Neoadjuvant HER2-Targeted Therapy and Immunotherapy With Pembrolizumab

What is the Purpose of this Study?

The purpose of this study is to determine the effects of an immune therapy drug called pembrolizumab when combined with standard-of-care, preoperative chemotherapy with HER2-directed therapy in patients with stage II/III HER2-positive, invasive, unilateral breast cancer prior to standard-of-care breast surgery. Participants will be randomly assigned to one of three study groups. Group 1 will receive standard-of-care drugs (trastuzumab, pertuzumab, and paclitaxel) before surgery. Group 2 will receive the standard of care drugs (trastuzumab, pertuzumab, and paclitaxel) plus immune therapy with pembrolizumab (study drug). Group 3 will receive the standard-of-care drugs (trastuzumab and paclitaxel) plus immune therapy with pembrolizumab (study drug).

Pembrolizumab is approved by the U.S. Food and Drug Administration (FDA) for various types of cancers, but it is not approved for the treatment of breast cancer. Pertuzumab, trastuzumab, and paclitaxel in combination are approved by the FDA for the treatment of HER2-positive breast cancer. However, the use of the pertuzumab, paclitaxel, trastuzumab, and pembrolizumab in combination (or trastuzumab, pembrolizumab, and paclitaxel) have not been approved by the FDA.

Eligibility

Male/female patients with histologically confirmed invasive HER2-positive (by American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines) unilateral breast cancer
Have previously untreated non-metastaic (M0), cT2-4N0 or cT1-4N1-3 (biopsies of clinically suspicious lymph nodes to confirm nodal status is encouraged).
Multifocal/centric disease is permitted if all suspicious foci have been biopsied and are consistent with HER2-positive (by ASCO/CAP guidelines) invasive breast cancer
Be a male or female subject 18 years of age on the day of signing informed consent

Inclusion Criteria:

Male/female patients with histologically confirmed invasive HER2-positive (by American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines) unilateral breast cancer
Have previously untreated non-metastaic (M0), cT2-4N0 or cT1-4N1-3 (biopsies of clinically suspicious lymph nodes to confirm nodal status is encouraged).
Multifocal/centric disease is permitted if all suspicious foci have been biopsied and are consistent with HER2-positive (by ASCO/CAP guidelines) invasive breast cancer
Be a male or female subject 18 years of age on the day of signing informed consent
Male Participants: A male participant must agree to use a contraception as detailed in Appendix C of this protocol during the treatment period and for at least 6 months after the last dose of study treatment and refrain from donating sperm during this period.
Female Participants: A female participant is eligible to participate if she is not pregnant (see Appendix C), not breastfeeding, and at least one of the following conditions applies: a.) Not a woman of childbearing potential (WOCBP) as defined in Appendix C OR b.) A WOCBP who agrees to follow the contraceptive guidance in Appendix C during the treatment period and for at least 6 months after the last dose of study treatment.
The participant (or legally acceptable representative if applicable) provides written informed consent for the trial.
Provides adequate archival tumor tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated. Formalin-fixed, paraffin embedded (FFPE) tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archived tissue. Note: If submitting unstained cut slides, newly cut slides should be submitted to the testing laboratory within 14 days from the date slides are cut.
Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
Have adequate organ function as defined by the following parameters. Specimens must be collected within 7 days prior to the start of study treatment.
Absolute neutrophil count (ANC) ≥1500/µL
Platelets ≥100 000/µL
Hemoglobin ≥9.0 g/dL or ≥5.6 mmol/La
Renal Creatinine (≤1.5 × ULN OR) OR Measured or calculated(b) creatinine clearance (≥30 mL/min for participant with creatinine levels) (GFR can also be used in place of creatinine or CrCl) (>1.5 × institutional ULN)
Hepatic Total bilirubin ≤1.5 ×ULN OR direct bilirubin ≤ULN for participants with total bilirubin levels >1.5 × ULN aspartate aminotransferase (AST, SGOT) and alanine aminotransferase (ALT, SGPT) ≤2.5 × ULN (≤5 × ULN for participants with liver metastases)
Coagulation International normalized ratio (INR) OR prothrombin time (PT) Activated partial thromboplastin time (aPTT) ≤1.5 × ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants
Cardiac Echocardiogram or MUGA (multigated radionuclide angiography) Baseline LVEF ≥ 55%

Exclusion Criteria:

A WOCBP who has a positive urine pregnancy test within 72 hours prior to randomization. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. Note: in the event that 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.
Has received prior therapy with an anti-PD-1 (programmed death protein 1), anti-PD-L1 (Programmed death-ligand 1), or anti PD L2 (Programmed death-ligand 2) agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX 40, CD137).
Has received prior systemic anti-cancer therapy including investigational agents within 4 weeks prior to randomization. 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-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (eg, FluMist®) are live attenuated vaccines and are not allowed.
Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment.
Note: Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent.
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 systemic treatment within the past 3 years. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g. breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy are not excluded.
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 (eg., 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.
Has an active infection requiring systemic therapy.
Has a known history of Human Immunodeficiency Virus (HIV).
Has a known active Hepatitis B (defined as Hepatitis B surface antigen [HBsAg] reactive) or Hepatitis C virus (i.d. HCV 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.
Has significant cardiovascular disease, such as:
History of myocardial infarction, acute coronary syndrome or coronary angioplasty/stenting/bypass grafting within the last 6 months
Congestive heart failure (CHF) New York Heart Association (NYHA) Class II-IV or history of CHF NYHA class III or IV
Angina pectoris requiring anti-anginal medication, uncontrolled arrhythmias, or uncontrolled hypertension (systolic blood pressure > 180mmHg and/or diastolic blood pressure > 100mmHg).

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Where can I participate?

Cedars-Sinai Cancer at Beverly Hills (THO)
Cedars-Sinai Cancer at Hunt Cancer Center - TMPNCC (CSMC Affiliate)
Cedars-Sinai Cancer at SOCC
Massachusetts General Hospital (Study Affiliate)
Providence Portland Medical Center (Study Affliliate)

More about this Clinical Trial

What is the full name of this clinical trial?

EIIT2023-NEOHP: Neoadjuvant Her2-targeted Therapy and Immunotherapy with Pembrolizumab

Study Details

Disease Type/Condition

Breast

Principal Investigator

Bitar, Jin Sun

Co-Investigators

Alain Mita, Alice Chung, Andrew Horodner, Armando Giuliano, Ashley Wachsman, Catherine Dang, David Chan, Dorothy Park, Farin Amersi, Farnaz Dadmanesh, Hugo Hool, Justin Wayne Tiulim, Maryliza El-Masry, Monica Mita, Philomena McAndrew, Scott Karlan, Stephen Shiao, Swati Sikaria, Syed Jilani, Thomas Lowe, Vanessa Dickey, Yuan Yuan

Age Group

Adult

Phase

IRB Number

Pro00053566

ClinicalTrials.gov ID

NCT03747120

Key Eligibility

ClinicalTrials.gov

How do I learn more about this study?

clinicaltrials@cshs.org