Breast CancerPhase 1NCT02619669
Neoadjuvant Run-In Study With TAK-228 Followed by Letrozole/TAK-228 in Women With High-Risk ER+/HER2- Breast Cancer
A Phase 1 study testing TAK-228 and Letrozole in people with Breast Cancer, run by Gary Schwartz at 1 site in United States.
Trial summary
Millennium has developed TAK-228, which is a novel, highly selective, orally bioavailable adenosine 5' triphosphate (ATP)-competitive inhibitor of the serine/threonine kinase referred to as the mechanistic target of rapamycin (mTOR). Read more about this study
- Who is it for?
- Ages 18 years and older, women only
- Conditions the study is for
- Breast Cancer
- What is being tested?
- TAK-228 and Letrozole
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 0 participants
- Where
- 1 siteUnited States
- Study dates
- 20 Apr 2017to 14 Jun 2019
- Phase
- Phase 1
- Are there results?
- None posted in the registry
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
- Women only
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Each patient must meet all of the following inclusion criteria to be enrolled in the study:
- Post-menopausal women ≥18 years of age with clinical stage I-IV, ER positive / HER2 negative, breast cancer that will be managed by surgical resection.
- The subject is post-menopausal if:
- She has had a prior bilateral oophorectomy
- Age is 60 or greater
- Age is under 60 but she has had at least 12 months or amenorrhea and with both follicle-stimulating hormone and estradiol levels in the post-menopausal range. Treatment with a luteinizing hormone-releasing hormone is not allowed for induction of ovarian suppression on this trial.
Show all 28Show fewer
- Patients with metastatic disease at diagnosis are eligible if clinically appropriate.
- The patient must have had a baseline MRI performed as standard-of-care that can be used to calculate the distance(s) of the longest dimension(s) of the primary tumor(s).
- Histologic documentation of breast cancer by core needle or incisional biopsy.
- Tumor size must be ≥ 2 cm in the longest dimension.
- Patients must be at high risk for recurrence, which will be defined during the pre-treatment screening period as meeting one of the following criteria:
- A histologically positive nodal deposit ≥0.2 mm
- Histologic Grade 3
- Peritumoral lymphatic vessel or vascular invasion
- Oncotype Dx score of 25 or greater
- The invasive cancer must be HER2-low, defined as IHC 0-1+, or with a FISH ratio of <1.8 if IHC is 2+ or if IHC has not been performed.
- The invasive cancer must be estrogen receptor alpha (ER)-positive, defined as having ER staining by IHC in ≥10% of malignant tumor cells.
- The subject must be deemd appropriate for neoadjuvant endocrine therapy by the referring medical oncologist.
- The subject must agree to 4 months (120 days) of neoadjuvant treatment with TAK-228 and Letrozole, have blood draws and urine samples obtained, have research tumor biopsies performed at baseline and after 10 days of TAK-228 treatment, and have a repeat MRI performed prior to surgery (MRI is part of routine clinical care).
- ECOG performance status 0-1.
- Life expectancy of 12 months or longer.
- Adequate hematologic, hepatic, renal, and glycemic function:
- Adequate bone marrow reserve: absolute neutrophil count (ANC) ≥ 1.5 x 109/L; platelet count ≥ 100 x 109/L; hemoglobin ≥ 9 g/dL;
- Hepatic: total bilirubin ≤ 1.5 x upper limit of normal (ULN), transaminases (aspartate aminotransferase/serum glutamic oxaloacetic transaminase-AST/SGOT and alanine aminotransferase/serum glutamic pyruvic transaminase-ALT/SGPT) ≤ 2.5 x ULN;
- Renal: creatinine clearance ≥50 mL/min based either on Cockcroft-Gault estimate from serum creatinine or based on urine collection (12 or 24 hour);
- Metabolic: fasting serum glucose (≤ 130 mg/dL) and fasting triglycerides ≤ 300 mg/dL;
- Ability to swallow oral medications and maintain an empty stomach state for two hours prior to the TAK-228 dose and for one hour following administration.
