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

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ClinicalTrials.gov Identifier: NCT03304080
Recruitment Status : Recruiting
First Posted : October 6, 2017
Last Update Posted : February 4, 2019
Sponsor:
Collaborators:
Herbert Irving Comprehensive Cancer Center
Weill Medical College of Cornell University
NYU Langone Health
Information provided by (Responsible Party):
Amy Tiersten, Icahn School of Medicine at Mount Sinai

Tracking Information
First Submitted Date  ICMJE October 3, 2017
First Posted Date  ICMJE October 6, 2017
Last Update Posted Date February 4, 2019
Actual Study Start Date  ICMJE December 20, 2017
Estimated Primary Completion Date November 1, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 3, 2017)
  • Dose-Limiting Toxicity (DLT) [ Time Frame: up to 3 months ]
    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.
  • Maximum Tolerated Dose (MTD) [ Time Frame: up to 3 months ]
    The maximum tolerated dose (MTD) for palbociclib when administered in combination with anastrozole, trastuzumab and pertuzumab. If > 33 % of patients experience a dose limiting toxicity (DLT) at any dose level, the dose level below that level will be considered the MTD. Or if the highest level has been reached and ≤ 33% of patients have experienced dose limiting toxicity (DLT), that will be considered the MTD.
  • Clinical Benefit Rate (CBR) [ Time Frame: average of 6 months ]
    CBR will be measured by the percentage of patients whose cancer shrinks or remains stable over the duration of the study. This will be measured as the sum of complete response, partial response, and stable disease for greater than or equal to 6 months.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03304080 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: October 3, 2017)
  • Progression Free Survival [ Time Frame: 2 years ]
    The time from the start of treatment until confirmed disease progression or death from any cause, whichever occurs first.
  • Incidence of adverse events [ Time Frame: 2 years ]
    incidence of adverse events as graded by the NCI CTCAE v4.0
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Anastrozole, Palbociclib, Trastuzumab and Pertuzumab in Her-positive, Her2-positive Metastatic Breast
Official Title  ICMJE A Multicenter, Phase I/II Trial of Anastrozole, Palbociclib, Trastuzumab and Pertuzumab in HeR-positive, Her2-positive Metastatic Breast Cancer
Brief Summary 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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Breast Neoplasms
  • Breast Diseases
Intervention  ICMJE
  • Drug: Anastrozole
    1 mg orally daily, day 1 to day 28
    Other Name: Arimidex
  • Drug: Palbociclib
    Dose I: 100 mg orally daily, day 1 to day 21, then 7 days off in a 28 day cycle (Phase 1 only) Dose II: 125 mg orally daily, day 1 to day 21, then 7 days off in a 28 day cycle
    Other Name: Ibrance
  • Drug: Trastuzumab
    8 mg/kg IV initial loading dose, followed by 6 mg/kg IV every 21 days
    Other Name: Herceptin
  • Drug: Pertuzumab
    840 mg IV followed by a maintenance dose of 420 mg IV every 21 days
    Other Name: Perjeta
Study Arms  ICMJE Experimental: HR-positive, Her2-positive Metastatic Breast Cancer
Women with HR-positive, Her2-positive Metastatic Breast Cancer on trial of anastrozole, palbociclib, trastuzumab and pertuzumab
Interventions:
  • Drug: Anastrozole
  • Drug: Palbociclib
  • Drug: Trastuzumab
  • Drug: Pertuzumab
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: October 3, 2017)
36
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE November 1, 2020
Estimated Primary Completion Date November 1, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 any evidence of ER or PR positivity in ≥ 1% cells in biopsy specimens from either a primary or metastatic site
  • Evidence of HER2 positive metastatic breast cancer in either a primary or metastatic site, 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.
    • Prior ovarian radiation for the purpose of ablation.
    • 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.

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 for the duration of the study and for 90 days after completion of therapy

Exclusion Criteria:

  • 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. (excluding radiation therapy for the purpose of ovarian ablation). 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 received prior endocrine therapy for fertility purposes will be eligible.
  • 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.
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Amy Tiersten, MD 212-824-8591 amy.tiersten@mssm.edu
Contact: Deborah Lehrer, RN 212-824-7308 deborah.lehrer@mssm.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03304080
Other Study ID Numbers  ICMJE GCO 17-0919
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: Data collected during the course of this clinical trial will primarily be shared with other investigators and University staff, the IRB, FDA, and other reporting agencies, and/or transferred to other collaborators. Prior to transfer, the data collected must comply with, and must be limited by, the MSH's guidelines for Protecting the Rights and Privacy of Human Subjects.
Responsible Party Amy Tiersten, Icahn School of Medicine at Mount Sinai
Study Sponsor  ICMJE Icahn School of Medicine at Mount Sinai
Collaborators  ICMJE
  • Herbert Irving Comprehensive Cancer Center
  • Weill Medical College of Cornell University
  • NYU Langone Health
Investigators  ICMJE
Principal Investigator: Amy Tiersten, MD Icahn School of Medicine at Mount Sinai
PRS Account Icahn School of Medicine at Mount Sinai
Verification Date January 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP