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Pegylated Liposomal Doxorubicin Hydrochloride and Carboplatin Followed by Surgery and Paclitaxel in Treating Patients With Triple Negative Stage II-III Breast Cancer

NCT02315196

Description:

This phase II trial studies how well pegylated liposomal doxorubicin hydrochloride and carboplatin followed by surgery and paclitaxel work in treating patients with stage II-III breast cancer that does not have estrogen receptors, progesterone receptors, or large amounts of human epidermal growth factor receptor 2 (HER2)/neu protein (triple negative). Drugs used in chemotherapy, such as pegylated liposomal doxorubicin hydrochloride, carboplatin, and paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving pegylated liposomal doxorubicin hydrochloride and carboplatin before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. Giving pegylated liposomal doxorubicin hydrochloride and carboplatin followed by surgery and paclitaxel may be an effective treatment for breast cancer.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Pegylated Liposomal Doxorubicin Hydrochloride and Carboplatin Followed by Surgery and Paclitaxel in Treating Patients With Triple Negative Stage II-III Breast Cancer
  • Official Title: A Phase 2 Trial of Liposomal Doxorubicin and Carboplatin in Patients With ER, PR, HER2 Negative Breast Cancer (TNBC)

Clinical Trial IDs

  • ORG STUDY ID: 041401
  • SECONDARY ID: NCI-2014-02029
  • SECONDARY ID: 041401
  • SECONDARY ID: P30CA072720
  • NCT ID: NCT02315196

Conditions

  • Estrogen Receptor-negative Breast Cancer
  • HER2-negative Breast Cancer
  • Progesterone Receptor-negative Breast Cancer
  • Stage IIA Breast Cancer
  • Stage IIB Breast Cancer
  • Stage IIIA Breast Cancer
  • Stage IIIB Breast Cancer
  • Stage IIIC Breast Cancer
  • Triple-negative Breast Cancer

Interventions

DrugSynonymsArms
pegylated liposomal doxorubicin hydrochlorideCAELYX, Dox-SL, DOXIL, doxorubicin hydrochloride liposome, LipoDoxTreatment (doxil, carboplatin, surgery, paclitaxel)
epirubicin hydrochloride4'-epi-doxorubicin HCl, 4'-epiadriamycinTreatment (doxil, carboplatin, surgery, paclitaxel)
carboplatinCarboplat, CBDCA, JM-8, Paraplat, ParaplatinTreatment (doxil, carboplatin, surgery, paclitaxel)
paclitaxelAnzatax, Asotax, TAX, TaxolTreatment (doxil, carboplatin, surgery, paclitaxel)

Purpose

This phase II trial studies how well pegylated liposomal doxorubicin hydrochloride and carboplatin followed by surgery and paclitaxel work in treating patients with stage II-III breast cancer that does not have estrogen receptors, progesterone receptors, or large amounts of human epidermal growth factor receptor 2 (HER2)/neu protein (triple negative). Drugs used in chemotherapy, such as pegylated liposomal doxorubicin hydrochloride, carboplatin, and paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving pegylated liposomal doxorubicin hydrochloride and carboplatin before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed. Giving pegylated liposomal doxorubicin hydrochloride and carboplatin followed by surgery and paclitaxel may be an effective treatment for breast cancer.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the rate of pathologic complete response with treatment of liposomal
      doxorubicin (pegylated liposomal doxorubicin hydrochloride) and carboplatin in patients with
      estrogen receptor (ER), progesterone receptor (PR), HER2 negative breast cancer (triple
      negative breast cancer [TNBC]).

      SECONDARY OBJECTIVES:

      I. To determine the recurrence free survival (RFS), 2-year RFS, and overall survival (OS)
      after treatment with neoadjuvant liposomal doxorubicin and carboplatin followed by definitive
      breast surgery and then weekly paclitaxel in patients with ER, progesterone receptor (PgR),
      HER2 negative breast cancer.

      II. To describe the mutational spectrum of tumors found in primary, untreated ER, PgR, HER2
      negative breast cancer and their association with pathologic complete response to neoadjuvant
      pegylated liposomal doxorubicin hydrochloride (doxil) and carboplatin.

      III. To determine functional significance of genomic landscape in predicting drug response
      using patient derived xenograft (PDX) and ex vivo models.

      OUTLINE:

      NEOADJUVANT: Patients receive pegylated liposomal doxorubicin hydrochloride* intravenously
      (IV) over 90 minutes and carboplatin IV over 30-60 minutes on day 1. Treatment repeats every
      28 days for 4 courses in the absence of disease progression or unacceptable toxicity.

      ADJUVANT: Patients undergo definitive surgery at the discretion of the treating physician.
      Patients then receive paclitaxel IV over 60 minutes once weekly for 12 weeks in the absence
      of disease progression or unacceptable toxicity.

      *NOTE: If there is a shortage of pegylated liposomal doxorubicin hydrochloride, patients
      receive epirubicin hydrochloride IV over 15-20 minutes on day 1.

      After completion of study treatment, patients are followed up every 6 months for up to 20
      years.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (doxil, carboplatin, surgery, paclitaxel)ExperimentalNEOADJUVANT: Patients receive pegylated liposomal doxorubicin hydrochloride* IV over 90 minutes and carboplatin IV over 30-60 minutes on day 1. Treatment repeats every 28 days for 4 courses in the absence of disease progression or unacceptable toxicity. ADJUVANT: Patients undergo definitive surgery at the discretion of the treating physician. Patients then receive paclitaxel IV over 60 minutes once weekly for 12 weeks in the absence of disease progression or unacceptable toxicity. *NOTE: If there is a shortage of pegylated liposomal doxorubicin hydrochloride, patients receive epirubicin hydrochloride IV over 15-20 minutes on day 1.
  • pegylated liposomal doxorubicin hydrochloride
  • epirubicin hydrochloride
  • carboplatin
  • paclitaxel

Eligibility Criteria

        Inclusion Criteria:

          -  Women with previously untreated, unilateral stage II-III breast cancer, ER/PgR/HER2
             negative (ER =< 5%, PgR =< 5%, HER2 0-1+ by immunohistochemistry [IHC] or fluorescence
             in situ hybridization [FISH] =< 2.0); if clinically negative lymph nodes, tumor size
             should be minimum 1.0 cm and identifiable under office-based ultrasound guidance

          -  Negative serum or urine beta-human chorionic gonadotropin (hCG) pregnancy test at
             screening for patients of child-bearing potential within one week prior to enrollment

          -  Patients with reproductive potential must use an adequate contraceptive method (e.g.
             abstinence, intrauterine device, oral contraceptives, barrier device with spermicide
             or surgical sterilization) during treatment and for three months after completing
             treatment

          -  Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status < 2

          -  Life expectancy >= 52 weeks excluding their diagnosis of breast cancer

          -  Absolute neutrophil count (ANC) >= 1,500 cells/mm^3

          -  Platelets >= 100,000 cells/mm^3

          -  Hemoglobin > 9.0 g/dL

          -  Creatinine < 2.5 mg/dL

          -  Total bilirubin < 1.5 X upper limit of normal (ULN)

          -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
             [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
             < 2.5 X institutional ULN

          -  Patients must have normal cardiac function, as evidenced by a left ventricular
             ejection fraction (LVEF) within institutional normal limits; echocardiogram may be
             used if multi gated acquisition (MUGA) scan is not available, but the same test must
             be used throughout the study to evaluate LVEF

          -  Computed tomography of the chest, abdomen, and pelvis (CT CAP) and bone scan performed
             within 30 days prior to study entry and does not demonstrate metastatic disease

          -  Patients may not receive concurrent treatment with other investigational or commercial
             agent(s) for treatment of their breast cancer

          -  The patient or, if applicable, her legally authorized representative must have signed
             and dated an Institutional Review Board (IRB)-approved consent form that conforms to
             federal and institutional guidelines

          -  Patients must be eligible to undergo surgery, either lumpectomy or mastectomy for
             local treatment of the breast cancer; surgical margins at discretion of surgeon per
             National Comprehensive Cancer Network (NCCN) guidelines; axillary exploration at
             discretion of surgeon but all patients minimally have sentinel lymph node evaluation
             at time of surgery

          -  Imaging by magnetic resonance imaging (MRI), ultrasound and/or mammogram and physical
             exam to document lesions size must be performed within 30 days of study entry

          -  Must not exhibit a non-healing wound or any skin breakdown

          -  Before administering liposomal doxorubicin, patients must wait 4-6 weeks after surgery

          -  Submission of tumor samples from the diagnostic biopsy and breast surgery is required
             for all patients

        Exclusion Criteria:

          -  Women who are pregnant or breastfeeding

          -  Second primary malignancy except most situ carcinoma (e.g. in situ carcinoma of the
             cervix, adequately treated non-melanomatous carcinoma of the skin) or other malignancy
             treated at least 5 years previously with no evidence of recurrence

          -  Definitive clinical or radiologic evidence of metastatic disease; imaging must have
             been performed no greater than 30 days prior to initiation of chemotherapy

          -  Diagnosis of inflammatory breast cancer

          -  History of hypersensitivity reactions attributed to a conventional formulation of
             doxorubicin hydrochloride (HCL) or the components of doxil, paclitaxel, or carboplatin

          -  Serious concomitant systemic disorders (including active infections or chronic
             infection requiring suppressive antibiotics) that would compromise the safety of the
             patient or compromise the patient's ability to complete the study, at the discretion
             of the investigator

