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Study of Pembrolizumab Plus Fulvestrant in Hormone Receptor Positive, HER-2 Negative Advanced/Metastatic Breast Cancer Patients

Primary Purpose

Breast Cancer

Status
Active
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Pembrolizumab
Fulvestrant
Sponsored by
Nancy Chan, MD
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Breast Cancer

Eligibility Criteria

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

Inclusion Criteria:

Subject must meet all of the following applicable inclusion criteria to participate in this study:

  • Written informed consent and HIPAA authorization for release of personal health information. NOTE: HIPAA authorization may be included in the informed consent or obtained separately.
  • Men [29] and women ≥ 18 years of age at the time of informed consent. NOTE: Both pre- and post-menopausal women are eligible. Patients who are premenopausal should either undergo bilateral oophorectomy or receive ovarian suppression according to institutional standards. Male patients will be treated as premenopausal females and receive a GnRH agonist.
  • ECOG Performance Status of 0 or 1 within 28 days prior to registration.
  • Histologic or cytologic diagnosis of metastatic breast cancer.
  • Has received no more than two lines of prior therapy for advanced non-resectable/metastatic disease. Prior lines can can be either chemotherapy or hormonal therapy. Prior or current fulvestrant is allowed. Combination therapy is considered as one regimen.
  • Tumor is estrogen receptor positive (ER+) and/or (PR+), HER-2 negative (HER2-). ER and PR positivity is defined as >1%. HER-2 negative is defined as by IHC (0, 1+) or FISH. HER2 positive test result includes: 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/CEP17 ratio ≥2.0 with an average HER2copy number <4.0 signals/cell; or Dual-probe HER2/CEP17 ratio < 2.0 with an average HER2 copy number ≥6.0 signals/cell. Equivocal findings for IHC as 2+ should be reflexed to FISH. Equivocal results by FISH may be considered with approval from the Sponsor-Investigator.
  • Measurable disease based on RECIST 1.1 within 28 days prior to registration. Except in patients with bone-only disease, in the absence of measurable disease, evaluable bone lesion is allowed. NOTE: Bone-only disease is the sole non-measurable disease site allowed and biopsy is required. Measurable disease is required in all other cases.
  • Be willing to provide tissue from a newly obtained core or excisional biopsy of a tumor lesion. NOTE: Subjects for whom newly-obtained fresh tissue samples cannot be provided (e.g. inaccessible or subject safety concern) may submit an archived specimen only upon agreement from the Sponsor-Investigator.
  • Normal cardiac function as determined by treating physician per institutional standards via echocardiogram (ECHO) performed within 28 days prior to registration.
  • Prior chemotherapy must be completed at least 28 days prior to registration or at least 14 days prior to registration for targeted therapy.
  • Prior hormonal therapy or radiation therapy must be completed at least 14 days prior to registration. If subject is currently receiving fulvestrant, it may continue without interruption as per standard of care.
  • The subject must have recovered from all reversible acute toxic effects of the regimen (other than alopecia) to ≤ Grade 1 or baseline. NOTE: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study. NOTE: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to study registration, as determined by the enrolling physician.
  • Demonstrate adequate organ function as defined in the table below; all screening labs will be performed within 28 days of study registration.

    • Hematological

      • Absolute Neutrophil Count (ANC): ≥ 1500/mm3
      • Platelets: ≥100,000 / mcL
      • Hemoglobin (Hgb): ≥ 9 g/dL or ≥5.6 mmol/L without transfusion or EPO dependency (within 7 days of assessment)
    • Renal

      ---Serum creatinine OR Measured or calculateda creatinine clearance (GFR can also be used in place of creatinine or CrCl): ≤1.5 × upper limit of normal (ULN) OR ≥30 mL/min for subjects with creatinine levels > 1.5 × institutional ULN

    • Hepatic

      • Serum total bilirubin: ≤ 1.5 X ULN OR
      • Direct bilirubin ≤ ULN for subjects with total bilirubin levels: > 1.5 ULN
      • AST (SGOT) and ALT (SGPT): ≤ 2.5 × ULN
      • Albumin: >2.5 mg/dL
    • Coagulation ---International Normalized Ratio (INR) or Prothrombin Time (PT) Activated Partial Thromboplastin Time (aPTT): ≤1.5 × ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants aCreatinine clearance will be calculated per institutional standard.
  • Females of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to study registration. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. NOTE: Females are considered of childbearing potential unless: they are postmenopausal; are surgically sterile; or they have a congenital or acquired condition that prevents childbearing. See the protocol for definitions. NOTE: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.
  • Females and males of reproductive potential must be willing to abstain from heterosexual activity which could result in pregnancy or agree to use an adequate method of contraception as outlined in the protocol. Hormonal contraceptives are contraindicated in this population and are not allowed. Contraception will begin from the time of informed consent through 120 days after the last dose of study drug(s).

