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A Study Of Pembrolizumab In Combination With Trastuzumab-DM1

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT03032107
Recruitment Status : Active, not recruiting
First Posted : January 26, 2017
Last Update Posted : June 28, 2021
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
Sara Tolaney, Dana-Farber Cancer Institute

Tracking Information
First Submitted Date  ICMJE January 23, 2017
First Posted Date  ICMJE January 26, 2017
Last Update Posted Date June 28, 2021
Actual Study Start Date  ICMJE February 17, 2017
Actual Primary Completion Date October 29, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: January 24, 2017)
Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] [ Time Frame: 21 days ]
The number and type of DLTs as defined in the protocol that occur during the first 21 days of treatment and all maximum grade of all treatment-related adverse events using CTCAE v4.0 will be used to identify a safe and tolerable dose
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 24, 2017)
  • Objective Response Rate [ Time Frame: 2 years ]
  • Progression Free Survival [ Time Frame: 2 years ]
  • Duration Of Response [ Time Frame: 2 years ]
  • Disease Control Rate [ Time Frame: 18 weeks ]
  • Overall Survival Rate [ Time Frame: 5 years ]
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 A Study Of Pembrolizumab In Combination With Trastuzumab-DM1
Official Title  ICMJE A Phase 1b Study Of Pembrolizumab In Combination With Trastuzumab-DM1 In Metastatic HER2-Positive Breast Cancer
Brief Summary

This research study is studying a combination of drugs as a possible treatment for metastatic breast cancer.

The interventions involved in this study are:

  • Pembrolizumab
  • Trastuzumab emtansine (also called T-DM1)
Detailed Description

This research study is a Phase I clinical trial, which tests the safety of an investigational intervention and also tries to define the appropriate dose of the investigational intervention to use for further studies. "Investigational" means that the intervention is being studied. It also means that the FDA (U.S. Food and Drug Administration) has not approved the combination of Pembrolizumab and T-DM1 for use in patients, including people with your type of cancer.

This study will determine what amount (or dose) of Pembrolizumab and of T-DM1 is safe for people to take and what effects, good or bad, this combination may have on participants and their disease.

The FDA has not approved Pembrolizumab for this specific disease but it has been approved in the United Sates for the treatment of other types of cancer.

The FDA has approved Trastuzumab emtansine (T-DM1) as a treatment option for this type of breast cancer

The combination of Pembrolizumab and T-DM1 is investigational. It is thought that together these drugs to help get the immune system to attack tumor cells and kill cancer cells that have the HER2 protein. However, it is not known if giving the two study drugs at the same time will have a better anti-cancer effect than giving each treatment on its own.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Breast Cancer
Intervention  ICMJE
  • Drug: T-DM1
    -T-DM1 will be administered intravenousely in clinic on day 1 of each 3-week cycle
    Other Name: Trastuzumab emtansine
  • Drug: Pembrolizumab
    -Pembrolizumab will be administered intravenousely in clinic on day 1 of each 3-week cycle
    Other Name: Keytruda
Study Arms  ICMJE Experimental: Pembrolizumab Combine With Trastuzumab Emtansine
  • Pembrolizumab will be administered intravenousely in clinic on day 1 of each 3-week cycle
  • Pembrolizumab will be administered prior to T-DM1 administration
  • Pembrolizumab will be given at a predetermine dose
  • T-DM1 will be administered intravenousely in clinic on day 1 of each 3-week cycle
  • T-DM1 will be given at a predetermine dose
  • Drug: T-DM1
  • Drug: Pembrolizumab
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Estimated Enrollment  ICMJE
 (submitted: January 24, 2017)
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE January 1, 2025
Actual Primary Completion Date October 29, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Patients must have histologically or cytologically confirmed invasive breast cancer, with stage IV disease. Patients without pathologic or cytologic confirmation of metastatic disease should have unequivocal evidence of metastasis from physical examination or radiologic evaluation.
  • Either the primary tumor and/or the metastasis must have been tested for ER, PR and HER2. Patient must have HER2+ breast cancer per ASCO CAP guidelines 2013.
  • Prior chemotherapy:

    • History of prior therapy with trastuzumab and a taxane, separately or in combination, is required.
    • Patients must have either received one line of prior therapy for metastatic breast cancer, or have developed a disease recurrence during or within 6 months after completing adjuvant therapy.
    • No prior treatment with T-DM1 is allowed.
    • Last dose of chemotherapy must be at least 21 days prior to registration.
  • Prior biologic therapy:

    --Patients must have discontinued all biologic or investigational therapy at least 21 days before registration.

  • Prior radiation therapy:

    • Patients may have received prior radiation therapy in either the metastatic or early-stage setting.
    • Radiation therapy must be completed at least 14 days prior to registration.
  • In the dose de-escalation cohort: Subjects must have evaluable disease. In the expansion cohort: Subjects must have at least one lesion that is not within a previously radiated field that is measurable on computerized tomography (CT) or magnetic resonance imaging (MRI) scan per RECIST version 1.1. Bone lesions are not considered measurable by definition.
  • Age is ≥18 years.
  • ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A)
  • Participants must have normal organ and marrow function as defined below:

    • absolute neutrophil count ≥1,500/μl
    • platelets ≥100,000/μl
    • hemoglobin ≥9 g/dL
    • total bilirubin ≤1.5mg/dL (≤2.0 in patients with known Gilberts syndrome)
    • AST(SGOT)/ALT(SGPT) ≤2.5 × institutional ULN. ≤5.0 × institutional ULN for patients with documented liver metastases.
    • albumin >2.5mg/dL
    • serum creatinine ≤1.5mg/dL or calculated GFR ≥60 mL/min
    • INR/PT ≤1.5 times ULN unless participant is receiving anticoagulant therapy, as long as PT or PTT is within therapeutic range of intended use of anticoagulants
    • aPTT/PTT ≤1.5 times ULN unless participant is receiving anticoagulant therapy, as long as PT or PTT is within therapeutic range of intended use of anticoagulants
  • Participants enrolling in the dose expansion must have tissue that is amenable to biopsy and be willing to undergo a fresh tissue biopsy at baseline. Participants who undergo an attempted research biopsy procedure for the purpose of this protocol, and in whom inadequate tissue is obtained, are not required to undergo a repeat biopsy in order to continue on protocol.
  • The effects of pembrolizumab on the developing human fetus are unknown. For this reason and because tratuzumab, a component of T-DM1, is known to be teratogenic, women of child-bearing potential and men of childbearing potential must agree to use adequate contraception starting with the first dose of study therapy, for the duration of study participation, and for an additional 120 days after the last dose of study medication. Note: abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject.

    • Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, the treating physician and principal investigator should be informed immediately.
    • While on the study, women should not breast-feed.
    • Subjects of childbearing potential are defined as those who have not been surgically sterilized and/or have had a menstrual period in the past year
  • Female subject of child-bearing potential must have a negative urine or serum pregnancy within 72 hours prior to receiving the first dose of study medication. If a urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.
  • Patients on bisphosphonates may continue receiving bisphosphonate therapy during study treatment.
  • Left ventricular ejection fraction (LVEF) must be within institutional limits of normal as assessed by echocardiogram or MUGA documented within 28 days prior to first dose of study drug.
  • Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

  • The subject has received another investigational agent within 21 days of the first dose of study drug.
  • The subject has received prior pembrolizumab or any other anti-PD-1 , anti-PD-L1, or anti-PD-L2 therapy, or has participated in any prior studies involving pembrolizumab.
  • Pre-existing neuropathy greater than or equal to grade 2.
  • Hypersensitivity to pembrolizumab or T-DM1 or any of their excipients.
  • The subject has any history or evidence of active, non-infectious pneumonitis or interstitial lung disease.
  • Known brain metastases that are untreated, symptomatic, or require therapy to control symptoms. Participants with previously diagnosed brain metastases are eligible if they have completed treatment at least one month prior to trial therapy initiation, are neurologically stable with an absence of new neurological symptoms for at least 4 weeks prior to study entry, and have recovered from effects of radiotherapy or surgery. Any corticosteroid use for brain metastases must have been discontinued without the subsequent appearance of symptoms for ≥2 weeks before the first study drug. Treatment for brain metastases may include whole brain radiotherapy, radiosurgery, or a combination as deemed appropriate by the treating physician.
  • Known carcinomatous meningitis.
  • The subject has an uncontrolled intercurrent illness including, but not limited to, uncontrolled hypertension, unstable angina pectoris, uncontrolled cardiac arrhythmia, congestive heart failure (New York Heart Association Class III or IV; see Appendix B), active ischemic heart disease, myocardial infarction within the previous six months, uncontrolled diabetes mellitus, chronic liver or renal disease, or severe malnutrition.
  • Concurrent use of potent CYP3A4 inhibitors (see Appendix C), such as ketoconazole and erythromycin, should be avoided during the study treatment with T-DM1.
  • Active infection requiring intravenous antibiotics at cycle 1 day 1.
  • Individuals with a history of a second malignancy are ineligible except for the following circumstances. Individuals with a history of other malignancies are eligible if they have been disease-free for at least 5 years and are deemed by the investigator to be at low risk for recurrence of that malignancy. Individuals with the following cancers are eligible if diagnosed and treated within the past 5 years: cervical cancer in situ, and non-melanoma cancer of the skin. Patients with other cancers diagnosed within the past 5 years and felt to be at low risk of recurrence should be discussed with the study sponsor to determine eligibility.
  • The subject has a medical condition that requires chronic systemic steroid therapy or any other form of immunosuppressive medication including disease modifiying agents, or has required such therapy in the last 2 years. Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
  • The subject has an active autoimmune disease or a documented history of autoimmune disease or syndrome that requires systemic steroids or immunosuppressive agents.
  • The participant is positive for Hepatitis B surface antigen, or Hepatitis C RNA.
  • Known HIV-positive participants. HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with pembrolizumab. In addition, these participants are at increased risk of lethal infections with bone marrow suppressive therapy, i.e. nab-paclitaxel. Appropriate studies will be undertaken in participants receiving combination antiretroviral therapy when indicated.
  • The subject has received a live vaccine within 28 days of planned start of study therapy. Note: seasonal influenza vaccines for infection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (i.e. Flu-Mist ®) are live attenuated vaccines, and are not allowed
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
Administrative Information
NCT Number  ICMJE NCT03032107
Other Study ID Numbers  ICMJE 16-492
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
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Sara Tolaney, Dana-Farber Cancer Institute
Study Sponsor  ICMJE Dana-Farber Cancer Institute
Collaborators  ICMJE Merck Sharp & Dohme Corp.
Investigators  ICMJE
Principal Investigator: Sara Tolaney, MD MPH Dana-Farber Cancer Institute
PRS Account Dana-Farber Cancer Institute
Verification Date June 2021

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