          -  Myocardial infarct or unstable angina within 6 months before enrollment, New York
             Heart Association (NYHA) class II or greater heart failure, uncontrolled angina,
             severe uncontrolled ventricular arrhythmias, clinically significant pericardial
             disease, valvular disease with documented compromise in cardiac function, or
             electrocardiographic evidence of acute ischemic or active conduction system
             abnormalities

          -  Prior anthracycline, platinum salt, or taxane for any malignancy

          -  Known or active hepatitis B or C with abnormal liver function tests

          -  Significant vascular disease (e.g., aortic aneurysm, aortic dissection)

          -  Symptomatic peripheral vascular disease

          -  Evidence of bleeding diathesis or coagulopathy

          -  Intrinsic lung disease resulting in moderate to severe dyspnea

          -  History of a major organ allograft or condition requiring chronic immunosuppression,
             e.g., kidney, liver, lung, heart, bone marrow transplant, or autoimmune diseases; this
             includes treatment with corticosteroids within one month (dose of >= 10 mg/day
             methylprednisolone equivalent) (excluding inhaled steroids); patients who have
             received corneal transplants, cadaver skin, or bone transplants are eligible

          -  Nervous system disorder (paresthesias, peripheral motor neuropathy, or peripheral
             sensory neuropathy) >= grade 2, per the Common Terminology Criteria for Adverse Events
             version 4.0 (CTCAE v4.0)

          -  Conditions that would prohibit administration of corticosteroids
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Rate of pathologic complete response (pCR) based on Response Evaluation Criteria in Solid Tumors criteria
Time Frame:Up to 20 years
Safety Issue:
Description:The pCR rate will first be determined as proportions and calculating its 95% confidence interval. To study the association between pCR response (yes/no) and the presence of gross residual disease, type and number of mutations, clinical lymph node status (positive/negative), tumor size (< 2 cm/>= 2 cm) based on p53, logistic regression analysis will be used, controlling for cancer treatment and disease stage and other covariates if numbers allow.

Secondary Outcome Measures

Measure:RFS, defined as time to local recurrence following surgery, regional recurrence, distant recurrence, or death from any cause prior to recurrence or second primary cancer following initiation of chemotherapeutic treatment
Time Frame:2 years
Safety Issue:
Description:Survival functions will be computed using the Kaplan-Meier method, and compared between mutation status using the log-rank test. Adjustment for additional covariates, such as cancer treatment and disease stage, will be performed using Cox proportional hazards regression analysis if numbers allow.
Measure:OS
Time Frame:Time from initiation of chemotherapy until death from any cause, assessed up to 20 years
Safety Issue:
Description:Survival functions will be computed using the Kaplan-Meier method, and compared between mutation status using the log-rank test. Adjustment for additional covariates, such as cancer treatment and disease stage, will be performed using Cox proportional hazards regression analysis if numbers allow.
Measure:Mutational spectrum of tumors
Time Frame:Up to 20 years
Safety Issue:
Description:The Cox model analysis will be used to study the association between cancer recurrence and the presence of specific mutations with IHC parameters, e.g. p53, Ki67, apoptotic markers (cleaved caspase 3), phosphorylated proteins in targeted pathways, gamma-H2A histone family, member X for deoxyribonucleic acid damage. All test procedures will be done at significance level 5%. It will be determined which tumors with gross residual disease are sensitive to targeted agent, cytotoxins, or the combination as a function of mutational profile and will be tested for additive and synergistic effects.
Measure:Sensitivity to paclitaxel or cyclophosphamide, targeted agents selected based on genomic profile, standard cytotoxins, or the combination of targeted agents with standard cytotoxins evaluated by patient derived xenograft and ex vivo models
Time Frame:Up to 5 years
Safety Issue:
Description:To demonstrate activity for the selected agents for a specific patient's tumor descriptive analysis (e.g., plots of tumor size vs. time since treatment, summary statistics and histograms) will be used to explore the distribution of data, identify outliers and inform any necessary transformations (e.g., logarithm) for subsequent statistical analysis. Mixed model analysis will be used to evaluate the treatment effect, represented by tumor inhibition ratio. Treatment, time (of repeated measurements) and the interaction of treatment and time will be included as fixed effects.
Measure:Quality of life, assessed using a quality of life survey instrument
Time Frame:Up to after dose 12 of paclitaxel
Safety Issue:
Description:Quality of life scores will be analyzed longitudinally for preservation of score within each segment of therapy and across the entire treatment regimen. Quality of life scores will also be compared to health care provider documented severity and presence of side effects. Quality of life scores will also be compared to outcome measures using pathologic complete response versus partial/stable response and survival data using logistic regression.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Rutgers, The State University of New Jersey

Last Updated

January 19, 2017