- Ability to give informed consent.
Who cannot join
- Patients meeting any of the following exclusion criteria are not to be enrolled in the study:
- Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol.
- Any other presurgical therapy for breast cancer.
- Prior anti-estrogen therapy within the last 5 years.
- Prior treatment with an mTOR, AKT, or PI3K inhibitor.
- Treatment within the past two years with a bisphosphonate or a Rank ligand inhibitor.
Show all 31Show fewer
- Manifestations of malabsorption due to prior gastrointestinal (GI) surgery, GI disease, or for an unknown reason that may alter the absorption of TAK-228. In addition, subjects with enteric stomata are also excluded.
- Poorly controlled diabetes mellitus defined as HbA1c > 7%. Subjects with a history of transient glucose intolerance due to corticosteroid administration are allowed in this study if all other inclusion/exclusion criteria are met.
- History of any of the following within the last 6 months prior to study entry:
- Ischemic myocardial event, including angina requiring therapy and artery revascularization procedures.
- Ischemic cerebrovascular event, including TIA and artery revascularization procedures.
- Requirement for inotropic support (excluding digoxin) or serious (uncontrolled) cardiac arrhythmia (including atrial flutter/fibrillation, ventricular fibrillation or ventricular tachycardia).
- Placement of a pacemaker for control of rhythm.
- New York Heart Association (NYHA) Class III or IV heart failure (See Appendix B).
- Pulmonary embolism.
- Significant active cardiovascular or pulmonary disease at the time of study entry, including:
- Uncontrolled high blood pressure (i.e., systolic blood pressure >180 mm Hg, diastolic blood pressure > 95 mm Hg)
- Pulmonary hypertension
- Uncontrolled asthma or O2 saturation < 90% by ABG (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 prolongation of the rate-corrected QT interval (QTc) (e.g., repeated demonstration of QTc interval > 480 milliseconds, or history of congenital long QT syndrome, or torsade de pointes) Confidential v03January2017 40
- Treatment with strong CYP3A4 and CYP2C19 inhibitors and/or inducers must be discontinued at least 1 week before administration of the first dose of study drug.(see Appendix C)
- Initiation of treatment with hematopoietic growth factors, transfusions of blood and blood products, or systemic corticosteroids (either IV or oral steroids, excluding inhalers) within 1 week before administration of the first dose of study drug (patients already receiving erythropoietin on a chronic basis for ≥ 4 weeks are eligible).
- Other clinically significant co-morbidities, such as uncontrolled pulmonary disease, active central nervous system disease, active infection, or any other condition that could compromise participation of the patient in the study.
- Central nervous system (CNS) metastasis.
- Known human immunodeficiency virus infection.
- Known hepatitis B surface antigen-positive, or known or suspected active hepatitis C infection.
- 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 study drug.
- 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 study drug.
Trial locations and contacts
1 site in 1 country.
United States1 site
Dartmouth Hitchcock Medical Center
Lebanon, New Hampshire, 03756
About this study
Official title: Phase 1b Neoadjuvant Run-In Study With TAK-228 Followed by Letrozole/TAK-228 in Women With High-Risk ER+/HER2- Breast Cancer
Millennium has developed TAK-228, which is a novel, highly selective, orally bioavailable adenosine 5' triphosphate (ATP)-competitive inhibitor of the serine/threonine kinase referred to as the mechanistic target of rapamycin (mTOR). TAK-228 (formerly INK128 or MLN0128) targets 2 distinct multiprotein complexes, mTORC1 and mTORC2. TAK-228 selectively and potently inhibits mTOR kinase (IC50 = 1.1 nM), inhibits mTORC1/2 signaling, and prevents cellular proliferation.
