Breast Cancer
Conditions
Keywords
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.
Interventions
DRUGT-DM1
-T-DM1 will be administered intravenousely in clinic on day 1 of each 3-week cycle
DRUGPembrolizumab
-Pembrolizumab will be administered intravenousely in clinic on day 1 of each 3-week cycle
Sponsors
Merck Sharp & Dohme LLC
Dana-Farber Cancer Institute
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate | 2 years | Objective Response Rate (ORR) is defined as the percentage of patients with complete or partial response evaluated by RECIST 1.1. Per RECIST 1.1: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. |
| Progression Free Survival | 2 years | Progression Free Survival, estimated via Kaplan-Meier method, is defined as the time from study registration to radiographic evidence of disease progression or death due to any cause, whichever occurred first. Progression is measured using RECIST 1.1 criteria, defined as at least a 20% increase in size in target lesion and/or unequivocal progression of non-target lesions and/or appearance of new lesions. Patients alive without disease progression are censored at the date of last disease evaluation. |
| Duration Of Response | 2 years | The duration of response, estimated via Kaplan-Meier method, is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started, or death due to any cause. Participants without events reported are censored at the last disease evaluation). |
| Disease Control Rate | 18 weeks | Disease Control Rate will be determined by looking at the number of subjects who have either a complete response, partial response, or stable disease for greater than or equal to 18 weeks, per RECIST 1.1 |
| Overall Survival Rate | 5 years | OS based on the Kaplan-Meier method is defined as the time from study entry to death or censored at date last known alive. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Pembrolizumab Combine With Trastuzumab Emtansine * All patients received 200mg Pembro + 3.6mg/kg T-DM1
* 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
T-DM1: -T-DM1 will be administered intravenousely in clinic on day 1 of each 3-week cycle
Pembrolizumab: -Pembrolizumab will be administered intravenousely in clinic on day 1 of each 3-week cycle | 20 |
| Total | 20 |
Baseline characteristics
| Characteristic | Pembrolizumab Combine With Trastuzumab Emtansine |
|---|---|
| Age, Continuous | 54 years |
| Disease-free interval ≤2 years | 5 Participants |
| Disease-free interval >2 years | 6 Participants |
| Disease-free interval Dates missing | 4 Participants |
| Disease-free interval De novo (metastatic disease at primary diagnosis) | 5 Participants |
| Disease sites at trial enrollment - Bone | 9 Participants |
| Disease sites at trial enrollment - Breast/chest wall | 10 Participants |
| Disease sites at trial enrollment - Central nervous system | 1 Participants |
| Disease sites at trial enrollment - Liver | 4 Participants |
| Disease sites at trial enrollment - Lung/pleura | 9 Participants |
| Disease sites at trial enrollment - Lymph node | 13 Participants |
| Disease sites at trial enrollment - Other soft tissue | 3 Participants |
| ECOG at baselin 0 | 14 Participants |
| ECOG at baselin 1 | 5 Participants |
| ECOG at baselin 2 | 1 Participants |
| ER/PR status at initial diagnosis ER and/or PR positive | 14 Participants |
| ER/PR status at initial diagnosis ER and PR negative | 6 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 20 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Lines of chemotherapy for metastatic disease | 1 Line |
| Prior therapy in any setting - Anthracycline chemotherapy | 5 Participants |
| Prior therapy in any setting - Pertuzumab | 20 Participants |
| Prior therapy in any setting - Taxane chemotherapy | 20 Participants |
| Prior therapy in any setting - T-DM1 | 0 Participants |
| Prior therapy in any setting - Trastuzumab | 20 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 16 Participants |
| Region of Enrollment United States | 20 participants |
| Sex: Female, Male Female | 20 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 7 / 20 |
| other Total, other adverse events | 20 / 20 |
| serious Total, serious adverse events | 2 / 20 |
Outcome results
Primary
Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]
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
Time frame: 21 days
Population: The analysis population is patients that were enrolled in the dose de-escalation (dose finding) stage.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pembrolizumab Combine With Trastuzumab Emtansine | Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] | 0 Participants |
Secondary
Disease Control Rate
Disease Control Rate will be determined by looking at the number of subjects who have either a complete response, partial response, or stable disease for greater than or equal to 18 weeks, per RECIST 1.1
Time frame: 18 weeks
Population: All participants who have received at least one dose of study medication at the recommended phase 2 dose and had measurable disease were assessed for disease control rate.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pembrolizumab Combine With Trastuzumab Emtansine | Disease Control Rate | 60 percentage of participants |
Secondary
Duration Of Response
The duration of response, estimated via Kaplan-Meier method, is measured from the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started, or death due to any cause. Participants without events reported are censored at the last disease evaluation).
Time frame: 2 years
Population: All participants who have received at least one dose of study medication at the recommended phase 2 dose and had measurable disease were assessed for duration of response
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab Combine With Trastuzumab Emtansine | Duration Of Response | 10.1 month |
Secondary
Objective Response Rate
Objective Response Rate (ORR) is defined as the percentage of patients with complete or partial response evaluated by RECIST 1.1. Per RECIST 1.1: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Time frame: 2 years
Population: All participants who have received at least one dose of study medication at the recommended phase 2 dose and had measurable disease were assessed for objective response rate.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pembrolizumab Combine With Trastuzumab Emtansine | Objective Response Rate | 20 percentage of participants |
Secondary
Overall Survival Rate
OS based on the Kaplan-Meier method is defined as the time from study entry to death or censored at date last known alive.
Time frame: 5 years
Population: All participants who have received at least one dose of study medication at the recommended phase 2 dose will be assessed for overall survival
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab Combine With Trastuzumab Emtansine | Overall Survival Rate | NA month |
Secondary
Progression Free Survival
Progression Free Survival, estimated via Kaplan-Meier method, is defined as the time from study registration to radiographic evidence of disease progression or death due to any cause, whichever occurred first. Progression is measured using RECIST 1.1 criteria, defined as at least a 20% increase in size in target lesion and/or unequivocal progression of non-target lesions and/or appearance of new lesions. Patients alive without disease progression are censored at the date of last disease evaluation.
Time frame: 2 years
Population: All participants who have received at least one dose of study medication at the recommended phase 2 dose were assessed for PFS
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pembrolizumab Combine With Trastuzumab Emtansine | Progression Free Survival | 9.6 month |