Exclusion Criteria:

  • Is currently receiving an investigational agent or has received an investigational agent or used an investigational device within 28 days of study registration.
  • Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to study registration. Subjects are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger.

NOTE: Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.

  • Has a known history of active TB (Bacillus Tuberculosis). NOTE: TB testing is not required.
  • Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). NOTE: HIV testing is not required.
  • Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).

NOTE: Hepatitis B and Hepatitis C testing is not required.

  • Hypersensitivity to pembrolizumab or any of its excipients.
  • Has received prior chemotherapy within 28 days prior to study registration or has received prior hormonal/targeted therapy within 14 days prior to study registration
  • More than two lines of chemotherapy or more than two lines of hormonal therapy excludes participation.
  • Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer.
  • Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.
  • Has known history of non-infectious pneumonitis/interstitial lung disease that required steroids or has any evidence of active pneumonitis/interstitial lung disease.
  • Has known history of, or any evidence of active interstitial lung disease, Class II-IV congestive heart failure, or myocardial infarction within 6 months from randomization.
  • Active infection requiring systemic therapy.
  • Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
  • Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
  • Breastfeeding during the projected duration of the trial, starting with the screening visit through 120 days after the last dose of trial treatment. NOTE: breast milk cannot be stored for future use while the mother is being treated on study.
  • Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent
  • Has received a live vaccine or live-attenuated vaccine within 30 days of study registration. Administration of killed vaccines is allowed.

Sites / Locations

  • Michigan State University, Breslin Cancer Center
  • University of Nebraska Medical Center
  • Rutgers Cancer Institute of New Jersey
  • New York University Clinical Cancer Center
  • University of Wisconsin

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Pembrolizumab + Fulvestrant

Arm Description

Pembrolizumab 200m IV q3W + Fulvestrant. Loading dose 500mg IV IM q2W x3 followed by 500mg IM q4W

Outcomes

Primary Outcome Measures

Clinical Benefit Ratio (CBR)
Clinical benefit ratio (CBR) is defined as the percentage of patients that achieve CR, PR, or stable disease for a minimum of four months. Patients will be evaluated for response by RECIST 1.1 and irRECIST.

Secondary Outcome Measures

Safety profile of pembrolizumab plus fulvestrant
To describe the toxicity profile of pembrolizumab plus fulvestrant in patients with hormone receptor positive, HER2 negative advanced/metastatic breast cancer. The toxicity profile will report all grade 3 and 4 toxicities as defined by the NCI Common Terminology Criteria for Adverse Events (NCI CTCAE) v4
Progression free survival (PFS)
Progression free survival is defined as the time from date of treatment start until the criteria for disease progression is met or death from any cause. PFS will be assessed by RECIST 1.1 and irRECIST
Durable response rate (DRR)
Durable response rate is defined as the number of months that a stable disease, partial or complete response is observed.
Overall Survival
Overall survival is defined as defined as the time from date of treatment start until death

Full Information

First Posted
January 2, 2018
Last Updated
July 3, 2023
Sponsor
Nancy Chan, MD
Collaborators
Merck Sharp & Dohme LLC
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1. Study Identification

Unique Protocol Identification Number
NCT03393845
Brief Title
Study of Pembrolizumab Plus Fulvestrant in Hormone Receptor Positive, HER-2 Negative Advanced/Metastatic Breast Cancer Patients
Official Title
A Phase II Study of Pembrolizumab Plus Fulvestrant in Hormone Receptor Positive, HER-2 Negative Advanced/Metastatic Breast Cancer Patients: Big Ten Cancer Research Consortium BTCRC-BRE16-042
Study Type
Interventional

2. Study Status

Record Verification Date
July 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
January 29, 2018 (Actual)
Primary Completion Date
June 26, 2023 (Actual)
Study Completion Date
September 1, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Nancy Chan, MD
Collaborators
Merck Sharp & Dohme LLC

