Dose Escalation Study of MLN0128 in Combination With Paclitaxel, With/Without Trastuzumab, in Subjects With Advanced Solid Malignancies

• Safety and tolerability of orally administered MLN0128 in combination with paclitaxel [ Time Frame: At screening/baseline; Cycle 1 and 2: Day 1, 2, 8, 15, and 22; Cycle 3, 4, 5 and thereafter: Day 1, 8, 15, and 22; and at termination visit ] [ Designated as safety issue: Yes ]
• Pharmacokinetic (PK) parameters including AUC, Cmax, Cmin, Tmax and t1/2 for MLN0128 [ Time Frame: Cycle 1 and 2: Day 1 and 2 ] [ Designated as safety issue: No ]
• Pharmacokinetic (PK) parameters including AUC, Cmax, Cmin, Tmax and t1/2 for paclitaxel [ Time Frame: Cycle 1 and 2: Day 1 and 2 ] [ Designated as safety issue: No ]
• To evaluate preliminary anti-tumor activity of MLN0128 [ Time Frame: At screening and thereafter every 2 cycles of treatment. Each cycle is a 28 day cycle ] [ Designated as safety issue: No ]
• To evaluate the safety and preliminary anti-tumor activity of combination of MLN0128, paclitaxel, and trastuzumab [ Time Frame: Safety: At screening/baseline; Cycle 1 and 2: Day 1, 2, 8, 15 and 22; Cycle 3, 4, 5 and thereafter: Day 1, 8, 15, and 22; and at termination visit. Preliminary anti-tumor activity: At screening and thereafter every 2 cycles of treatment. ] [ Designated as safety issue: Yes ]

This is a Phase I, Open Label, Dose Escalation Study of Oral Administration of MLN0128 in Combination With Paclitaxel, With/Without Trastuzumab, in Subjects With Advanced Solid Malignancies

This is a Phase I, open-label study consisting of a dose escalation phase in advanced solid malignancies to determine the MTD of oral administration of MLN0128 in 1 or more dosing schedules, combined with paclitaxel on Days 1, 8 and 15 of each cycle, followed by an expansion phase for further safety and preliminary efficacy. Once the MTD is determined for each of the dosing schedules evaluated, a dose and schedule will be selected for the expansion phase, which may enroll subjects into 2 arms in parallel:

• Arm A will consist of HER2-/unknown cancer subjects receiving MLN0128+paclitaxel
• Arm B will consist of HER2+ cancer subjects receiving MLN0128+paclitaxel plus weekly trastuzumab

• Advanced Solid Malignancies
• Hematologic Malignancies

• Drug: MLN0128 + paclitaxel
  MLN0128 will be orally administered QDX3d QW or QDX5d QW in combination with IV paclitaxel on Days 1, 8 and 15 of each cycle
• Drug: MLN0128 + paclitaxel + trastuzumab
  MLN0128 will be orally administered QDX3d QW or QDX5d QW in combination with IV paclitaxel on Days 1, 8 and 15 of each cycle and IV trastuzumab on Days 1, 8, 15 and 22 of each cycle

• Experimental: MLN0128P
  MLN0128 + paclitaxel
  Intervention: Drug: MLN0128 + paclitaxel
• Experimental: MLN0128PH
  MLN0128 + paclitaxel + trastuzumab
  Intervention: Drug: MLN0128 + paclitaxel + trastuzumab

Inclusion Criteria:

• Voluntary written consent
• Locally advanced or metastatic solid tumors with the exception of primary brain tumor, and have failed or are not eligible for standard of care therapy
• Eastern Cooperative Oncology Group (ECOG) performance status 0-1
• Ability to swallow oral medications
• For women of child-bearing potential, negative serum or urine pregnancy test within 14 days prior to the first study drug administration and use of physician-approved method of birth control from 30 days prior to 30 days following the last study drug administration
• Male subjects must be surgically sterile or must agree to use physician-approved contraception during the study and for 30 days following the last study drug administration
• Clinical laboratory values as specified in the protocol
• For expansion phase (Arm A) - HER2-/unknown subjects will be enrolled
• For expansion phase (Arm B) - HER2+ cancer subjects will be enrolled

Exclusion Criteria:

• Diagnosis of primary brain tumor
• Have received prior cancer or other investigational therapy within 2 weeks prior to the first administration of study drug
• Known impaired cardiac function or clinically significant cardiac disease
• Known treatment with systemic corticosteroid within one week prior to the first administration of study drug
• Diabetes mellitus
• HIV infection
• Known active cardiovascular disease condition as specified in protocol
• Pregnancy (positive serum or urine pregnancy test) or breast feeding
• Malabsorption due to prior gastrointestinal (GI) surgery, GI disease
• Other clinically significant co-morbidities

Please note that there are additional inclusion and exclusion criteria. The study center will determine if you meet all of the criteria.

Site personnel will explain the trial in detail and answer any question you may have if you do qualify for the study. You can then decide whether or not you wish to participate. If you do not qualify for the trial, site personnel will explain the reasons