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
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.
View more details from ClinicalTrials.gov.
For more information about a clinical trial, clinical trial eligibility, or informed consent, contact our research nurses by phone or email:
Please Note: Any eligibility criteria noted are subject to change. Our research nurses can provide you with the most current eligibility and exclusion criteria. Any study involvement to be undertaken must ultimately be determined on an individual basis.