The mTOR complex (mTORC) is an important therapeutic target that is generally stable (i.e., low tendency to mutate) and is a key intracellular point of convergence for a number of cellular signaling pathways. Inhibiting mTOR may inhibit abnormal cell proliferation, tumor angiogenesis, and abnormal cellular metabolism, thus providing the rationale for mTOR inhibitors as potential agents in the treatment of a number of indications including solid tumor and hematological malignancies, as either monotherapy or in combination with other chemotherapeutic agents. Like rapamycin, several newly approved rapalogs (temsirolimus and everolimus) are specific and allosteric inhibitors of mTORC1, and only partially inhibit mTORC1 signaling pathways. They do not directly inhibit mTORC2, which has shown to be an emerging target in cancer research. TAK-228 was developed to address the incomplete inhibition of the mTOR pathway by rapalogs.
Read more
Eligible subjects will have a research biopsy and baseline blood and urine studies done within two weeks prior to start of study treatment. Subjects will then be treated with TAK-228 for 10 days, and a repeat biopsy and pharmacokinetics will be done on day 11.
The subject will then be treated with the combination of TAK-228 and letrozole for an additional 110 days, before undergoing resection of the primary tumor. Subjects will be treated at the recommended Phase II dose of TAK-228 of 3 mg once daily, and a dose deescalation to 2 mg daily will be performed if dose-limiting toxicity is seen in 1/3 or more of the subjects at the first dose level. The maximum tolerated dose cohort will be expanded to include six to ten subjects.
- Conditions
- Breast Cancer
- Being tested
- TAK-228, Letrozole
- Keywords
- Neoadjuvant, TAK-228 (MLN0128), Letrozole, ER+, HER2-
- 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
Millennium has developed TAK-228, which is a novel, highly selective, orally bioavailable adenosine 5' triphosphate (ATP)-competitive inhibitor of the serine/threonine kinase referred to as the mechanistic target of rapamycin (mTOR). TAK-228 (formerly INK128 or MLN0128) targets 2 distinct multiprotein complexes, mTORC1 and mTORC2. TAK-228 selectively and potently inhibits mTOR kinase (IC50 = 1.1 nM), inhibits mTORC1/2 signaling, and prevents cellular proliferation.
LetrozoleDrug
Also called Femara
An aromatase inhibitor that has a greater inhibitory effect on Ki67 (marker of cell proliferation).
| Study group | Role | What they receive |
|---|---|---|
| TAK-228 followed by TAK-228 plus Letrozole | Experimental | Eligible subjects will have a research biopsy and baseline blood and urine studies done within two weeks prior to start of study treatment. Subjects will then be treated with TAK-228 for 10 days, and a repeat biopsy and pharmacokinetics will be done on day 11.
The subject will then be treated with the combination of TAK-228 and letrozole for an additional 110 days, before undergoing resection of the primary tumor. Subjects will be treated at the recommended Phase II dose of TAK-228 of 3 mg once daily, and a dose deescalation to 2 mg daily will be performed if dose-limiting toxicity is seen in 1/3 or more of the subjects at the first dose level. The maximum tolerated dose cohort will be expanded to include six to ten subjects. Receives: Drug: TAK-228; Drug: Letrozole |
What is being measured
The primary outcome is the main question the study is designed to answer.
Evaluation of Treatment-Related Adverse Events as Assessed by NCI CTCAE v4.0
Determine the safety of the combination of TAK-228 and Letrozole in women with early-stage ER+/HER2- breast cancer at high risk for recurrence.
Measured: 1 year
Secondary outcomes (1)
Pathologic Response Assessed by Analysis of Tissue Samples and RECIST Criteria
Determine the rates of clinical and pathologic response to treatment with the combination of TAK-228 and Letrozole in women with early-stage ER+/HER2- breast cancer at high risk for recurrence.
Measured: 1 year
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted2 Dec 2015 (estimated)
- Study start20 Apr 2017
- Primary completion14 Jun 2019
- Study completion14 Jun 2019
Why it stopped: The study was withdrawn, because no participants were enrolled in two years.
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Breast CancerStudies of the same condition, open and under way.
