Breast Cancer
Conditions
Keywords
Breast Cancer
Brief summary
This research study is exploring chemotherapy in combination with immunotherapy (a therapy that uses the body's own immune system to control cancer) as a possible treatment for hormone receptor positive breast cancer. The interventions involved in this study are: * Pembrolizumab (MK-3475; Keytruda™) * Nab-Paclitaxel (Abraxane
Detailed description
This research study is a Pilot Study, which is the first time investigators are examining this study intervention. In this research study, the investigators are looking at how the participants body and tumor respond to the combination of Nab-paclitaxel and Pembrolizumab. Also, the investigators will be examining the participants tumor tissue to learn more about the disease. The FDA (the U.S. Food and Drug Administration) has not approved Pembrolizumab for this specific disease; but it has been approved in the United States for the treatment of other diseases. The FDA has not approved Nab-paclitaxel as a treatment option for this type of breast cancer; but it has been approved in the United States for the treatment of metastatic breast cancer (breast cancer that has spread to other parts of the body). Pembrolizumab is a medicine that may treat cancer by working with the participant's immune system. The immune system is the body's natural defense against disease. The immune system sends types of cells called "T cells" throughout the body to detect and fight infections and diseases, including cancer. For some types of cancer, the T cells do not work as they should and are prevented from attacking the tumors. Pembrolizumab is thought to work by blocking a protein in the T cells called PD-1 ("programmed death 1"), which then allows these cells and other parts of the immune system to attack tumors. Nab-paclitaxel (Abraxane) is part of a class of medications called antimicrotubule agents. It works by stopping the growth and spread of cancer cells by blocking the action of proteins called microtubules. The combination of Pembrolizumab and Nab-paclitaxel is investigational. "Investigational" means that the combination of study drugs is being studied. The study drugs, when given separately, work in different ways to stop the cancer cells from growing and spreading. 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
DRUGPembrolizumab
Pembrolizumab will be administered in clinic every three weeks.
DRUGNab-Paclitaxel
Nab-Paclitaxel will be administered in clinic every week.
PROCEDUREBiopsy
Biopsies for research purposes will be performed at three separate timepoints during treatment.
Sponsors
Adrienne G. Waks
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participants must have histologically or cytologically confirmed invasive breast cancer. * Participants must have operable breast cancer, with tumors greater than or equal to 2 cm in size; Participants must not have any evidence of distant metastatic disease. Inflammatory breast cancer is permitted. * All confirmed invasive disease must have been tested for ER, PR, and HER2 and participants must have hormone receptor-positive, HER2-negative breast cancer (ER\>1% or PR\>1%, AND HER2-negative per ASCO CAP guidelines, 2013). * Participants with multicentric, multifocal, and/or contralateral cancers are allowed as long as one lesion meets eligibility and no biopsied tumor is HER2+. * Prior systemic therapy: No prior chemotherapy, biologic therapy, hormonal therapy or investigational therapy for this operable breast cancer. * Prior radiation therapy: No prior radiation to the ipsilateral breast. * The participant is ≥18 years old * The participant has an Eastern Cooperative Oncology Group (ECOG) performance status ≤1 (see Appendix A) * Participants must have normal organ and marrow function as defined below: * Absolute neutrophil count ≥1500/mm3 * Platelets ≥100,000/mm3 * Hemoglobin ≥9 g/dL * Total Bilirubin ≤1.5 mg/dL (\< 2.0 in participants with known Gilbert's syndrome) * Serum creatinine ≤1.5 mg/dL OR calculated GFR ≥60mL/min * Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 times the upper limit of normal. * International normalized ratio (INR) or Prothrombin Time (PT) \<1.5 times the upper limit of normal unless subject is receiving anticoagulant therapy, as long as PT or PTT is within therapeutic range of intended use of anticoagulants. * Activated Partial Thromboplastin Time (aPTT) \<1.5 times the upper limit of normal unless subject is receiving anticoagulant therapy, as long as PT or PTT is within therapeutic range of intended use of anticoagulants. * The participant is capable of understanding and complying with the protocol and has signed the informed consent document. * The participant must be willing to undergo the three required research biopsies over the course of protocol therapy. 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, both women and men of child-bearing potential must agree to use adequate contraception (Section 5.5.2) starting with the first dose of study therapy and for the duration of study participation, through 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, she should inform her treating physician immediately. While on the study, women may not breast-feed. Women of childbearing potential are defined as those who have not been surgically sterilized or have not been free from menses for \> 1 year. * Female subject of childbearing potential should have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. * Participants on bisphosphonates may continue receiving bisphosphonate therapy during study treatment.
