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

Official title

BRE-08: A Phase II Study of an All-Oral Adjuvant Chemotherapy Regimen of Cyclophosphamide, Methotrexate, and Capecitabine (CMC) for Early-Stage Breast Cancer

Overview

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.

Detailed description

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

Interventions

• Drug Cyclophosphamide
  60mg/m2 PO once a day (21 continuous days)
• Drug Methotrexate
  10mg/m2 PO BID on days 1, 8, and 15
• Drug Capecitabine
  825mg/m2 PO BID on days 1-14

Primary outcome measures

• Relative Dose Intensity (RDI) in patients treated with the CMC regimen. RDI is defined as the sum total of delivered drug in mg/m2/week for each drug in the CMC regimen per the number of participants that have equal to or greater than 85% [Time frame: 1 year]

Secondary outcome measures (10)

• Safety of oral CMC regime per the number of participants experiencing adverse events [Time frame: 1 year]
• Invasive Disease Free Survival (iDFS) [Time frame: 10 years]
• Distant Disease Free Survival (DDFS) [Time frame: 10 years]
• Overall Survival (OS) [Time frame: 10 years]
• Participant outcomes using the Quality of Life (QOL) and EORTC QOL-C30 questionnaires [Time frame: 10 years]
• Protocol therapy interruption [Time frame: 10 years]
• Discontinuation of protocol therapy [Time frame: 10 years]
• Rates of dose reduction of cyclophosphamide [Time frame: 10 years]
• Rates of dose reduction of methotrexate [Time frame: 10 years]
• Rates of dose reduction of capecitabine [Time frame: 10 years]

Eligibility criteria

Inclusion criteria

I• 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 < 90 days prior to date of signed consent.
• No evidence of distant metastatic disease
• No prior systemic therapy for this cancer other than pre-operative endocrine therapy
• 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.
• AJCC pathologic stage:

o pT1-3/pN0-2 based on sentinel lymph node biopsy or axillary dissection

• 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 (pN1mic/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 stage IIIA (pT3/pN1 or pT1-3/pN2)

Age > 50 and any of the following:

• Primary tumor > 5 cm (pT3)
• stage IIIA (pT3/pN1 or pT1-3/pN2)

• 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.
• Patients with history of HIV/AIDS (acquired immunodeficiency syndrome) are eligible for this study if they are receiving anti-retroviral therapy and it does not include any medications known to alter metabolism or tolerability of component drugs in the CMC regimen (see Appendix), and either of the following criteria are met:

• Patients without a history of AIDS-defining opportunistic infections.
• Patients with a history of AIDS-defining opportunistic infections, but they have not had an opportunistic infection within the past 12 months.
• Patients with Hepatitis B (HBV): chronic carriers of HBV infection (HBsAg-positive) or individuals who have serologic evidence of a resolved prior HBV infection (i.e., HBsAg-negative and anti-HBc-positive) are eligible if they are receiving appropriate suppressive antiviral therapy that does not include medications known to alter metabolism or tolerability of component drugs in CMC (see Appendix) prior to initiation of cancer therapy, and liver function tests meet study eligibility criteria.
• Patients with Hepatitis C (HCV): patients with a history of HCV infection who have completed curative antiviral treatment are eligible if the HCV RNA viral load is below the limit of quantification within 90 days of study enrollment. Patients on concurrent HCV treatment must have HCV RNA viral load below the limit of quantification within 30 days of study enrollment. Patients must also meet liver function test eligibility requirements and antiviral therapy does not include medications known to alter metabolism or tolerability of component drugs in CMC.

Exclusion criteria

Subjects meeting any of the criteria below are ineligible for this study:

• 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
• Untreated HIV/AIDS
• Documented DYPD deficiency
• 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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 1 center

• University of Illinois — Chicago

Identifiers

NCT: NCT06085742 · 2023-0429

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