Anthracycline-Free Neoadjuvant Chemoimmunotherapy for Triple Negative Breast Cancer Patients

Summary

This is a multi-institute, single-arm Phase II study to assess the efficacy of a 12-18-week neoadjuvant carboplatin, paclitaxel, and pembrolizumab (CPP) regimen in a response-adaptive manner for triple-negative breast cancer (TNBC) patients who are ineligible for anthracycline-based therapy due to underlying cardiac conditions.

Eligibility

Inclusion Criteria:

1. Measurable or evaluable tumor in the breast larger than 1cm with or without axillary involvement.
2. Ability to be followed by a cardiologist and/or primary care physician (PCP) for medication optimization of cardiac co-morbidities.
3. Medically fit to undergo curative surgery as per the standard of care.
4. Ability and willingness to comply with all study procedures.
5. Ability and willingness to sign and date a written informed consent.
6. Female or Male.
7. Age 18 and above.
8. Histologically confirmed TNBC Stage II or Stage IIIA/B.

   1. The invasive tumor must be hormone receptor-negative or low, defined as both estrogen receptor (ER) and or progesterone receptor (PR) staining present in \<10% of invasive cancer cells by IHC.
   2. HER2 negativity will be based on current ASCO-CAP guidelines for HER2 testing.
9. In patients with multifocal disease, all the tumors should be HER2-negative.
10. No previous chemotherapy, immunotherapy, radiation therapy, or surgery for this breast cancer.
11. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2.
12. Have adequate organ function at the time of screening visit as defined below:

    a. Hematological: i. Absolute neutrophil count ≥ 1,500/uL ii. Platelets ≥ 100,000/uL iii. Leukocytes ≥ 3,000/uL iv. Hemoglobin ≥ 9.0 g/dL or ≥ 5.6 mmol/L (criteria must be met without erythropoietin dependency and without packed red blood cell transfusion within last 2 weeks).

    b. Renal: i. Creatinine ≤ 1.5 mg/dL and/or creatinine clearance ≥ 50 mL/min.

1\. Patients with a creatinine clearance (CrCl) between 30 and 50 mL/min may be eligible for the study at the discretion of the Principal Investigator. Given that paclitaxel is primarily metabolized by the liver and not significantly affected by renal function, and that carboplatin dosing can be safely adjusted based on CrCl, enrollment of these patients is permissible following individual assessment and approval.

c. Hepatic: i. Total bilirubin ≤ 1.5x IULN, OR direct bilirubin ≤ IULN for participants with total bilirubin levels \> 1.5x IULN. Participants with a history of Gilbert's disease must have total bilirubin ≤ 5x IULN. ii. AST(SGOT) and ALT(SPGT) ≤ 2.5x IULN.

d. Coagulation: i. International normalized ratio (INR) of coagulation OR prothrombin time (PT) OR activated partial thromboplastin time (aPTT) ≤ 1.5x IULN unless the patient is receiving anticoagulant therapy. If the patient is receiving anticoagulant therapy, PT or PTT is within the therapeutic range of the intended use of anticoagulants. e. Serum albumin ≥ 3.0 g/dL. 13. Patients with clinically and/or radiologically abnormal axillary lymph nodes should have pathological confirmation with image-guided biopsy/fine needle aspiration. 14. Patients should have staging scans to exclude the possibility of metastatic disease when axillary imaging shows two or more abnormal lymph nodes, if there are clinical signs concerning for metastatic disease or at the treating physician's discretion. Patients with bilateral breast cancer are eligible if they meet other eligibility criteria and both tumors are HER2 negative.

15\. Baseline neuropathy grade ≤2. 16. A WOCBP must be willing and able to use highly effective contraception from the time of informed consent throughout the study period and at least six months after the last dose of trial treatment.

17\. Patient is ineligible for anthracycline treatment, as of at least one of the following of A, B, C, or D: A. Individuals identified as being at high risk for cardiotoxicity from anthracycline treatment.

1. Preexisting cardiomyopathy with Ejection Fraction (EF) between 25-49%.
2. Severe valvular disease on echocardiogram.
3. Previous exposure to Anthracyclines.
4. Previous exposure to high dose chest wall radiation \>30Gy.
5. Participants who have experienced myocardial infarction, unstable angina pectoris, an arterial thrombotic event, or stroke, within the last 12 months but not less than 3 months ago. B. Medium and High Risk for Congestive Heart Failure (CHF) at 3 years as defined by the Cardiotoxicity prediction tool from Ezaz et al C. Patients declining anthracycline therapy after thorough discussion regarding its significant role in treating TNBC. D. Patients who are deemed ineligible for anthracycline due to underlying medical conditions, as determined by the primary oncologist and confirmed by the study PI.

18\. Breast and axillary imaging (including ultrasound and MRI) within 42 days (6 weeks) prior to registration.

Exclusion Criteria:

1. Subject is planning to participate, 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.
2. Current diagnosis of metastatic or inflammatory breast cancer.
3. Patients deemed unfit to undergo curative surgery according to the standard of care.
4. Patients who have concomitant and/or previous malignancies within the last 5 years.

   Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (e.g., ductal carcinoma in situ (DCIS), carcinoma in situ of the cervix) that have undergone potential curative therapy are NOT excluded.
5. History of hypersensitivity to compounds that are similar to carboplatin and paclitaxel
6. Has received major surgery and has not recovered adequately from the toxicity and/or complications before starting study treatment.
7. Subject 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 or COVID 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.
8. 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 (7-day clearance period for immunosuppressant therapy prior to starting study treatment, if applicable).
9. Has active autoimmune disease that has required systemic treatment in the past 1 year (i.e., with the use of disease-modifying agents, corticosteroids, or immunosuppressive drugs).
10. Has a history of solid organ transplant.
11. Has a history of non-infectious pneumonitis that required high-dose steroids and/or has current pneumonitis.
12. Has an active bacterial infection requiring systemic therapy.
13. History of Human Immunodeficiency Virus (HIV).
14. History of Hepatitis B (defined as Hepatitis B surface antigen \[HBsAg\] reactive) or known active Hepatitis C virus (defined as detectable HCV RNA) infection.
15. Known psychiatric or substance abuse disorders that would interfere with the requirements of the trial.
16. Pregnant or breastfeeding, or expecting to conceive within the projected duration of the study, starting with the screening visit through 180 days after the last dose of trial treatment.
17. Subject is a WOCBP who has had a positive urine pregnancy test within 24 hours prior to initiation of study treatment. Females will be determined to be not of child-bearing potential with a history of hysterectomy or with postmenopausal status of \>12 months.
18. Uncontrolled hypertension (systolic BP \> 180 bpm or diastolic BP \> 100 bpm), or uncontrolled or symptomatic arrhythmia at the time of screening visit.
19. At time of screening visit, EF less than 25%

Conditions3

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