Clinical Trials /

TAK-228 Plus Tamoxifen in Patients With ER-Positive, HER2-negative Breast Cancer

NCT02988986

Description:

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.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Completed

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: TAK-228 Plus Tamoxifen in Patients With ER-Positive, HER2-negative Breast Cancer
  • Official Title: Open Label, Phase II Trial of Neoadjuvant TAK-228 Plus Tamoxifen in Patients With Estrogen Receptor (ER)-Positive, Human Epidermal Growth Factor Receptor 2 (HER2)-Negative Breast Cancer

Clinical Trial IDs

  • ORG STUDY ID: Pro00016065
  • NCT ID: NCT02988986

Conditions

  • Estrogen Receptor Positive Breast Cancer

Interventions

DrugSynonymsArms
TAK-228INK128, MLN0128TAK-228 Plus Tamoxifen
TamoxifenApo-Tamox, Gen-Tamoxifen, Nolvadex, Novo-TamoxifenTAK-228 Plus Tamoxifen

Purpose

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.

Detailed Description

The mTOR pathway is commonly dysregulated in ER-positive breast cancers and represents a key resistance mechanism to endocrine therapy such as tamoxifen. We plan to target the mTOR pathway with mTORC1/2 inhibitor TAK-228 to overcome tamoxifen resistance in early-stage ER-positive breast cancer. An open label phase II clinical trial will be conducted to determine the efficacy, toxicity, and safety of TAK-228 plus tamoxifen in patients with newly diagnosed ER-positive, HER2-negative breast cancer. TAK-228 (30 mg weekly) plus tamoxifen (20 mg daily) will be administered for 16 weeks. Patients will undergo tumor biopsy before starting the study treatment and after 6 weeks of study treatment. Blood samples for pharmacokinetics analysis will be obtained 1 hour before and after TAK-228 dosing on days 1 and 15 of the study.

Trial Arms

NameTypeDescriptionInterventions
TAK-228 Plus TamoxifenExperimentalTAK-228 will be orally administered at 30 mg weekly for 16 weeks. Tamoxifen will be orally administered at 20 mg daily for 16 weeks.
  • TAK-228
  • Tamoxifen

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 of childbearing potential must agree to simultaneously practice 1 highly effective method of contraception and 1 additional effective (barrier) method from the time of signing the informed consent form (ICF) through 90 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.

6. Male patients of childbearing potential must agree to use an adequate method of contraception from the time of signing the ICF through 90 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.

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 ≤ 1.5 mg/dL;

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, aromatase inhibitor) or mTOR inhibitors (everolimus, sirolimus).

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.

Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Change in Ki67 expression
Time Frame:16 weeks
Safety Issue:
Description:Change in baseline Ki67 expression at 16 weeks

Secondary Outcome Measures

Measure:Pathological complete response (pCR) rate
Time Frame:16 weeks
Safety Issue:
Description:Evaluate the pCR rate after treatment with TAK-228 plus tamoxifen
Measure:Preoperative endocrine prognostic index (PEPI) score
Time Frame:16 weeks
Safety Issue:
Description:Evaluate the PEPI score after treatment with TAK-228 plus tamoxifen
Measure:Number of participants with treatment-related adverse events
Time Frame:16 weeks
Safety Issue:
Description:Number of participants with treatment-related adverse events as assessed by NCI CTCAE v4.03

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Jenny C. Chang, MD

Trial Keywords

  • mTOR
  • Tamoxifen
  • Breast Cancer

Last Updated

December 22, 2016