- 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 1
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 0 participants (actual)
Sponsor and investigators
- Lead sponsor
- Gary Schwartz
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor-investigator, Gary Schwartz, Dartmouth-Hitchcock Medical Center
- Investigators
- Gary Schwartz, MD, Principal investigator, Dartmouth-Hitchcock Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02619669
- Sponsor's protocol ID
- D14012
- Status last verified
- Mar 2020
- First submitted
- 25 Nov 2015
- Last updated
- 12 Mar 2020
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 12 Mar 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase 1b Neoadjuvant Run-In Study With TAK-228 Followed by Letrozole/TAK-228 in Women With High-Risk ER+/HER2- Breast Cancer
- ClinicalTrials.gov ID
- NCT02619669
- Acronym / sponsor ID
- D14012
- Conditions
- Breast Cancer
- Keywords
- Neoadjuvant, TAK-228 (MLN0128), Letrozole, ER+, HER2-
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- WithdrawnReason stopped: The study was withdrawn, because no participants were enrolled in two years.
- Enrolment
- 0 participants (actual)
- Lead sponsor
- Gary SchwartzUniversity, hospital or other
- Study start
- 20 Apr 2017 (actual)
- Primary completion
- 14 Jun 2019 (actual)
- Study completion
- 14 Jun 2019 (actual)
- First posted
- 2 Dec 2015 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Millennium has developed TAK-228, which is a novel, highly selective, orally bioavailable adenosine 5' triphosphate (ATP)-competitive inhibitor of the serine/threonine kinase referred to as the mechanistic target of rapamycin (mTOR). TAK-228 (formerly INK128 or MLN0128) targets 2 distinct multiprotein complexes, mTORC1 and mTORC2. TAK-228 selectively and potently inhibits mTOR kinase (IC50 = 1.1 nM), inhibits mTORC1/2 signaling, and prevents cellular proliferation.
The mTOR complex (mTORC) is an important therapeutic target that is generally stable (i.e., low tendency to mutate) and is a key intracellular point of convergence for a number of cellular signaling pathways. Inhibiting mTOR may inhibit abnormal cell proliferation, tumor angiogenesis, and abnormal cellular metabolism, thus providing the rationale for mTOR inhibitors as potential agents in the treatment of a number of indications including solid tumor and hematological malignancies, as either monotherapy or in combination with other chemotherapeutic agents. Like rapamycin, several newly approved rapalogs (temsirolimus and everolimus) are specific and allosteric inhibitors of mTORC1, and only partially inhibit mTORC1 signaling pathways. They do not directly inhibit mTORC2, which has shown to be an emerging target in cancer research. TAK-228 was developed to address the incomplete inhibition of the mTOR pathway by rapalogs.
Eligible subjects will have a research biopsy and baseline blood and urine studies done within two weeks prior to start of study treatment. Subjects will then be treated with TAK-228 for 10 days, and a repeat biopsy and pharmacokinetics will be done on day 11.
The subject will then be treated with the combination of TAK-228 and letrozole for an additional 110 days, before undergoing resection of the primary tumor. Subjects will be treated at the recommended Phase II dose of TAK-228 of 3 mg once daily, and a dose deescalation to 2 mg daily will be performed if dose-limiting toxicity is seen in 1/3 or more of the subjects at the first dose level. The maximum tolerated dose cohort will be expanded to include six to ten subjects.
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 followed by TAK-228 plus Letrozole | Experimental | Drug: TAK-228, Drug: LetrozoleEligible subjects will have a research biopsy and baseline blood and urine studies done within two weeks prior to start of study treatment. Subjects will then be treated with TAK-228 for 10 days, and a repeat biopsy and pharmacokinetics will be done on day 11. The subject will then be treated with the combination of TAK-228 and letrozole for an additional 110 days, before undergoing resection of the primary tumor. Subjects will be treated at the recommended Phase II dose of TAK-228 of 3 mg once daily, and a dose deescalation to 2 mg daily will be performed if dose-limiting toxicity is seen in 1/3 or more of the subjects at the first dose level. The maximum tolerated dose cohort will be expanded to include six to ten subjects. |
Who may qualify
- Ages
- 18 years and older
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (28 listed)
- Each patient must meet all of the following inclusion criteria to be enrolled in the study:
- Post-menopausal women ≥18 years of age with clinical stage I-IV, ER positive / HER2 negative, breast cancer that will be managed by surgical resection.
