stable sequelae acceptable if treatment has been completed; these lesions cannot be used as target lesions)

• Patients who have a history of allergic reactions attributed to compounds of similar chemical or biologic composition to denosumab are not eligible (i.e. same class of drugs) (Note: prior bisphosphonates are allowed; patients could have received bisphosphonates or be bisphosphonate-naive; patients who were previously on bisphosphonates can be enrolled in the study, as long as they have a wash-out period of 2 weeks prior to registration)

• Patients who are on corticosteroids or immunosuppressant's are not eligible; a 2 week wash-out period for is required before registration

• Patients who have a known additional malignancy that is progressing or requires active treatment are not eligible; patients who have had a prior diagnosis of cancer and if it has been < 3 years since their last treatment are also not eligible; NOTE: exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer

• Patients who have an uncontrolled intercurrent illness including, but not limited to any of the following, are not eligible:

• Hypertension (defined as 160/90 mmHg for 3 consecutive readings 2-5 mins apart) that is not controlled on medication

• Symptomatic congestive heart failure

• Unstable angina pectoris

• Psychiatric illness/social situations that would limit compliance with study requirements

• Any other illness or condition that the treating investigator feels would interfere with study compliance or would compromise the patient's safety or study endpoints

• Subject is pregnant or breast feeding, or planning to become pregnant within 5 months after the end of treatment

• Known human immunodeficiency virus (HIV)-positive patients who are on combination antiretroviral therapy; (this is because of the potential for pharmacokinetic interactions with denosumab)

• No known prior history or current evidence of osteonecrosis/osteomyelitis of the jaw

• No known prior history or current evidence of untreated local gum or oral infection

• No known/planned active dental or jaw condition which requires oral surgery, including tooth extraction

• No known non-healed dental/oral surgery, including tooth extraction

• Patients have planned invasive dental procedures during the course of the study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Northwestern University	Chicago	Illinois	United States	60611
2	Northwestern University- Lake Forest Hospital	Lake Forest	Illinois	United States	60045

Sponsors and Collaborators

• Northwestern University
• Amgen
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Sarika Jain, MD, Northwestern University

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jul 19, 2018

More Information

Publications

None provided.

• Responsible Party: Northwestern University
• ClinicalTrials.gov Identifier: NCT03070002
• Other Study ID Numbers: NU 16B09; STU00203216; NU 16B09; P30CA060553; NCI-2017-00015
• First Posted: Mar 3, 2017
• Last Update Posted: Nov 20, 2018
• Last Verified: Oct 1, 2018

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Breast Neoplasms; Neoplastic Cells, Circulating; Denosumab

Study Results

Participant Flow

Recruitment Details	The study opened for enrollment on March 23, 2017 with an accrual goal of 42 patients. The first patient started treatment on study October 19, 2017. The study closed permanently to enrollment on March 6 2018 with one patient enrolled, due to low accrual and before total accrual to the study could be met.

Arm/Group Title	Treatment (Denosumab)
Arm/Group Description	Patients receive denosumab SC on day 1. Treatment repeats every 28 days for up to 3 courses in the absence of disease progression, unexpected toxicity, or patient withdrawal or death. Denosumab: Given SC Laboratory Biomarker Analysis: Correlative studies
Period Title: 3 Cycles of Treatment
STARTED	1
COMPLETED	1
NOT COMPLETED	0
Period Title: 3 Cycles of Treatment
STARTED	1
COMPLETED	0
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	Treatment (Denosumab)
Arm/Group Description	Patients receive denosumab SC on day 1. Treatment repeats every 28 days for up to 3 courses in the absence of disease progression, unexpected toxicity, or patient withdrawal or death. Denosumab: Given SC Laboratory Biomarker Analysis: Correlative studies
Overall Participants	1
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	1 100%
>=65 years	0 0%
Sex: Female, Male (Count of Participants)
Female	1 100%
Male	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	1 100%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	1 100%
More than one race	0 0%
Unknown or Not Reported	0 0%
Region of Enrollment (Count of Participants)
United States	1 100%

Outcome Measures

1. Primary Outcome

Title	Fraction of Patients With Reduction in CTCs
Description	Assess the effect of denosumab in Her2/neu negative ER+ and/ or PR+ metastatic breast cancer patients who are in Partial Response (PR) or Stable Disease (SD) after starting systemic therapy with bone metastases and ≥ 5 CTCs by measuring the fraction of patients with reduction in CTCs.
Time Frame	Up to 3 months

Outcome Measure Data

Analysis Population Description

Data was not collected or analyzed for this outcome measure. The study was terminated early with only 1 patient enrolled.

Arm/Group Title	Treatment (Denosumab)
Arm/Group Description	Patients receive denosumab SC on day 1. Treatment repeats every 28 days for up to 3 courses in the absence of disease progression, unexpected toxicity, or patient withdrawal or death. Denosumab: Given SC Laboratory Biomarker Analysis: Correlative studies
Measure Participants	0

2. Secondary Outcome

Title	Percent Change in CTCs
Description	Evaluate the effect of denosumab on CTCs enumeration by assessing the percent change from baseline.
Time Frame	Baseline up to 3 months

Outcome Measure Data

Analysis Population Description

Data was not collected or analyzed for this outcome measure. The study was terminated early with only 1 patient enrolled.

Arm/Group Title	Treatment (Denosumab)
Arm/Group Description	Patients receive denosumab SC on day 1. Treatment repeats every 28 days for up to 3 courses in the absence of disease progression, unexpected toxicity, or patient withdrawal or death. Denosumab: Given SC Laboratory Biomarker Analysis: Correlative studies
Measure Participants	0

3. Secondary Outcome

Title	Median Progression Free Survival
Description	Assess median progression free survival (m-PFS) using statistical analysis evaluating the relationship between longitudinal CTC counts and PFS. PRS will be measured from the time of treatment up until progressive disease.
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

Data was not collected or analyzed for this outcome measure. The study was terminated early with only 1 patient enrolled.

Arm/Group Title	Treatment (Denosumab)
Arm/Group Description	Patients receive denosumab SC on day 1. Treatment repeats every 28 days for up to 3 courses in the absence of disease progression, unexpected toxicity, or patient withdrawal or death. Denosumab: Given SC Laboratory Biomarker Analysis: Correlative studies
Measure Participants	0

Adverse Events

Time Frame	Adverse events were collected for 3 cycles of treatment and up to 30 days past the last treatment, where 1 cycle of treatment equals 28 days.
Arm/Group Title	Treatment (Denosumab)
Arm/Group Description	Patients receive denosumab SC on day 1. Treatment repeats every 28 days for up to 3 courses in the absence of disease progression, unexpected toxicity, or patient withdrawal or death. Denosumab: Given SC Laboratory Biomarker Analysis: Correlative studies
All Cause Mortality
	Treatment (Denosumab)
	Affected / at Risk (%)	# Events
Total	1/1 (100%)
Serious Adverse Events
	Treatment (Denosumab)
	Affected / at Risk (%)	# Events
Total	0/1 (0%)
Other (Not Including Serious) Adverse Events
	Treatment (Denosumab)
	Affected / at Risk (%)	# Events
Total	1/1 (100%)
Blood and lymphatic system disorders
Anemia	1/1 (100%)
Gastrointestinal disorders
Nausea	1/1 (100%)
Gastrointestinal pain	1/1 (100%)
Abdominal pain	1/1 (100%)
Investigations
Alanine aminotransferase increased	1/1 (100%)
Aspartate aminotransferase increased	1/1 (100%)
Alkaline phosphatase increased	1/1 (100%)
Metabolism and nutrition disorders
Hypercalcemia	1/1 (100%)
Hypokalemia	1/1 (100%)
Hypoabuminemia	1/1 (100%)
Musculoskeletal and connective tissue disorders
Bone pain	1/1 (100%)
Back pain	1/1 (100%)
Nervous system disorders
Dizziness	1/1 (100%)
Respiratory, thoracic and mediastinal disorders
Hoarsness	1/1 (100%)

Limitations/Caveats

The study was terminated early with only 1 patient enrolled due to slow accrual.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.