Phase I Study of MLN0128 and MLN8237 in Patients With Advanced Solid Tumors and Metastatic Triple-negative Breast Cancer

Inclusion Criteria

Each patient must meet all of the following inclusion criteria to be enrolled in the study:

• Male or female patients 18 years or older.
• Dose Escalation Cohort: Patients must have a diagnosis of a histologically confirmed solid tumor that is incurable and refractory to standard therapy or for which no standard therapy exists.
• Dose Expansion Cohort Group 1 and 2: Patients must have a diagnosis of histologically confirmed metastatic TNBC defined as negative for estrogen receptor, progesterone receptor and HER2. Patients must have received either adjuvant or first line chemotherapy for metastatic disease. Negative for Estrogen and Progesterone Receptor includes the following:
• Local Pathology report classifies them as negative
• Allred Score of 2 or below
• LLN of the institutional standard of normal as measured by echocardiogram (ECHO) or multiple gated acquisition scan (MUGA) within 4 weeks prior to first study drug administration.
• Ability to swallow oral medications.
• 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of any study related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.
• Patients who have a history of brain metastasis are eligible for the study provided that all the following criteria are met:
• Brain metastases which have been treated
• No evidence of disease progression for ≥ 4 weeks or hemorrhage after treatment
• Off-treatment with dexamethasone for 2 weeks before administration of the first dose of MLN0128
• No ongoing requirement for dexamethasone or anti-epileptic drugs.

Exclusion Criteria

Patients meeting any of the following exclusion criteria are not to be enrolled in the study:

• Other clinically significant co-morbidities, 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.
• Known human immunodeficiency virus infection.
• Radiation therapy to more than 25% of the bone marrow. Whole pelvic radiation is considered to be over 25%.
• Known history of uncontrolled sleep apnea syndrome and other conditions that could result in excessive daytime sleepiness, such as severe chronic obstructive pulmonary disease; requirement for supplemental oxygen.
• Systemic infection requiring IV antibiotic therapy within 14 days preceding the first dose of study drug, or other severe infection.
• Known hepatitis B surface antigen-positive, or known or suspected active hepatitis C infection.
• Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol.
• Diagnosed or treated for another malignancy within 2 years before administration of the first dose of study drug, or previously diagnosed with another malignancy and have any evidence of residual disease. Patients with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection.
• Breast feeding or pregnant.
• Manifestations of malabsorption due to prior gastrointestinal (GI) surgery, GI disease, or for an unknown reason that may alter the absorption of MLN0128. In addition, patients with enteric stomata are also excluded.
• Treatment with any investigational products within 3 weeks before the first dose of study drug.
• History of any of the following within the last 6 months before administration of the first dose of the drug:
• 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