Exclusion criteria
* The participant 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 * Hypersensitivity to pembrolizumab or any of its excipients. * The participant has any history or evidence of active, non-infectious pneumonitis or interstitial lung disease. * The participant 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 nab-paclitaxel. * Pregnant women are excluded from this study because pembrolizumab has the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with pembrolizumab, breastfeeding should be discontinued if the mother is treated with pembrolizumab. * Active infection requiring intravenous antibiotics at week 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. Participants 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 participant has a medical condition that requires chronic systemic steroid therapy or any other form of immunosuppressive medication including disease modifying 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 participant has an active autoimmune disease or a documented history of autoimmune disease or syndrome that requires systemic steroids or immunosuppressive agents. * The participant is known to be positive for Hepatitis B surface antigen, or Hepatitis C RNA. Testing for screening is not required. * 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. Testing for screening is not required. * The participant has received a live vaccine within 28 days of planned start of study therapy. * 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 |
|---|---|---|
| Change in the Biomarker (PD-L1) Expression | 2 weeks | PDL1 H-Score by Immunohistochemistry (≥ 100 versus 0-99) change from baseline biopsy to biopsy after 2-week monotherapy (from C1D1 to C3D1). The minimum score is 0 and the higher the score the worse. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Percentage of Stromal Tumor Infiltrating Lymphocytes After Monotherapy Treatment | from C1D1 to C3D1 (2 weeks) | stromal tumor infiltrating lymphocytes (sTIL) is measured at C1D1 and C3D1 of the treatment. |
| Pathologic Complete Response Rate | 2 years | Response is measured by RCB score.RCB 0 (equal to pCR), RCB I(minimal burden), RCB II (moderate burden) and RCB III(extensive burden) |
| Overall Response Rate | 2 years | Overall response rate, assessed radiographically by both Response Evaluation Criteria In Solid Tumors Criteria (RECIST 1.1) following treatment with combination nab-paclitaxel and pembrolizumab in the neoadjuvant setting. Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Stable disease (SD), Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as reference the baseline LD. Overall response = CR+PR+SD |
| Disease-Free Survival | 3 years from randomization | Disease-free survival (DFS) will be defined from the time of randomization until the occurrence of the first of the following events: * Local/regional recurrence: a recurrent or new invasive ipsilateral breast cancer, invasive breast cancer in the axilla, regional lymph nodes, chest wall, or skin of the ipsilateral breast. * Contralateral invasive breast cancer, * Distant recurrence: metastatic disease that has either been biopsy confirmed or clinically diagnosed as recurrent invasive breast cancer. A single new lesion on a bone scan without evidence of lytic disease on x-ray and without symptoms does not in and of itself constitute distant recurrence, but multiple new bone lesions, or increased isotope uptake associated with new bone symptoms are more likely due to metastases. Bone metastases must be documented with x-rays and clinical description. * Death from any cause |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORAdrienne Gropper Waks, MD
Dana-Farber Cancer Institute
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Nab-Paclitaxel * 2 weeks Nab-Paclitaxel Run in
* Biopsy will be performed
* Post mono therapy Nab-Paclitaxel administered weekly
* Post mono therapy Pembrolizumab administered every 3 weeks
* Agents administered for a total of 15 weeks
Pembrolizumab: Pembrolizumab will be administered in clinic every three weeks.
