Trastuzumab (Herceptin), Bevacizumab, and Docetaxel (Taxotere) Trial in Stage IV Metastatic Breast Cancer (MBC) Patients

• Sponsor: Bhuvaneswari Ramaswamy (Other)
• Overall Status: Completed
• CT.gov ID: NCT00428922
• Collaborator: Genentech, Inc. (Industry), Case Comprehensive Cancer Center (Other), University of Pittsburgh (Other)
• Enrollment: 26
• Locations: 3
• Arm: 1
• Actual Duration (Months): 115.8
• Patients Per Site: 8.7
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The primary objectives are to determine the progression-free survival (PFS) and to evaluate safety of the trastuzumab, bevacizumab and docetaxel regimen.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer	Drug: Trastuzumab; Drug: Bevacizumab; Drug: Docetaxel	Phase 2

Detailed Description

Rationale: Antibodies are proteins that are normally part of the immune system that bind to foreign agents in the body. Researchers manufacture antibodies outside of the human body that bind to specific targets such as proteins in cancer cells. Herceptin is a monoclonal antibody that binds to the human epidermal growth factor receptor (HER-2), and can kill HER2-positive cancer cells. Herceptin is used to treat breast cancer that is HER2-positive, and has spread after treatment with other drugs. Bevacizumab is a signal transduction inhibitor that works by preventing the growth of new blood vessels from surrounding tissue into tumors. Bevacizumab specifically inhibits the vascular endothelial growth factor (VEGF), a substance made by cells that stimulates new blood vessel formation. Research indicates that HER-2 signaling helps to induce VEGF expression. Therefore, cancer treatments targeting both HER-2 and VEGF may improve anti-cancer efficacy in patients. Docetaxel is a chemotherapy agent used against breast and other types of cancer. The current study builds on previous research suggesting the safety and potential for efficacy with combination trastuzumab, bevacizumab, and docetaxel.

Purpose: The primary objectives are to determine the progression free survival and evaluate the safety of trastuzumab, bevacizumab, and docetaxel. Secondary objectives are to assess early changes in circulating tumor cells and circulating endothelial cells as predictors of progression free survival and clinical benefit, as well as to determine the overall clinical benefit rate.

Treatment: Study participants will be given trastuzumab, bevacizumab, and docetaxel. All study drugs will be given through intravenous infusions once every 21 days. A cycle is considered 3 weeks. A minimum of 6 study treatment cycles is required unless study participants experience disease growth or intolerable toxicity. The decision to stop docetaxel after 6 cycles is up to the discretion of the treating physician and the patient. Study participants who are deriving a benefit from the study drugs may continue on trastuzumab and bevacizumab alone. Several tests and exams will be given throughout the study to closely monitor study participants.

Study Design

• Study Type: Interventional
• Actual Enrollment: 26 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Trial of Trastuzumab (Herceptin), Bevacizumab, and Docetaxel (Taxotere) Trial in Stage IV Metastatic Breast Cancer (MBC) Patients
• Actual Study Start Date: Jun 14, 2007
• Actual Primary Completion Date: Nov 1, 2012
• Actual Study Completion Date: Feb 7, 2017

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Trastuzumab, Bevacizumab, and Docetaxel Trastuzumab [6mg/kg], Bevacizumab [15mg/kg], and Docetaxel [75 mg/M²]

Drug: Trastuzumab; administered every three weeks on day 1, every 21 days. The dose given will be 6 mg/kg. The initial loading dose is 8mg/kg and is administered as a 90-minute infusion. Thereafter, the maintenance dose is 6mg/kg every three weeks administered as a 30 minute infusion (unless the treating physician indicates a longer infusion duration is warranted). Trastuzumab is given prior to bevacizumab. Trastuzumab is to be continued until disease progression or unacceptable toxicity.; Other Names: Herceptin ; Drug: Bevacizumab; administered every three weeks on day 1, every 21 days. The dose given will be 15 mg/kg. The initial dose is administered over 90 minutes. If the first infusion is well tolerated, the second dose is given over 60 minutes, and if that is well tolerated, then subsequent doses may be given over 30 minutes. Avastin is given after trastuzumab and prior to docetaxel.; Other Names: Avastin ; Drug: Docetaxel; administered every three weeks on day 1, every 21 days. The dose given will be 75 mg/M². All doses of docetaxel are administered over 60 minutes. Docetaxel is given after trastuzumab and bevacizumab.; Other Names: Taxotere

Outcome Measures

Primary Outcome Measures

1. Progression-free Survival (PFS) and to Evaluate Safety of the Trastuzumab, Bevacizumab and Docetaxel Regimen. [up to 3 years]

   The trial was designed as a single-stage phase II rather then usual two-stage design because of the progression free survival (PFS) primary endpoint, as it is impractical to wait to assess PFS for patients in the first stage. We will consider a PFS of 50% at twelve months (median PFS of 12 months) or less uninteresting and a PFS of 70% at twelve months (median PFS of twenty months) worthy of pursuing the regimen in a future trials. The single-stage design is as follows: p0=0.50, p1=0.70, α=0.10, β= 0.10. This leads to a total sample size of 39 patients, 24 or higher of who are progression-free at 12 months.

