Clinical Trials /

Anastrozole, Palbociclib, Trastuzumab and Pertuzumab in Her-positive, Her2-positive Metastatic Breast

NCT03304080

Description:

This is a multicenter, phase I/II trial of anastrozole, palbociclib, trastuzumab, and pertuzumab is proposed as first-line therapy in metastatic hormone receptor-positive, HER2-positive breast cancer patients. In this phase I/II clinical trial, the researchers aim to establish the safety and efficacy of dual HER2 therapy in combination with palbociclib and anastrozole, which represents a novel and all biologic approach to the treatment of HR+, HER2+ metastatic breast cancer. Additionally, the researchers aim to examine potential biomarkers of response to palbociclib including cyclin D1, cyclin E1 and cyclin E2 expression levels, cdk 2, 4, and 6 levels, phosphorylated retinoblastoma expression and p16 levels. The researchers intend to use RNA sequencing to assess for other predictors of response in an unbiased manner to see if this correlates with inhibition of Ki-67 and phosphorylated retinoblastoma expression as well as evaluate for potential mechanisms of resistance.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Anastrozole, Palbociclib, Trastuzumab and Pertuzumab in Her-positive, Her2-positive Metastatic Breast
  • Official Title: A Multicenter, Phase I/II Trial of Anastrozole, Palbociclib, Trastuzumab and Pertuzumab in HeR-positive, Her2-positive Metastatic Breast Cancer

Clinical Trial IDs

  • ORG STUDY ID: GCO 17-0919
  • NCT ID: NCT03304080

Conditions

  • Breast Neoplasms
  • Breast Diseases

Interventions

DrugSynonymsArms
AnastrozoleArimidexHR-positive, Her2-positive Metastatic Breast Cancer
PalbociclibIbranceHR-positive, Her2-positive Metastatic Breast Cancer
TrastuzumabHerceptinHR-positive, Her2-positive Metastatic Breast Cancer
PertuzumabPerjetaHR-positive, Her2-positive Metastatic Breast Cancer

Purpose

This is a multicenter, phase I/II trial of anastrozole, palbociclib, trastuzumab, and pertuzumab is proposed as first-line therapy in metastatic hormone receptor-positive, HER2-positive breast cancer patients. In this phase I/II clinical trial, the researchers aim to establish the safety and efficacy of dual HER2 therapy in combination with palbociclib and anastrozole, which represents a novel and all biologic approach to the treatment of HR+, HER2+ metastatic breast cancer. Additionally, the researchers aim to examine potential biomarkers of response to palbociclib including cyclin D1 expression levels, phosphorylated retinoblastoma expression and p16 levels. The researchers intend to use RNA sequencing to assess for other predictors of response in an unbiased manner to see if this correlates with inhibition of Ki-67 and phosphorylated retinoblastoma expression as well as evaluate for potential mechanisms of resistance.

Trial Arms

NameTypeDescriptionInterventions
HR-positive, Her2-positive Metastatic Breast CancerExperimentalWomen with HR-positive, Her2-positive Metastatic Breast Cancer on trial of anastrozole, palbociclib, trastuzumab and pertuzumab
  • Anastrozole
  • Palbociclib
  • Trastuzumab
  • Pertuzumab

Eligibility Criteria

        Inclusion Criteria:

          -  Women with metastatic breast cancer, measurable or evaluable disease including bone
             metastasis only (as per the Response Evaluation Criteria in Solid Tumors [RECIST]
             v1.1)

          -  No prior systemic treatment for metastatic breast cancer

          -  Pathologic confirmation of metastatic breast cancer diagnosed by core needle biopsy

          -  Metastatic breast cancer with ER or PR positivity in ≥ 1% cells is eligible

          -  HER2 positive metastatic breast cancer if 3+ by an IHC method defined as uniform
             membrane staining for HER2 in 10% or more of tumor cells or demonstrate HER2 gene
             amplification by an ISH method (single probe, average HER2 copy number ≥6.0
             signals/cell; dual probe HER2/CEP17 ratio ≥2.0 with an average HER2 copy number ≥4.0
             signals/cell; dual probe HER2/chromosome enumeration probe (CEP) 17 ratio ≥2.0 with an
             average HER2 cop number <4.0 signals/cell; and HER2/CEP17 ratio <2.0 with an average
             HER2 copy number ≥6.0 signals/cell) or amplified by FISH > 2.0. High average copy
             number of HER2 (≥6.0 signals/cell) is considered positive regardless of the HER2/CEP17
             ratio.

