Use of PRO Onc Assay to Assess HER2 in Patients With Metastatic Breast Cancer

• Sponsor: SCRI Development Innovations, LLC (Other)
• Overall Status: Completed
• CT.gov ID: NCT01048099
• Collaborator: Prometheus Laboratories (Industry), Genentech, Inc. (Industry)
• Enrollment: 283
• Locations: 7
• Arm: 1
• Duration (Months): 42
• Patients Per Site: 40.4
• Patients Per Site Per Month: 1

Study Details

Study Description

Brief Summary

This trial will evaluate the clinical significance of the PRO Onc assay and will assess the efficacy of HER2-targeted therapy in patients with HER2-negative breast cancer who have been identified as having HER2 overexpression/activation by the PRO Onc Assay.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer	Procedure: PRO Onc Assay and Treatment; Drug: Trastuzumab; Drug: Pertuzumab	N/A

Detailed Description

This two-part trial is designed to evaluate the clinical significance of the PRO Onc assay when used in patients with metastatic HER2-negative breast cancer. The first part of this study will determine the incidence of HER overexpression/activation, as determined by the PRO Onc assay, in patients previously judged to have HER2-negative breast cancer by FISH analysis. Blood specimens will be obtained from patients with HER2-negative breast cancer; CTCs will then be isolated and tested for HER2 overexpression/activation using the PRO Onc Assay. When clinically indicated, fine needle aspiration biopsy will also be obtained and submitted for the PRO Onc Assay. If the incidence of HER2 overexpression/activation, as determined by the PRO Onc Assay, is >10%, the study will proceed to Part 2. Part 2 of this study will assess the efficacy of HER2-targeted therapy in a group of patients with HER2-negative breast cancer who are identified as having HER2 overexpression/activation by the PRO Onc Assay. Patients will be treated with either trastuzumab or pertuzumab. Patients who progress during the first 8 weeks will have HER2-targeted treatment discontinued and will be removed from study. After 8 weeks, patients who have stable disease will be allowed to add chemotherapy to HER2-targeted therapy. Patients who have an objective response to single-agent, HER2-targeted therapy after 8 weeks will continue single-agent therapy.

Study Design

• Study Type: Interventional
• Actual Enrollment: 283 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Use of the PRO Onc Assay to Assess HER2 Overexpression and Activation in Patients With Metastatic Breast Cancer Whose Tumors Are HER2-Negative by Standard FISH Testing
• Study Start Date: Jan 1, 2011
• Actual Primary Completion Date: Jul 1, 2014
• Actual Study Completion Date: Jul 1, 2014

Arms and Interventions

Arm

Intervention/Treatment

Experimental: PRO Onc Assay and Treatment Blood specimens tested for circulating tumor cells followed by systemic treatment based on assay results with either trastuzumab or pertuzumab

Procedure: PRO Onc Assay and Treatment; Patients with HER2-negative metastatic breast cancer will be identified, and blood specimens will be obtained from each participant. The PRO Onc Assay will be performed on CTCs isolated from these specimens. When clinically indicated, fine needle aspiration biopsy will also be obtained and submitted for the PRO Onc Assay.; Other Names: blood draw fine needle aspiration circulating tumor cells ; Drug: Trastuzumab; 8 mg/kg IV loading dose, followed by 6 mg /kg IV every 3 weeks until progressive disease or unacceptable toxicity with evaluations performed every 8 weeks; Other Names: Herceptin ; Drug: Pertuzumab; 840 mg IV loading dose, followed by 420 IV every 3 weeks until progressive disease or unacceptable toxicity with evaluations performed every 8 weeks; Other Names: Perjeta

Outcome Measures

Primary Outcome Measures

1. Part II: Objective Response Rate of HER2-negative Metastatic Breast Cancer (by FISH Testing) [18 months]

   The percentage of HER2-negative metastatic breast cancer (MBC) patients having an objective benefit from treatment per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI or CT: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. Includes patients with HER2 overexpression/activation as detected by PRO Onc Assay.