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Pembrolizumab Plus Fulvestrant in Hormone Receptor Positive, HER-2 Negative Advanced/Metastatic Breast Cancer Patients
Detailed Description
This is a non-randomized, multi-site, open-label Phase II trial for subjects with metastatic, hormone receptor positive, HER2 negative breast cancer. The study will enroll 47 patients to evaluate the anti-tumor activity of pembrolizumab with fulvestrant as measured by RECIST 1.1 tumor response and by progression free survival. We expect that if the immune response is augmented by the addition of pembrolizumab, significant change in durability of response will be noted. Patients will be treated with pembrolizumab dosed at 200 mg intravenous infusion in combination with standard fulvestrant 500mg intramuscular injection.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Breast Cancer

7. Study Design

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

8. Arms, Groups, and Interventions

Arm Title
Pembrolizumab + Fulvestrant
Arm Type
Experimental
Arm Description
Pembrolizumab 200m IV q3W + Fulvestrant. Loading dose 500mg IV IM q2W x3 followed by 500mg IM q4W
Intervention Type
Drug
Intervention Name(s)
Pembrolizumab
Other Intervention Name(s)
Keytruda
Intervention Description
Pembrolizumab 200mg IV, 21 day cycles
Intervention Type
Drug
Intervention Name(s)
Fulvestrant
Other Intervention Name(s)
Faslodex
Intervention Description
Fulvestrant, 500mg IM, Loading dose: C1 D1 & 15. Thereafter, Q4 wks
Primary Outcome Measure Information:
Title
Clinical Benefit Ratio (CBR)
Description
Clinical benefit ratio (CBR) is defined as the percentage of patients that achieve CR, PR, or stable disease for a minimum of four months. Patients will be evaluated for response by RECIST 1.1 and irRECIST.
Time Frame
36 months
Secondary Outcome Measure Information:
Title
Safety profile of pembrolizumab plus fulvestrant
Description
To describe the toxicity profile of pembrolizumab plus fulvestrant in patients with hormone receptor positive, HER2 negative advanced/metastatic breast cancer. The toxicity profile will report all grade 3 and 4 toxicities as defined by the NCI Common Terminology Criteria for Adverse Events (NCI CTCAE) v4
Time Frame
36 months
Title
Progression free survival (PFS)
Description
Progression free survival is defined as the time from date of treatment start until the criteria for disease progression is met or death from any cause. PFS will be assessed by RECIST 1.1 and irRECIST
Time Frame
36 months
Title
Durable response rate (DRR)
Description
Durable response rate is defined as the number of months that a stable disease, partial or complete response is observed.
Time Frame
36 months
Title
Overall Survival
Description
Overall survival is defined as defined as the time from date of treatment start until death
Time Frame
36 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Subject must meet all of the following applicable inclusion criteria to participate in this study: Written informed consent and HIPAA authorization for release of personal health information. NOTE: HIPAA authorization may be included in the informed consent or obtained separately. Men [29] and women ≥ 18 years of age at the time of informed consent. NOTE: Both pre- and post-menopausal women are eligible. Patients who are premenopausal should either undergo bilateral oophorectomy or receive ovarian suppression according to institutional standards. Male patients will be treated as premenopausal females and receive a GnRH agonist. ECOG Performance Status of 0 or 1 within 28 days prior to registration. Histologic or cytologic diagnosis of metastatic breast cancer. Has received no more than two lines of prior therapy for advanced non-resectable/metastatic disease. Prior lines can can be either chemotherapy or hormonal therapy. Prior or current fulvestrant is allowed. Combination therapy is considered as one regimen. Tumor is estrogen receptor positive (ER+) and/or (PR+), HER-2 negative (HER2-). ER and PR positivity is defined as >1%. HER-2 negative is defined as by IHC (0, 1+) or FISH. HER2 positive test result includes: 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/CEP17 ratio ≥2.0 with an average HER2copy number <4.0 signals/cell; or Dual-probe HER2/CEP17 ratio < 2.0 with an average HER2 copy number ≥6.0 signals/cell. Equivocal findings for IHC as 2+ should be reflexed to FISH. Equivocal results by FISH may be considered with approval from the Sponsor-Investigator. Measurable disease based on RECIST 1.1 within 28 days prior to registration. Except in patients with bone-only disease, in the absence of measurable disease, evaluable bone lesion is allowed. NOTE: Bone-only disease is the sole non-measurable disease site allowed and biopsy is required. Measurable disease is required in all other cases. Be willing to provide tissue from a newly obtained core or excisional biopsy of a tumor lesion. NOTE: Subjects for whom newly-obtained fresh tissue samples cannot be provided (e.g. inaccessible or subject safety concern) may submit an archived specimen only upon agreement from the Sponsor-Investigator. Normal cardiac function as determined by treating physician per institutional standards via echocardiogram (ECHO) performed within 28 days prior to registration. Prior chemotherapy must be completed at least 28 days prior to registration or at least 14 days prior to registration for targeted therapy. Prior hormonal therapy