          -  Women 18 years and older

          -  Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2

          -  Stable brain metastasis allowed (>2 weeks, clinically stable post treatment with
             surgery +/- radiation or radiation alone and off steroids)

          -  Transthoracic echocardiogram with ejection fraction > 50%

          -  Postmenopausal status or receiving ovarian ablation with a GnRH agonist such as
             goserelin or leuprolide. Postmenopausal status is defined by any one of the following
             criteria:

               -  Prior bilateral oophorectomy.

               -  Age ≥ 60 years.

               -  Age < 60 and amenorrhea for 12 or more months (in the absence of chemotherapy,
                  tamoxifen, or ovarian suppression) and FSH, LH, and estradiol in the
                  postmenopausal range per local normal.

        If the patient does not meet criteria for postmenopausal status but is receiving ovarian
        ablation therapy with a gonadotropin-releasing hormone (GnRH) agonist such as goserelin or
        leuprolide, the patient is eligible for the study, provided that the GnRH agonist is
        started at least 2 weeks prior to C1D1 of anti-estrogen therapy.

        3.1.11 Laboratory values (≤ 28 days prior to registration)

          -  Absolute Neutrophil Count (ANC) ≥ 1,500/mm3

          -  Platelet Count ≥ 75,000/ mm3

          -  Hg >9 g/dL

          -  Total Bilirubin ≤1.5 x upper limits of normal (ULN)

          -  Serum ALT and AST ≤ 2.5 x ULN (≤ 5 x ULN in patients with liver metastasis)

          -  Creatinine ≤ 1.5 x ULN

               -  Written informed consent prior to beginning specific protocol procedures,
                  including expected cooperation of the patients for the treatment and follow-up,
                  must be obtained and documented according to the local regulatory requirements

               -  A baseline CT chest/abdomen/pelvis and bone scan or PET/CT

               -  Negative serum or urine pregnancy test within 7 days prior to starting treatment

               -  Women of child-bearing potential and men must agree to use adequate contraception
                  prior to study entry, for the duration of study participation, and for 90 days
                  following completion of therapy. Should a woman become pregnant or suspect she is
                  pregnant while participating in this study, she should inform her treating
                  physician immediately.

        Note: Recommended methods of birth control are: The consistent use of an intrauterine
        device (IUD), Double barrier methods (Diaphragm with spermicidal gel or condoms with
        contraceptive foam), Sexual abstinence (no sexual intercourse) or Sterilization.

        Men must agree to use a condom and not father a child or donate sperm for the duration of
        the study and for 90 days after completion of therapy

        A female of child-bearing potential is any woman (regardless of sexual orientation, having
        undergone a tubal ligation, or remaining celibate by choice) who meets the following
        criteria:

          -  Has not undergone a hysterectomy or bilateral oophorectomy; or

          -  Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has
             had menses at any time in the preceding 12 consecutive months).

        Exclusion Criteria:

          -  Estrogen receptor negative metastatic breast carcinoma as defined as less than 1%
             stained cell

          -  HER2 negative metastatic breast carcinoma defined as 0 or 1+ by IHC or with a FISH
             ratio (HER2 gene copy/ chromosome 17) <2 if IHC 2+ by local institution standard
             protocol

          -  Any prior treatment for metastatic breast cancer. Note: Prior adjuvant therapy with
             trastuzumab and pertuzumab is permitted after a 6 month window following completion of
             adjuvant therapy has passed.