2. Part II: Objective Response Rate of Trastuzumab Therapy [18 months]

   The percentage of patients having an objective benefit from treatment per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI or CT: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. Includes patients with HER2 overexpression as identified by the PRO Onc Assay.

3. Part II: Objective Response Rate of Pertuzumab Therapy [18 months]

   The percentage of patients with HER2 activation (no overexpression) as identified by the PRO Onc Assay who experience an objective benefit from treatment, per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI or CT: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.

Secondary Outcome Measures

1. Part 1: The Incidence of HER2 Overexpression/Activation as Measured by the PRO Onc Assay [12 months]

   Includes patients with HER2-negative metastatic breast cancer (MBC) as determined by FISH testing.

2. Part I: The Incidence of Isolation of Circulating Tumor Cells (CTCs) From Blood Specimens [12 months]

   Percentage of HER2-negative MBC patients (identified by FISH testing) having CTCs present in blood specimens.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

Part I

1. Women with HER2-negative breast cancer, as defined by FISH testing. (FISH testing may have been performed on the primary tumor, or subsequently on a biopsy of a metastatic lesion.)

2. Patients should be currently receiving chemotherapy, or scheduled to start chemotherapy (second-line or subsequent), for HER2-negative metastatic breast cancer.

3. To begin protocol treatment, patients must have progressed after at least 1 previous chemotherapy regimen for metastatic breast cancer.

4. Patients who are ER/PR positive or negative are eligible. ER/PR positive patients should be refractory to hormonal therapy, or not good candidates for hormonal therapy due to clinical features.

5. ECOG performance status of 0, 1 or 2.

6. Adequate recovery from recent surgery; ≥ 1 week must have elapsed from the time of a minor surgery; ≥ 4 weeks must have elapsed from the time of a major surgery.

7. Patients must have measurable disease per RECIST criteria.

8. Laboratory values as follows: Absolute neutrophil count (ANC) ≥1500/μL Hemoglobin (Hgb) ≥10 g/dL Platelets ≥100,000/L AST or ALT and alkaline phosphatase (ALP) must be <2.5 x ULN, or <5 x ULN in patients with liver metastases. Total bilirubin <1.5 x the institutional ULN Serum creatinine <1.5 x institutional ULN or calculated creatinine clearance ≥45 mL/min

Patients from Part 1 who have HER2 overexpression/activation identified by the PRO Onc Assay may enter the treatment portion of Part 2, if they meet all Part 2 eligibility criteria.

1. Life expectancy of ≥ 12 weeks.

2. Patient must be accessible for treatment and follow-up.

3. Patients must be able to understand the investigational nature of this study and give written informed consent prior to study entry.

Part II

1. Women with HER2-negative breast cancer, as defined by FISH testing. (FISH testing may have been performed on the primary tumor, or subsequently on a biopsy of a metastatic lesion.)

2. Patients should be currently receiving chemotherapy, or scheduled to start chemotherapy, for HER2-negative metastatic breast cancer.

3. Patients who are ER/PR positive or negative are eligible. ER/PR positive patients should be refractory to hormonal therapy, or not good candidates for hormonal therapy due to clinical features.

4. ECOG performance status of 0, 1 or 2.

5. Adequate recovery from recent surgery; ≥ 1 week must have elapsed from the time of a minor surgery; ≥ 4 weeks must have elapsed from the time of a major surgery.

6. Patients must have measurable disease per RECIST criteria.

7. Laboratory values as follows:

• Absolute neutrophil count (ANC) ≥1500/μL

• Hemoglobin (Hgb) ≥10 g/dL

• Platelets ≥100,000/uL

• AST or ALT and alkaline phosphatase (ALP) must be <2.5 x ULN, or <5 x ULN in patients with liver metastases.

