A Study of MLN0264 in Patients With Pancreatic Cancer

The drug being tested in this study is called MLN0264. MLN0264 is being tested to treat
tumors in people who have metastatic adenocarcinoma of the pancreas expressing guanylyl
cyclase C (GCC). This study will assess tumor size reduction in patients who are
administered MLN0264.

The study will enroll 42 to 81 patients. All participants will be administered MLN0264 at
1.8 mg/kg as a single, 30-minute, intravenous (IV) infusion on Day 1 of each 3-week
treatment cycle, followed by a rest period of 20 days. Participants will continue to receive
MLN0264 for up to 1 year or until disease progression or unacceptable toxicity occurs.

This multi-centre trial will be conducted worldwide. The overall time to participate in this
study is approximately 19 months. Participants will make 3 to 6 visits to the clinic per
treatment cycle, an end-of-treatment visit will occur 30 days after the last dose of study
medication, and follow-up assessments will occur every 12 weeks until death or 6 months
after the last patient completes treatment - whichever occurs first.

Inclusion Criteria:

1. Male or female participants 18 years of age or older when written informed consent is
obtained.

2. Histologically confirmed metastatic or advanced inoperable adenocarcinoma of the
pancreas with immunohistochemistry (IHC) evidence of guanylyl cyclase C (GCC)
expression indicated by an H-score of 10 or greater.

3. Treatment with 1 or more prior chemotherapies for advanced or metastatic
adenocarcinoma of the pancreas.

4. Measurable disease as defined by Response Evaluation Criteria in Solid Tumors
(RECIST) version 1.1 guidelines. All scans and x-rays used to document measurable
disease must be done within 28 days before enrollment (ascites and bone lesions are
not considered measureable disease).

5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 within 14 days
before enrollment.

6. 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
through 30 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 4 months 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.)

7. Voluntary written consent must be given 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.

8. Adequate organ and hematological function as evidenced by the following laboratory
values within 14 days before enrollment:

- Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L

- Platelet count ≥ 100 x 10^9/L

- Hemoglobin ≥ 9 g/dL

- Activated partial thromboplastin time (aPTT) ≤ 1.5 x the upper limit of the
normal range (ULN) per institutional laboratory normal range

- International normalized ratio (INR) ≤ 1.5 x ULN

- Serum creatinine ≤ 1.5 x ULN

- Total bilirubin ≤ 1.5 x ULN

- Albumin ≥ 3g/dL

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN

- Serum lipase ≤ 3 x ULN and serum amylase within the normal range

9. Resolution of all toxic effects of prior treatments except alopecia to Grade 0 or 1
by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI
CTCAE) version 4.03.

10. Willing and able to comply with scheduled visits, treatment plan, laboratory tests,
and other trial procedures.

Exclusion Criteria:

1. Radiotherapy within 4 weeks before enrollment.

2. Concurrent treatment or treatment within 4 weeks of study entry with any other
investigational agent or chemotherapy.

3. Female participants who are lactating and breastfeeding or have a positive pregnancy
test during the Screening period.

4. Uncontrolled, clinically significant, symptomatic cardiovascular disease within 6
months before enrollment, including myocardial infarction, unstable angina, Grade 2
or greater peripheral vascular disease, cerebrovascular accident, transient ischemic
attack, congestive heart failure, or arrhythmias not controlled by outpatient
medication.

5. Treatment with any medication that has a clinically relevant potential risk of
prolonging the QT interval or inducing torsades de pointes that cannot be
discontinued or switched to a different medication before starting study drug.

6. Participants with electrocardiogram (ECG) abnormalities considered by the
investigator to be clinically significant, or repeated baseline prolongation of the
rate-corrected QT interval (QTc).

7. Ongoing or clinically significant active infection as judged by the investigator.

8. Signs of peripheral neuropathy (PN) ≥ NCI CTCAE Grade 2.

9. Concomitant chemotherapy, hormonal therapy, immunotherapy, or any other form of
cancer treatment.

10. Use of strong cytochrome P450 (CYP) 3A4 inhibitors within 2 weeks before the first
dose of study drug.

11. Any preexisting medical condition of sufficient severity to prevent full compliance
with the study.

12. History of or current neoplasm other than gastric adenocarcinoma, except for
curatively treated nonmelanoma skin cancer or in situ carcinoma of the cervix uteri.

13. Known diagnosis of human immunodeficiency virus (HIV) infection (testing is not
mandatory).

14. Symptomatic brain metastases.

15. Ongoing anticoagulant therapy (eg, aspirin, coumadin, heparin).