Estrogen Receptor Positive Breast CancerPhase 2ANETTNCT02988986
TAK-228 Plus Tamoxifen in Patients With ER-Positive, HER2-negative Breast Cancer
A Phase 2 study testing TAK-228 and Tamoxifen in people with Estrogen Receptor Positive Breast Cancer, run by The Methodist Hospital Research Institute at 3 sites in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Estrogen Receptor Positive Breast Cancer
- What is being tested?
- TAK-228 and Tamoxifen
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 28 participants
- Where
- 3 sitesUnited States
- Study dates
- 24 Apr 2017to 30 Mar 2019
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Female or male ≥ 18 years of age.
- 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.
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- 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.
- Eastern Cooperative Oncology Group performance status and/or other performance status of ≤ 1.
- 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).
- 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.
- Screening clinical laboratory values as specified below:
- 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;
- 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;
- Renal status: Creatinine clearance ≥50 mL/min based on Cockcroft-Gault estimate or based on urine collection (12 or 24 hour);
- Metabolic status: HbA1c < 7.0%, fasting serum glucose ≤ 130 mg/dL, and fasting triglycerides ≤ 300 mg/dL.
- Ability to swallow oral medications.
- 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.
- Negative serum pregnancy test within 7 days prior to the administration of the study drugs for female patients of childbearing potential.
- Patient must be accessible for treatment and follow-up.
- Patient must be willing to undergo breast biopsies as required by the study protocol.
Who cannot join
- Any patient with metastatic disease.
- 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.
- Known human immunodeficiency virus infection.
- Known hepatitis B surface antigen-positive or known or suspected active hepatitis C infection.
- Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of the protocol-specified treatment.
- 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.
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- Breastfeeding or pregnant.
- 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.
- Treatment with any investigational products within 2 weeks before administration of the first dose of the study drugs.
- 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.
- 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
- 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)
- Treatment with strong inhibitors and/or inducers of CYP3A4, CYP2C9, or CYP2C19 within 7 days preceding the first dose of the study drugs.
- 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.
- 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.
- Patients unwilling or unable to comply with the study protocol.
- Patients previously treated with hormonal therapy (tamoxifen, AI) or PI3K, AKT, dual PI3K/mTOR, TORC1/2, or mTORC1 inhibitors.
- Patients who are currently being treated with cancer therapy (chemotherapy, radiation therapy, immunotherapy, or biologic therapy) other than the trial therapy.
- Patients with hypersensitivity to mTOR inhibitors or tamoxifen.
Trial locations and contacts
3 sites in 1 country.
United States3 sites
Houston Methodist Hospital
Houston, Texas, 77030
Houston Methodist Hospital Willowbrook
Houston, Texas, 77070
Houston Methodist Hospital Sugar Land
Sugar Land, Texas, 77479
About this study
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
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.
Read the 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.
- Conditions
- Estrogen Receptor Positive Breast Cancer
- Being tested
- TAK-228, Tamoxifen
- Keywords
- mTOR, Tamoxifen, Breast Cancer
- Medical subject headings
- Breast Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
TAK-228Drug
Also called INK128, MLN0128
MTORC1/2 inhibitor
TamoxifenDrug
Also called Apo-Tamox, Gen-Tamoxifen, Nolvadex, Novo-Tamoxifen
Non-steroidal anti-estrogen
| Study group | Role | What they receive |
|---|---|---|
| TAK-228 Plus Tamoxifen | Experimental | 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. Receives: Drug: TAK-228; Drug: Tamoxifen |
What is being measured
The primary outcome is the main question the study is designed to answer.
Ki67 Expression
Ki67 expression change from baseline to 6 weeks
Measured: Baseline to 6 weeks
Secondary outcomes (2)
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)
Measured: 16 weeks
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).
Measured: 16 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted12 Dec 2016 (estimated)
- Study start24 Apr 2017
- Primary completion1 Feb 2019
- Study completion30 Mar 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Estrogen Receptor Positive Breast CancerStudies of the same condition, open and under way.
- More trials run by The Methodist Hospital Research InstituteThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 28 participants (actual)
Sponsor and investigators
- Lead sponsor
- The Methodist Hospital Research Institute
- Sponsor type
- University, hospital or other
- Collaborators
- Millennium Pharmaceuticals, Inc.