• Total bilirubin <1.5 x the institutional ULN

• Serum creatinine <1.5 x institutional ULN or calculated creatinine clearance ≥45 mL/min

1. Life expectancy of ≥ 12 weeks.

2. Patient must be accessible for treatment and follow-up.

3. Patients must be able to understand the investigational nature of this study and give written informed consent prior to study entry.

4. Patients who are eligible for HER2-targeted treatment will begin this treatment at the first time a treatment change is necessary (i.e. at the next progression of metastatic breast cancer). This may occur immediately after PRO Onc assay results are received, or may be several months later, for patients responding well to their current chemotherapy.

5. Patients must continue to meet all inclusion and exclusion criteria for the Part 2 screening population at the time they are ready to start HER2-targeted treatment.

6. Ejection fraction ≥ 50%, as measured by echocardiogram (ECHO) or MUGA.

Exclusion Criteria:

Part I:

1. Patients currently responding to hormonal therapy.

2. Previous treatment with any HER2-targeted agent.

3. Patients with meningeal metastases.

4. Patients who are not considered likely candidates for subsequent therapy after next progression of metastatic breast cancer.

5. Women who are pregnant or lactating.

6. Patients with New York Heart Association class II or greater congestive heart failure.

7. Any of the following ≤6 months prior to starting study treatment:

• myocardial infarction;

• severe unstable angina;

• ongoing cardiac dysrhythmia

1. Concurrent severe, intercurrent illness including, but not limited to, ongoing or active infection, or psychiatric illness/social situations that would limit safety and compliance with study requirements.

2. Mental condition that would prevent patient comprehension of the nature of, and risk associated with, the study.

3. Use of any non-approved or investigational agent ≤ 30 days of administration of the first dose of study drug. Patients may not receive any other investigational or anti-cancer treatments while participating in this study.

Part II

1. Patients currently responding to hormonal therapy.

2. Previous treatment with any HER2-targeted agent.

3. Patients with meningeal metastases.

4. Patients with active brain metastases. Patients who have received radiation or surgery for brain metastases are eligible if there is no evidence of central nervous system (CNS) disease progression, and at least 4 weeks have elapsed since treatment. Ideally, patients should not still require use of seizure medication or steroids.

5. Patients who are not considered likely candidates for subsequent therapy after next progression of metastatic breast cancer.

6. Women who are pregnant or lactating.

7. Patients with New York Heart Association class II or greater congestive heart failure.

8. Any of the following ≤6 months prior to starting study treatment:

• myocardial infarction;

• severe unstable angina;

• ongoing cardiac dysrhythmia.

1. Concurrent severe, intercurrent illness including, but not limited to, ongoing or active infection, or psychiatric illness/social situations that would limit safety and compliance with study requirements.

2. Mental condition that would prevent patient comprehension of the nature of, and risk associated with, the study.

3. Use of any non-approved or investigational agent ≤ 30 days of administration of the first dose of study drug. Patients may not receive any other investigational or anti-cancer treatments while participating in this study.

4. Past or current history of neoplasm other than the entry diagnosis with the exception of treated non-melanoma skin cancer or carcinoma in situ of the cervix, or other cancers cured by local therapy alone and a DFS ≥5 years.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Florida Cancer Specialists	Fort Myers	Florida	United States	33916
2	Florida Cancer Specialists	St. Petersburg	Florida	United States	33705
3	Oncology Hematology Care, Inc.	Cincinnati	Ohio	United States	45242
4	Chattanooga Oncology Hematology Associates	Chattanooga	Tennessee	United States	37404
5	Tennessee Oncology, PLLC	Nashville	Tennessee	United States	37023
6	Center for Cancer and Blood Disorders	Fort Worth	Texas	United States	76104
7	Virginia Cancer Institute	Richmond	Virginia	United States	23230

Sponsors and Collaborators

• SCRI Development Innovations, LLC
• Prometheus Laboratories
• Genentech, Inc.

