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. 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.
⁃ 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.
• 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.