Trial of Paclitaxel/Bevacizumab +/- Everolimus for Patients With HER2-Negative Metastatic Breast Cancer
Information source: SCRI Development Innovations, LLC
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Metastatic Breast Cancer
Intervention: Everolimus (Drug); Bevacizumab (Drug); Paclitaxel (Drug); Placebo (Drug); Bevacizumab (Drug); Paclitaxel (Drug)
Phase: Phase 2
Status: Completed
Sponsored by: SCRI Development Innovations, LLC Official(s) and/or principal investigator(s): Denise A. Yardley, M.D., Study Chair, Affiliation: SCRI Development Innovations, LLC
Summary
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.
Clinical Details
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)
Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Treatment
Primary outcome: Progression-Free Survival (PFS)
Secondary outcome: Number of Patients With Treatment-related Adverse Events (AEs) as a Measure of Safety and TolerabilityOverall Response Rate (ORR) Duration of Response (DOR) Overall Survival (OS)
Eligibility
Minimum age: 18 Years.
Maximum age: N/A.
Gender(s): Both.
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.
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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.
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Locations and Contacts
Wilshire Oncology Medical Group, LaVerne, California 91750, United States
Eastern Connecticut Hematology Oncology, Norwich, Connecticut 06360, United States
Aventura Medical Center, Aventura, Florida 33180, United States
Florida Cancer Specialists, Fort Myers, Florida 33901, United States
Mercy Hospital, Portland, Maine 04101, United States
Center for Cancer and Blood Disorders, Bethesda, Maryland 20817, United States
National Capital Clinical Research Associates, Bethesda, Maryland 20817, United States
Oncology Hematology Care, Cincinnati, Ohio 45242, United States
Mid Ohio Oncology/Hematology, Inc./ The Mark H. Zangmeister Center, Columbus, Ohio 43219, United States
South Carolina Oncology Associates, PA, Columbia, South Carolina 29210, United States
Chattanooga Oncology Hematology Associates, Chattanooga, Tennessee 37404, United States
Tennessee Oncology, PLLC, Nashville, Tennessee 37023, United States
Texas Oncology, Dallas, Texas 75246, United States
Fairfax Northern Virginia Hem-Onc, Fairfax, Virginia 22031, United States
Virginia Cancer Institute, Richmond, Virginia 23235, United States
Additional Information
Starting date: July 2009
Last updated: December 11, 2014
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