A Phase 2 Study of PCS6422 With Capecitabine in Patients With Advanced or Metastatic Breast Cancer

This is an adaptive Phase 2, open-label, randomized, multi-center study evaluating up to 2 regimens of PCS6422 with capecitabine (Cap) vs. standard dose of Cap alone in patients with advanced or metastatic breast cancer. The goal of the study is to assess the efficacy and safety of PCS6422 + Cap as a treatment option for patients with advanced or metastatic breast cancer who are not eligible for anthracycline- or taxane-containing therapies, or other available therapies, including PD-1 or PARP inhibitors.

This is an adaptive Phase 2, open-label, randomized, multi-center study evaluating up to 2 regimens of PCS6422 with Cap vs. standard dose of Cap alone in patients with advanced or metastatic breast cancer who are not eligible for anthracycline- or taxane-containing therapies, or other available therapies, including PD-1 or PARP inhibitors. The goal of the study is to assess the efficacy and safety of PCS6422 + Cap as a treatment option for patients with advanced or metastatic breast cancer who have been treated with chemotherapy in the metastatic setting.

Eligibility Criteria:
Inclusion Criteria:

1. Aged ≥18 years at Screening
2. Diagnosis of histologically confirmed breast cancer that is unresectable. The following subsets of breast cancer are included:

   1. Patients with triple-negative breast cancer, advanced or metastatic
   2. Patients with hormone receptor (HR) positive, ER positive, HER2 negative advanced or metastatic breast cancer
3. Has measurable disease in accordance with RECIST 1.1 obtained by imaging within 28 days prior to C1D1
4. Other therapies are not indicated (eg, resistant or intolerant to taxanes and/or an anthracycline-containing regimen) for treatment of advanced or metastatic breast cancer
5. Has a life expectance of at least 24 weeks
6. Has Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0 or 1 at screening
7. Has adequate bone marrow, liver, and renal function as assessed by the following laboratory requirements conducted within 7 days before C1D1 (Note: labs will also be repeated pre-dose on C1D1 to confirm eligibility): a. Hemoglobin ≥9 g/dL (≥90 g/L) b. Adequate renal function by estimated glomerular filtration rate (eGFR) defined as a creatinine clearance \>50 mL/min (\>0.84 mL/s) (Cockcroft-Gault equation) and normalized to body surface area c. Peripheral absolute neutrophil count (ANC) of ≥1.5×109/L d. Platelet count of ≥100×109/L without growth factor/transfusion e. Total bilirubin \<1.5× upper limit of normal (ULN); or ≤3×ULN if the patient has Gilbert's disease f. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \<2.5×ULN, with liver metastasis \<5×ULN g. International normalized ratio (INR) \<1.5 and prothrombin time (PT) ≤1.5×ULN, unless both of the following conditions are met: i. Patient is receiving anticoagulant therapy, and ii. PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulant h. Activated partial thromboplastin time (aPTT) ≤1.5×ULN, unless both of the following conditions are met: i. Patient is receiving anticoagulant therapy, and ii. PT or PTT is within therapeutic range of intended use of anticoagulants

Exclusion Criteria:

1. Received any line of treatment for advanced or metastatic breast cancer within 21 days or 5 half-lives (whichever is longer) prior to randomization
2. Currently receiving any hormone replacement therapy, unless discontinued within 21 days prior to randomization
3. Received IV 5-FU or oral 5-FU analog in the 4 weeks prior to C1D1
4. Received DPD inhibitor within 4 weeks prior to C1D1
5. Has homozygous or compound heterozygous DPYD variants that result in complete or near-complete absence of DPD activity
6. Cardiac:

   1. Has history or presence of clinically significant abnormal 12-lead electrocardiogram (ECG) results, in the Medical Monitor or Investigator's opinion
   2. Has prolonged QTc (with Fridericia's correction) of \>480 msec performed at Screening
   3. Has a history of prolonged QTc interval, ventricular tachycardia/fibrillation or significant ventricular arrhythmia, or Torsades de Pointes, or a history of ventricular ablation for arrhythmia
   4. Has congenital long QT syndrome or a family history of long QT syndrome
   5. Has other clinically significant cardiac disease including, but not limited to, myocardial infarction, unstable angina, cardiac or other vascular stenting, angioplasty, or surgery ≤12 months prior to randomization, congestive heart failure

      * Class II per the New York Heart Association, or history of myocarditis
7. Is pregnant or breastfeeding