Clinical Trials /

Liposomal Doxorubicin, Bevacizumab, and Everolimus in Patients With Locally Advanced TNBC With Tumors Predicted Insensitive to Standard Chemotherapy; A Moonshot Initiative



This phase II trial studies how well pegylated liposomal doxorubicin, bevacizumab, and everolimus work in treating patients with triple-negative breast cancer with tumors predicted insensitive to standard chemotherapy. Drugs used in chemotherapy, such as pegylated liposomal doxorubicin, work in different ways to stop the growth of tumor cells by stopping them from dividing.Monoclonal antibodies, such as bevacizumab binds to VEGF receptor, thus halting vessel growth in the tumor and thereby causing cell death. Everolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving pegylated liposomal doxorubicin together with bevacizumab and everolimus may kill more tumor cells.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:



Phase 2

Trial Eligibility



  • Brief Title:Women's Triple-Negative First-Line Study: Liposomal Doxorubicin, Bevacizumab and Everolimus (DAE) in Patients With Localized Triple-Negative Breast Cancer (TNBC) With Tumors Predicted Insensitive to Standard Neoadjuvant Chemotherapy
  • Official Title:Women's Triple-Negative First-Line Study: A Phase II Trial of Liposomal Doxorubicin, Bevacizumab and Everolimus (DAE) in Patients With Localized Triple-Negative Breast Cancer (TNBC) With Tumors Predicted Insensitive to Standard Neoadjuvant Chemotherapy

Clinical Trial IDs

  • ORG STUDY ID: 2015-0087
  • SECONDARY ID: NCI-2015-01556
  • NCT ID: NCT02456857

Trial Conditions

  • Breast Cancer

Trial Interventions

EverolimusAfinitorZortressRAD001Bevacizumab + Liposomal Doxorubicin + Everolimus
Liposomal DoxorubicinDoxilDoxorubicin Hydrochloride (Liposomal)Bevacizumab + Liposomal Doxorubicin + Everolimus
BevacizumabAvastinAnti-VEGF Monoclonal AntibodyrhuMAb-VEGFBevacizumab + Liposomal Doxorubicin + Everolimus

Trial Purpose

The goal of this clinical research study is to learn if receiving 4 cycles of experimental chemotherapy before surgery can help to shrink the size of tumors in the breast and/or lymph nodes before they are removed through surgery. The safety of this combination will also be studied.

Detailed Description

Study Drug Administration:

If you are found eligible to take part in this study, you will have 4 cycles of chemotherapy before surgery. Each cycle is 21 days.

On Day 1 of each cycle, you will receive liposomal doxorubicin by vein over about 3 hours, and bevacizumab by vein over about 90 minutes (about 4½ hours total). You will also be given a 21-day supply of everolimus which you will take by mouth at about the same time every day during the cycle.

To reduce the possibility of side effects from surgery, you will not receive bevacizumab during the 4th cycle.

Do not skip any doses unless your study doctor tells you to do so. If you throw up after taking everolimus, you should NOT take another tablet that day. Let your study doctor know that you vomited. If you forget to take everolimus one day, do not take any extra doses the next day. Call your study doctor and ask for advice.

If you have side effects, the study doctor may decide to lower your study drug dose or have you stop taking the drug. If this happens, the study doctor and staff will let you know when it is safe to restart the study drug later at the same or a lower dose. The study doctor will discuss this with you. If study drug is stopped for a while, you may have extra clinic visits for safety tests.

Study Visits:

On Day 1 of each cycle:

- You will have a physical exam.

- Blood (about 2 teaspoons) and urine will be collected for routine tests.

After you have received 4 cycles of chemotherapy, or at any time that the disease appears to get worse, you will have imaging scans similar to the ones you had at screening to check the status of the disease. If the disease gets worse, you may come off study and might have either more chemotherapy or surgery.

You may then have surgery to remove the disease. You will be given a surgery consent form that describes the procedure and its risks.

Length of Treatment:

You may receive up to 4 cycles of chemotherapy. You will no longer be able to take the study drugs if the disease gets worse, if intolerable side effects occur, or if you are unable to follow study directions.

Your participation on the study will be over after the follow-up visit.


About 2-3 weeks after surgery, you will have a follow-up visit in which you are asked about how you are doing. The following test will be preformed:

- You will have a physical exam.

- Blood (about 2 teaspoons) and urine will be collected for routine tests.

- If your doctor thinks it is needed, you will have an ultrasound, MRI, or CT scan of your chest to check the status of the disease.

This is an investigational study. Liposomal doxorubicin is FDA approved and commercially available for the treatment of breast cancer. Bevacizumab and everolimus have both been FDA approved for other conditions and types of cancer. However, neither bevacizumab nor everolimus are FDA-approved for triple-negative breast cancer. They are currently being used for research purposes only in this setting as triple-negative breast cancer treatment before surgery.

The study doctor can explain how these study drugs are designed to work.

Up to 37 participants will be enrolled in this study. All will take part at MD Anderson.

Trial Arms

Bevacizumab + Liposomal Doxorubicin + EverolimusExperimentalOn Day 1 of each cycle, participants receive Liposomal Doxorubicin by vein over about 3 hours, and Bevacizumab and Temsirolimus by vein over about 90 minutes each (6 hours total). To reduce the possibility of side effects from surgery, participants will not receive Bevacizumab during the 4th cycle. Participants take Everolimus by mouth at about the same time every day during the cycle. Participants receive 4 cycles of chemotherapy before surgery. Each cycle is 21 days.
  • Everolimus
  • Liposomal Doxorubicin
  • Bevacizumab

Eligibility Criteria

Inclusion Criteria:

1. Age >/= 18 years.

2. ECOG performance status of 0 or 1.

3. Confirmed invasive triple-negative breast cancer defined as ER<10%; PR<10% by immunohistochemistry (IHC) and HER2 0-1+ (by IHC), or 2+ (FISH <2, gene copy number <4).

