This is a 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.

Clinical trial participation among patients with cardiac co-morbidities is limited, creating challenges for oncologists managing aggressive cancers like Triple Negative Breast Cancer (TNBC) in this demographic. At MUSC and its affiliated rural sites, a significant portion of our patient population presents with complex medical histories and co-morbidities that increase their risk for anthracycline-induced cardiotoxicity. Therefore, proposing a dedicated study focused on patients with pre-existing cardiomyopathy or those at high risk for cardiotoxicity-using a non-anthracycline-based regimen-is both timely and essential.

Rationale for Using Paclitaxel, and Carboplatin with Immunotherapy:

It is estimated that around 60% of TNBC patients exhibit a "BRCAness" phenotype, which mirrors the clinical characteristics of tumors with BRCA mutations. Consequently, the use of DNA-damaging agents, like platinum-based therapies, has gained prominence as a viable treatment option for these patients. Several studies have demonstrated that adding carboplatin to neoadjuvant chemotherapy regimens improves the pCR rates in TNBC patients. While some trials have also shown improvements in disease-free survival, others have not observed this benefit. Notably, a recent study from India highlighted an overall survival advantage, specifically in TNBC patients under the age of 50, when carboplatin was included in their treatment.

Platinums have also been shown to modulate the immune system and cause immunogenic mediated cell death whereby they can increase major histocompatibility complex (MHC) class I expression on cancer cells thus promoting T-cell activation. Although platinums on their own could induce an immune response, a combination with taxanes like paclitaxel has been shown to augment this response as evidenced by decreasing T regulatory cells and increasing the proportions of T-helper cells and natural killer cells. In a mouse study looking at combining cisplatin with paclitaxel and immunotherapy, it was found that chemotherapy enhanced immune-mediated cancer cell death by decreasing intratumoral T regulatory cells and increasing the recruitment of cytokine-induced killer cells.

Beyond its direct cytotoxic activity as a microtubule-stabilizing agent, paclitaxel exerts potent immunomodulatory effects that make it an attractive chemotherapeutic backbone for combination with immune checkpoint inhibitors in triple-negative breast cancer (TNBC). Three key preclinical mechanisms support this rationale. First, paclitaxel functions as a Toll-like receptor 4 (TLR4) agonist by directly binding the MD-2 accessory molecule of the TLR4 complex on myeloid cells, mimicking bacterial lipopolysaccharide and activating TLR4/TRIF/IRF3 signaling to induce type I interferons and CTL-attracting chemokines within the tumor microenvironment; this TLR4 activation reprograms tumor-associated macrophages from an immunosuppressive M2 phenotype to a pro-inflammatory M1 phenotype, enhances antigen cross-presentation, and is associated with upregulated IFNα/IFNγ signaling in paclitaxel responders. Second, paclitaxel enhances dendritic cell maturation and antigen-presenting function through TLR4 signaling, increasing expression of co-stimulatory molecules (CD80, CD86, CD40), MHC class II, and IL-12, and generating CD8⁺ T cells with markedly increased lytic activity against tumor cells; in vivo, paclitaxel treatment expands antigen-specific, IFNγ-secreting CD8⁺ T cells in vaccine-draining lymph nodes, an effect abrogated by TLR4 blockade. Third, paclitaxel induces immunogenic cell death, with treated tumor cells exposing calreticulin and releasing HMGB1 and other DAMPs that promote phagocytic uptake and TLR4-dependent innate immune activation, while cytoplasmic DNA from dying cells triggers cGAS/STING/IRF3 signaling and further type I interferon and chemokine production, functionally mimicking an in situ vaccination. Collectively, TLR4-mediated macrophage reprogramming, enhanced dendritic cell maturation, and immunogenic cell death converge to convert the tumor microenvironment from immunologically "cold" to "hot," creating optimal conditions for PD-1/PD-L1 blockade. In TIL-high TNBC, where a pre-existing adaptive immune response is present, paclitaxel amplifies this endogenous immunity, providing a strong mechanistic rationale for its use as the chemotherapeutic backbone in a de-escalated chemoimmunotherapy regimen.

Rationale for Weekly Paclitaxel Over Taxotere:

In the ECOG E1199 trial, 4,954 patients with stage II-III breast cancer received AC×4 followed by randomization to paclitaxel or docetaxel given either every 3 weeks or weekly, in a 2×2 factorial design with DFS as the primary endpoint. After 12.1 years of follow-up, both weekly paclitaxel and every-3-week docetaxel produced significantly superior DFS and numerically better OS compared with every-3-week paclitaxel, whereas the other experimental arm (weekly docetaxel) did not. In the triple-negative subset (n≈1,025), weekly paclitaxel emerged as the most effective regimen, yielding a ~30% relative reduction in recurrence and death (HR 0.69 for both DFS and OS) and the highest 10-year DFS (69%) and OS (75%) among the four taxane schedules.

