All Treatment Arms:
1. Informed consent.
2. Male or female participants 18 years or older.
3. Participants who, in the opinion of the treating physician, have failed standard
therapies and for whom a phase 1 trial is an appropriate option.
4. Radiographically or clinically evaluable tumor. For Expansion phase: Tumors must be
measurable and of the protocol specified genetic mutational status, where applicable.
5. Recovered (ie, Grade 1 toxicity) from adverse effects (except alopecia) of prior
6. Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
7. Expected survival time of at least 3 months in the opinion of the investigator.
8. Block of banked tumor tissue and/or 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.
9. Suitable vein access for the study-required blood sampling.
10. 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.
11. Left ventricular ejection fraction (LVEF) of 50% or greater, as measured by
echocardiogram (ECHO) or multiple-gated acquisition scan (MUGA), within 28 days
before the first dose of MLN2480
12. 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.
13. Male patients 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.
14. 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
15. 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
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 CYP2C8 inhibitor) within 14 days before the first
dose of MLN2480. 14. History of or current illicit drug use, drug abuse, or alcohol
10. Major surgery within 14 days before the first dose of study drug.
11. Inability to comply with study requirements.
12. Other unspecified reasons that, in the opinion of the investigator or Millennium,
make the patient unsuitable for enrollment.
13. Expansion phase only: Prior treatment with RAF, MEK, or other inhibitors of the MAPK
14. 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
15. 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).
16. Additional exclusion criteria for Arm 5 Only (MLN2480 + irinotecan):
1. Use of strong or moderate CYP3A inhibitors days of the first dose of
Minimum Eligible Age: 18 Years
Maximum Eligible Age: N/A
Eligible Gender: Both
Cmax: Maximum Observed Plasma Concentration for MLN2480, MLN0128, Alisertib, cetuximab, and irinotecan
Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for MLN2480, MLN0128, Alisertib, cetuximab, and irinotecan
AUC(0-tau): Area Under the Plasma Concentration-time Curve from Time 0 to Time tau Over the Dosing Interval for MLN2480, MLN0128, Alisertib, cetuximab, and irinotecan
Cmax: Maximum Observed Plasma Concentration for Paclitaxel
AUC(0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for Paclitaxel
Terminal Elimination Half-life (T1/2) Pharmacokinetic Parameter for Paclitaxel
Objective Response Rate (ORR) Based on Response Evaluation Criteria in Solid Tumors (RECIST)
Time to Response
Duration of Response
Progression Free Survival (PFS)
AUC(0-tlast): Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration for Paclitaxel