Secondary Outcome Measures

1. Changes in CTCs as Predictors of PFS and Clinical Benefit [Day 1 and Day 22]

   Circulating tumor cells (CTCs) evaluated at baseline (day 1 of treatment) and after 1 treatment cycle (day 22 prior to cycle 2 treatment).

2. Overall Clinical Benefit Rate (CR+PR+SD) [at least 24 weeks]

   Defined as best response of CR or PR or stable disease for at least 24 weeks. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI and/or CT: Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), neither sufficient shrinkage to qualify for a Partial Response nor sufficient increase to qualify for Progression of Disease (POD); POD, 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions; Complete Response (CR), Disappearance of all target lesions

3. Changes in CECs as Predictors of PFS and Clinical Benefit [Day 1 and Day 22]

   Circulating endothelial cells (CECs) are to be collected day 1 prior to treatment and day 22 prior to treatment. These samples are to be collected at the PI's discretion based upon the availability of the cell processing laboratory, the patients will be informed when consented if the samples will collected or not.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Histologically confirmed breast cancer with evidence of metastatic disease

• HER2 3+ or FISH (fluorescent in situ hybridization)+

• Age ≥ 18 years

• No prior trastuzumab, except as given in the adjuvant or neoadjuvant setting.

• No prior chemotherapy in the metastatic setting.

Exclusion Criteria:

• CNS (central nervous system) metastases

• Prior radiation therapy within the last 4 weeks

• Pregnant (positive pregnancy test) or lactating women

• Major surgical procedure, open biopsy, non-healing wounds, or significant traumatic injury within 28 days prior to starting study or anticipation of need for major surgical procedure during the study

• Minor surgical procedures such as fine needle aspirations or core biopsies within 7 days prior to start of study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Cleveland Clinic Foundation	Cleveland	Ohio	United States	44195
2	Ohio State University	Columbus	Ohio	United States	43210
3	University of Pittsburgh	Pittsburgh	Pennsylvania	United States	15213

Sponsors and Collaborators

• Bhuvaneswari Ramaswamy
• Genentech, Inc.
• Case Comprehensive Cancer Center
• University of Pittsburgh

Investigators

• Principal Investigator: Bhuvaneswari Ramaswamy, MD, Ohio State University

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Jamesline

Publications

None provided.

• Responsible Party: Bhuvaneswari Ramaswamy, Principal Investigator, Ohio State University Comprehensive Cancer Center
• ClinicalTrials.gov Identifier: NCT00428922
• Other Study ID Numbers: OSU-06027; NCI-2011-03219
• First Posted: Jan 30, 2007
• Last Update Posted: Aug 9, 2018
• Last Verified: Jul 1, 2018

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Bhuvaneswari Ramaswamy, Principal Investigator, Ohio State University Comprehensive Cancer Center: Metastatic; Breast Cancer; MBC
• Additional relevant MeSH terms: Breast Neoplasms; Bevacizumab; Trastuzumab; Docetaxel

Study Results

Participant Flow

Recruitment Details	September 2007 and November 2012

Arm/Group Title	Trastuzumab, Bevacizumab, and Docetaxel
Arm/Group Description	Trastuzumab [6mg/kg], Bevacizumab [15mg/kg], and Docetaxel [75 mg/M²]
Period Title: Overall Study
STARTED	26
COMPLETED	26
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Trastuzumab, Bevacizumab, and Docetaxel
Arm/Group Description	Trastuzumab [6mg/kg], Bevacizumab [15mg/kg], and Docetaxel [75 mg/M²]
Overall Participants	26
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	54
Sex: Female, Male (Count of Participants)
Female	26 100%
Male	0 0%
Region of Enrollment (patients) [Number]
United States	26

Outcome Measures

1. Primary Outcome

Title	Progression-free Survival (PFS) and to Evaluate Safety of the Trastuzumab, Bevacizumab and Docetaxel Regimen.
Description	The trial was designed as a single-stage phase II rather then usual two-stage design because of the progression free survival (PFS) primary endpoint, as it is impractical to wait to assess PFS for patients in the first stage. We will consider a PFS of 50% at twelve months (median PFS of 12 months) or less uninteresting and a PFS of 70% at twelve months (median PFS of twenty months) worthy of pursuing the regimen in a future trials. The single-stage design is as follows: p0=0.50, p1=0.70, α=0.10, β= 0.10. This leads to a total sample size of 39 patients, 24 or higher of who are progression-free at 12 months.
Time Frame	up to 3 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Trastuzumab, Bevacizumab, and Docetaxel
Arm/Group Description	Trastuzumab [6mg/kg], Bevacizumab [15mg/kg], and Docetaxel [75 mg/M²]
Measure Participants	26
Median (95% Confidence Interval) [months]	14.3

2. Secondary Outcome

Title	Changes in CTCs as Predictors of PFS and Clinical Benefit
Description	Circulating tumor cells (CTCs) evaluated at baseline (day 1 of treatment) and after 1 treatment cycle (day 22 prior to cycle 2 treatment).
Time Frame	Day 1 and Day 22

Outcome Measure Data

Analysis Population Description

Due to sample size, could not perform any statistical analysis to correlate the baseline CTCs with PFS and response rate. Samples only available for 50% of the patients.