          -  Patients currently receiving anticancer therapies or who have received anticancer
             therapies within 2 weeks of the start of study drug (including chemotherapy, radiation
             therapy, and biologics)

          -  Patients, who have had a major surgery or significant traumatic injury within 4 weeks
             of start of study drug, patients who have not recovered from the side effects of any
             major surgery (defined as requiring general anesthesia) or patients that may require
             major surgery during the course of the study

          -  Prior treatment with any investigational drug within the preceding 2 weeks

          -  Co-administration with strong CYP3A4 inducers (e.g., phenytoin, rifampin,
             carbamazepine, St John's Wort, bosentan, efavirenz, etravirine, modafinil, and
             nafcillin), strong CYP3A4 inhibitors (e.g., clarithromycin, indinavir, itraconazole,
             ketoconazole, lopinavir/ritonavir, nefazodone, nelfinavir, posaconazole, ritonavir,
             saquinavir, telaprevir, telithromycin, verapamil, and voriconazole), and CYP3A4
             substrates (e.g., alfentanil, cyclosporine, dihydroergotamine, ergotamine, everolimus,
             fentanyl, pimozide, quinidine, sirolimus and tacrolimus). For a current table of
             Substrates, Inhibitors and Inducers please access the following
             website:http://www.fda.gov/Drugs/DevelopmentApprovalProcess/" See Appendix C.

          -  Uncontrolled brain metastases

          -  Leptomeningeal metastases

          -  Other malignancies within the past 3 years except for adequately treated carcinoma of
             the cervix or basal or squamous cell carcinomas of the skin.

          -  Patients who have any severe and/or uncontrolled medical conditions or other
             conditions that could affect their participation in the study such as:

               -  Symptomatic congestive heart failure of New York heart Association Class III or
                  IV

               -  Unstable angina pectoris, symptomatic congestive heart failure, myocardial
                  infarction within 6 months of start of study drug, serious uncontrolled cardiac
                  arrhythmia or any other clinically significant cardiac disease

               -  Severely impaired lung function as defined as spirometry and DLCO that is 50% of
                  the normal predicted value and/or 02 saturation that is 89% or less at rest on
                  room air

               -  Uncontrolled diabetes as defined by fasting serum glucose >1.5 x ULN

               -  Active (acute or chronic) or uncontrolled severe infections

               -  Liver disease such as cirrhosis, chronic active hepatitis or chronic persistent
                  hepatitis

          -  Impairment of gastrointestinal function or gastrointestinal disease that may
             significantly alter the absorption of Palbociclib (e.g., ulcerative disease,
             uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel
             resection)

          -  Patients with an active, bleeding diathesis

          -  History of noncompliance to medical regimens

          -  Patients unwilling to or unable to comply with the protocol

          -  Ongoing alcohol or drug addiction

          -  Female patients who are pregnant or breast feeding, or adults of reproductive
             potential who are not using effective birth control methods. If barrier contraceptives
             are being used, these must be continued throughout the trial by both sexes. Hormonal
             contraceptives are not acceptable as a method of contraception. (Women of childbearing
             potential must have a negative urine or serum pregnancy test within 7 days prior to
             starting treatment)

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to palbociclib, anastrozole, trastuzumab or pertuzumab.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Dose-Limiting Toxicity (DLT)
Time Frame:up to 3 months
Safety Issue:
Description:The dose-limiting toxicity (DLT) for palbociclib when administered in combination with anastrozole, trastuzumab and pertuzumab. A DLT will be defined as: Grade 3 or 4 non-hematologic toxicity Grade 3 neutropenia lasting greater than 21 days Grade 3 or 4 neutropenia with neutropenic fever or Grade 4 hematologic toxicity events experienced within the first 4 weeks (1 cycle) of study treatment. These will be assessed via the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI's CTCAE) v4.0 toxicity criteria.

Secondary Outcome Measures

Measure:Progression Free Survival
Time Frame:2 years
Safety Issue:
Description:The time from the start of treatment until confirmed disease progression or death from any cause, whichever occurs first.
Measure:Incidence of adverse events
Time Frame:2 years
Safety Issue:
Description:incidence of adverse events as graded by the NCI CTCAE v4.0

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Icahn School of Medicine at Mount Sinai

Trial Keywords

  • Breast Neoplasms
  • Breast Diseases
  • Palbociclib
  • Trastuzumab
  • Pertuzumab
  • Hormone Antagonists

Last Updated

October 3, 2017