Investigators

• Study Chair: John D. Hainsworth, M.D., SCRI Development Innovations, LLC

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: SCRI Development Innovations, LLC
• ClinicalTrials.gov Identifier: NCT01048099
• Other Study ID Numbers: SCRI BRE 166
• First Posted: Jan 13, 2010
• Last Update Posted: Jan 29, 2016
• Last Verified: Dec 1, 2015

• Keywords provided by SCRI Development Innovations, LLC: Breast Cancer; Metastatic; PRO Onc Assay; FISH Testing; HER Negative; HER Overexpression; HER Activation
• Additional relevant MeSH terms: Breast Neoplasms; Trastuzumab; Pertuzumab

Study Results

Participant Flow

Recruitment Details	Pts with HER2-negative, metastatic breast cancer were enrolled. Blood was collected to perform the PRO Onc Circulating Tumor Cell (CTC). Pts without CTCs present were taken off-study. Following the assay, pts without detected HER2 overexpression/activation were taken off-study. Of the remaining pts, those FISH-positive for HER2 came off-study.

Arm/Group Title	All Patients
Arm/Group Description
Period Title: Patients Enrolled and Blood Collected
STARTED	283
COMPLETED	226
NOT COMPLETED	57
Period Title: Patients Enrolled and Blood Collected
STARTED	226
COMPLETED	24
NOT COMPLETED	202
Period Title: Patients Enrolled and Blood Collected
STARTED	24
COMPLETED	14
NOT COMPLETED	10
Period Title: Patients Enrolled and Blood Collected
STARTED	14
COMPLETED	0
NOT COMPLETED	14

Baseline Characteristics

Arm/Group Title	Patients Treated
Arm/Group Description	Patients who received study treatment
Overall Participants	14
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	65
Sex: Female, Male (Count of Participants)
Female	14 100%
Male	0 0%
Region of Enrollment (participants) [Number]
United States	14 100%

Outcome Measures

1. Secondary Outcome

Title	Part 1: The Incidence of HER2 Overexpression/Activation as Measured by the PRO Onc Assay
Description	Includes patients with HER2-negative metastatic breast cancer (MBC) as determined by FISH testing.
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	All Patients Evaluated by PRO Onc Assay
Arm/Group Description
Measure Participants	226
HER2 overexpressed	11 78.6%
HER2 activated	10 71.4%
HER2 overexpressed and activated	3 21.4%
No HER2 overexpression/activation detected	202 1442.9%

2. Primary Outcome

Title	Part II: Objective Response Rate of HER2-negative Metastatic Breast Cancer (by FISH Testing)
Description	The percentage of HER2-negative metastatic breast cancer (MBC) patients having an objective benefit from treatment per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI or CT: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. Includes patients with HER2 overexpression/activation as detected by PRO Onc Assay.
Time Frame	18 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Patients Treated
Arm/Group Description	Patients who received study treatment
Measure Participants	14
Number [percentage of participants]	7 50%

3. Secondary Outcome

Title	Part I: The Incidence of Isolation of Circulating Tumor Cells (CTCs) From Blood Specimens
Description	Percentage of HER2-negative MBC patients (identified by FISH testing) having CTCs present in blood specimens.
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

Includes all patients with blood drawn and analyzed for CTCs

Arm/Group Title	All Patients
Arm/Group Description
Measure Participants	283
Number [percentage of participants]	80 571.4%

4. Primary Outcome

Title	Part II: Objective Response Rate of Trastuzumab Therapy
Description	The percentage of patients having an objective benefit from treatment per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI or CT: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. Includes patients with HER2 overexpression as identified by the PRO Onc Assay.
Time Frame	18 months

Outcome Measure Data

Analysis Population Description

Includes patients with HER2 overexpression detected by the PRO Onc Assay

Arm/Group Title	Patients Treated
Arm/Group Description	Patients who received study treatment
Measure Participants	10
Number [percentage of participants]	10 71.4%

5. Primary Outcome

Title	Part II: Objective Response Rate of Pertuzumab Therapy
Description	The percentage of patients with HER2 activation (no overexpression) as identified by the PRO Onc Assay who experience an objective benefit from treatment, per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI or CT: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Time Frame	18 months

