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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 : Recruiting
First Posted : May 29, 2015
Last Update Posted : September 24, 2018
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

Brief Summary:
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, may interfere with the ability of tumor cells to grow and spread. 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.

Condition or disease Intervention/treatment Phase
Estrogen Receptor Negative HER2/Neu Negative Invasive Breast Carcinoma Progesterone Receptor Negative Triple-Negative Breast Carcinoma Biological: Bevacizumab Drug: Everolimus Other: Laboratory Biomarker Analysis Drug: Pegylated Liposomal Doxorubicin Hydrochloride Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

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. Correlate pathologic response with vimentin expression as measured by immunohistochemistry (IHC).

III. Determine toxicity associated 4 cycles of DAE in the neoadjuvant setting. IV. Compare 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.

VI. Determine pathologic response rates for all patients who discontinue study drug due to toxicity.

TERTIARY OBJECTIVES:

I. Determine the correlation between vimentin expression by IHC and the presence of mesenchymal gene signatures at the time of initial tumor biopsy prior to neoadjuvant chemotherapy (NACT).

II. Determine rates of pCR in patients with mesenchymal tumors identified by gene signatures and compare to pCR rates in non-mesenchymal tumors.

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) daily. Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. Patients will not receive bevacizumab during course 4 of therapy. Patients then undergo surgery.

After completion of study treatment, patients are followed up at 2-3 weeks.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 37 participants
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 : January 31, 2020
Estimated Study Completion Date : January 31, 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
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 daily. Treatment repeats every 21 days for up to 4 courses in the absence of disease progression or unacceptable toxicity. Patients will not receive bevacizumab during course 4 of therapy. Patients then undergo surgery.
Biological: Bevacizumab
Given IV
Other Names:
  • Anti-VEGF
  • Anti-VEGF Humanized Monoclonal Antibody
  • Anti-VEGF rhuMAb
  • Avastin
  • Bevacizumab Biosimilar BEVZ92
  • Bevacizumab Biosimilar BI 695502
  • Bevacizumab Biosimilar CBT 124
  • Bevacizumab Biosimilar FKB238
  • Bevacizumab Biosimilar MIL60
  • Bevacizumab Biosimilar QL 1101
  • BEVACIZUMAB, LICENSE HOLDER UNSPECIFIED
  • Immunoglobulin G1 (Human-Mouse Monoclonal rhuMab-VEGF Gamma-Chain Anti-Human Vascular Endothelial Growth Factor), Disulfide With Human-Mouse Monoclonal rhuMab-VEGF Light Chain, Dimer
  • Recombinant Humanized Anti-VEGF Monoclonal Antibody
  • rhuMab-VEGF

Drug: Everolimus
Given PO
Other Names:
  • 42-O-(2-Hydroxy)ethyl Rapamycin
  • Afinitor
  • Certican
  • RAD 001
  • RAD001
  • Votubia
  • Zortress

Other: Laboratory Biomarker Analysis
Correlative studies

Drug: Pegylated Liposomal Doxorubicin Hydrochloride
Given IV
Other Names:
  • ATI-0918
  • Caelyx
  • DOX-SL
  • Doxil
  • Doxilen
  • Doxorubicin HCl Liposome
  • doxorubicin hydrochloride liposome
  • Duomeisu
  • Evacet
  • LipoDox
  • Liposomal Adriamycin
  • liposomal doxorubicin hydrochloride
  • Liposomal-Encapsulated Doxorubicin
  • Pegylated Doxorubicin HCl Liposome
  • S-Liposomal Doxorubicin
  • Stealth Liposomal Doxorubicin
  • TLC D-99




Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. 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.

  2. Treatment received [ Time Frame: At the end of 4 courses ]
    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.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. 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
Criteria

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 for vimentin
  • 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
  • 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
  • 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

Information from the National Library of Medicine

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


Contacts
Contact: Stacy Moulder 713-792-2817 smoulder@mdanderson.org

Locations
United States, Texas
M D Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Stacy L. Moulder    713-792-2817      
Principal Investigator: Stacy L. Moulder         
Sponsors and Collaborators
M.D. Anderson Cancer Center
National Cancer Institute (NCI)
Investigators
Principal Investigator: Stacy Moulder M.D. Anderson Cancer Center

Additional Information:
Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT02456857     History of Changes
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 )
P30CA016672 ( U.S. NIH Grant/Contract )
First Posted: May 29, 2015    Key Record Dates
Last Update Posted: September 24, 2018
Last Verified: September 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Carcinoma
Breast Neoplasms
Triple Negative Breast Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Neoplasms by Site
Breast Diseases
Skin Diseases
Bevacizumab
Liposomal doxorubicin
Doxorubicin
Everolimus
Sirolimus
Endothelial Growth Factors
Antibodies
Immunoglobulins
Antibodies, Monoclonal
Immunoglobulin G
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors
Antineoplastic Agents
Immunologic Factors
Antibiotics, Antineoplastic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors