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

• Sponsor: The Methodist Hospital Research Institute (Other)
• Overall Status: Completed
• CT.gov ID: NCT02988986
• Collaborator: Millennium Pharmaceuticals, Inc. (Industry)
• Enrollment: 28
• Locations: 3
• Arm: 1
• Actual Duration (Months): 23.2
• Patients Per Site: 9.3
• Patients Per Site Per Month: 0.4

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Estrogen Receptor Positive Breast Cancer	Drug: TAK-228; Drug: Tamoxifen	Phase 2

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

• Study Type: Interventional
• Actual Enrollment: 28 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: Apr 24, 2017
• Actual Primary Completion Date: Feb 1, 2019
• Actual Study Completion Date: Mar 30, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 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.	Drug: TAK-228; MTORC1/2 inhibitor; Other Names: INK128, MLN0128 ; Drug: Tamoxifen; Non-steroidal anti-estrogen; Other Names: Apo-Tamox, Gen-Tamoxifen, Nolvadex, Novo-Tamoxifen

Outcome Measures

Primary Outcome Measures

1. Ki67 Expression [Baseline to 6 weeks]

   Ki67 expression change from baseline to 6 weeks

Secondary Outcome Measures

1. 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)

2. 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 Outcome Measures

1. Plasma Concentrations of TAK-228 Plus Tamoxifen [16 weeks]

   Measure plasma concentrations of TAK-228 plus tamoxifen over time

2. 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

3. 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

4. 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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts 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.

1. 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.

2. Eastern Cooperative Oncology Group performance status and/or other performance status of ≤ 1.

3. 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).

1. 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.

1. Screening clinical laboratory values as specified below:

2. 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;

3. 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;

4. Renal status: Creatinine clearance ≥50 mL/min based on Cockcroft-Gault estimate or based on urine collection (12 or 24 hour);

5. Metabolic status: HbA1c < 7.0%, fasting serum glucose ≤ 130 mg/dL, and fasting triglycerides ≤ 300 mg/dL.

6. Ability to swallow oral medications.

7. 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.

8. Negative serum pregnancy test within 7 days prior to the administration of the study drugs for female patients of childbearing potential.

9. Patient must be accessible for treatment and follow-up.

10. 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

1. 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)

1. Treatment with strong inhibitors and/or inducers of CYP3A4, CYP2C9, or CYP2C19 within 7 days preceding the first dose of the study drugs.

2. 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.

3. 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.

4. Patients unwilling or unable to comply with the study protocol.

5. Patients previously treated with hormonal therapy (tamoxifen, AI) or PI3K, AKT, dual PI3K/mTOR, TORC1/2, or mTORC1 inhibitors.

6. Patients who are currently being treated with cancer therapy (chemotherapy, radiation therapy, immunotherapy, or biologic therapy) other than the trial therapy.

7. Patients with hypersensitivity to mTOR inhibitors or tamoxifen.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Houston Methodist Hospital	Houston	Texas	United States	77030
2	Houston Methodist Hospital Willowbrook	Houston	Texas	United States	77070
3	Houston Methodist Hospital Sugar Land	Sugar Land	Texas	United States	77479

Sponsors and Collaborators

• The Methodist Hospital Research Institute
• Millennium Pharmaceuticals, Inc.

Investigators

• Principal Investigator: Jenny C Chang, M.D., Houston Methodist Cancer Center

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jun 25, 2018

More Information

Publications

None provided.

• Responsible Party: Jenny C. Chang, MD, Houston Methodist Cancer Center Director, The Methodist Hospital Research Institute
• ClinicalTrials.gov Identifier: NCT02988986
• Other Study ID Numbers: Pro00016065
• First Posted: Dec 12, 2016
• Last Update Posted: Sep 22, 2021
• Last Verified: Aug 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Jenny C. Chang, MD, Houston Methodist Cancer Center Director, The Methodist Hospital Research Institute: mTOR; Tamoxifen; Breast Cancer
• Additional relevant MeSH terms: Breast Neoplasms; Tamoxifen

