A Phase 1B Study of MLN2480 in Combination With MLN0128 or Alisertib, or Paclitaxel, or Cetuximab, or Irinotecan in Adult Participants With Advanced Nonhematologic Malignancies

The drug being tested in this study is called MLN2480. MLN2480 is being tested to evaluate
side effects and determine the maximum tolerated dose (MTD) and recommended dose for future
studies when administered in combination with three other medications. This study will assess
the safety of MLN2480 as well as how it is processed by the body in participants with solid
nonhematologic malignancies who have failed standard therapies.

The study will be conducted in two phases, the dose escalation phase and the dose expansion
phase. Approximately 49 participants will be enrolled in the escalation phase. Participants
in this phase will be assigned to one of the five treatment groups:

- MLN2480 + MLN0128

- MLN2480 + Alisertib

- MLN2480 + Paclitaxel

- MLN2480 + Cetuximab

- MLN2480 + Irinotecan

Once the MTD for each combination treatment arm has been established in the escalation phase,
one or more of the combination treatments will be selected for the expansion phase.
Approximately 76 participants will be enrolled in the expansion phase.

This multi-centre trial will be conducted worldwide. The overall time to participate in this
study is approximately 14 months. Participants will make approximately 43 visits to the
clinic including an end of study visit 30 days after last dose of study drug for a follow-up
assessment.

Inclusion Criteria:

All Treatment Arms:

1. Male or female participants 18 years or older.

2. Participants who, in the opinion of the treating physician, have failed standard
therapies and for whom a phase 1 trial is an appropriate option.

3. Radiographically or clinically evaluable tumor. For expansion phase: Tumors must be
measurable and of the protocol specified genetic mutational status, where applicable.

4. Recovered (ie, less than or equal to [<=] Grade 1 toxicity) from adverse effects
(except alopecia) of prior therapy.

5. Eastern Cooperative Oncology Group (ECOG) performance status 0-1.

6. Expected survival time of at least 3 months in the opinion of the investigator.

7. Block of banked tumor tissue and/or greater than or equal to (>=) 10 unstained slides.
Participants who satisfy all other eligibility criteria but do not have banked
tissue/slides may be asked to consent to baseline biopsy.

8. Suitable vein access for the study-required blood sampling.

9. Thyroid function tests consistent with stable thyroid function. Note: Participants on
a stable dose of thyroid replacement therapy for a suggested minimum of 12 weeks
before Cycle 1, Day 1 are eligible.

10. Left ventricular ejection fraction (LVEF) of 50 percent (%) or greater, as measured by
echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA), within 28 days before
the first dose of MLN2480

11. Female participants who are post menopausal for at least 1 year, surgically sterile,
or agree to practice 2 effective methods of contraception through 120 days (4 months)
after the last dose of study drug for participants in Arms 1, 2, and 5, and through 6
months for participants in Arms 3 and 4, or agree to practice true abstinence.

12. Male participants who, even if surgically sterilized, agree to practice effective
barrier contraception through 120 days (4 months) after the last dose of study drug
for participants in Arms 1, 2, and 5, and through 6 months for participants in Arms 3,
and 4, or agree to practice true abstinence.

13. Additional inclusion criteria for arm 3 expansion only (MLN2480 + paclitaxel):

a. Participants with KRAS exon 2 or BRAF non-V600 mutation-positive non small cell
lung cancer (NSCLC) who have received a minimum of 1 but not more than 2 prior
cytotoxic-approved regimens.

14. Additional inclusion criteria for arms 4 and 5 expansion only (MLN2480 + cetuximab;
MLN2480 + irinotecan):

1. Participants with CRC who have received a minimum of 1 but not more than 2 prior
cytotoxic-approved regimens.

Exclusion Criteria:

All treatment arms:

1. Female participants who are pregnant or currently breastfeeding.

2. History of any serious medical or psychiatric illness that could, in the
investigator's opinion, potentially interfere with safe protocol completion.

3. History of uncontrolled brain metastasis unless: previously treated with surgery,
whole-brain radiation, or stereotactic radiosurgery; stable disease for >= 60 days
without steroid use (or stable steroid dose established for >= 28 days before the
first dose of MLN2480).

4. Ongoing seizure disorder or a requirement for antieplieptics.

5. Recent prior therapies, including: chemotherapy and hormonal therapy <= 4 weeks or 4
half lives, whichever occurs first, before administration of study drug;
immunotherapy/monoclonal antibody use <= 4 weeks before administration of MLN2480; or
radiation therapy <= 3 weeks before administration of study drug.

6. Chronic therapeutic corticosteroid use with the exception of replacement therapy for
adrenal insufficiency or corticosteroid inhalers.

7. Known history of human immunodeficiency virus infection, hepatitis B, or hepatitis C;
Prior allogeneic bone marrow or organ transplantation, or active condition of chronic
immune suppression is not allowed.

8. Concomitant use, or administration <= 14 days before first dose of study drug(s), of
clinically significant enzyme inducers.

9. Treatment with gemfibrozil (strong Cytochrome P4502C8 [CYP2C8] inhibitor) within 14
days before the first dose of MLN2480.

10. History of or current illicit drug use, drug abuse, or alcohol abuse.

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

12. Inability to comply with study requirements.

13. Other unspecified reasons that, in the opinion of the investigator or Millennium, make
the participant unsuitable for enrollment.

14. Additional exclusion criteria for arms 3, 5, and 6 expansion only (MLN2480 +
paclitaxel; MLN2480 + irinotecan; MLN2480 monotherapy):

a. Prior treatment with rapidly accelerated fibrosarcoma (RAF), extracellular
signal-regulated kinases (MEK), or other inhibitors of the mitogen-activated protein
kinase (MAPK) pathway.

15. Additional exclusion criteria for arm 2 only (MLN2480 + alisertib):

a. History of uncontrolled sleep apnea syndrome and other conditions that could result
in excessive daytime sleepiness, such as severe chronic obstructive pulmonary disease.

16. Additional exclusion criteria for arm 3 only (MLN2480 + paclitaxel):

a. Known hypersensitivity to paclitaxel or its components or other drugs formulated in
Cremophor® EL (polyoxyethylated castor oil).

17. Additional exclusion criteria for arm 5 only (MLN2480 + irinotecan):

1. Use of strong or moderate Cytochrome P4503A (CYP3A) inhibitors <= days of the
first dose of irinotecan.