Trial of Paclitaxel/Bevacizumab +/- Everolimus for Patients With HER2-Negative Metastatic Breast Cancer
Condition: Metastatic Breast Cancer
MeSH terms: Breast Neoplasms
Intervention: Everolimus; Bevacizumab; Paclitaxel; Placebo; Bevacizumab; Paclitaxel
Intervention description: Everolimus 10mg PO daily continuously for all 28 days of a cycle; Bevacizumab 10mg/kg IV Days 1 and 15 of 28 day cycle; 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.; Placebo PO daily continuously for all 28 days of a cycle; Bevacizumab 10mg/kg IV days 1 and 15 of 28 day cycle; 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.
Intervention MeSH terms: Paclitaxel; Albumin-Bound Paclitaxel; Bevacizumab; Everolimus
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Enrollment: 113.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Metastatic Breast Cancer; Paclitaxel; Bevacizumab; Everolimus

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.
    

Eligibility 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.

             -