Study Results

Participant Flow

Arm/Group Title	TAK-228 Plus Tamoxifen
Arm/Group Description	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
Period Title: Overall Study
STARTED	28
COMPLETED	25
NOT COMPLETED	3

Baseline Characteristics

Arm/Group Title	TAK-228 Plus Tamoxifen
Arm/Group Description	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
Overall Participants	28
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	28 100%
>=65 years	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	52 (11.6)
Sex: Female, Male (Count of Participants)
Female	28 100%
Male	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	3 10.7%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	4 14.3%
White	17 60.7%
More than one race	4 14.3%
Unknown or Not Reported	0 0%
Region of Enrollment (Count of Participants)
United States	28 100%
Stage I-III ER-positive, HER-2 negative breast cancer (Count of Participants)
Count of Participants [Participants]	28 100%

Outcome Measures

1. Primary Outcome

Title	Ki67 Expression
Description	Ki67 expression change from baseline to 6 weeks
Time Frame	Baseline to 6 weeks

Outcome Measure Data

Analysis Population Description

Change in baseline Ki67 expression at 6 weeks

Arm/Group Title	TAK-228 Plus Tamoxifen
Arm/Group Description	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
Measure Participants	23
Ki67 expression at baseline	15
Ki67 expression at 6 weeks	10

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	TAK-228 Plus Tamoxifen
	Comments	The primary endpoint was the change in Ki67 after 6 weeks of treatment.
	Type of Statistical Test	Superiority
	Comments	Based on prior data for Ki67 changes in the tamoxifen arm alone, we will assume null hypothesis and alternative hypotheses of 60% and 80% reduction in Ki67, respectively. A sample of 25 patients will provide 86% power to detect the hypothesized reduction in Ki67 with 5% alpha based on a two-sided, one sample t-test of mean percent change in Ki67 level.
Statistical Test of Hypothesis	p-Value	=0.0023
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

2. Secondary Outcome

Title	Number of Participants Meeting Certain Preoperative Endocrine Prognostic Index (PEPI)
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Tamoxifen
Arm/Group Description	20 mg p.o QW x16 weeks
Measure Participants	21
PEPI score of 0	0 0%
PEPI score of 1-3	6 21.4%
PEPI score of >4	15 53.6%

3. Secondary Outcome

Title	Number of Participants With Pathological Complete Response (pCR)
Description	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	TAK-228 Plus Tamoxifen
Arm/Group Description	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
Measure Participants	23
Count of Participants [Participants]	0 0%

4. Other Pre-specified Outcome

Title	Plasma Concentrations of TAK-228 Plus Tamoxifen
Description	Measure plasma concentrations of TAK-228 plus tamoxifen over time
Time Frame	16 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

5. Other Pre-specified Outcome

Title	Correlation Between Change in Ki67 Expression and pCR to TAK-228 Plus Tamoxifen
Description	Assess the correlation between change in Ki67 expression and pCR to TAK-228 plus tamoxifen
Time Frame	16 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

6. Other Pre-specified Outcome

Title	Correlation Between Tumor Mutational Status and Response to TAK-228 Plus Tamoxifen
Description	Assess correlation between tumor mutational status and response to TAK-228 plus tamoxifen
Time Frame	16 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

7. Other Pre-specified Outcome

Title	Correlation Between Change in mTOR Expression and pCR to TAK-228 Plus Tamoxifen
Description	Assess the correlation between change in mTOR expression and pCR to TAK-228 plus tamoxifen
Time Frame	16 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	Up to 16 weeks
Arm/Group Title	TAK-228 and Tamoxifen
Arm/Group Description	20 mg p.o QW x16 weeks
All Cause Mortality
	TAK-228 and Tamoxifen
	Affected / at Risk (%)	# Events
Total	0/28 (0%)
Serious Adverse Events
	TAK-228 and Tamoxifen
	Affected / at Risk (%)	# Events
Total	1/28 (3.6%)
Endocrine disorders
hyperglycemia	1/28 (3.6%)	1
Other (Not Including Serious) Adverse Events
	TAK-228 and Tamoxifen
	Affected / at Risk (%)	# Events
Total	28/28 (100%)
Gastrointestinal disorders
Nausea	28/28 (100%)	28

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.