Arm/Group Title	Trastuzumab, Bevacizumab, and Docetaxel
Arm/Group Description	Trastuzumab [6mg/kg], Bevacizumab [15mg/kg], and Docetaxel [75 mg/M²]
Measure Participants	13
Number [patients with detected CTCs]	7

3. Secondary Outcome

Title	Overall Clinical Benefit Rate (CR+PR+SD)
Description	Defined as best response of CR or PR or stable disease for at least 24 weeks. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI and/or CT: Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), neither sufficient shrinkage to qualify for a Partial Response nor sufficient increase to qualify for Progression of Disease (POD); POD, 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions; Complete Response (CR), Disappearance of all target lesions
Time Frame	at least 24 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Trastuzumab, Bevacizumab, and Docetaxel
Arm/Group Description	Trastuzumab [6mg/kg], Bevacizumab [15mg/kg], and Docetaxel [75 mg/M²]
Measure Participants	26
Number (95% Confidence Interval) [percent of patients]	69

4. Secondary Outcome

Title	Changes in CECs as Predictors of PFS and Clinical Benefit
Description	Circulating endothelial cells (CECs) are to be collected day 1 prior to treatment and day 22 prior to treatment. These samples are to be collected at the PI's discretion based upon the availability of the cell processing laboratory, the patients will be informed when consented if the samples will collected or not.
Time Frame	Day 1 and Day 22

Outcome Measure Data

Analysis Population Description

CEC data was not collected and available for analysis

Arm/Group Title	Trastuzumab, Bevacizumab, and Docetaxel
Arm/Group Description	Trastuzumab [6mg/kg], Bevacizumab [15mg/kg], and Docetaxel [75 mg/M²]
Measure Participants	0

Adverse Events

Adverse Event Reporting Description	NCI Common Toxicity Criteria (CTC) version 3.0 was utilize the CTC for adverse event reporting.
Arm/Group Title	Trastuzumab, Bevacizumab, and Docetaxel
Arm/Group Description	Trastuzumab [6mg/kg], Bevacizumab [15mg/kg], and Docetaxel [75 mg/M²]
All Cause Mortality
	Trastuzumab, Bevacizumab, and Docetaxel
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Trastuzumab, Bevacizumab, and Docetaxel
	Affected / at Risk (%)	# Events
Total	0/26 (0%)
Other (Not Including Serious) Adverse Events
	Trastuzumab, Bevacizumab, and Docetaxel
	Affected / at Risk (%)	# Events
Total	26/26 (100%)
Blood and lymphatic system disorders
Anemia	11/26 (42.3%)	11
Febrile Neutropenia	2/26 (7.7%)	2
Cardiac disorders
decreased LVEF	3/26 (11.5%)	3
Eye disorders
Vision changes	12/26 (46.2%)	12
Increased lacrimation	12/26 (46.2%)	12
Gastrointestinal disorders
Abdominal Pain	12/26 (46.2%)	12
Constipation	12/26 (46.2%)	12
Diarrhea	19/26 (73.1%)	19
Nausea	18/26 (69.2%)	18
Vomiting	14/26 (53.8%)	14
Mucositis	19/26 (73.1%)	19
General disorders
Neutropenia	4/26 (15.4%)	4
Fever without neutropenia	8/26 (30.8%)	8
Fatigue	24/26 (92.3%)	24
Infections and infestations
Infection	24/26 (92.3%)	24
Musculoskeletal and connective tissue disorders
Arthralgia	21/26 (80.8%)	21
Myalgia	19/26 (73.1%)	19
Nervous system disorders
Headaches	15/26 (57.7%)	15
Renal and urinary disorders
Proteinuria	3/26 (11.5%)	3
Respiratory, thoracic and mediastinal disorders
Dyspnea	16/26 (61.5%)	16
Epistaxis	22/26 (84.6%)	22
Skin and subcutaneous tissue disorders
Rash	11/26 (42.3%)	11
Hand-foot syndrome	9/26 (34.6%)	9
Wound Complication	2/26 (7.7%)	2
Vascular disorders
Hypertension	7/26 (26.9%)	7

Limitations/Caveats

[Not Specified]

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.