- Responsible party
- Principal investigator, Jenny C. Chang, MD, The Methodist Hospital Research Institute
- Investigators
- Jenny C Chang, M.D., Principal investigator, Houston Methodist Cancer Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02988986
- Sponsor's protocol ID
- Pro00016065
- Acronym
- ANETT
- Status last verified
- Aug 2021
- First submitted
- 30 Nov 2016
- Last updated
- 22 Sep 2021
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: Data and materials on human subjects will be shared with other eligible investigators through appropriate means in accordance with the NIH policy on Sharing Research Data (NIH Guide, February 26, 2003). Data will be also shared with the funding agency and regulatory agencies as required. Data will be shared with other investigators within the limits of HIPAA and other patient confidentiality requirements. This will generally require removal of all patient identifiers for all source documents and the use of arbitrarily assigned one-way identifiers. In some cases, requestors will be asked to sign a formal data sharing agreement that will provide for a commitment to use data only for research purposes and not to identify individuals, keep the data secure, and destroy or return data after analyses are complete. Prior approval will be obtained from collaborating investigators, research sponsors, and/or other stake-holders before sharing if proprietary information or products are involved.
Study at a glance
From the registry record, last updated by the sponsor on 22 Sep 2021. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT02988986
- Acronym / sponsor ID
- ANETT / Pro00016065
- Conditions
- Estrogen Receptor Positive Breast Cancer
- Keywords
- mTOR, Tamoxifen, Breast Cancer
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 28 participants (actual)
- Lead sponsor
- The Methodist Hospital Research InstituteUniversity, hospital or other
- Collaborators
- Millennium Pharmaceuticals, Inc.
- Study start
- 24 Apr 2017 (actual)
- Primary completion
- 1 Feb 2019 (actual)
- Study completion
- 30 Mar 2019 (actual)
- First posted
- 12 Dec 2016 (estimated)
- Results
- Posted 27 Jul 2021
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| TAK-228 Plus Tamoxifen | Experimental | Drug: TAK-228, Drug: TamoxifenTAK-228 will be orally administered at 30 mg weekly for 16 weeks. Tamoxifen will be orally administered at 20 mg daily for 16 weeks. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (27 listed)
- Female or male ≥ 18 years of age.
- 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:
- 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.
- Eastern Cooperative Oncology Group performance status and/or other performance status of ≤ 1.
- Female patients who:
Key exclusion criteria (32 listed)
- Any patient with metastatic disease.
- 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.
- Known human immunodeficiency virus infection.
- Known hepatitis B surface antigen-positive or known or suspected active hepatitis C infection.
- Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of the protocol-specified treatment.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| TAK-228Also: INK128, MLN0128MTORC1/2 inhibitor | Drug | TAK-228 Plus Tamoxifen |
| TamoxifenAlso: Apo-Tamox, Gen-Tamoxifen, Nolvadex, Novo-TamoxifenNon-steroidal anti-estrogen | Drug | TAK-228 Plus Tamoxifen |
Primary outcome
Ki67 Expression
Time frame: Baseline to 6 weeks
Ki67 expression change from baseline to 6 weeks
2 secondary outcomes
Number of Participants Meeting Certain Preoperative Endocrine Prognostic Index (PEPI)
Time frame: 16 weeks
Number of Participants With Pathological Complete Response (pCR)
Time frame: 16 weeks
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 22 Sep 2021.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Individual participant dataSharing planned: Yes. Data and materials on human subjects will be shared with other eligible investigators through appropriate means in accordance with the NIH policy on Sharing Research Data (NIH Guide, February 26, 2003). Data will be also shared with the funding agency and regulatory agencies as required. Data will be shared with other investigators within the limits of HIPAA and other patient confidentiality requirements. This will generally require removal of all patient identifiers for all source documents and the use of arbitrarily assigned one-way identifiers. In some cases, requestors will be asked to sign a formal data sharing agreement that will provide for a commitment to use data only for research purposes and not to identify individuals, keep the data secure, and destroy or return data after analyses are complete. Prior approval will be obtained from collaborating investigators, research sponsors, and/or other stake-holders before sharing if proprietary information or products are involved.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Jenny C Chang, M.D. principal investigator
Houston Methodist Cancer Center
3 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing TAK-228 and Tamoxifen in people with Estrogen Receptor Positive Breast Cancer, run by The Methodist Hospital Research Institute at 3 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 27 inclusion and 32 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 22 Sep 2021. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 3 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 27 Jul 2021). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Ki67 Expression (time frame: Baseline to 6 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 22 Sep 2021.