Phase II Study of FTD/TPI (Lonsurf) in Metastatic Breast Cancers With or Without Prior Exposure to Fluoropyrimidines (LONBRECA)

Phase Ib Patients will be treated with twice-daily dosing of FTD/TPI in a 3+3 dose escalation design Phase II

Oral FTD/TPI at RP2D will be administered until disease progression, intolerable toxicity or patient withdrawal.

2 parallel cohorts of patients will be enrolled : Cohort A : patients with prior exposure to fluoropyrimidines Cohort B : patients without prior exposure to fluoropyrimidines

Inclusion criteria

• Age ≥ 21 years.
• Histological or cytological diagnosis of breast carcinoma.
• ECOG 0-2.
• HER2 negative tumor (IHC 0 -1+ or IHC 2+ and confirmed on HER2 FISH to be negative based on histological report).
• Patients with HER2 positive tumor may be enrolled if they have failed at least two lines of anti-HER2 based therapies in the metastatic setting, or are intolerant to trastuzumab
• Any hormone receptor status.
• Any number of lines of prior palliative endocrine therapy for patients with hormone receptor positive cancer.
• Has measureable or evaluable disease based on RECIST 1.1 criteria
• Estimated life expectancy of at least 12 weeks.
• Has documented progressive disease from last line of therapy.
• Has recovered from acute toxicities from prior anti-cancer therapies
• Adequate organ function including the following:

oBone marrow: (I) Absolute neutrophil (segmented and bands) count (ANC) ≥1.5 x 109/L (ii) Platelets ≥100 x 109/L (ii) Hemoglobin ≥8 x 109/L oHepatic: (I)Bilirubin ≤ 1.5 x upper limit of normal (ULN), (ii)ALT or AST ≤ 2.5x ULN, (or ≤ 5 X with liver metastases) oRenal: (I) Creatinine ≤1.5x ULN

• Signed informed consent from patient or legal representative.
• Able to comply with study-related procedures.
• Prior therapy (patients enrolled in phase Ib may be enrolled if they fulfil prior therapy criteria for either Cohort A or Cohort B)

• Cohort A only: Has received at least 2 lines of palliative systemic therapy, including prior fluropyrimidines (capecitabine, TS-1 or 5-fluorouracil) in the palliative setting, or in the adjuvant setting; patients who have only prior exposure to adjuvant fluoropyrimidines must have relapsed within 12 months of completing adjuvant fluoropyrimidines
• Cohort B only: Any number of prior lines of palliative chemotherapy and has not received fluoropyrimidines (capecitabine, TS-1 or 5-fluorouracil) in the palliative setting or in the adjuvant setting; patients who have prior exposure to adjuvant fluoropyrimidines are eligible if they have relapsed 12 months from completion of adjuvant fluoropyrimidines.

Exclusion criteria

• Treatment within the last 30 days with any investigational drug.
• Concurrent administration of any other tumour therapy, including cytotoxic chemotherapy, hormonal therapy, and immunotherapy.
• Major surgery within 28 days of study drug administration.
• Active infection that in the opinion of the investigator would compromise the patient's ability to tolerate therapy.
• Pregnancy.
• Breast feeding.
• Serious concomitant disorders that would compromise the safety of the patient or compromise the patient's ability to complete the study, at the discretion of the investigator.
• Active bleeding disorder or bleeding site.
• Non-healing wound.
• Poorly controlled diabetes mellitus.
• Second primary malignancy that is clinically detectable at the time of consideration for study enrollment.
• Symptomatic brain metastasis.
• History of significant neurological or mental disorder, including seizures or dementia.
• Unable to comply with study procedures

Phase Ib lead-in can recruit patients who fulfil criteria for either Cohort A or Cohort B AND all other inclusion/exclusion criteria