Liposomal Doxorubicin, Bevacizumab, and Everolimus in Patients With Locally Advanced TNBC With Tumors Predicted Insensitive to Standard Chemotherapy; A Moonshot Initiative
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ClinicalTrials.gov Identifier: NCT02456857 |
Recruitment Status :
Active, not recruiting
First Posted : May 29, 2015
Last Update Posted : March 7, 2022
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Condition or disease | Intervention/treatment | Phase |
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Invasive Breast Carcinoma Triple-Negative Breast Carcinoma | Biological: Bevacizumab Drug: Everolimus Other: Laboratory Biomarker Analysis Drug: Pegylated Liposomal Doxorubicin Hydrochloride | Phase 2 |
PRIMARY OBJECTIVE:
I. Determine excellent clinical response rates (pathologic complete response [pCR]/residual cancer burden [RCB]-0 or minimal residual disease [RCB-I]) in patients with anthracycline-based chemotherapy insensitive, localized triple-negative breast cancer (TNBC) who receive 4 cycles of pegylated liposomal doxorubicin hydrochloride, bevacizumab, and everolimus (DAE) following anthracycline-based chemotherapy in the neoadjuvant setting.
SECONDARY OBJECTIVES:
I. Determine response rate after 4 cycles of DAE using radiographic imaging. II. Determine toxicity associated 4 cycles of DAE in the neoadjuvant setting. III. Pathologic response rates to 4 cycles of DAE in mesenchymal tumors versus (vs.) non-mesenchymal tumors.
V. Compare pathologic response rates in mesenchymal tumors to 4 cycles of DAE vs. 12 weeks of weekly paclitaxel (using data collected from standard of care treatment).
EXPLORATORY OBJECTIVES:
I. Determine the correlation between vimentin expression by immunohistochemistry (IHC) and the presence of mesenchymal gene signatures at the time of initial tumor biopsy prior to neoadjuvant chemotherapy (NACT).
II. Determine the correlation between mutations in PIK3CA, PTEN or NF2 or PTEN loss by IHC and the presence of mesenchymal gene signatures at the time of initial tumor biopsy prior to NACT.
III. Determine rates of pCR in patients with mesenchymal tumors identified by gene signatures and compare to pCR rates in non-mesenchymal tumors.
IV. Correlate pathologic response with degree of vimentin expression as measured by IHC.
V. Determine rates of pCR in patients whose tumors contain mutations in PIK3CA, PTEN or NF2 or PTEN loss by IHC and compare to pCR rates in patients whose tumors lacks mutations in these genes.
OUTLINE:
Patients receive pegylated liposomal doxorubicin hydrochloride intravenously (IV) over about 3 hours on day 1, bevacizumab IV over 90 minutes on day 1, and everolimus orally (PO) once daily (QD) on days 1-21. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients will not receive bevacizumab during cycle 4 of therapy. Patients then undergo surgery.
After completion of study treatment, patients are followed up within 30 days of surgery.
Study Type : | Interventional (Clinical Trial) |
Actual Enrollment : | 17 participants |
Allocation: | N/A |
Intervention Model: | Single Group Assignment |
Masking: | None (Open Label) |
Primary Purpose: | Treatment |
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 |
Actual Study Start Date : | January 12, 2016 |
Estimated Primary Completion Date : | December 31, 2022 |
Estimated Study Completion Date : | December 31, 2022 |

Arm | Intervention/treatment |
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Experimental: Treatment (DAE)
Patients receive pegylated liposomal doxorubicin hydrochloride IV over about 3 hours on day 1, bevacizumab IV over 90 minutes on day 1, and everolimus PO QD on days 1-21. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Patients will not receive bevacizumab during cycle 4 of therapy. Patients then undergo surgery.
