Carboplatin with or without Pembrolizumab in Treating Patients with Advanced Breast Cancer with Locally Recurrent Chest Wall Disease That Cannot Be Removed by Surgery
This randomized phase II trial studies how well carboplatin with or without pembrolizumab work in treating patients with breast cancer that has spread to other places in the body (advanced) with chest wall disease that has come back (locally recurrent) and cannot be removed by surgery. Drugs used in chemotherapy, such as carboplatin, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.
- Advanced breast cancer with locally recurrent chest wall disease not amenable to surgical excision * Distant sites of disease are allowed * Prior radiation to the chest wall is not required
- The following disease subtypes are eligible: * Triple negative disease (defined as estrogen receptor [ER] < 10%, progesterone receptor [PR] < 10%, HER2 negative) * Hormone receptor positive, HER2 negative disease with evidence of progression on at least two prior lines of hormone therapy * HER2 positive disease with evidence of disease progression on trastuzumab, pertuzumab, T-DM1 and oral tyrosine kinase inhibitor unless contraindicated with no other HER2 targeted therapy options available (patients in this category will be classified by ER status) ** Histologically confirmed HER2+ breast carcinoma, with HER2+ defined by in situ hybridization (ISH) or fluorescence in situ hybridization (FISH) or immunohistochemistry (IHC) methodology using standard criteria. ** Cardiac function must be determined within 4 weeks of study entry to be >= 50% using electrocardiography (ECHO) or multigated acquisition scan (MUGA)
- Any number of prior lines of therapy are allowed * Prior platinum based therapy is allowed in the following settings: ** Treatment in the neoadjuvant and/or adjuvant setting without clear progression of disease ** Treatment in the metastatic setting without clear progression of disease
- At least two weeks from last systemic chemotherapy for breast cancer, with recovery of all treatment related toxicity to grade 1 or less; subjects with =< grade 2 neuropathy are an exception to this criterion; no specific window is required for hormone therapy
- At least two weeks from last radiation therapy, with recovery of all treatment related toxicity to grade 1 or less (excluding alopecia)
- Prior central nervous system (CNS) disease is allowed if stable for at least one month since whole brain radiation therapy, and 2 weeks since stereotactic radiotherapy, and not requiring steroids; patients whose CNS disease was surgically treated may be enrolled if stable for at least one month, and not requiring steroids
- Able to provide tissue from a newly obtained core or excisional biopsy of a chest wall tumor lesion; newly-obtained is defined as a specimen any time after the last systemic or local therapy utilized to treat the disease; subjects for whom newly-obtained samples cannot be provided (e.g. inaccessible or subject safety concern) may submit an archived specimen only upon agreement from the study chair
- Willing and able to provide written informed consent
- Eastern Cooperative Oncology Group (ECOG) performance status of less than or equal to 2
- Absolute neutrophil count (ANC) >= 1,000 /mcL (within 10 days of treatment initiation)
- Platelets >= 100,000/mcL (within 10 days of treatment initiation)
- Hemoglobin >= 9 g/dL or >= 5.6 mmol/L without transfusion or erythropoietin (EPO) dependency (within 7 days of assessment) (within 10 days of treatment initiation)
- Serum creatinine =< 1.5 X upper limit of normal (ULN) OR measured or calculated creatinine clearance (glomerular filtration rate [GFR] can also be used in place of creatinine or CrCl) >= 60 mL/min for subject with creatinine levels > 1.5 X institutional ULN (within 10 days of treatment initiation) * Creatinine clearance should be calculated per institutional standard
- Serum total bilirubin =< 1.5 X ULN OR direct bilirubin =< ULN for subjects with total bilirubin levels > 1.5 ULN (within 10 days of treatment initiation)
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 X ULN OR =< 5 X ULN for subjects with liver metastases (within 10 days of treatment initiation)
- Albumin >= 2.5 g/dL (within 10 days of treatment initiation)
- International normalized ratio (INR) or prothrombin time (PT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants (within 10 days of treatment initiation)
- Activated partial thromboplastin time (aPTT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants (within 10 days of treatment initiation)
- Female subjects of childbearing potential should have a negative urine or serum pregnancy 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
