Neoadjuvant Run-In Study With TAK-228 Followed by Letrozole/TAK-228 in Women With High-Risk ER+/HER2- Breast Cancer

NCT02619669 | Withdrawn Phase 1 DMC FDA Drug

• 1 other identifier: D14012
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief 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). 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.

Conditions

Breast Cancer

Keywords

Neoadjuvant; TAK-228 (MLN0128); Letrozole; ER+; HER2-

Outcome Measures

Primary Outcomes (1)

• 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.

  1 year

Secondary Outcomes (1)

• Pathologic Response Assessed by Analysis of Tissue Samples and RECIST Criteria

  1 year

Other Outcomes (1)

• Tumor Effects Assessed by Analysis of Tissue Samples

  1 year

Study Arms (1)

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.

Drug: TAK-228; Drug: Letrozole

Interventions

TAK-228 DRUG

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.

TAK-228 followed by TAK-228 plus Letrozole

Letrozole DRUG

An aromatase inhibitor that has a greater inhibitory effect on Ki67 (marker of cell proliferation).

Also known as: Femara

TAK-228 followed by TAK-228 plus Letrozole

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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.

You may not qualify if:

• 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.
• 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.
• 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)

Sponsors & Collaborators

• Gary Schwartz: lead

Study Sites (1)

Dartmouth Hitchcock Medical Center

Lebanon, New Hampshire, 03756, United States

Location

MeSH Terms

Conditions

Breast Neoplasms

Interventions

sapanisertib; Letrozole

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Nitriles; Organic Chemicals; Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Gary Schwartz, MD

  Dartmouth-Hitchcock Medical Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Staff Physician, Hematology-Oncology

Study Record Dates

• First Submitted: November 25, 2015
• First Posted: December 2, 2015
• Study Start: April 20, 2017
• Primary Completion: June 14, 2019
• Study Completion: June 14, 2019
• Last Updated: March 12, 2020

Record last verified: 2020-03

Locations

US (1)