BRE-08 Phase II Study of CMC Regimen for Early Stage Breast Cancer

This is a non-randomized, single arm phase 2 trial of oral CMC based on conversion of doses that would be delivered with conventional metronomic CMF chemotherapy.

Participants who require adjuvant radiotherapy for locoregional management may opt to initiate radiotherapy following the fourth cycle of CMC with the final 4 cycles held during radiotherapy. Following completion of radiation therapy, participants may then resume with cycle 5 of CMC. The washout period before and after radiation therapy is a minimum of 2 weeks. Alternatively, patients may receive adjuvant radiotherapy after the completion of the final (8) cycle of CMC.

The study team will collect data on cyclophosphamide, methotrexate, and capecitabine compliance at routine clinical visits every 3 weeks. In addition, standard electrolyte, chemistry and liver function laboratory monitoring will be conducted at each clinic visit

Eligibility Criteria:
Inclusion Criteria:

* Age ≥ 18 years of age at time of consent
* ECOG performance status 0, 1, or 2
* Histologically confirmed invasive breast cancer documented by biopsy or surgical excision.
* Underwent potentially curative resection of primary breast tumor(s) with no gross residual local-regional disease (patients with microscopically positive margins are eligible if adjuvant radiotherapy is planned), with most recent breast or axillary surgery \< 120 days prior to date of signed consent.
* No evidence of distant metastatic disease
* Treating Oncologist recommends adjuvant chemotherapy without concurrent biologic/targeted therapy. Patients may receive a CDK4/6 inhibitor after completion of all study treatment, concurrently with adjuvant endocrine therapy. Patients with a germline pathogenic/likely pathogenic variant in a DNA homologous repair gene (e.g. BRCA1, BRCA2, PALB2) may receive adjuvant PARP inhibitor therapy after completion of all study treatment.
* Tumor is estrogen receptor (ER)-positive (\> 10% by IHC) and/or progesterone receptor (PR)-positive (\> 10% by IHC), HER2-negative by IHC or FISH according to 2018 ASCO-CAP guidelines.
* High risk gene expression profile (either luminal B on MammaPrint/BluePrint, or Recurrence Score \> 25 on Oncotype Dx). Study participants are not required to have a high risk gene expression profile if they have a clinical high-risk tumor, defined as:

Age \< 50 and any of the following:

* Involvement of 1-3 axillary lymph nodes with metastatic carcinoma (N1mic/N1)
* grade 1 tumor \> 3 cm; or grade 2 tumor \> 2 cm; or grade 3 tumors \> 1 cm (size based on pathological assessment of the maximal dimension of the invasive component of the tumor)
* pT1c-T2 and Ki-67 \> 20%
* Presence of lymphovascular invasion

Age \> 50 and the following:

* Primary tumor \> 5 cm (pT3)

  • AJCC pathologic stage:
* pT1-2/pN0-1 based on sentinel lymph node biopsy or axillary dissection
* stage IIIA (pT3N1 or pT1-3/N2) tumors are eligible . A high risk gene expression profile is not required for pathologic stage IIIA patients.

  * Adequate organ function as defined in Table 1. All screening labs to be obtained within 30 days prior to registration.
  * Patients with synchronous bilateral primary breast tumors or multiple ipsilateral primary breast tumors are eligible if the treating Oncologist determines that the CMC regimen is appropriate therapy for all primary tumors requiring chemotherapy.
  * Able to provide written informed consent and HIPAA authorization for release of personal health information.
  * Women of childbearing potential must agree to use 2 methods of birth control, at least one being a barrier form of contraception if they are sexually active with a male partner unless they are considered highly unlikely to conceive as defined in section 8.6, and cannot be pregnant or breast-feeding. A negative serum or urine pregnancy test is required per institutional practice guidelines.
  * As determined at the discretion of the enrolling physician or protocol designee, ability of the subject to understand and comply with study procedures for the entire length of the study.

Hematological Leukocytes ≥2,500/mm3 Platelet count ≥ 100,000/mm3 Absolute Neutrophil Count (ANC) ≥ 1,200/mm3 Hemoglobin (Hgb) ≥ 9.0 g/dL Renal Creatinine/Calculated creatinine clearance (CrCl) Cr \< 1.5 x upper limit of normal (ULN) or CrCl ≥ 50 mL/min using the Cockcroft-Gault formula Hepatic Bilirubin Bilirubin ≤ 1.5 × ULN. Subjects with Gilbert's syndrome may have a bilirubin \> 1.5 × ULN, if no evidence of biliary obstruction exists Aspartate aminotransferase (AST) ≤ 2.5 × ULN Alanine aminotransferase (ALT) ≤ 2.5 × ULN

Exclusion Criteria:

* Prior cytotoxic chemotherapy for this breast cancer
* Any investigational agents administered during or within 2 weeks prior to start of CMC chemotherapy
* AJCC stage IIIB-IIIC or stage IV
* Active infection requiring systemic therapy
* Uncontrolled HIV/AIDS or active viral hepatitis
* Pregnant or nursing
* Require anticoagulation with warfarin. Anticoagulation with low molecular weight heparins, heparin, or direct oral anticoagulants (DOACs) is permitted.
* Any prior or concurrent malignancy whose natural history or treatment has the potential to interfere with the safety or efficacy assessment of this investigational regimen, as determined by the treating medical oncologist.
* Any mental or medical condition that prevents the patient from giving informed consent or participating in the trial.
* Other major comorbidity (e.g. advanced cardiopulmonary disease, uncontrolled diabetes mellitus) that may affect the safety or efficacy assessment of this investigational regimen, as determined by study PI
* Inability to swallow pills
* Any medical condition interfering with absorption of oral medications
* Any contraindication for any chemotherapy drug used in the CMC regimen
* Active and ongoing use of medicines known to alter metabolism or tolerability of component drugs in CMC.
* Prisoners
* Unable or unwilling to take a large number of oral pills