AKT Inhibitor, Ipatasertib, With Endocrine and CDK 4/6 Inhibitor for Patients With Metastatic Breast Cancer (TAKTIC)

Inclusion Criteria:

• Adult women (≥ 18 years of age) with biopsy proven HR+/HER2 negative breast cancer;HR+ defined as ≥1% positivity for ER, and/or PR (≥1%), as per local assessment. HER2as per standard CAP guidelines (local assessment).

• Postmenopausal women with locally advanced or metastatic BC. Patients must bepostmenopausal women as defined by one of the following:

• Women >60 years OR

• Women ≤60 years, and any one of following:

• LH and FSH level in the postmenopausal range according to institutionalstandards

• s/p post bilateral surgical oophorectomy.

• Premenopausal/perimenopausal women on gonadotropin-releasing hormoneagonist (to be continued during study) and estradiol level in thepostmenopausal range according to institutional standards

• Disease progression on at least one prior therapy for metastatic disease, includingendocrine therapy with/without CDK 4/6 inhibitor (palbociclib or ribociclib orabemaciclib). Disease recurrence during/within 12 month of (neo)adjuvant endocrinetherapy (with/without CDK 4/6 inhibitor) will count as one prior therapy for thisdefinition.

• ECOG Performance Status 0 - 2

• Left ventricular ejection fraction (LVEF) ≥ 50%

• Evaluable or measurable disease: at least one lesion that can be accurately measuredin at least one dimension ≥ 20 mm with conventional imaging techniques or ≥ 10 mmwith spiral CT or MRI. Bone lesions in the absence of measurable disease as definedabove is also acceptable.

• Discontinuation of prior breast cancer therapies, including endocrine therapy, for 14 days (non-myelosuppressive) or 21 days (myelosuppressive). Wash-out forFulvestrant and tamoxifen will be 28 days.

• Prior mTOR inhibitor and/or PI3K inhibitor allowed (all arms)

• Prior aromatase inhibitor is allowed (all arms)

• Adequate bone marrow function: ANC ≥ 1000/mm3, hemoglobin ≥9 g/dl, and platelets ≥ 100,000/mm3.

• Adequate hepatic function: Total bilirubin < 1.5mg/dL, AST and ALT < 3XInstitutional ULN (or 5 X Institutional ULN in presence of hepatic mets).

• Adequate renal function: Calculated creatinine clearance ≥ 30 mL/min

• Fasting blood glucose <140 mg/dL, and hemoglobin A1c <7.

• Signed informed consent and agree to comply with study procedures.

Exclusion Criteria:

• Participants with progressive CNS metastatic disease. Patients with stable CNSmetastasis would be eligible, provided mets radiologically stable for atleast onemonth, and patient is not actively taking steroids.

• Participants who have had chemotherapy or radiotherapy within 4 weeks (6 weeks fornitrosoureas or mitomycin C) prior to entering the study or those who have notrecovered from adverse events due to agents administered more than 4 weeks earlier.

• Prior use of AKT inhibitor (any setting)

• Treatment with strong CYP3A inhibitors or strong CYP3A inducers within 14 days or 5drug-elimination half-lives, whichever is longer, prior to initiation of studytreatment. Because the lists of these agents are constantly changing, it isimportant to regularly consult a frequently-updated list such ashttp://medicine.iupui.edu/clinpharm/ddis/table.aspx; medical reference texts such asthe Physicians' Desk Reference may also provide this information. As part of theenrollment/informed consent procedures, the patient will be counseled on the risk ofinteractions with other agents, and what to do if new medications need to beprescribed or if the patient is considering a new over-the-counter medicine orherbal product.

• Uncontrolled inter-current illness including, but not limited to, ongoing or activeinfection, symptomatic congestive heart failure, unstable angina pectoris, cardiacarrhythmia, or psychiatric illness/social situations that would limit compliancewith study requirements. Patient has impairment of gastrointestinal (GI) function orGI disease that may significantly alter the absorption of the study drugs (e.g.,inflammatory bowel disease, ulcerative diseases, uncontrolled nausea, vomiting,diarrhea, malabsorption syndrome, or small bowel resection).

• Clinically significant, uncontrolled heart disease and/or cardiac repolarizationabnormality including any of the following:

• History of angina pectoris, symptomatic pericarditis, coronary artery bypassgraft (CABG) or myocardial infarction within 6 months prior to study entry.

• Documented cardiomyopathy.

• History of cardiac failure, significant/symptomatic bradycardia, Long QTsyndrome, family history of idiopathic sudden death or congenital long QTsyndrome or any of the following:

• Known risk to prolong the QT interval or induce Torsade's de Pointes.

• Uncorrected hypomagnesemia or hypokalemia.

• Systolic Blood Pressure (SBP) >160 mmHg or <90 mmHg.

• Bradycardia (heart rate <50 at rest), by ECG or pulse.

• On screening, inability to determine the QTcF interval on the ECG (i.e.:unreadable or not interpretable) or QTcF >450 screening ECG (based on a mean of 3 ECGs).

• HIV-positive participants on combination antiretroviral therapy are ineligible.These participants are at increased risk of lethal infections when treated withmarrow-suppressive therapy. Appropriate studies will be undertaken in participantsreceiving combination antiretroviral therapy when indicated.

• History of Type I or Type II diabetes mellitus requiring insulin. Patients who areon a stable dose of oral diabetes medication ≥ 2 weeks prior to initiation of studytreatment are eligible for enrollment. Patients must meet the laboratory eligibilitycriteria for fasting blood glucose and hemoglobin A1c as outlined in the inclusioncriteria.

• Pregnant women are excluded from this study because the safety of study medicationsis not established in pregnant women.

• Women of child-bearing potential, defined as all women physiologically capable ofbecoming pregnant, unless they are using highly effective methods of contraceptionthroughout the study and for 8 weeks after study drug discontinuation. Women areconsidered post-menopausal and not of child bearing potential if they have had 12months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateraloophorectomy (with or without hysterectomy) or tubal ligation at least six weeksago. In the case of bilateral oophorectomy alone, only when the reproductive statusof the woman has been confirmed by follow up hormone level assessment is sheconsidered not of child bearing potential. Highly effective contraception methodsinclude:

• Total abstinence when this is in line with the preferred and usual lifestyle of thepatient. Periodic abstinence (e.g., calendar, ovulation, symptothermal,post-ovulation methods) and withdrawal are not acceptable methods of contraception

• Female sterilization (have had surgical bilateral oophorectomy with or withouthysterectomy), total hysterectomy, or tubal ligation at least six weeks beforetaking study treatment. In case of oophorectomy alone, only when the reproductivestatus of the woman has been confirmed by follow up hormone level assessment

• Use of oral, injected or implanted hormonal methods of contraception or placement ofan intrauterine device (IUD) or intrauterine system (IUS), or other forms ofhormonal contraception that have comparable efficacy (failure rate <1%), for examplehormone vaginal ring or transdermal hormone contraception.

• In case of use of oral contraception, women should have been stable on the same pillfor a minimum of 3 months before taking study treatment. Note: While oralcontraceptives are allowed, they should be used in conjunction with a barrier methodof contraception due to unknown effect of drug-drug interaction.

• For Arm A only: patients who have received prior fulvestrant.

• For Arm C only: h/o of intolerable toxicity to CDK 4/6 inhibitor resulting intreatment discontinuation due to toxicity