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Anastrozole, Palbociclib, Trastuzumab and Pertuzumab in HR-positive, HER2-positive Metastatic Breast

Primary Purpose

Breast Neoplasms, Breast Diseases

Status
Active
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Anastrozole
Palbociclib
Trastuzumab
Pertuzumab
Sponsored by
Icahn School of Medicine at Mount Sinai
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Breast Neoplasms focused on measuring Breast Neoplasms, Breast Diseases, Palbociclib, Trastuzumab, Pertuzumab, Hormone Antagonists, Anastrozole, Arimidex, Ibrance, Perjeta

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Women or men 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 or men 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.
  • 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

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

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.

Sites / Locations

  • Mount Sinai Beth Israel Comprehensive Cancer Center West
  • Perlmutter Cancer Center NYU Langone
  • Mount Sinai West
  • New York Presbyterian Columbia Irving Comprehensive Cancer Center
  • New York Presbyterian Weill Cornell Medical Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

HR-positive, Her2-positive Metastatic Breast Cancer

Arm Description

Women and men with HR-positive, HER2-positive Metastatic Breast Cancer on trial of anastrozole, palbociclib, trastuzumab and pertuzumab

Outcomes

Primary Outcome Measures

Dose-Limiting Toxicity (DLT)
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)
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)
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.

Secondary Outcome Measures

Progression Free Survival
The time from the start of treatment until confirmed disease progression or death from any cause, whichever occurs first.
Incidence of adverse events
incidence of adverse events as graded by the NCI CTCAE v4.0

Full Information

First Posted
October 3, 2017
Last Updated
September 5, 2023
Sponsor
Icahn School of Medicine at Mount Sinai
Collaborators
Herbert Irving Comprehensive Cancer Center, Weill Medical College of Cornell University, NYU Langone Health
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1. Study Identification

Unique Protocol Identification Number
NCT03304080
Brief Title
Anastrozole, Palbociclib, Trastuzumab and Pertuzumab in HR-positive, HER2-positive Metastatic Breast
Official Title
A Multicenter, Phase I/II Trial of Anastrozole, Palbociclib, Trastuzumab and Pertuzumab in HR-positive, HER2-positive Metastatic Breast Cancer
Study Type
Interventional

2. Study Status

Record Verification Date
September 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
December 20, 2017 (Actual)
Primary Completion Date
July 2024 (Anticipated)
Study Completion Date
December 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Icahn School of Medicine at Mount Sinai
Collaborators
Herbert Irving Comprehensive Cancer Center, Weill Medical College of Cornell University, NYU Langone Health

4. Oversight

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
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Breast Neoplasms, Breast Diseases
Keywords
Breast Neoplasms, Breast Diseases, Palbociclib, Trastuzumab, Pertuzumab, Hormone Antagonists, Anastrozole, Arimidex, Ibrance, Perjeta

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
44 (Actual)

8. Arms, Groups, and Interventions

Arm Title
HR-positive, Her2-positive Metastatic Breast Cancer
Arm Type
Experimental
Arm Description
Women and men with HR-positive, HER2-positive Metastatic Breast Cancer on trial of anastrozole, palbociclib, trastuzumab and pertuzumab
Intervention Type
Drug
Intervention Name(s)
Anastrozole
Other Intervention Name(s)
Arimidex
Intervention Description
1 mg orally daily, day 1 to day 28
Intervention Type
Drug
Intervention Name(s)
Palbociclib
Other Intervention Name(s)
Ibrance
Intervention Description
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
Intervention Type
Drug
Intervention Name(s)
Trastuzumab
Other Intervention Name(s)
Herceptin
Intervention Description
8 mg/kg IV initial loading dose, followed by 6 mg/kg IV every 21 days
Intervention Type
Drug
Intervention Name(s)
Pertuzumab
Other Intervention Name(s)
Perjeta
Intervention Description
840 mg IV followed by a maintenance dose of 420 mg IV every 21 days
Primary Outcome Measure Information:
Title
Dose-Limiting Toxicity (DLT)
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.
Time Frame
up to 3 months
Title
Maximum Tolerated Dose (MTD)
Description
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.
Time Frame
up to 3 months
Title
Clinical Benefit Rate (CBR)
Description
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.
Time Frame
average of 6 months
Secondary Outcome Measure Information:
Title
Progression Free Survival
Description
The time from the start of treatment until confirmed disease progression or death from any cause, whichever occurs first.
Time Frame
2 years
Title
Incidence of adverse events
Description
incidence of adverse events as graded by the NCI CTCAE v4.0
Time Frame
2 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Women or men 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 or men 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. 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 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 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Amy Tiersten, MD
Organizational Affiliation
Icahn School of Medicine at Mount Sinai
Official's Role
Principal Investigator
Facility Information:
Facility Name
Mount Sinai Beth Israel Comprehensive Cancer Center West
City
New York
State/Province
New York
ZIP/Postal Code
10011
Country
United States
Facility Name
Perlmutter Cancer Center NYU Langone
City
New York
State/Province
New York
ZIP/Postal Code
10016
Country
United States
Facility Name
Mount Sinai West
City
New York
State/Province
New York
ZIP/Postal Code
10019
Country
United States
Facility Name
New York Presbyterian Columbia Irving Comprehensive Cancer Center
City
New York
State/Province
New York
ZIP/Postal Code
10032
Country
United States
Facility Name
New York Presbyterian Weill Cornell Medical Center
City
New York
State/Province
New York
ZIP/Postal Code
10065
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing 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.

Learn more about this trial

Anastrozole, Palbociclib, Trastuzumab and Pertuzumab in HR-positive, HER2-positive Metastatic Breast

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