Estrogen Receptor Positive Breast Cancer
Conditions
Keywords
mTOR, Tamoxifen, Breast Cancer
Brief 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.
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.
Interventions
DRUGTAK-228
MTORC1/2 inhibitor
DRUGTamoxifen
Non-steroidal anti-estrogen
Sponsors
Millennium Pharmaceuticals, Inc.
The Methodist Hospital Research Institute
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Ki67 Expression | Baseline to 6 weeks | Ki67 expression change from baseline to 6 weeks |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Meeting Certain Preoperative Endocrine Prognostic Index (PEPI) | 16 weeks | Evaluate the number of participants meeting certain PEPI score after treatment with TAK-228 plus tamoxifen. PEPI score of 0 indicates low risk of disease recurrence (better outcome) PEPI score of 1-3 indicates intermediate risk of of disease recurrence (worse outcome) PEPI score of \>4 indicates high risk of of disease recurrence (worst outcome) |
| Number of Participants With Pathological Complete Response (pCR) | 16 weeks | Pathologic complete response was defined as the absence of residual invasive cancer on hematoxylin and eosin evaluation of the complete resected breast specimen and all sampled regional lymph nodes following completion of neoadjuvant systemic therapy (i.e., ypT0 ypN0 or ypTis ypN0 in the current American Joint Committee on Cancer staging system). |
Other
| Measure | Time frame | Description |
|---|---|---|
| Correlation Between Change in mTOR Expression and pCR to TAK-228 Plus Tamoxifen | 16 weeks | Assess the correlation between change in mTOR expression and pCR to TAK-228 plus tamoxifen |
| Correlation Between Tumor Mutational Status and Response to TAK-228 Plus Tamoxifen | 16 weeks | Assess correlation between tumor mutational status and response to TAK-228 plus tamoxifen |
| Plasma Concentrations of TAK-228 Plus Tamoxifen | 16 weeks | Measure plasma concentrations of TAK-228 plus tamoxifen over time |
| Correlation Between Change in Ki67 Expression and pCR to TAK-228 Plus Tamoxifen | 16 weeks | Assess the correlation between change in Ki67 expression and pCR to TAK-228 plus tamoxifen |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| TAK-228 Plus Tamoxifen TAK-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: MTORC1/2 inhibitor
Tamoxifen: Non-steroidal anti-estrogen | 28 |
| Total | 28 |
Baseline characteristics
| Characteristic | TAK-228 Plus Tamoxifen |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 28 Participants |
| Age, Continuous | 52 years STANDARD_DEVIATION 11.6 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants |
| Race (NIH/OMB) More than one race | 4 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 17 Participants |
| Region of Enrollment United States | 28 Participants |
| Sex: Female, Male Female | 28 Participants |
| Sex: Female, Male Male | 0 Participants |
| Stage I-III ER-positive, HER-2 negative breast cancer | 28 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 28 |
| other Total, other adverse events | 28 / 28 |
| serious Total, serious adverse events | 1 / 28 |
Outcome results
Primary
Ki67 Expression
Ki67 expression change from baseline to 6 weeks
Time frame: Baseline to 6 weeks
Population: Change in baseline Ki67 expression at 6 weeks
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| TAK-228 Plus Tamoxifen | Ki67 Expression | Ki67 expression at baseline | 15 Percentage of cells with Ki67 expression |
| TAK-228 Plus Tamoxifen | Ki67 Expression | Ki67 expression at 6 weeks | 10 Percentage of cells with Ki67 expression |
Comparison: The primary endpoint was the change in Ki67 after 6 weeks of treatment.p-value: =0.0023Wilcoxon (Mann-Whitney)
Secondary
Number of Participants Meeting Certain Preoperative Endocrine Prognostic Index (PEPI)
Evaluate the number of participants meeting certain PEPI score after treatment with TAK-228 plus tamoxifen. PEPI score of 0 indicates low risk of disease recurrence (better outcome) PEPI score of 1-3 indicates intermediate risk of of disease recurrence (worse outcome) PEPI score of \>4 indicates high risk of of disease recurrence (worst outcome)
Time frame: 16 weeks
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| TAK-228 Plus Tamoxifen | Number of Participants Meeting Certain Preoperative Endocrine Prognostic Index (PEPI) | PEPI score of 0 | 0 Participants |
| TAK-228 Plus Tamoxifen | Number of Participants Meeting Certain Preoperative Endocrine Prognostic Index (PEPI) | PEPI score of 1-3 | 6 Participants |
| TAK-228 Plus Tamoxifen | Number of Participants Meeting Certain Preoperative Endocrine Prognostic Index (PEPI) | PEPI score of >4 | 15 Participants |
Secondary
Number of Participants With Pathological Complete Response (pCR)
Pathologic complete response was defined as the absence of residual invasive cancer on hematoxylin and eosin evaluation of the complete resected breast specimen and all sampled regional lymph nodes following completion of neoadjuvant systemic therapy (i.e., ypT0 ypN0 or ypTis ypN0 in the current American Joint Committee on Cancer staging system).
Time frame: 16 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| TAK-228 Plus Tamoxifen | Number of Participants With Pathological Complete Response (pCR) | 0 Participants |
Other Pre-specified
Correlation Between Change in Ki67 Expression and pCR to TAK-228 Plus Tamoxifen
Assess the correlation between change in Ki67 expression and pCR to TAK-228 plus tamoxifen
Time frame: 16 weeks
Other Pre-specified
Correlation Between Change in mTOR Expression and pCR to TAK-228 Plus Tamoxifen
Assess the correlation between change in mTOR expression and pCR to TAK-228 plus tamoxifen
Time frame: 16 weeks
Other Pre-specified
Correlation Between Tumor Mutational Status and Response to TAK-228 Plus Tamoxifen
Assess correlation between tumor mutational status and response to TAK-228 plus tamoxifen
Time frame: 16 weeks
Other Pre-specified
Plasma Concentrations of TAK-228 Plus Tamoxifen
Measure plasma concentrations of TAK-228 plus tamoxifen over time
Time frame: 16 weeks