- Patients with metastatic disease at diagnosis are eligible if clinically appropriate.
- The patient must have had a baseline MRI performed as standard-of-care that can be used to calculate the distance(s) of the longest dimension(s) of the primary tumor(s).
- Histologic documentation of breast cancer by core needle or incisional biopsy.
Key exclusion criteria (31 listed)
- Patients meeting any of the following exclusion criteria are not to be enrolled in the study:
- Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol.
- Any other presurgical therapy for breast cancer.
- Prior anti-estrogen therapy within the last 5 years.
- Prior treatment with an mTOR, AKT, or PI3K inhibitor.
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-228Millennium has developed TAK-228, which is a novel, highly selective, orally bioavailable adenosine 5' triphosphate (ATP)-competitive inhibitor of the serine/threonine kinase referred to as the mechanistic target of rapamycin (mTOR). TAK-228 (formerly INK128 or MLN0128) targets 2 distinct multiprotein complexes, mTORC1 and mTORC2. TAK-228 selectively and potently inhibits mTOR kinase (IC50 = 1.1 nM), inhibits mTORC1/2 signaling, and prevents cellular proliferation. | Drug | TAK-228 followed by TAK-228 plus Letrozole |
| LetrozoleAlso: FemaraAn aromatase inhibitor that has a greater inhibitory effect on Ki67 (marker of cell proliferation). | Drug | TAK-228 followed by TAK-228 plus Letrozole |
Primary outcome
Evaluation of Treatment-Related Adverse Events as Assessed by NCI CTCAE v4.0
Time frame: 1 year
Determine the safety of the combination of TAK-228 and Letrozole in women with early-stage ER+/HER2- breast cancer at high risk for recurrence.
1 secondary outcome
Pathologic Response Assessed by Analysis of Tissue Samples and RECIST Criteria
Time frame: 1 year
Results and safety
The study was withdrawn before enrolling participants, so there are no results.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 12 Mar 2020.
Related trials for Breast Cancer
Active, not recruiting
Streamlined Geriatric and Oncological Evaluation Based On IC Technology
Breast Cancer, Comorbidities and Coexisting Conditions
RecruitingPhase 2
Gene Signatures to Guide HR+MBC Therapy in a Diverse Cohort
Invasive Mammary Carcinoma, Metastatic Breast Cancer
Not yet recruitingObservational study
Comparison of Reliability, Time Cost, and Participant Comfort of Lymphedema Assessments in Upper Extremity
Lymphedema, Upper Extremity Lymphedema
RecruitingPhase 3
A Study of Camrelizumab Plus Chemotherapy in Combination With or Without Famitinib as Neoadjuvant Therapy in Participants With Triple Negative Breast Cancer (BCTOP-T-N01)
TNBC - Triple-Negative Breast Cancer
RecruitingPhase 3
Testing Whether Hormone Therapy With Ribociclib is as Effective as Chemotherapy Followed by Hormone Therapy With Ribociclib for the Treatment of High Anatomic Stage Breast Cancer With Low Recurrence Risk, The RxFINE-Low Trial
Anatomic Stage II Breast Cancer AJCC v8, Anatomic Stage IIIA Breast Cancer AJCC v8
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.
Gary Schwartz, MD principal investigator
Dartmouth-Hitchcock Medical Center
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing TAK-228 and Letrozole in people with Breast Cancer, run by Gary Schwartz at 1 site 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 28 inclusion and 31 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: withdrawn, as of the sponsor's last update on 12 Mar 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site 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 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was withdrawn before enrolling participants, so there are no results.
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?
Evaluation of Treatment-Related Adverse Events as Assessed by NCI CTCAE v4.0 (time frame: 1 year). 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 12 Mar 2020.