A Phase II Study of High Dose Radiotherapy in Combination With Pembrolizumab Plus Chemotherapy in Patients With PD-L1 Positive Metastatic Triple Negative Breast Cancer
This phase II trial tests how well radiation therapy with pembrolizumab and chemotherapy (paclitaxel or nab-paclitaxel or carboplatin and gemcitabine) works in treating patients with PD-L1 positive triple negative breast cancer that has spread from where it first started (primary site) to other places in the body (metastatic). Radiation therapy uses high energy x-rays, particles, or radioactive seeds to kill tumor cells and shrink tumors. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the tumor, and may interfere with the ability of tumor cells to grow and spread. Paclitaxel is in a class of medications called antimicrotubule agents. It stops cancer cells from growing and dividing and may kill them. Nab-paclitaxel is an albumin-stabilized nanoparticle formulation of paclitaxel which may have fewer side effects and work better than other forms of paclitaxel. Carboplatin is in a class of medications known as platinum-containing compounds. It works by killing, stopping or slowing the growth of cancer cells. Gemcitabine is a chemotherapy drug that blocks the cells from making DNA and may kill cancer cells. High dose radiation therapy with pembrolizumab and chemotherapy may effective in treating patients with PD-L1 positive metastatic triple negative breast cancer.
• Biopsy proven metastatic PD-L1 positive triple negative breast cancer with at least 2 sites of measurable metastatic disease on imaging
‣ Estrogen receptor (ER) and progesterone receptor (PR) negativity are defined as ≤ 10% of cells expressing hormonal receptors via immunohistochemistry (IHC) analysis
⁃ HER2 negativity is defined as either of the following by local laboratory assessment
• In situ hybridization (ISH) non-amplified (ratio of HER2 to CEP17 \< 2.0 or single probe average HER2 gene copy number \< 4 signals/cell) or
∙ IHC 0 or IHC 1+. If more than one test result is available and not all results meet the inclusion criterion definition, all results should be discussed with the Medical Monitor to establish eligibility of the patient
• PD-L1 positive as defined by Dako 22c3 assay PD-L1 combined positive score (CPS) ≥ 10
• Appropriate stage for study entry based on the following diagnostic workup:
‣ History and physical examination within 60 days prior to registration
⁃ Clinical grade CT scans of the chest, abdomen, and pelvis with radionuclide bone scan or whole body positron emission tomography (PET)/CT documenting metastatic disease within 4 weeks of the start of radiotherapy on this protocol with or without magnetic resonance imaging (MRI), as needed, documenting site of metastatic disease to be treated on protocol
• Patient must be eligible for radiotherapy as determined by their treating physician
• Patient must be eligible for immunotherapy and taxane chemotherapy as determined by their treating physician
• At least 1 metastatic site amenable to high dose radiotherapy
• Be willing and able to provide written informed consent for the trial
• Ages ≥ 18 years of age
• Biopsy proven metastatic PD-L1 positive triple negative breast cancer with at least 2 sites of measurable metastatic disease on imaging
‣ Estrogen receptor (ER) and progesterone receptor (PR) negativity are defined as ≤ 10% of cells expressing hormonal receptors via immunohistochemistry (IHC) analysis
⁃ HER2 negativity is defined as either of the following by local laboratory assessment
• In situ hybridization (ISH) non-amplified (ratio of HER2 to CEP17 \< 2.0 or single probe average HER2 gene copy number \< 4 signals/cell) or
∙ IHC 0 or IHC 1+. If more than one test result is available and not all results meet the inclusion criterion definition, all results should be discussed with the Medical Monitor to establish eligibility of the patient
• PD-L1 positive as defined by Dako 22c3 assay PD-L1 combined positive score (CPS) ≥ 10
• Appropriate stage for study entry based on the following diagnostic workup:
‣ History and physical examination within 60 days prior to registration
⁃ Clinical grade CT scans of the chest, abdomen, and pelvis with radionuclide bone scan or whole body positron emission tomography (PET)/CT documenting metastatic disease within 4 weeks of the start of radiotherapy on this protocol with or without magnetic resonance imaging (MRI), as needed, documenting site of metastatic disease to be treated on protocol
• Patient must be eligible for radiotherapy as determined by their treating physician
• Patient must be eligible for immunotherapy and taxane chemotherapy as determined by their treating physician
• At least 1 metastatic site amenable to high dose radiotherapy
• Be willing and able to provide written informed consent for the trial
• Ages ≥ 18 years of age
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-2, Karnofsky performance status (KPS) ≥ 60%
• Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1)
• Absolute neutrophil count ≥ 1500/mcL (obtained within 14 days prior to first study treatment)
• Platelet count ≥ 100,000/mcL (obtained within 14 days prior to first study treatment)
• Hemoglobin ≥ 9.0 g/dL (obtained within 14 days prior to first study treatment) (Note: The use of transfusion or other intervention to achieve hemoglobin \[Hgb\] ≥ 9.0g/dL is acceptable)
• Aspartate aminotransferase (AST), alanine aminotransferase (ALT) ≤ 2.5 x the upper limit of normal (ULN) with the following exceptions (obtained within 14 days prior to first study treatment):
• \* Patients with documented liver metastases: AST and ALT ≤ 5 x ULN
• Serum bilirubin ≤ 1.5 x ULN (obtained within 14 days prior to first study treatment)
• \* Patients with known Gilbert disease who have serum bilirubin level ≤ 3 x ULN may be enrolled
• Calculated creatinine clearance ≥ 30 mL/min (obtained within 14 days prior to first study treatment)
• For females of child-bearing potential, negative serum or urine pregnancy test within 14 days prior to radiation simulation
• The patient or a legally authorized representative must provide study-specific informed consent prior to study entry
• Prior Treatment:
‣ Patients may or may not have received radiotherapy or neoadjuvant or adjuvant chemotherapy in the treatment of their initial, non-metastatic breast cancer, but must be entered on study after their last dose of radiotherapy, last cycle of chemotherapy and biologic therapy (if applicable) and have sufficient resolution of side effects per physician assessment at time of radiotherapy. Prior immunotherapy for treatment of early stage breast cancer is allowed if metastatic recurrence occurs ≥ 6 months after last dose of immunotherapy
⁃ Patients must have not active wound healing issues from surgery and sufficient resolution of surgical side effects, per physician assessment, at time of radiotherapy
⁃ Patients are not eligible if they have received chemotherapy in the advanced/metastatic setting
⁃ During radiotherapy, no other investigation or commercial agents or therapy for cancer other than bisphosphonate or receptor activator nuclear kappaB ligand (RANK-L) inhibitor, pembrolizumab, and nab-paclitaxel, paclitaxel, carboplatin or gemcitabine should be administered
⁃ Patients may have received bisphosphonates or rank ligand inhibitors prior to enrollment on study