TAK-228 Plus Tamoxifen in Patients With ER-Positive, HER2-negative Breast Cancer
Condition: Estrogen Receptor Positive Breast Cancer
MeSH terms: Breast Neoplasms
Intervention: TAK-228; Tamoxifen
Intervention description: MTORC1/2 inhibitor; Non-steroidal anti-estrogen
Intervention MeSH terms: Tamoxifen
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 28.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: mTOR; Tamoxifen; Breast Cancer

Summary:

      This is an open label phase II clinical trial to determine the efficacy, toxicity, and safety
      of TAK-228 plus tamoxifen in patients with newly diagnosed ER-positive, HER2-negative breast
      cancer.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Female or male ≥ 18 years of age.

          2. Newly diagnosed ER-positive, HER2-negative breast cancer. ER-positive is defined as ≥
             1% immunohistochemical (IHC) staining of any intensity. HER2 test result is negative
             if a single test (or both tests) performed show:

               -  IHC 1+ or 0

               -  In situ hybridization negative based on:

                    -  Single-probe average HER2 copy number < 4.0 signals/cell

                    -  Dual-probe HER2/CEP17 ratio < 2 with an average HER2 copy number < 4.0
                       signals/cell.

          3. Patients with stage II-III breast cancer are eligible if they are deemed appropriate
             for neoadjuvant endocrine therapy by the referring or treating medical oncologist.
             Patients with stage I disease are eligible if they are deemed borderline candidates
             for breast conservation and the treating surgeon recommends preoperative therapy to
             increase the chances of breast conservation.

          4. Eastern Cooperative Oncology Group performance status and/or other performance status
             of ≤ 1.

          5. Female patients who:

               -  Are postmenopausal for at least 1 year before the screening visit, OR

               -  Are surgically sterile, OR

               -  If they are of childbearing potential, agree to practice 1 effective method of
                  contraception and 1 additional effective (barrier) method, at the same time, from
                  the time of signing the ICF through 90 days (or longer, as mandated by local
                  labeling [e.g., United Surgical Partners International, summary of product
                  characteristics, etc.] after the last dose of the study drugs, OR

               -  Agree to practice true abstinence, when this is in line with the preferred and
                  usual lifestyle of the patient (periodic abstinence [e.g., calendar, ovulation,
                  symptothermal, postovulation methods] and withdrawal, spermicides only, and
                  lactational amenorrhea are not acceptable methods of contraception. Female and
                  male condom should not be used together).

          6. Male patients, even if surgically sterilized (i.e., status post-vasectomy), who:

               -  Agree to practice highly effective barrier contraception during the entire study
                  treatment period and through 120 days after the last dose of the study drugs, OR

               -  Agree to practice true abstinence, when this is in line with the preferred and
                  usual lifestyle of the patient

               -  Agree not to donate sperm during the course of this study or within 120 days
                  after receiving their last dose of the study drugs.

          7. Screening clinical laboratory values as specified below:

               1. Bone marrow reserve consistent with: absolute neutrophil count ≥ 1.5 x 109/L,
                  platelet count ≥ 100 x 109/L, and hemoglobin ≥ 9 g/dL (without transfusion)
                  within 1 week preceding the administration of the study drugs;

               2. Hepatic status: Serum total bilirubin ≤ 1 x upper limit of normal (ULN; in the
                  case of known Gilbert's syndrome, a higher serum total bilirubin [< 1.5 x ULN] is
                  allowed), aspartate aminotransferase and alanine aminotransferase ≤ 1.5 x ULN,
                  and alkaline phosphatase ≤ 1.5 x ULN;

               3. Renal status: Creatinine clearance ≥50 mL/min based on Cockcroft-Gault estimate
                  or based on urine collection (12 or 24 hour);

               4. Metabolic status: HbA1c < 7.0%, fasting serum glucose ≤ 130 mg/dL, and fasting
                  triglycerides ≤ 300 mg/dL.

          8. Ability to swallow oral medications.

          9. Voluntary written consent must be given before performance of any study-related
             procedure not part of standard medical care, with the understanding that consent may
             be withdrawn by the patient at any time without prejudice to future medical care.

         10. Negative serum pregnancy test within 7 days prior to the administration of the study
             drugs for female patients of childbearing potential.

         11. Patient must be accessible for treatment and follow-up.

         12. Patient must be willing to undergo breast biopsies as required by the study protocol.

        Exclusion Criteria:

          1. Any patient with metastatic disease.

          2. Other clinically significant comorbidities, such as uncontrolled pulmonary disease,
             active central nervous system disease, active infection, or any other condition that
             could compromise the patient's participation in the study.

          3. Known human immunodeficiency virus infection.

          4. Known hepatitis B surface antigen-positive or known or suspected active hepatitis C
             infection.

          5. Any serious medical or psychiatric illness that could, in the investigator's opinion,
             potentially interfere with the completion of the protocol-specified treatment.

          6. Diagnosed or treated for another malignancy within 2 years before administration of
             the first dose of the study drugs or previously diagnosed with another malignancy and
             have any evidence of residual disease. Patients with non-melanoma skin cancer or
             carcinoma in situ of any type are not excluded if they have undergone complete
             resection.

          7. Breastfeeding or pregnant.

          8. Manifestations of malabsorption due to prior gastrointestinal surgery,
             gastrointestinal disease, or an unknown reason that may alter the absorption of
             TAK-228. Patients with enteric stomata are also excluded.

          9. Treatment with any investigational products within 2 weeks before administration of
             the first dose of the study drugs.

         10. Poorly controlled diabetes mellitus (defined as HbA1c > 7%). Patients with a history
             of transient glucose intolerance due to corticosteroid administration may be enrolled
             in the study if all other inclusion criteria and none of the other exclusion criteria
             are met.

         11. History of any of the following within the last 6 months before administration of the
             first dose of the study drugs:

               -  Ischemic myocardial event, including angina requiring therapy and artery
                  revascularization procedures

               -  Ischemic cerebrovascular event, including transient ischemic attack and artery
                  revascularization procedures

               -  Requirement for inotropic support (excluding digoxin) or serious (uncontrolled)
                  cardiac arrhythmia (including atrial flutter/fibrillation, ventricular
                  fibrillation, and ventricular tachycardia)

               -  Placement of a pacemaker for control of rhythm

               -  New York Heart Association Class III or IV heart failure

               -  Pulmonary embolism

         12. Significant active cardiovascular or pulmonary disease including:

               -  Uncontrolled hypertension (i.e., systolic blood pressure > 180 mm Hg, diastolic
                  blood pressure > 95 mm Hg). Use of antihypertensive agents to control
                  hypertension before week 1, day 1 is allowed.

               -  Pulmonary hypertension

               -  Uncontrolled asthma or O2 saturation < 90% by arterial blood gas analysis or
                  pulse oximetry on room air

               -  Significant valvular disease, severe regurgitation, or stenosis by imaging
                  independent of symptom control with medical intervention or history of valve
                  replacement

               -  Medically significant (symptomatic) bradycardia

               -  History of arrhythmia requiring an implantable cardiac defibrillator

               -  Baseline QTc prolongation (e.g., repeated demonstration of QTc interval > 480
                  milliseconds or history of congenital long QT syndrome or torsades de pointes)

         13. Treatment with strong inhibitors and/or inducers of CYP3A4, CYP2C9, or CYP2C19 within
             7 days preceding the first dose of the study drugs.

         14. Patients receiving systemic corticosteroids (either IV or oral steroids, excluding
             inhalers or low-dose hormone replacement therapy) within 1 week before administration
             of the first dose of the study drugs.

         15. Daily or chronic use of a proton pump inhibitor (PPI) and/or having taken a PPI within
             7 days before receiving the first dose of the study drugs.

         16. Patients unwilling or unable to comply with the study protocol.

         17. Patients previously treated with hormonal therapy (tamoxifen, AI) or PI3K, AKT, dual
             PI3K/mTOR, TORC1/2, or mTORC1 inhibitors.

         18. Patients who are currently being treated with cancer therapy (chemotherapy, radiation
             therapy, immunotherapy, or biologic therapy) other than the trial therapy.

         19. Patients with hypersensitivity to mTOR inhibitors or tamoxifen.