In terms of chemotherapy-related toxicities, every 3-week docetaxel was associated with higher levels of grade 4 toxicities than weekly paclitaxel 50% versus 4% respectively and most of the side effects are related to grade 4 neutropenia (46% vs 2%), febrile neutropenia (16% vs 1%), grade 3-4 stomatitis, fatigue, and myalgias. Conversely, the paclitaxel group had a higher level of grade 3 or 4 neuropathy of around 8% versus 4%. Unique to docetaxel, patients can also experience fluid retention syndrome often requiring prophylaxis with corticosteroids. This can manifest as peripheral edema, pleural effusions, ascites, or generalized weight gain. The condition is dose-dependent and typically more pronounced in patients receiving higher cumulative doses of docetaxel. In patients with underlying cardiomyopathy, this adverse effect can pose significant clinical challenges. Therefore, docetaxel is avoided in the NeoCARD study to reduce the risk of neutropenia, fluid overload and cardiac decompensation in this vulnerable population.

Rationale for a 12-Week Regimen:

The effectiveness of regimens featuring weekly taxanes with carboplatin is highlighted in studies like the WSG-ADAPT TN study and the NeoN phase 2 study by Loi et al. A 12-week platinum/taxane/pembrolizumab protocol may achieve pCR in chemo-sensitive patients without the need for prolonged chemotherapy. However, individuals with poor response rates may require extended therapy. Early identification of responders through radiographic methods could enable de-escalation strategies, potentially reducing long-term toxicities such as neuropathy that significantly impact quality of life.

Rationale for Response Adaptive Study Design:

MRI stands out as the most accurate imaging modality for assessing pCR in TNBC patients, with reported accuracy rates exceeding 86%. Therefore, MRI is endorsed as the optimal tool for assessing response by the American College of Radiology (ACR) and the Society of Breast Imaging (SBI).

A prospective, multi-institutional trial (ACRIN 6657/I-SPY TRIAL) demonstrated that MRI-based functional tumor volume measurements after neoadjuvant chemotherapy not only predict pathologic response but also correlate with recurrence-free survival. Specifically, functional tumor volume measured by MRI was shown to predict recurrence-free survival in patients with stage II or III breast cancer undergoing neoadjuvant therapy.

Overall, MRI response adaptive neoadjuvant therapy in breast cancer provides early detection of changes in tumor size and morphology, facilitating prompt assessment of treatment response. Additionally, MRI findings, including alterations in tumor enhancement patterns, can predict pathologic response to therapy, informing decisions about achieving a complete response. These MRI results also guide tailored treatment planning, determining the necessity of additional therapy and suitability for breast-conserving surgery versus mastectomy.

Inclusion Criteria:

To be eligible to participate in this study, an individual must meet all of the following criteria:

1. Histologically confirmed triple-negative breast cancer (TNBC) or hormone receptor-low invasive breast carcinoma, with clinical anatomic Stage II or Stage IIIA/B disease as defined by the AJCC 8th Edition Breast Cancer Stating System.

   a) The invasive tumor must be hormone receptor-negative or low, defined as estrogen receptor (ER) and/or progesterone receptor (PR) staining present in ≤10% of invasive cancer cells by immunohistochemistry (IHC).

   b) HER2-negative disease, defined in accordance with current ASCO-CAP HER2 guidelines.

2. Measurable or evaluable tumor in the breast larger than 1 cm, with or without axillary involvement.

3. Patients with multifocal or multicentric disease are eligible, provided the dominant tumor focus is ER and/or PR ≤10% and HER2 negative.

4. Female or male, age ≥18 years.

5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.

6. Medically fit to undergo curative-intent breast surgery per institutional standard of care.

7. No prior chemotherapy, immunotherapy, radiation therapy, or surgery for the current breast cancer (diagnostic core or vacuum-assisted biopsies allowed).

8. Ability to be followed by a cardiologist and/or primary care physician for optimization of cardiac comorbidities, as needed.

