Trial of Paclitaxel/Bevacizumab +/- Everolimus for Patients With HER2-Negative Metastatic Breast Cancer

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Novartis
Information provided by (Responsible Party):
SCRI Development Innovations, LLC
ClinicalTrials.gov Identifier:
NCT00915603
First received: June 4, 2009
Last updated: September 10, 2014
Last verified: September 2014
  Purpose

This randomized, double blind, placebo controlled trial will evaluate the impact of adding everolimus to the combination of weekly paclitaxel plus bevacizumab in the first-line treatment of women with HER2-negative metastatic breast cancer. Patients will be randomized (1:1) to receive either paclitaxel/bevacizumab/everolimus (Treatment Arm 1) or paclitaxel/ bevacizumab/placebo (Treatment Arm 2). Patients will be evaluated for response to treatment every 8 weeks; responding and/or stable patients will continue treatment, with re-evaluations every 8 weeks, until tumor progression or

intolerable toxicity occurs. Outcomes will be assessed for each treatment arm

separately. This trial is not intended to compare treatment arms primarily. Any such analyses are exploratory and will be conducted without adjustment for multiple hypothesis testing.


Condition Intervention Phase
Metastatic Breast Cancer
Drug: Everolimus
Drug: Bevacizumab
Drug: Paclitaxel
Drug: Placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
Official Title: A Randomized, Double-Blind, Placebo-Controlled Phase II Trial of Weekly Paclitaxel/Bevacizumab +/- Everolimus as First-Line Chemotherapy for Patients With HER2-Negative Metastatic Breast Cancer (MBC)

Resource links provided by NLM:


Further study details as provided by SCRI Development Innovations, LLC:

Primary Outcome Measures:
  • To assess the PFS for weekly paclitaxel/bevacizumab/everolimus and for weekly paclitaxel/bevacizumab/placebo in the first-line treatment of patients with HER2-negative metastatic breast cancer [ Time Frame: 18 months ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • To assess the safety profiles of the two treatment arms [ Time Frame: 18 months ] [ Designated as safety issue: Yes ]
  • To determine the response rates (complete response [CR] plus partial response [PR]) and rates of clinical benefit (CR + PR + stable disease [SD]) of the two treatment arms [ Time Frame: 18 months ] [ Designated as safety issue: No ]
  • To determine the duration of objective response with each of the treatment arms [ Time Frame: 18 months ] [ Designated as safety issue: No ]
  • To assess the overall survival with each of the treatment arms [ Time Frame: 18 months ] [ Designated as safety issue: No ]

Enrollment: 112
Study Start Date: July 2009
Estimated Study Completion Date: December 2014
Primary Completion Date: June 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: paclitaxel/bevacizumab/everolimus
Systemic Therapy
Drug: Everolimus
Everolimus 10mg PO daily continuously for all 28 days of a cycle
Other Names:
  • Systemic therapy
  • Everolimus
  • RAD001
  • Afinitor
Drug: Bevacizumab
Bevacizumab 10mg/kg IV Days 1 and 15 of 28 day cycle
Other Names:
  • Systemic therapy
  • Bevacizumab
  • Avastin
Drug: Paclitaxel
Paclitaxel 90mg/m2 1-hour IV infusion Days 1, 8 and 15 of 28 day cycle. Patients will receive standard pre-medication before each paclitaxel treatment to prevent a hypersensitivity reaction.
Other Names:
  • Systemic therapy
  • Paclitaxel
  • Taxol
Placebo Comparator: paclitaxel/bevacizumab/placebo
Systemic Therapy
Drug: Placebo
Placebo PO daily continuously for all 28 days of a cycle
Other Names:
  • Systemic therapy
  • Placebo
Drug: Bevacizumab
Bevacizumab 10mg/kg IV days 1 and 15 of 28 day cycle
Other Names:
  • Systemic therapy
  • Bevacizumab
  • Avastin
Drug: Paclitaxel
Paclitaxel 90mg/m2 1-hour IV infusion Days 1, 8 and 15 of 28 day cycle. Patients will receive standard pre-medication before each paclitaxel treatment to prevent a hypersensitivity reaction.
Other Names:
  • Systemic therapy
  • Paclitaxel
  • Taxol

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Female or male patients >=18 years of age.
  2. Histologically confirmed invasive breast cancer, locally unresectable or metastatic.
  3. No prior chemotherapy for MBC. Patients may have received adjuvant or

    neoadjuvant chemotherapy (including taxanes and/or bevacizumab) as long as

    treated was completed >12 months prior to relapse. Prior hormonal therapy in the

    adjuvant or metastatic setting will be permitted.