Nab-Paclitaxel: Nab-Paclitaxel will be administered in clinic every week.
Biopsy: Biopsies for research purposes will be performed at three separate timepoints during treatment. | 15 |
| Pembrolizumab * 2 weeks Pembrolizumab Run in
* Biopsy will be performed
* Post mono therapy Nab-Paclitaxel administered weekly
* Post mono therapy Pembrolizumab administered every 3 weeks
* Agents administered for a total of 14 weeks
Pembrolizumab: Pembrolizumab will be administered in clinic every three weeks.
Nab-Paclitaxel: Nab-Paclitaxel will be administered in clinic every week.
Biopsy: Biopsies for research purposes will be performed at three separate timepoints during treatment. | 14 |
| Total | 29 |
Baseline characteristics
| Characteristic | Pembrolizumab | Total | Nab-Paclitaxel |
|---|---|---|---|
| Adjuvant radiation No | 7 Participants | 11 Participants | 4 Participants |
| Adjuvant radiation Yes | 7 Participants | 18 Participants | 11 Participants |
| Age, Continuous | 41.5 years | 42 years | 46 years |
| Breast surgery Lumpectomy | 6 Participants | 12 Participants | 6 Participants |
| Breast surgery Mastectomy | 8 Participants | 16 Participants | 8 Participants |
| Breast surgery No breast surgery | 0 Participants | 1 Participants | 1 Participants |
| Contralateral invasive breast ca at diagnosis No | 14 Participants | 28 Participants | 14 Participants |
| Contralateral invasive breast ca at diagnosis Yes | 0 Participants | 1 Participants | 1 Participants |
| ECOG PS = 0 at Baseline | 14 Participants | 29 Participants | 15 Participants |
| Ethnicity Hispanic or Latino | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity Non-Hispanic | 13 Participants | 26 Participants | 13 Participants |
| Ethnicity Unknown | 1 Participants | 2 Participants | 1 Participants |
| Grade 1 | 1 Participants | 2 Participants | 1 Participants |
| Grade 2 | 7 Participants | 14 Participants | 7 Participants |
| Grade 3 | 5 Participants | 12 Participants | 7 Participants |
| Grade Unknown | 1 Participants | 1 Participants | 0 Participants |
| HER2 status negative | 14 Participants | 29 Participants | 15 Participants |
| HER2 status positive | 0 Participants | 0 Participants | 0 Participants |
| Histology Both | 2 Participants | 3 Participants | 1 Participants |
| Histology Ductal | 11 Participants | 22 Participants | 11 Participants |
| Histology Lobular | 1 Participants | 4 Participants | 3 Participants |
| Hormone receptor status ER low+/PR- | 3 Participants | 5 Participants | 2 Participants |
| Hormone receptor status ER+/PR- | 1 Participants | 4 Participants | 3 Participants |
| Hormone receptor status ER+/PR+ | 8 Participants | 17 Participants | 9 Participants |
| Hormone receptor status ER+/PR low+ | 2 Participants | 3 Participants | 1 Participants |
| N Stage N0 | 3 Participants | 8 Participants | 5 Participants |
| N Stage N1 | 11 Participants | 21 Participants | 10 Participants |
| Race/Ethnicity, Customized Race Asian | 2 Participants | 2 Participants | 0 Participants |
| Race/Ethnicity, Customized Race More than one race | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Race White | 12 Participants | 26 Participants | 14 Participants |
| Sex: Female, Male Female | 14 Participants | 29 Participants | 15 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
| Size of breast tumor by physical exam (cm) | 5 cm | 4.5 cm | 4 cm |
| Stage II | 10 Participants | 20 Participants | 10 Participants |
| Stage III | 4 Participants | 9 Participants | 5 Participants |
| T Stage T2 | 10 Participants | 20 Participants | 10 Participants |
| T Stage T3 | 4 Participants | 8 Participants | 4 Participants |
| T Stage T4 | 0 Participants | 1 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 15 | 0 / 15 | 1 / 29 |
| other Total, other adverse events | 6 / 15 | 1 / 15 | 29 / 29 |
| serious Total, serious adverse events | 1 / 15 | 0 / 15 | 4 / 29 |
Outcome results
Primary
Change in the Biomarker (PD-L1) Expression
PDL1 H-Score by Immunohistochemistry (≥ 100 versus 0-99) change from baseline biopsy to biopsy after 2-week monotherapy (from C1D1 to C3D1). The minimum score is 0 and the higher the score the worse.
