A Study of Olaparib and Pembrolizumab in People with Triple Negative Breast Cancer or Hormone Receptor-Positive HER2-Negative Breast Cancer
This phase II trial tests whether olaparib and pembrolizumab before standard of care chemotherapy and surgery works to shrink tumors in patients with triple negative or hormone receptor positive, HER2-negative breast cancer. Olaparib is a type of medication called a PARP (poly ADP ribose polymerase) inhibitor. PARP is a protein that helps repair damage to deoxyribonucleic acid (DNA), the genetic material that serves as the body’s instruction book. Changes (mutations) in DNA can cause tumor cells to grow quickly and out of control. But PARP inhibitors have been shown to prevent PARP from working, so tumor cells can’t repair themselves, and they stop growing. 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. Giving olaparib and pembrolizumab before standard of care chemotherapy and surgery may help shrink and stabilize tumors in patients with triple negative or hormone receptor positive HER2-negative breast cancer.
Inclusion Criteria
- Signed informed consent form
- Ability to comply with protocol, in the investigator’s judgment
- Women or men aged >= 18 years
- Newly diagnosed histologically confirmed stage T1c-3N0-3: * Triple negative breast cancer (TNBC) (estrogen receptor [ER]/progesterone receptor [PgR] negativity will be defined using immunohistochemistry (IHC) per American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) criteria/HER2-negativity will be defined using in situ hybridization (ISH) or IHC assays per ASCO/CAP criteria) OR * Hormone receptor-positive, HER2-negative breast cancer defined as per ASCO/CAP criteria
- Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1
- Minimum tumor size of 1.5 cm
- All patients must have a germline mutation in BRCA1, BRCA2, PALB2, RAD51C, or RAD51D
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- Patient agreement to undergo appropriate surgical management including, if indicated, axillary lymph node surgery and partial or total mastectomy after completion of neoadjuvant treatment. Note: consideration of neoadjuvant treatment will be determined by disease management team based on the subtypes and minimum size the tumor has to be
- Baseline left ventricular ejection fraction (LVEF) >= 53% measured by echocardiogram (ECHO) or multiple-gated acquisition (MUGA) scans
- Absolute neutrophil count (ANC) >= 1500/uL (obtained within 14 days prior to the first study treatment)
- Platelets >= 100 000/uL (obtained within 14 days prior to the first study treatment)
- Hemoglobin >= 9.0 g/dL or >= 5.6 mmol/L (obtained within 14 days prior to the first study treatment) * Criteria must be met without erythropoietin dependency and without packed red blood cell (pRBC) transfusion within last 2 weeks
- 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) >= 30 mL/min for participant with creatinine levels > 1.5 x institutional ULN (obtained within 14 days prior to the first study treatment)
- Total bilirubin =< 1.5 x ULN OR direct bilirubin =< ULN for participants with total bilirubin levels > 1.5 x ULN (obtained within 14 days prior to the first study treatment) * Patients with known Gilbert syndrome who have serum bilirubin level =< 3 X ULN may be enrolled
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x ULN (obtained within 14 days prior to the first study treatment)
- International normalized ratio (INR) OR prothrombin time (PT) =< 1.5 x ULN unless participant is receiving anticoagulant therapy as long as PT or activated partial thromboplastin time (aPTT) is within therapeutic range of intended use of anticoagulants (obtained within 14 days prior to the first study treatment)
- Activated partial thromboplastin time (aPTT) =< 1.5 x ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants (obtained within 14 days prior to the first study treatment)
- A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: * Not a woman of childbearing potential (WOCBP) as defined by institutional guidelines OR * A WOCBP who agrees to follow the contraceptive guidance starting at the time of informed consent, during the treatment period and for at least 120 days after the last dose of study treatment (pembrolizumab, olaparib) according to local standard of care
- Male participants must agree to use contraception starting at the time of informed consent, during the treatment period and for at least 120 days after the last dose of study treatment (pembrolizumab, olaparib) and refrain from donating sperm during this period
Exclusion Criteria
- Prior history of invasive breast cancer
- Stage IV (metastatic) breast cancer
- Prior systemic therapy for treatment and prevention of breast cancer
- Contraindication to MRI scan and/or allergy to intravenous contrast-gadolinium
- Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137)
- Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks * Note: Participants must have recovered from all adverse events (AEs) due to previous therapies to =< grade 1 or baseline. Participants with =< grade 2 neuropathy may be eligible. Note: If participant received major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study treatment
- Has received prior radiotherapy within 2 weeks of start of study treatment. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis
- Has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette–Guerin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist) are live attenuated vaccines and are not allowed
- Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug
- Has a known additional malignancy that is progressing or has required active treatment within the past X 3 years prior to screening. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or cervical carcinoma in situ are not excluded. Patients with prior ductal/lobular carcinoma in situ are not excluded if they were treated exclusively with mastectomy > 3 years prior to diagnosis of current breast cancer
- Has severe hypersensitivity (>= grade 3) to pembrolizumab or olaparib and/or any of its excipients
- 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 a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis
- Severe infections within 4 weeks prior to initiation of study treatment, including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia
- Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment * Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection or to prevent chronic obstructive pulmonary disease exacerbation) are eligible for the study
- Has a known history of human immunodeficiency virus (HIV)
- Has a known history of hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive) or known active hepatitis C virus (defined as hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is detected) infection
- Has a known history of active TB Bacillus Tuberculosis
- Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject’s participation for the full duration of the study, 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 study, starting with the screening visit through 120 days after the last dose of trial treatment
- A WOCBP who has a positive urine pregnancy test within 72 hours prior to study start. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required * Note: If 72 hours have elapsed between the screening pregnancy test and the first dose of study treatment, another pregnancy test (urine or serum) must be performed and must be negative in order for subject to start receiving study medication * Patients who have undergone human chorionic gonadotropin (hCG)-stimulation for egg harvest as part of fertility preservation within 7 days before treatment initiation are permitted to receive treatment despite a positive pregnancy test
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT05203445.