or radiation therapy must be completed at least 14 days prior to registration. If subject is currently receiving fulvestrant, it may continue without interruption as per standard of care. The subject must have recovered from all reversible acute toxic effects of the regimen (other than alopecia) to ≤ Grade 1 or baseline. NOTE: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify for the study. NOTE: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to study registration, as determined by the enrolling physician. Demonstrate adequate organ function as defined in the table below; all screening labs will be performed within 28 days of study registration. Hematological Absolute Neutrophil Count (ANC): ≥ 1500/mm3 Platelets: ≥100,000 / mcL Hemoglobin (Hgb): ≥ 9 g/dL or ≥5.6 mmol/L without transfusion or EPO dependency (within 7 days of assessment) Renal ---Serum creatinine OR Measured or calculateda creatinine clearance (GFR can also be used in place of creatinine or CrCl): ≤1.5 × upper limit of normal (ULN) OR ≥30 mL/min for subjects with creatinine levels > 1.5 × institutional ULN Hepatic Serum total bilirubin: ≤ 1.5 X ULN OR Direct bilirubin ≤ ULN for subjects with total bilirubin levels: > 1.5 ULN AST (SGOT) and ALT (SGPT): ≤ 2.5 × ULN Albumin: >2.5 mg/dL Coagulation ---International Normalized Ratio (INR) or Prothrombin Time (PT) Activated Partial Thromboplastin Time (aPTT): ≤1.5 × ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants aCreatinine clearance will be calculated per institutional standard. Females of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to study registration. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. NOTE: Females are considered of childbearing potential unless: they are postmenopausal; are surgically sterile; or they have a congenital or acquired condition that prevents childbearing. See the protocol for definitions. NOTE: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject. Females and males of reproductive potential must be willing to abstain from heterosexual activity which could result in pregnancy or agree to use an adequate method of contraception as outlined in the protocol. Hormonal contraceptives are contraindicated in this population and are not allowed. Contraception will begin from the time of informed consent through 120 days after the last dose of study drug(s). Exclusion Criteria: Is currently receiving an investigational agent or has received an investigational agent or used an investigational device within 28 days of study registration. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to study registration. Subjects are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger. NOTE: Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. Has a known history of active TB (Bacillus Tuberculosis). NOTE: TB testing is not required. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). NOTE: HIV testing is not required. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected). NOTE: Hepatitis B and Hepatitis C testing is not required. Hypersensitivity to pembrolizumab or any of its excipients. Has received prior chemotherapy within 28 days prior to study registration or has received prior hormonal/targeted therapy within 14 days prior to study registration More than two lines of chemotherapy or more than two lines of hormonal therapy excludes participation. Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability. Has known history of non-infectious pneumonitis/interstitial lung disease that required steroids or has any evidence of active pneumonitis/interstitial lung disease. Has known history of, or any evidence of active interstitial lung disease, Class II-IV congestive heart failure, or myocardial infarction within 6 months from randomization. Active infection requiring systemic therapy. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. Breastfeeding during the projected duration of the trial, starting with the screening visit through 120 days after the last dose of trial treatment. NOTE: breast milk cannot be stored for future use while the mother is being treated on study. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent Has received a live vaccine or live-attenuated vaccine within 30 days of study registration. Administration of killed vaccines is allowed.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Nancy Chan
Organizational Affiliation
Rutgers Cancer Institute of New Jersey
Official's Role
Principal Investigator
Facility Information:
Facility Name
Michigan State University, Breslin Cancer Center
City
Lansing
State/Province
Michigan
ZIP/Postal Code
48910
Country
United States
Facility Name
University of Nebraska Medical Center
City
Omaha
State/Province
Nebraska
ZIP/Postal Code
68198
Country
United States
Facility Name
Rutgers Cancer Institute of New Jersey
City
New Brunswick
State/Province
New Jersey
ZIP/Postal Code
08903
Country
United States
Facility Name
New York University Clinical Cancer Center
City
New York
State/Province
New York
ZIP/Postal Code
10016
Country
United States
Facility Name
University of Wisconsin
City
Madison
State/Province
Wisconsin
ZIP/Postal Code
53705
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
Undecided

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Study of Pembrolizumab Plus Fulvestrant in Hormone Receptor Positive, HER-2 Negative Advanced/Metastatic Breast Cancer Patients

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