Time frame: 2 weeks
Population: Patients with biomarker sample available at both C1D1 and C3D1 time point.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Nab-Paclitaxel | Change in the Biomarker (PD-L1) Expression | <100 | 11 Participants |
| Nab-Paclitaxel | Change in the Biomarker (PD-L1) Expression | >=100 | 0 Participants |
| Pembrolizumab | Change in the Biomarker (PD-L1) Expression | <100 | 12 Participants |
| Pembrolizumab | Change in the Biomarker (PD-L1) Expression | >=100 | 0 Participants |
p-value: 1McNemar
p-value: 1McNemar
Secondary
Change in Percentage of Stromal Tumor Infiltrating Lymphocytes After Monotherapy Treatment
stromal tumor infiltrating lymphocytes (sTIL) is measured at C1D1 and C3D1 of the treatment.
Time frame: from C1D1 to C3D1 (2 weeks)
Population: We are including patients who have biopsy both at C1D1 and C3D1.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Nab-Paclitaxel | Change in Percentage of Stromal Tumor Infiltrating Lymphocytes After Monotherapy Treatment | 7.2 percentage of stromal TILs |
| Pembrolizumab | Change in Percentage of Stromal Tumor Infiltrating Lymphocytes After Monotherapy Treatment | 0.5 percentage of stromal TILs |
Secondary
Disease-Free Survival
Disease-free survival (DFS) will be defined from the time of randomization until the occurrence of the first of the following events: * Local/regional recurrence: a recurrent or new invasive ipsilateral breast cancer, invasive breast cancer in the axilla, regional lymph nodes, chest wall, or skin of the ipsilateral breast. * Contralateral invasive breast cancer, * Distant recurrence: metastatic disease that has either been biopsy confirmed or clinically diagnosed as recurrent invasive breast cancer. A single new lesion on a bone scan without evidence of lytic disease on x-ray and without symptoms does not in and of itself constitute distant recurrence, but multiple new bone lesions, or increased isotope uptake associated with new bone symptoms are more likely due to metastases. Bone metastases must be documented with x-rays and clinical description. * Death from any cause
Time frame: 3 years from randomization
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Nab-Paclitaxel | Disease-Free Survival | 92 percentage of DFS patients |
| Pembrolizumab | Disease-Free Survival | 100 percentage of DFS patients |
Secondary
Overall Response Rate
Overall response rate, assessed radiographically by both Response Evaluation Criteria In Solid Tumors Criteria (RECIST 1.1) following treatment with combination nab-paclitaxel and pembrolizumab in the neoadjuvant setting. Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Stable disease (SD), Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as reference the baseline LD. Overall response = CR+PR+SD
Time frame: 2 years
Population: 19 patients (9 in Arm A and 10 in Arm B) who had MRI scans during study.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Nab-Paclitaxel | Overall Response Rate | 7 Participants |
| Pembrolizumab | Overall Response Rate | 8 Participants |
Secondary
Pathologic Complete Response Rate
Response is measured by RCB score.RCB 0 (equal to pCR), RCB I(minimal burden), RCB II (moderate burden) and RCB III(extensive burden)
Time frame: 2 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Nab-Paclitaxel | Pathologic Complete Response Rate | 2 Participants |
| Pembrolizumab | Pathologic Complete Response Rate | 1 Participants |