Clinical Trials /

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

NCT02456857

Description:

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:
  • Invasive Breast Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Liposomal Doxorubicin, Bevacizumab, and Everolimus in Patients With Locally Advanced TNBC With Tumors Predicted Insensitive to Standard Chemotherapy; A Moonshot Initiative
  • 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
  • SECONDARY ID: 2015-0087
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT02456857

Conditions

  • Estrogen Receptor Negative
  • HER2/Neu Negative
  • Invasive Breast Carcinoma
  • Progesterone Receptor Negative
  • Triple-Negative Breast Carcinoma

Interventions

DrugSynonymsArms
BevacizumabAnti-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 HD204, Bevacizumab Biosimilar HLX04, Bevacizumab Biosimilar IBI305, Bevacizumab Biosimilar LY01008, Bevacizumab Biosimilar MIL60, Bevacizumab Biosimilar QL 1101, Bevacizumab Biosimilar SCT501, HD204, 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, SCT501Treatment (DAE)
Everolimus42-O-(2-Hydroxy)ethyl Rapamycin, Afinitor, Certican, RAD 001, RAD001, Votubia, ZortressTreatment (DAE)
Pegylated Liposomal Doxorubicin HydrochlorideATI-0918, Caelyx, DOX-SL, Doxil, Doxilen, Doxorubicin HCl Liposomal, Doxorubicin HCl Liposome, doxorubicin hydrochloride liposome, Duomeisu, Evacet, LipoDox, Lipodox 50, Liposomal Adriamycin, liposomal doxorubicin hydrochloride, Liposomal-Encapsulated Doxorubicin, Pegylated Doxorubicin HCl Liposome, S-Liposomal Doxorubicin, Stealth Liposomal Doxorubicin, TLC D-99Treatment (DAE)

Purpose

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.

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.

      EXPLORATORY 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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (DAE)ExperimentalPatients 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.
  • Bevacizumab
  • Everolimus
  • Pegylated Liposomal Doxorubicin Hydrochloride

Eligibility 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; 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

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

Primary Outcome Measures

Measure: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
Safety Issue:
Description: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

Measure:Biomarkers of response
Time Frame:Up to 3 weeks after completion of study treatment
Safety Issue:
Description: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.
Measure:Treatment received
Time Frame:At the end of 4 courses
Safety Issue:
Description: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.
Measure:Three gene signatures of interest (claudin-low, metaplastic, and mesenchymal)
Time Frame:Up to 3 weeks after completion of study treatment
Safety Issue:
Description: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.
Measure:Interaction of treatment and each signature
Time Frame:Up to 3 weeks after completion of study treatment
Safety Issue:
Description: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.
Measure: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
Safety Issue:
Description:The progression-free survival distribution will be estimated using the Kaplan-Meier method.
Measure:Overall survival
Time Frame:Up to 3 weeks after completion of study treatment
Safety Issue:
Description:The overall survival distribution will be estimated using the Kaplan-Meier method.
Measure:Incidence of toxicity
Time Frame:Up to 3 weeks after completion of study treatment
Safety Issue:
Description:Graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:M.D. Anderson Cancer Center

Last Updated

December 20, 2019