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Biological: Bevacizumab
Given IV
Other Names:
Drug: Everolimus Given PO
Other Names:
Other: Laboratory Biomarker Analysis Correlative studies Drug: Pegylated Liposomal Doxorubicin Hydrochloride Given IV
Other Names:
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- Proportion of patients with pathologic complete response (residual cancer burden-0) or minimal residual disease (residual cancer burden-I) as the response rate [ Time Frame: Up to 3 weeks after completion of study treatment ]An appropriate 95% confidence interval will be estimated as the proportion of patients in the remaining residual cancer burden categories with 95% confidence intervals.
- Biomarkers of response [ Time Frame: Up to 3 weeks after completion of study treatment ]Potential biomarkers of response will be correlated with pathologic response to pegylated liposomal doxorubicin hydrochloride, bevacizumab, and everolimus using appropriate statistical analyses for the biomarker of interest. For genomic mutations, multivariate logistic regression models will be fitted to the data that include three explanatory variables; namely dichotomous variables for treatment (pegylated liposomal doxorubicin hydrochloride, bevacizumab, and everolimus versus paclitaxel), gene mutation, and the interaction. The interaction will be examined to investigate if excellent pathologic response (residual cancer burden-0 or 1) due to a therapy is associated with gene mutation status. Statistical significance will be defined as p < 0.05.
- Treatment received [ Time Frame: At the end of 4 cycles (each cycle is 28 days) ]A multivariate logistic regression model will be fitted to the data that treatment received. To assess the fit of all logistic regressions models, the area under the curve for the receiver operating characteristic curve, the Hosmer and Lemeshow statistic, and Nagelkerke's R2 will be investigated and reported. Odds ratios and Wald confidence limits for each logistic regression explanatory will be reported. Statistical significance will be defined as p < 0.05.
- Three gene signatures of interest (claudin-low, metaplastic, and mesenchymal) [ Time Frame: Up to 3 weeks after completion of study treatment ]A multivariate logistic regression model will be fitted to the data that each of the three gene signatures of interest. To assess the fit of all logistic regressions models, the area under the curve for the receiver operating characteristic curve, the Hosmer and Lemeshow statistic, and Nagelkerke's R2 will be investigated and reported. Odds ratios and Wald confidence limits for each logistic regression explanatory will be reported. Statistical significance will be defined as p < 0.05.
- Interaction of treatment and each signature [ Time Frame: Up to 3 weeks after completion of study treatment ]A multivariate logistic regression model will be fitted to the data that each of the three gene signatures of interest. To assess the fit of all logistic regressions models, the area under the curve for the receiver operating characteristic curve, the Hosmer and Lemeshow statistic, and Nagelkerke's R2 will be investigated and reported. Odds ratios and Wald confidence limits for each logistic regression explanatory will be reported. Statistical significance will be defined as p < 0.05.
- Progression-free survival [ Time Frame: From the date of enrollment onto this study until the date of progression or death without evidence of progression, assessed up to 3 weeks ]The progression-free survival distribution will be estimated using the Kaplan-Meier method.
- Overall survival [ Time Frame: Up to 3 weeks after completion of study treatment ]The overall survival distribution will be estimated using the Kaplan-Meier method.
- Incidence of toxicity [ Time Frame: Up to 3 weeks after completion of study treatment ]Graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0.

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Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
Sexes Eligible for Study: | Female |
Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- Confirmed invasive triple-negative breast cancer defined as estrogen receptor (ER) < 10%; progesterone receptor (PR) < 10% by immunohistochemistry (IHC) and human epidermal growth factor receptor 2 (HER2) 0-1+ (by IHC), or 2+ (fluorescence in situ hybridization [FISH] < 2, gene copy number < 4)
- Primary tumor sample collected before NACT started and
- Undergone molecular testing for integral biomarkers including immunohistochemical staining; the tumor must have evidence of mesenchymal differentiation defined as metaplastic breast cancer, or vimentin >= 50% by IHC
- Received at least one dose of an anthracycline-based NACT; patients are eligible if therapy was discontinued due to disease progression or therapy intolerance
- At least 1.0 cm of measurable residual disease after neoadjuvant anthracycline-based chemotherapy
- Baseline multi-gated acquisition (MUGA) scan or echocardiogram showing left ventricular ejection fraction (LVEF) >= 50% at least 6 weeks prior to initiation of NACT
- Absolute neutrophil count (ANC) >= 1.5 x 10^9/L
- Platelets >= 100 x 10^9/L
- Hemoglobin (Hb) > 9 g/dL
- Total serum bilirubin =< 2.0 mg/dL
- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x upper limit of normal (ULN) (=< 5 x ULN in patients with liver metastases)
- International normalized ratio (INR) =< 2
- Serum creatinine =< 1.5 x ULN
- Fasting serum cholesterol =< 300 mg/dL OR =< 7.75 mmol/L, AND fasting triglycerides =< 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
- Signed informed consent obtained prior to any screening procedures
Exclusion Criteria:
- Pregnant or lactating woman
- Presence of metastatic disease
- Prior therapy with bevacizumab, liposomal doxorubicin, or everolimus
- Prior radiation therapy of the primary breast carcinoma or axillary lymph nodes
- 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
- Prior cumulative dose of doxorubicin of greater than 360 mg/m^2 or epirubicin of greater than 640 mg/m^2
- 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
- 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 cardiovascular accident (CVA) within 6 months of protocol registration; history of PR prolongation or atrioventricular (AV) block
- Known intolerance or hypersensitivity to rapamycin analogs (e.g. sirolimus, temsirolimus)
- Known impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral everolimus
- Uncontrolled diabetes mellitus as defined by hemoglobin A1c (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
- 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 hepatitis B virus [HBV]-deoxyribonucleic acid [DNA] and/or positive surface antigen of the hepatitis B virus [HBsAg], quantifiable hepatitis C virus [HCV]-ribonucleic acid [RNA]), c. known severely impaired lung function (spirometry and Diffusing capacity of the lungs for carbon monoxide [DLCO] 50% or less of normal and oxygen (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)
- Chronic treatment with corticosteroids or other immunosuppressive agents; topical or inhaled corticosteroids are allowed
- Known history of human immunodeficiency virus (HIV) seropositivity
- 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, bacillus Calmette-Guerin (BCG), yellow fever, varicella and TY21a typhoid vaccines
- 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
- Patients who are currently part of or have participated in any clinical investigation with an investigational drug within 1 month prior to dosing
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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 the following:
- Placement of an intrauterine device (IUD) or intrauterine system (IUS);
- Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository;
- Total abstinence or;
- Male/female sterilization.
- Note: Women are considered post-menopausal and not of child-bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation at least six weeks prior to treatment; in the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child-bearing potential
- 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

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02456857
United States, Texas | |
M D Anderson Cancer Center | |
Houston, Texas, United States, 77030 |
Principal Investigator: | Clinton Yam | M.D. Anderson Cancer Center |
Responsible Party: | M.D. Anderson Cancer Center |
ClinicalTrials.gov Identifier: | NCT02456857 |
Other Study ID Numbers: |
2015-0087 NCI-2015-01556 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ) 2015-0087 ( Other Identifier: M D Anderson Cancer Center ) |
First Posted: | May 29, 2015 Key Record Dates |
Last Update Posted: | March 7, 2022 |
Last Verified: | February 2022 |
Studies a U.S. FDA-regulated Drug Product: | Yes |
Studies a U.S. FDA-regulated Device Product: | No |
Carcinoma Breast Neoplasms Neoplasms, Glandular and Epithelial Neoplasms by Histologic Type Neoplasms Neoplasms by Site Breast Diseases Skin Diseases Bevacizumab Antineoplastic Agents, Immunological Doxorubicin Liposomal doxorubicin Everolimus Endothelial Growth Factors Antibodies |
Immunoglobulins Antibodies, Monoclonal Immunoglobulin G Antineoplastic Agents Angiogenesis Inhibitors Angiogenesis Modulating Agents Growth Substances Physiological Effects of Drugs Growth Inhibitors Immunologic Factors Antibiotics, Antineoplastic Topoisomerase II Inhibitors Topoisomerase Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action |