  4. Prior hormonal therapy in the adjuvant or metastatic setting is permitted. Estrogen receptor positive patients should be considered candidates for chemotherapy.
  5. HER2-negative breast cancer, defined as follows:

    • FISH-negative (FISH ratio <2.2), or
    • IHC 0-1+, or
    • IHC 2-3+ AND FISH-negative (FISH ratio <2.2).
  6. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
  7. Adequate hematologic function, defined by:

    · Absolute neutrophil count (ANC) >1500/mm3

    • Platelet count >=100,000/mm3
    • Hemoglobin >9 g/dL
  8. Adequate liver function, defined by:

    · AST and ALT <=2.5 x the upper limit of normal (ULN) or <=5 x ULN in

    presence of liver metastases

    • Total bilirubin <=1.5 x ULN
  9. Adequate renal function, defined by:

    · Serum creatinine <=1.5 x ULN or calculated creatinine clearance of

    >=40 ml/min

  10. International normalized ratio (INR) <=1.5 or prothrombin time (PT)/partial

    thromboplastin time (PTT) within normal limits (WNL) of the institution (if patient is not on anti-coagulation therapy). Patients receiving anti-coagulation treatment with an agent such as warfarin or heparin are eligible if the INR is stable and within the therapeutic range prior to study treatment initiation.

  11. Adequate lipid profile: total cholesterol <=300 mg/dL OR <=7.75 mmol/L and fasting triglyceride 2.5 x ULN. Note: In case one or both of these thresholds are exceeded,the patient can only be included after initiation of appropriate lipid lowering medication.
  12. Patients with proteinuria at screening as demonstrated by either:

    · Urine protein creatinine (UPC) ration >1.0 at screening

    or

    • Urine dipstick for proteinuria >=2+ (patients discovered to have

    >=2+ proteinuria on dipstick urinalysis at baseline should undergo a 24 hour

    urine collection and must demonstrate <1 g of protein in 24 hours to be

    eligible).

  13. Measurable disease by RECIST criteria.
  14. Life expectancy >=12 weeks.
  15. Ability to swallow oral medications.
  16. Adequate cardiac function, defined by baseline left ventricular ejection fraction (LVEF) value >= normal per institutional guidelines by MUGA scan or

    echocardiogram (ECHO).

  17. Adequate recovery from recent surgery.

    • Major surgical procedure >28 days from study entry
    • Minor surgical procedure >7 days from study entry (Portacath placement

    excepted - patients can start treatment <7 days after portacath placement.)

  18. Patients with previous history of invasive cancers (including breast cancer) are eligible if definitive treatment was completed more than 5 years prior to initiating current study treatment, and there is no evidence of recurrent disease.
  19. Patient must be accessible for treatment and follow-up.
  20. All patients must be able to understand the investigational nature of the study and give written informed consent prior to study entry.

    -

Exclusion Criteria:

  1. Patients with active brain metastases or meningeal metastases. Patients who have had brain metastases resected, or have received brain radiation therapy >4 weeks prior to study entry are eligible, if they meet all of the following criteria: 1) residual symptoms < grade 2, 2) no dexamethasone requirement, and 3) follow-up MRI shows regression of lesions after treatment and no new lesions appearing.
  2. Previous treatment with an m-TOR inhibitor (sirolimus, temsirolimus, everolimus) or anti-angiogenesis agent unless:

    • in the adjuvant setting, and
    • >=12 months prior to recurrence.
  3. Previous radiotherapy for metastatic disease completed <2 weeks prior to study treatment initiation.
  4. Patients who are current receiving systemic cancer therapy or have received

    previous systemic therapy within 4 weeks of the start of study drug (e.g.

    chemotherapy, antibody therapy, targeted agents).

  5. Women who are pregnant or lactating. All patients with reproductive potential must agree to use effective contraception from time of study entry until at least 3 months after the last administration of study drug.
  6. Uncontrolled hypertension defined as systolic blood pressure >150 mmHg or

    diastolic pressure >100 mmHg, despite optimal medical management.