- Female subjects of childbearing potential should be willing to use an acceptable form of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication; subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year
- Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy
- Treatment with an investigational agent within 4 weeks of the first dose of treatment
- A diagnosis of immunodeficiency or is currently receiving systemic steroid therapy at any dose or is receiving any other form of immunosuppressive therapy; steroid therapy is not allowed within 7 days prior to the first dose of trial treatment; however, topical and intranasal corticosteroids are allowed, and not an exclusion for participation
- Known active TB (Bacillus tuberculosis); patients with a distant history of tuberculosis that was appropriately treated and have no evidence of active infection are eligible to participate; patients with a history of latent tuberculosis that was appropriately treated are also eligible to participate
- Hypersensitivity to pembrolizumab or any of its excipients
- Hypersensitivity to carboplatin or cisplatin
- Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events due to a previously administered agent * Note: Subjects with =< grade 2 neuropathy are an exception to this criterion * Note: If subject received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy
- 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
- Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs); 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 active pneumonitis requiring treatment with steroids or active interstitial lung disease
- Has an 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
- Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, screening visit through 120 days after the last dose of trial treatment
- Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent; has been on any prior Merck MK-3475 (pembrolizumab) studies
- Has a known history of human immunodeficiency virus (HIV) (HIV 1/2 antibodies)
- Has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected)
- Has received a live vaccine within 30 days of planned start of study therapy; Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist) are live attenuated vaccines, and are not allowed
Locations & Contacts
Contact: Hope S. Rugo
District of Columbia
Contact: Paula Raffin Pohlmann
Contact: Rita Nanda
Contact: Kathy Durham Miller
Contact: Neelima Vidula
Contact: Minetta C. Liu
Contact: Rachel C. Jankowitz
Contact: Vandana Gupta Abramson
Trial Objectives and Outline
I. To determine the disease control rate (including complete response [CR], partial response [PR] and stable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 at 18 weeks of treatment in breast cancer patients with chest wall disease treated with pembrolizumab and carboplatin or carboplatin alone.
I. To determine the disease control rate (including CR, PR and stable disease as defined by immune-related (ir)RECIST at 18 weeks of treatment in breast cancer patients with chest wall disease treated with pembrolizumab and carboplatin or carboplatin alone.
II. To determine progression free survival in patients treated with pembrolizumab and carboplatin versus (vs.) carboplatin alone.
III. To determine the toxicity of pembrolizumab and carboplatin vs. carboplatin alone.
IV. To determine 18 week disease control rate based on tumor PD-L1 expression via immunohistochemistry.
V. To determine the overall response rate of patients treated with pembrolizumab and carboplatin vs. carboplatin alone.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM A: Patients receive carboplatin intravenously (IV) and pembrolizumab IV over 30 minutes on day 1. Patients who are HER2+ also receive trastuzumab IV every 3 weeks. Treatment repeats every 3 weeks for a least 6 cycles in the absence of disease progression or unacceptable toxicity. After completion of 6 cycles of carboplatin and pembrolizumab, patients may discontinue carboplatin and receive pembrolizumab alone . Cycles repeat every 3 weeks in the absence of disease progression or unacceptable toxicity.
ARM B: Patients receive carboplatin IV on day 1. Patients who are HER2+ also receive trastuzumab IV every 3 weeks. Cycles repeat every 3 weeks in the absence of disease progression or unacceptable toxicity. Patients with disease progression then receive pembrolizumab IV over 30 minutes on day 1 in the cross over (Arm Bx). Patients may also receive carboplatin IV on day 1 at the discretion of the investigator. Cycles repeat every 3 weeks in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up for 30 days.
Trial Phase & Type
UCSF Medical Center-Mount Zion
Hope S. Rugo
Secondary IDs NCI-2018-00010, 167513, 16-20911, TBCRC 44
Clinicaltrials.gov ID NCT03095352