Pharmacokinetics and Safety of Epidiferphane and Taxanes in Breast Cancer Patients

Overview

Patients with breast cancer are commonly treated with taxane chemotherapy. Some very common side effects of taxanes, such as anemia and peripheral neuropathy, are often as not well addressed during treatment, resulting in dose reductions, dose delays and early discontinuation (collectively called relative dose intensity) of these chemotherapy agents in 15-80 % of patients on these drugs. This reduction in relative dose intensity (RDI) results in worse clinical outcomes such as progression free and overall survival. Pre-clinical studies in mouse models subjected to standardized chemotherapy regimens containing paclitaxel or oxaliplatin have shown that the nutritional supplement Epidiferphane reduces both neuropathy and anemia. This study will investigate whether the use of Epidiferphane in patients with breast cancer receiving taxane chemotherapy results in an attenuation of the side effects experienced, as well as an improvement in tumor response rate. The safety and maximum tolerated dose of Epidiferphane in this patient population will also be determined in this study.

Interventions

• Drug Epidiferphane
  During the phase I portion of the study, subjects will be assigned to take either two (half target dose) or four (full target dose) Epidiferphane tablets orally three times daily following a 3 + 3 design. Three subjects will be sequentially enrolled at each of the 2 dose levels (beginning with the half target dose) until at least one dose-limiting toxicity (DLT) occurs. Dosing escalation will be stopped if two or more DLTs occur at either dose level. The maximum tolerated dose will be one dose l
• Drug Taxane Chemotherapy
  All subjects on both phases of the study will be concurrently treated with a taxane regimen containing either paclitaxel given weekly, nab-paclitaxel given weekly or every 3 weeks or docetaxel given every 3 weeks. The choice of taxane regimen will be determined by the treating physician prior to consenting to participate in this trial.

Primary outcome measures

• Cmax of Epidiferphane's components [Time frame: 24 hours]
• Cmax of taxanes [Time frame: 24 hours]
• Concentration at 24 hours (C24 hours) of Epidiferphane's components [Time frame: 24 hours]
• Concentration at 24 hours (C24 hours) of taxanes [Time frame: 24 hours]
• Maximum tolerated dose of Epidiferphane in patients with breast cancer who are being treated with taxanes [Time frame: 4 months]
• Rate of Common Terminology Criteria for Adverse Events (CTCAE) v5.0 grade 2 or higher neuropathy [Time frame: 4 months]
• Rate of Common Terminology Criteria for Adverse Events (CTCAE) v5.0 grade 1 or higher anemia [Time frame: 4 months]

Secondary outcome measures (7)

• Effect of Epidiferphane on quality of life, as measured by the EORTC QLQ-C30 scale [Time frame: 3 months]
• Effect of Epidiferphane on quality of life, as measured by the FACT-Taxane scale [Time frame: 3 months]
• Objective response rate [Time frame: 3 months]
• Concentration of the neuropathy marker NF-kB, as measured by multiplex cytokine bead analysis or ELISA (enzyme-linked immunosorbent assay) [Time frame: 3 months]
• Concentration of the neuropathy marker VEGFA, as measured by multiplex cytokine bead analysis or ELISA (enzyme-linked immunosorbent assay) [Time frame: 3 months]
• Concentration of the neuropathy marker Nrf2, as measured by multiplex cytokine bead analysis or ELISA (enzyme-linked immunosorbent assay) [Time frame: 3 months]
• Concentration of the neuropathy marker IL18, as measured by multiplex cytokine bead analysis or ELISA (enzyme-linked immunosorbent assay) [Time frame: 3 months]

Eligibility criteria

Inclusion criteria

• Must be at least 18 years of age
• Subjects on the phase I portion must either be initiating neoadjuvant chemotherapy or have a clinical diagnosis of metastatic breast cancer. Subjects on the phase II portion must have a clinical diagnosis of breast cancer of any stage and histology.
• Must be about to start a new treatment regimen containing either paclitaxel given weekly or docetaxel given every 3 weeks or nab-paclitaxel given weekly or every 3 weeks at UF Health, at one of the following doses:

• Paclitaxel weekly at 80-90 mg/m2
• Nab-paclitaxel weekly at 75-125 mg/m2 or every three weekly at 260 mg/m2
• Docetaxel every three weeks at 75-100 mg/m2
• An ECOG Performance Status less than or equal to 3 based on treating physician assessment
• Must continue cancer therapy at UF Health for at least the next three months
• Must not have more than one active malignancy at the time of enrollment (Subjects with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen \[as determined by the treating physician and approved by the PI\] may be included.
• A functioning digestive tract with no obstruction
• Subjects must be willing to avoid regular consumption of green tea and curcumin supplements for the duration of trial participation.
• Written informed consent obtained from the subject and the ability for the subject to comply with all the study-related procedures.
• Subjects of childbearing potential (SOCBP) must be using an adequate method of contraception to avoid pregnancy throughout the study.
• Subjects with partners of child-bearing potential must agree to use physician-approved contraceptive methods (e.g., abstinence, condoms, vasectomy) throughout the study.

Exclusion criteria

• Must not be receiving any other investigational agents
• Subjects of childbearing potential who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and following completion of taxane therapy for an additional 6 months for subjects of child bearing potential and 3 months for subjects with partners of child bearing potential.
• Subjects who are pregnant or breastfeeding
• Active systemic infection considered to be opportunistic, life threatening or clinically significant at the time of treatment.
• Psychiatric illness or social situation that would limit compliance with trial requirements.
• Known allergy to turmeric, broccoli, or green tea.
• Subjects must not be on treatment with strong CYP3A4 inhibitors such as tacrolimus or on verapamil during the trial.
• History of any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding (e.g. hemoglobin < 10 mg/dL, CTCAE v 5.0 grade 3 or higher neutropenia or thrombocytopenia) giving reasonable suspicion of a disease or condition that contraindicates the use of protocol therapy or that might affect the interpretation of the results of the study or that puts the subject at high risk for treatment complications, in the opinion of the treating physician.
• Prisoners or subjects who are involuntarily incarcerated.
• Subjects who are compulsorily detained for treatment of either a psychiatric or physical illness.
• Subjects demonstrating an inability to comply with the study and/or follow-up procedures.
• CTCAE v 5.0 grade 2 or higher peripheral sensory or motor neuropathy
• CTCAE v 5.0 grade 1 or higher paresthesia
• Alanine aminotransferase (ALT) or Aspartate aminotransferase (AST) >2.5 × the upper limit of normal (ULN)
• Total bilirubin (TBL) >1.5 × ULN or >3 × ULN in the presence of documented Gilbert's Syndrome (unconjugated hyperbilirubinemia)
• Glomerular filtration rate (GFR) <50 mL/min
• Red blood cell infusions < 30 days prior to treatment

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

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 1 center

• University of Florida — Gainesville

Identifiers

NCT: NCT05074290 · UF-BRE-007

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