  7. Concurrent use of CYP3A4 inhibitors and inducers from 72 hours prior to initiation of study treatment until the end of treatment with everolimus.
  8. Cardiac disease, including: congestive heart failure (CHF) > Class II per New York Heart Association (NYHA) classification; unstable angina (anginal symptoms at rest) or new-onset angina (i.e., began within the last 3 months), or myocardial infarction within the past 6 months; symptomatic CHF, unstable angina pectoris, or cardiac ventricular arrhythmias requiring anti-arrhythmic therapy.
  9. History of stroke or transient ischemic attack within 6 months prior to first

    bevacizumab dose.

  10. Patients with any non-healing wound, ulcer, or long-bone fracture.
  11. Patients with clinical history of hemoptysis or hematemesis.
  12. Patients with any history of a bleeding diathesis or coagulopathy.
  13. Patients with a PEG or G tube cannot be enrolled into this trial.
  14. History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to beginning bevacizumab.
  15. Patients with an impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of everolimus (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection).
  16. Patients who have any severe and/or uncontrolled medical conditions or other

    conditions that could affect their participation such as:

    • severe impaired lung functions as defined as spirometry and DLCO that is 50% of the normal predicted value and/or 02 saturation that is 88% or less at rest on room air
    • uncontrolled diabetes as defined by fasting serum glucose >1.5 x ULN.
  17. History of any other disease, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates use of an investigational drug, or that might affect interpretation of the results of this study, or render the subject at high risk for treatment complications.
  18. History of hypersensitivity to Cremophor EL (polyoxyethylated castor oil) or a drug formulated in Cremophor EL, such as paclitaxel.
  19. Patients may not receive any other investigational or anti-cancer treatments while participating in this study.
  20. Patients receiving chronic, systemic treatment with corticosteroids or another immunosuppressive agent. Topical or inhaled corticosteroids are allowed.
  21. Patients should not receive immunization with attenuated live vaccines within one week of study entry or during study period.
  22. Concurrent severe, uncontrolled infection or intercurrent illness including, but not limited to, ongoing or active infection, or psychiatric illness/social situations that would limit compliance with study requirements.
  23. Patients with a known hypersensitivity to RAD001 (everolimus) or other rapamycins (sirolimus, temsirolimus) or its excipients.
  24. Patients with a known HIV seropositivity.

    -

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00915603

Locations
United States, California
Wilshire Oncology Medical Group
LaVerne, California, United States, 91750
United States, Connecticut
Eastern Connecticut Hematology Oncology
Norwich, Connecticut, United States, 06360
United States, Florida
Aventura Medical Center
Aventura, Florida, United States, 33180
Florida Cancer Specialists
Fort Myers, Florida, United States, 33901
United States, Maine
Mercy Hospital
Portland, Maine, United States, 04101
United States, Maryland
National Capital Clinical Research Associates
Bethesda, Maryland, United States, 20817
Center for Cancer and Blood Disorders
Bethesda, Maryland, United States, 20817
United States, Ohio
Oncology Hematology Care
Cincinnati, Ohio, United States, 45242
Mid Ohio Oncology/Hematology, Inc./ The Mark H. Zangmeister Center
Columbus, Ohio, United States, 43219
United States, South Carolina
South Carolina Oncology Associates, PA
Columbia, South Carolina, United States, 29210
United States, Tennessee
Chattanooga Oncology Hematology Associates
Chattanooga, Tennessee, United States, 37404
Tennessee Oncology, PLLC
Nashville, Tennessee, United States, 37023
United States, Texas
Texas Oncology
Dallas, Texas, United States, 75246
United States, Virginia
Fairfax Northern Virginia Hem-Onc
Fairfax, Virginia, United States, 22031
Virginia Cancer Institute
Richmond, Virginia, United States, 23235
Sponsors and Collaborators
SCRI Development Innovations, LLC
Novartis
Investigators
Study Chair: Denise A. Yardley, M.D. SCRI Development Innovations, LLC
  More Information

No publications provided

Responsible Party: SCRI Development Innovations, LLC
ClinicalTrials.gov Identifier: NCT00915603     History of Changes
Other Study ID Numbers: SCRI BRE 154
Study First Received: June 4, 2009
Last Updated: September 10, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by SCRI Development Innovations, LLC:
Metastatic Breast Cancer
Paclitaxel
Bevacizumab
Everolimus

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Everolimus
Sirolimus
Bevacizumab
Paclitaxel
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Anti-Bacterial Agents
Anti-Infective Agents
Therapeutic Uses
Antibiotics, Antineoplastic
Antineoplastic Agents
Antifungal Agents
Antineoplastic Agents, Phytogenic
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Growth Inhibitors

ClinicalTrials.gov processed this record on September 14, 2014