PRIMARY OBJECTIVE:
I. Determine the rate of pathologically negative magnetic resonance imaging (MRI)-guided biopsy after neoadjuvant combination olaparib-pembrolizumab therapy at 12 weeks, in the patient population.
SECONDARY OBJECTIVES:
I. Determine the safety and tolerability of combination olaparib-pembrolizumab therapy in the neoadjuvant setting.
II. Determine the rate of pathologically negative MRI-guided biopsy after neoadjuvant combination olaparib-pembrolizumab therapy at 12 weeks, in the subpopulation of patients with PD-L1-positive disease.
III. Evaluate the association of pathologically negative MRI-guided biopsy and imaging complete response on MRI after neoadjuvant combination olaparib-pembrolizumab therapy at 12 weeks, in the patient population.
IV. Evaluate the association of pathologically negative MRI-guided biopsy at 12 weeks and the rate of pathologic complete response at the time of surgery after neoadjuvant combination olaparib-pembrolizumab therapy +/- standard of care (SOC) chemotherapy, in the patient population.
V. Determine the rate of pathologic complete response after pre-operative treatment including neoadjuvant combination olaparib-pembrolizumab therapy +/- SOC chemotherapy, in the patient population.
EXPLORATORY OBJECTIVES:
I. To evaluate changes in tissue expression of selected immune markers at baseline, on-treatment and post-treatment from patients receiving neoadjuvant pembrolizumab/olaparib.
II. To evaluate the potential effects of neoadjuvant pembrolizumab/olaparib on cGAS-STING pathway expression, by comparing tissues obtained at baseline, on-treatment and post-treatment period.
III. To perform high-throughput sequencing of the TCR-beta CDR3 region in both tumor specimens and peripheral blood mononuclear cells (PBMCs) using the ImmunoSEQ immune profiling system to describe T-cell repertoire dynamics in patients receiving neoadjuvant pembrolizumab/olaparib.
IV. To characterize the genomic alterations and evolution of disease during neoadjuvant pembrolizumab/olaparib in patient with germline mutations in DNA damage repair genes.
V. To assess whether early circulating tumor DNA response can predict pathologic response.
VI. To evaluate the potential effects of neoadjuvant pembrolizumab/olaparib on malignant and immune cell diversity, by comparing baseline, on-treatment and posttreatment tissues analyzed with ultra-high resolution single cell genomics and transcriptomics techniques.
VII. To evaluate a novel Echo-planar imaging (EPI) based Magnetic Resonance Fingerprinting (MRF) sequence for rapid measurements of quantitative susceptibility mapping, proton Density (PD), T1 and T2 relaxation maps, which would enable quantitative evaluation of the tumor over time and determine the ability of these parameters to predict breast cancer pathologic response.
VIII. To evaluate a novel Chemical exchange saturation transfer Magnetic Resonance Fingerprinting (CEST-MRF) sequence, which is a multiparametric molecular imaging method for rapid simultaneous measurement of the water T1 and T2 relaxation maps, the pH-dependent amide exchange rate and volume fraction, and the macromolecular exchange rate and volume fraction and determine the ability of these parameters to predict breast cancer pathologic response.
OUTLINE:
Patients receive olaparib orally (PO) twice daily (BID) and pembrolizumab intravenously (IV) over 30 minutes on day 1 of each week. Treatment continues for 6 weeks in the absence of disease progression or unacceptable toxicity.
GROUP 1: Patients with a decrease in tumor size after 6 weeks of study treatment receive an additional 6 weeks of olaparib and pembrolizumab in the absence of disease progression or unacceptable toxicity. Patients then receive SOC chemotherapy + pembrolizumab and undergo surgery. Treatment with pembrolizumab continues for 1 year (before and after surgery) in the absence of disease progression or unacceptable toxicity.
GROUP 2: Patients with an increase in tumor size (0% to 25%) may choose between an additional 6 weeks of olaparib and pembrolizumab or to proceed directly to SOC chemotherapy and surgery.
GROUP 3: Patients with an increase in tumor size (> 25%) proceed directly to SOC chemotherapy and surgery.
Patients undergo echocardiography or multigated acquisition (MUGA) scan during screening, blood sample collection throughout the study and may undergo computed tomography (CT) scan, magnetic resonance imaging (MRI) or position emission tomography (PET) scan. Patients also undergo biopsy on trial.
After completion of study treatment, patients follow up at 30 days.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationMemorial Sloan Kettering Cancer Center
Principal InvestigatorAyca Gucalp
- Primary ID21-018
- Secondary IDsNCI-2022-01230
- ClinicalTrials.gov IDNCT05203445