Ipatasertib Plus Non-Taxane Chemotherapy for Advanced or Metastatic Triple-Negative Breast Cancer

Inclusion Criteria:

1. Signed Informed Consent Form (ICF) prior to participation in any study-relatedactivities.

2. Female patients ≥ 18 years at the time of signing ICF.

3. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.

4. Life expectancy of ≥ 12 weeks.

5. Histologically confirmed Triple Negative Breast Cancer (TNBC) per American Societyof Clinical Oncology (ASCO)/College of American Pathologists (CAP) criteria based onlocal testing on the most recent analyzed biopsy. Triple-negative is defined as <1%expression for estrogen receptor (ER) and progesterone receptor (PgR) and negativefor Human Epidermal Growth Factor Receptor 2 (HER2) (0-1+ by immunohistochemistry (IHC) or 2+ and negative by in situ hybridization [ISH) test].

6. Unresectable locally advanced or metastatic disease documented by computerizedtomography (CT) scan or magnetic resonance imaging (MRI) that is not amenable toresection with curative intent.

7. Measurable or evaluable disease as per RECIST v.1.1. Patients with only bone lesionsare also eligible.

8. Refractory to or relapsed after one or two prior standard of care chemotherapyregimens for unresectable locally advanced or metastatic breast cancer (MBC).Earlier adjuvant or neoadjuvant therapy for more limited disease will be consideredas one of the required prior regimens if the development of unresectable locallyadvanced or metastatic disease occurred within a 12-month period of time aftercompletion of chemotherapy. Note: Exclusive tumor marker elevation will not be considered sufficient fordiagnosis of disease progression.

9. Prior therapy must have included a taxane in any combination or order and either inthe early, locally advanced, or metastatic setting. Note: Exclusive priortaxane-based therapy as adjuvant or neoadjuvant treatment is also allowed if thepatient had a disease-free interval of less than 12 months after completing thistreatment.

10. Eligible for one of the chemotherapy options (eribulin, capecitabine, carboplatinplus gemcitabine) as per local investigator assessment and slots availability.Patients treated with (neo)adjuvant platinum salts or capecitabine and who haverelapsed more than one year after the last dose of either treatment may be allowedto be included in the treatment arm based on ipatasertib (GDC-0068) in combinationwith carboplatin plus gemcitabine and capecitabine, respectively.

11. Previous treatment with androgen receptor antagonists, poly ADP-ribose Polymerase (PARP) inhibitors, and immunotherapy is allowed. Those patients who have previouslyreceived a PARP inhibitor will not be included in the carboplatin and gemcitabinearm unless PARP inhibitors were used in the early breast cancer setting and theperiod between the end of PARP inhibitor-based regimen and onset of metastaticdisease is at least of 12 months.

12. Resolution of all acute toxic effects of prior anti-cancer therapy to grade inferioror equal to 1 as determined by the NCI-CTCAE v.5.0 (except for alopecia or othertoxicities not considered a safety risk for the patient at investigator'sdiscretion).

13. Willingness and ability to provide a tumor biopsy from a metastatic site or theprimary breast tumor at the time of the inclusion in order to perform exploratorystudies. If not feasible, patient eligibility should be evaluated by a Sponsor'squalified designee. Note: Subjects for whom tumor biopsies cannot be obtained (e.g.,inaccessible tumor or subject safety concern) may submit an archived metastatictumor specimen only upon agreement from the Sponsor.

14. Patients agree to give blood samples (liquid biopsy) at the time of inclusion, aftertwo cycles of study treatment, and upon progression or study termination.

15. Adequate hematologic and organ function within 14 days before the first studytreatment on Day 1 of Cycle 1, defined by the following:

16. Hematological: White blood cell (WBC) count > 3.0 x 109/L, absolute neutrophilcount (ANC) > 1.5 x 109/L, platelet count > 100.0 x109/L, and hemoglobin > 9.0g/dL.

17. Hepatic: Serum albumin ≥ 3 g/dL; Bilirubin ≤ 1.5 times the upper limit ofnormal (× ULN) (≤ 3 x ULN in the case of Gilbert's disease); aspartatetransaminase (AST) and alanine transaminase (ALT) ≤ 2.5 × ULN (in the case ofliver metastases ≤ 5 × ULN); alkaline phosphatase (ALP) ≤ 2 × ULN (≤ 5 × ULN inthe case of liver and/or bone metastases ≤ 5 × ULN).

18. Renal: Serum creatinine < 1.5 × ULN or creatinine clearance ≥ 50 mL/min basedon Cockcroft-Gault glomerular filtration rate estimation.

19. Coagulation: Partial Thromboplastin Time (PTT) (or activated PartialThromboplastin Time [aPTT]) and International Normalized Ratio (INR) ≤ 1.5 ×ULN (except for patients receiving anticoagulation therapy). Note: Patients receiving heparin treatment should have a PTT (or aPTT) ≤ 2.5 × ULN (or patient value before starting heparin treatment). Patients receiving coumarinderivatives should have an INR between 2.0 and 3.0 assessed in two consecutivemeasurements one to four days apart. Patients should be on a stable anticoagulantregimen.

