Dose Escalation, Multi-arm Study of MLN4924 Plus Docetaxel, Gemcitabine, or Combination of Carboplatin and Paclitaxel in Patients With Solid Tumors

Inclusion Criteria:

- Male or female patients 18 years of age or older

- ECOG PS 0 or 1

- Patients must have a histologically or cytologically confirmed metastatic or locally
advanced and incurable solid tumor that is felt to be appropriate for treatment with 1
of the 3 chemotherapy regimens in this study, or have progressed despite standard
therapy, or for whom conventional therapy is not considered effective. The tumor must
be radiographically or clinically evaluable and/or measurable

- Recovered from the effects of prior antineoplastic therapy

- Female patients who are post menopausal, surgically sterile, or agree to practice 2
effective methods of contraception or agree to practice true abstinence

- Male patients who agree to practice effective barrier contraception or agree to
practice true abstinence

- Voluntary written consent must be given before performance of any study-related
procedure

- Suitable venous access for the study-required blood sampling

- Adequate clinical laboratory values during the screening period as specified in the
protocol

- Patients who are willing to refrain from donating blood for at least 90 days after
their final dose of MLN4924 and (for male patients) willing to refrain from donating
semen for at least 4 months after their final dose of MLN4924

- Availability of fixed tumor specimen (block or slides) for exploratory biomarker
analysis. If no slides or block are available, fresh tumor biopsies should be obtained
and used for these assessments

Exclusion Criteria:

- Major surgery within 14 days before the first dose of study drug

- Female patients who are lactating or pregnant

- Active uncontrolled infection or severe infectious disease

- Receiving antibiotic therapy within 14 days before the first dose of study treatment

- Life-threatening illness unrelated to cancer

- Known hypersensitivity to study-assigned chemotherapy

- Prior treatment with MLN4924; however, prior treatment with docetaxel,
paclitaxel,carboplatin, and gemcitabine is allowed

- History of severe hypersensitivity reactions to docetaxel (polysorbate 80-based
formulations) for patients to be enrolled in Arm 1 (MLN4924 + docetaxel), history of
hypersensitivity to carboplatin for patients to be enrolled in Arm 2 (MLN4924 +
paclitaxel + carboplatin), or history of severe hypersensitivity to paclitaxel
(cremophor-based formulations) for patients to be enrolled in Arm 2

- Persistent diarrhea (greater than Grade 2) lasting > 3 days within 2 weeks before the
first dose of study treatment

- Systemic antineoplastic therapy within 21 days before the first dose of study drug

- Radiotherapy within 14 days preceding the first dose of study treatment

- Prior treatment with radiation therapy involving ≥ 25% of the hematopoietically active
bone marrow

- Treatment with CYP3A inducers within 14 days before the first dose of MLN4924.
Treatment with CYP3A inhibitors within 14 days before the first dose of MLN4924;
however, voriconazole and fluconazole need only be stopped for 3 days before MLN4924.
Patients must have no history of amiodarone use in the 6 months before the first dose
of MLN4924

- Clinically uncontrolled central nervous system (CNS) involvement

- Any serious medical or psychiatric illness

- Treatment with any investigational products 21 days prior to treatment

- Patients currently taking statins who are unwilling or unable to refrain from using
statins 24 hours before, the day of, and 24 hours after each MLN4924 administration

- Known human immunodeficiency virus (HIV) positive or hepatitis B surface
antigen-positive status, or known or suspected active hepatitis C infection

- Known hepatic cirrhosis

- Known cardiac/cardiopulmonary disease

- Left ventricular ejection fraction

- Patients with a cardiac pacer whose heart rate is set at a fixed rate and patients on
concomitant medication that may limit increase in heart rate in response to
hypotension

- History of severe intolerance to cytotoxic agent(s) given in the assigned arm