4. Clinical or radiologic primary tumor size of at least 1.5cm prior to enrollment onto protocol 2014-0185.

5. Primary tumor sample collected before NACT started (on protocol 2014-0185) and

6. Undergone molecular testing for integral biomarkers including immunohistochemical staining for vimentin.

7. Received at least one dose of an anthracycline-based NACT. Patients are eligible if therapy was discontinued due to disease progression or therapy intolerance.

8. At least 1.0 cm of measurable residual disease after neoadjuvant anthracycline-based chemotherapy.

9. Baseline MUGA or echocardiogram showing LVEF >/=50% at least 6 weeks prior to initiation of NACT.

10. Adequate bone marrow function as shown by: ANC >/=1.5 x 10^9/L, Platelets >/=100 x 10^9/L, Hb >9 g/dL;

11. Adequate liver function as shown by: Total serum bilirubin </=2.0 mg/dL, ALT and AST </=2.5x ULN (</=5x ULN in patients with liver metastases), INR </=2;

12. Adequate renal function as shown by: Serum creatinine </=1.5x ULN;

13. Fasting serum cholesterol </=300 mg/dL OR </=7.75 mmol/L, AND fasting triglycerides </=2.5x 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;

14. Signed informed consent obtained prior to any screening procedures.

Exclusion Criteria:

1. Pregnant or lactating woman.

2. Presence of metastatic disease.

3. Prior therapy with bevacizumab, liposomal doxorubicin, or everolimus.

4. Prior radiation therapy of the primary breast carcinoma or axillary lymph nodes.

5. Patients who have a history of another primary malignancy, with the exceptions of: non-melanoma skin cancer, and carcinoma in situ of the cervix, uterus, or breast from which the patient has been disease free for </= 3 years.

6. Prior cumulative dose of doxorubicin of greater than 360 mg/m2 or epirubicin of greater than 640 mg/m2.

7. Any serious medical illness, other than treated by this study, which would limit survival to less than 1 month or psychiatric illness which would limit informed consent.

8. Patients with history of serious cardiac events defined as: New York Heart Association Class 3 or 4 heart failure, history of myocardial infarction, Unstable angina, or CVA within 6 months of protocol registration. History of PR prolongation or AV block.

9. Known intolerance or hypersensitivity to rapamycin analogs (e.g. sirolimus, temsirolimus).

10. Known impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral Everolimus;

11. Uncontrolled diabetes mellitus as defined by HbA1c >8% despite adequate therapy. Patients with a known history of impaired fasting glucose or diabetes mellitus (DM) may be included, however blood glucose and antidiabetic treatment must be monitored closely throughout the trial and adjusted as necessary;

12. Patients who have any severe and/or uncontrolled medical conditions such as: a. serious uncontrolled cardiac arrhythmia, or any other clinically significant cardiac disease b. active (acute or chronic) or uncontrolled severe infection, liver disease such as cirrhosis, decompensated liver disease, and active and chronic hepatitis (i.e. quantifiable HBV-DNA and/or positive HBsAg, quantifiable HCV-RNA), c. known severely impaired lung function (spirometry and DLCO 50% or less of normal and O2 saturation 88% or less at rest on room air), d. active, bleeding diathesis; e. Moderate or severe hepatic impairment (Child-Pugh B or C)

13. Chronic treatment with corticosteroids or other immunosuppressive agents. Topical or inhaled corticosteroids are allowed;

14. Known history of HIV seropositivity;

15. Patients who have received live attenuated vaccines within 1 week of start of Everolimus and during the study. Patient should also avoid close contact with others who have received live attenuated vaccines. Examples of live attenuated vaccines include intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella and TY21a typhoid vaccines;

16. Patients with a history of non-compliance to medical regimens or who are considered potentially unreliable or will not be able to complete the entire study;

17. Patients who are currently part of or have participated in any clinical investigation with an investigational drug within 1 month prior to dosing;

18. Women of child-bearing potential (WOCBP), defined as all women physiologically capable of becoming pregnant, must use highly effective methods of contraception during the study and 8 weeks after. Highly effective contraception methods include combination of any two of those listed in the protocol.

19. Male patients whose sexual partner(s) are WOCBP who are not willing to use adequate contraception, during the study and for 8 weeks after the end of treatment.

Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Both
Healthy Volunteers:No

Primary Outcome Measures

Measure:Clinical Response Rates
Time Frame:84 days
Safety Issue:Yes
Description:Radiographic criteria of response based on regional ultrasound examination (decrease in size of the primary tumor and/or fatty replacement in regional lymph nodes). A decrease in size of the product of the two largest dimensions should =/> 50% considered a partial response. Complete disappearance of primary tumor by physical exam and or ultrasound and normalization of lymph nodes by ultrasound considered a complete clinical response. Progression of disease defined as 30% increase in size of primary tumor and/or lymph nodes on physical exam and/or ultrasound.

Secondary Outcome Measures

Trial Keywords

  • Breast cancer
  • Triple-Negative Breast Cancer
  • TNBC
  • Tumors insensitive to standard neoadjuvant chemotherapy
  • Temsirolimus
  • CCI-779
  • Torisel
  • Liposomal Doxorubicin
  • Doxil
  • Doxorubicin Hydrochloride (Liposomal)
  • Bevacizumab
  • Avastin
  • Anti-VEGF Monoclonal Antibody
  • rhuMAb-VEGF