Outcome Measure Data

Analysis Population Description

Includes patients with only HER2 activation (no overexpression) as detected by the PRO Onc Assay

Arm/Group Title	Patients Treated
Arm/Group Description	Patients who received study treatment
Measure Participants	4
Number [percentage of participants]	0 0%

Adverse Events

Time Frame	18 Months
Arm/Group Title	All Treated Patients
Arm/Group Description	Includes all patients with HER2 overexpression/activation (as identified by the PRO Onc Assay) who received study treatment
All Cause Mortality
	All Treated Patients
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	All Treated Patients
	Affected / at Risk (%)	# Events
Total	5/14 (35.7%)
Gastrointestinal disorders
Ileus	1/14 (7.1%)	1
General disorders
General disorders and administration site conditions - Other, disease progression	2/14 (14.3%)	2
Infections and infestations
Infections and infestations - Other, pneumonia	1/14 (7.1%)	2
Renal and urinary disorders
Acute kidney injury	1/14 (7.1%)	1
Other (Not Including Serious) Adverse Events
	All Treated Patients
	Affected / at Risk (%)	# Events
Total	13/14 (92.9%)
Blood and lymphatic system disorders
Anemia	2/14 (14.3%)
Endocrine disorders
Hyperthyroidism	1/14 (7.1%)
Hypothyroidism	1/14 (7.1%)
Gastrointestinal disorders
Nausea	3/14 (21.4%)
Abdominal pain	2/14 (14.3%)
Constipation	2/14 (14.3%)
Diarrhea	2/14 (14.3%)
Ascites	1/14 (7.1%)
Ileus	1/14 (7.1%)
General disorders
Fatigue	7/14 (50%)
Infusion related reaction	4/14 (28.6%)
Edema	2/14 (14.3%)
Non-cardiac chest pain	1/14 (7.1%)
Fever	1/14 (7.1%)
Hepatobiliary disorders
Hepatobiliary disorders - Other, liver dysfunction	1/14 (7.1%)
Immune system disorders
Allergic reaction	2/14 (14.3%)
Infections and infestations
Urinary Tract Infection	4/14 (28.6%)
Skin infection	1/14 (7.1%)
Investigations
Platelet count decreased	1/14 (7.1%)
Weight loss	1/14 (7.1%)
Metabolism and nutrition disorders
Anorexia	3/14 (21.4%)
Dehydration	2/14 (14.3%)
Musculoskeletal and connective tissue disorders
Generalized muscle weakness	1/14 (7.1%)
Nervous system disorders
Headache	1/14 (7.1%)
Peripheral sensory neuropathy	1/14 (7.1%)
Dysgeusia	1/14 (7.1%)
Psychiatric disorders
Anxiety	1/14 (7.1%)
Insomnia	1/14 (7.1%)
Renal and urinary disorders
Acute kidney injury	1/14 (7.1%)
Renal and urinary disorders - Other, hydronephrosis	1/14 (7.1%)
Urinary frequency	1/14 (7.1%)
Respiratory, thoracic and mediastinal disorders
Dyspnea	3/14 (21.4%)
Allergic rhinitis	1/14 (7.1%)
Cough	1/14 (7.1%)
Hypoxia	1/14 (7.1%)
Pulmonary hypertension	1/14 (7.1%)
Respiratory, thoracic and mediastinal disorders - Other, thoracic pain	1/14 (7.1%)
Skin and subcutaneous tissue disorders
Rash	2/14 (14.3%)
Alopecia	1/14 (7.1%)
Vascular disorders
Thromboembolic event	1/14 (7.1%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The sponsor can review/embargo results communications prior to public release for a period that is >60 but =180 days from date submitted to sponsor, who may require changes to the communication in order to remove specifically identified confidential information (other than study data) and/or delay the proposed publication to enable the sponsor to seek patent protection for inventions. The PI may not publish its results until 18 mos. after the trial has been completed at all sites