20. For women of childbearing potential: agreement to remain abstinent (refrain fromheterosexual intercourse), or to use a highly effective non-hormonal form ofcontraception, or two effective forms of contraception, as defined in the protocolduring the treatment period and for at least 28 days after the last dose ofipatasertib (GDC-0068), three months after the last dose of eribulin, and six monthsafter the last dose of carboplatin and gemcitabine or capecitabine, whichever occurslater, and agreement to refrain from donating eggs during this same period. Women ofchildbearing potential must have a negative serum pregnancy test before studytreatment initiation.

Exclusion Criteria:

1. Inability to comply with study and follow-up procedures.

2. Previous treatment with PI3K, mTOR, or AKT inhibitors.

3. Known active uncontrolled or symptomatic central nervous system (CNS) metastases,carcinomatous meningitis, or leptomeningeal disease as indicated by clinicalsymptoms, cerebral edema, and/or progressive growth. Patients with a history of CNSmetastases or cord compression are eligible if they have been definitively treated (e.g., radiotherapy, stereotactic surgery), are clinically stable, and offanticonvulsants and steroids for at least two weeks before first dose of studytreatment.

4. Radiotherapy or limited-field palliative radiotherapy within seven days prior tostudy enrolment, or patients who have not recovered from radiotherapy-relatedtoxicities to baseline or grade ≤ 1 and/or from whom ≥ 25% of the bone marrow hasbeen previously irradiated.

5. Major surgery (defined as requiring general anesthesia) or significant traumaticinjury within 28 days of start of study drug, or patients who have not recoveredfrom the side effects of any major surgery.

6. Grade ≥ 2 peripheral neuropathy.

7. Grade ≥ 2 uncontrolled or untreated hypercholesterolemia or hypertriglyceridemia.

8. History of type I or type II diabetes mellitus either requiring insulin or with abaseline fasting glucose > 150 mg/dL (8.3 mmol/L) or high hemoglobin A1c (HbA1c) asdefined as > 7%. Patients who are on a stable dose of oral diabetes medicationduring at least weeks prior to initiation of study treatment are eligible forenrolment.

9. Lung disease: pneumonitis, interstitial lung disease, idiopathic pulmonary fibrosis,cystic fibrosis, Aspergillosis, active tuberculosis, or history of opportunisticinfections (pneumocystis pneumonia or cytomegalovirus pneumonia).

10. History of malabsorption syndrome or other condition that would interfere withenteral absorption or results in the inability or unwillingness to swallow pills.

11. History of or active inflammatory bowel disease (e.g., Crohn's disease andulcerative colitis) or active bowel inflammation (e.g., diverticulitis).

12. Known hypersensitivity reaction to any investigational or therapeutic compound ortheir incorporated substances.

13. Patients have a concurrent malignancy or malignancy within five years of studyenrollment with the exception of carcinoma in situ of the cervix, non-melanoma skincarcinoma, or stage I uterine cancer. For other cancers considered to have a lowrisk of recurrence, discussion with the Medical Monitor is required.

14. Current known infection with HIV, hepatitis B virus (HBV), or hepatitis C virus (HCV). Patients with past HBV infection or resolved HBV infection (defined as havinga negative hepatitis B surface antibody [HBsAg] test and a positive hepatitis B coreantibody [HBcAb] test, accompanied by a negative HBV DNA test) are eligible.Patients positive for HCV antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA.

15. Active uncontrolled infection at the time of enrollment.

16. Congenital long QT syndrome or screening QT interval corrected using Fridericia'sformula (QTcF) > 480 milliseconds.

17. Patients have an active cardiac disease or a history of cardiac dysfunctionincluding any of the following:

18. Unstable angina pectoris or documented myocardial infarction within six monthsprior to study entry.

19. Symptomatic pericarditis.

20. Documented congestive heart failure (New York Heart Association functionalclassification III- IV).

21. Left ventricular ejection fraction (LVEF) < 50% as determined by multiple gatedacquisition (MUGA) scan or echocardiogram (ECHO).

22. Patients have any of the following cardiac conduction abnormalities:

23. Ventricular arrhythmias except for benign premature ventricular contractions.

24. Supraventricular and nodal arrhythmias requiring a pacemaker or not controlledwith medication.

25. Conduction abnormality requiring a pacemaker.

26. Other cardiac arrhythmia not controlled with medication.

27. Patients have any other concurrent severe and/or uncontrolled medical condition thatwould, in the investigator's judgment contraindicate patient participation in theclinical study.

28. Treatment with strong CYP3A inhibitors or strong CYP3A inducers within 14 days orfive drug-elimination half-lives, whichever is longer, prior to initiation of studytreatment.

29. Pregnant, breastfeeding, or intending to become pregnant during the study or within 28 days after the last dose of ipatasertib (GDC-0068), three months after the lastdose of eribulin, and six months after the last dose of carboplatin and gemcitabineor capecitabine, whichever occurs later.

30. Treatment with approved or investigational cancer therapy within 14 days prior toinitiation of study drug.

31. Concurrent participation in other interventional clinical trial.