A Safety, Tolerability, and Pharmacokinetics Study of MLN0128 as a Single Agent and in Combination With Paclitaxel in Adults With Advanced Nonhematologic Malignancies

Inclusion Criteria

• Age is ≥ 18 years, including males and females.
• Has Advanced nonhematologic malignancies, with the exception of primary brain tumor, and have failed or are not eligible for standard of care therapy. History of brain metastasis may be allowed if all the following criteria are met: brain metastases have been treated, there is no evidence of progression or hemorrhage after treatment, dexamethasone discontinued for ≥ 4 weeks before first study drug administration, and there is no ongoing requirement for dexamethasone or anti-epileptic drugs.
• Has received not more than 4 prior lines of systemic cytotoxic chemotherapy for advanced or metastatic disease.
• Has Eastern Cooperative Oncology Group (ECOG) Performance Status 0 to 1.
• Has adequate organ function, including the following:
• Bone marrow reserve consistent with absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L; platelet count ≥ 100 x 10^9/L; and hemoglobin ≥ 9 g/dL without transfusion in the last 2 weeks
• Hepatic: total bilirubin ≤ 1.5 x the upper limit of the normal range (ULN), transaminases (aspartate aminotransferase [AST]/serum glutamic oxaloacetic transaminase [SGOT] and alanine aminotransferase [ALT]/serum glutamic pyruvic transaminase [SGPT]) ≤ 2.5 x ULN (≤ 5 x ULN if liver metastases are present)
• Renal: normal serum creatinine or calculated creatinine clearance ≥ 60 mL/min based either on Cockcroft-Gault estimate or based on urine collection (12- or 24-hour)
• Metabolic: fasting serum glucose (≤ 130 mg/dL) and fasting triglycerides ≤ 300 mg/dL
• Has left ventricular ejection fraction (LVEF) within 5 absolute percentage points of institutional standard of normal as measured by echocardiogram (ECHO) or multiple gated acquisition scan (MUGA) within 4 weeks before first study drug administration (ie, if the institutional normal is 50%, participant's LVEF may be as low as 45% to be eligible for the study).
• Is a female participants 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 2 effective methods of contraception, at the same time, from the time of signing the informed consent form through 90 days after the last dose of study drug, or
• Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the participant. (Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation methods] and withdrawal are not acceptable methods of contraception.)

Male participants, even if surgically sterilized (ie, status postvasectomy), who:

• Agree to practice effective barrier contraception during the entire study treatment period and through 90 days after the last dose of study drug, or
• Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the participant. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation methods for the female partner] and withdrawal are not acceptable methods of contraception.)
• Has ability to swallow oral medications.
• Has voluntary written consent obtained before performance of any study-related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the participant at any time without prejudice to future medical care.

Exclusion Criteria

• Has a diagnosis of primary brain tumor.
• Has untreated brain metastasis or history of leptomeningeal disease or spinal cord compression.
• Has failed to recover from the reversible effects of prior anticancer therapies with the exception of alopecia, and after-effects associated with prior tyrosine kinase inhibitor therapy, such as hair depigmentation, hypothyroidism, and/or splinter hemorrhage.
• Has received prior cancer therapy or other investigational therapy within 2 weeks before the first administration of study drug. For prior therapies with a half-life longer than 3 days, the interval must be