9. Adequate organ function at the time of screening, defined as:

   a) Hematologic

   1. Absolute neutrophil count ≥1,500/µL.
   2. Platelet count ≥100,000/µL.
   3. Leukocytes ≥3,000/µL.
   4. Hemoglobin ≥9.0 g/dL or ≥5.6 mmol/L (without erythropoietin dependency and without packed red blood cell transfusion within 14 days prior to testing).

   b) Renal

   a. Serum creatinine ≤1.5 mg/dL or creatinine clearance ≥50 mL/min. Note: Patients with creatinine clearance 30-50 mL/min may be enrolled at the discretion of the Principal Investigator, given that paclitaxel is primarily hepatically metabolized and carboplatin dosing can be adjusted to renal function.

   c) Hepatic

   1. AST (SGOT) and ALT (SGPT) ≤2.5 × ULN.
   2. Serum albumin ≥3.0 g/dL.
   3. Participants without a history of Gilbert's syndrome must meet one of the following:

   i. Total bilirubin ≤1.5 × IULN, or ii. Total bilirubin >1.5 × IULN with direct bilirubin ≤ULN. d. Participants with a history of Gilbert's syndrome must have total bilirubin ≤5 × ULN.

   d) Coagulation

   a. For patients receiving anticoagulant therapy, PT and/or aPTT within the therapeutic range for the intended use of anticoagulants.

   b. For patients not receiving anticoagulant therapy, INR, PT, and aPTT ≤1.5 × ULN.

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

11. Patients with clinically and/or radiologically abnormal axillary lymph nodes must have pathological confirmation with image-guided core biopsy or fine needle aspiration showing metastatic carcinoma.

12. Patients should undergo staging scans to exclude metastatic disease if any of the following apply:

    a) Axillary imaging shows two or more abnormal lymph nodes, or b) There are clinical signs or symptoms concerning for metastatic disease, or c) At the treating physician's discretion.

13. Patients with bilateral breast cancer are eligible if both tumors are HER2 negative and all other eligibility criteria are met (eligibility should be determined based on the higher-risk side when applicable).

14. Baseline peripheral neuropathy grade ≤2 (per CTCAE).

15. An individual of childbearing potential must be willing and able to use highly effective contraception from the time of informed consent, throughout study treatment, and for at least 6 months after the last dose of trial therapy.

    Note: Highly effective contraception is defined as methods with a failure rate <1% per year when used consistently and correctly, and include: copper intrauterine device (IUD); bilateral tubal ligation/occlusion or other documented surgical sterilization; vasectomized partner with documented azoospermia, provided this is the sole sexual partner; or true sexual abstinence, defined as complete abstinence from heterosexual intercourse, when this is the participant's usual and preferred lifestyle. Use of hormonal contraceptive methods (including combined oral contraceptives, progestin-only pills, injectables, implants, hormonal IUDs, patches, or vaginal rings) is not permitted during the study.

16. Ability and willingness to comply with all study procedures, including scheduled visits, treatment plans, laboratory tests, and other study requirements.

17. Ability and willingness to sign and date written informed consent prior to initiation of any study-specific procedures.

18. Participants with known human immunodeficiency virus (HIV) infection must be on effective anti-retroviral therapy at registration and have undetectable viral load test on the most recent test results obtained within 6 months prior to registration.

19. Participants with evidence of chronic hepatitis B virus (HBV) infection must have undetectable HBV load while on suppressive therapy on the most recent test results obtained within 6 months prior to registration, if indicated. NOTE: No testing for Hepatitis B is required unless mandated by local health authority.

20. Participants with a history of hepatitis C virus (HCV) must have been treated and cured. Participants currently being treated for HCV infection must have undetectable HCV viral load test on the most recent test results obtained within 6 months prior to randomization, if indicated. NOTE: No testing for Hepatitis C is required unless mandated by local health authority.

21. Patient is ineligible for anthracycline treatment due to at least one of the following of A, B, C, or D:

    1. Individuals identified as being at high risk for cardiotoxicity from anthracycline treatment have one or more of the following characteristics.

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 or high risk for Congestive Heart Failure (CHF) at 3 years as defined by the Cardiotoxicity Prediction Tool from Ezaz et al. [24]

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 other medical conditions not listed here, as determined by the primary oncologist and confirmed by the study PI.

Exclusion Criteria:

An individual who meets any of the following criteria will be excluded from participation in this study:

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. Known psychiatric or substance abuse disorders that would interfere with the requirements of the trial.

14. 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.

15. 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.

16. Uncontrolled hypertension (systolic BP > 180 mmHg or diastolic BP > 100 mmHg), or uncontrolled or symptomatic arrhythmia at the time of screening visit.

17. At the time of the screening visit, EF is less than 25%.