Study of Ixazomib and Erlotinib in Solid Tumors

Study Groups:

If you are found to be eligible to take part in this study, you will be assigned to a dose
level of ixazomib and erlotinib based on when you join this study. Up to 4 dose levels of
ixazomib will be tested. Up to 18 participants may be enrolled at each dose level. The first
group of participants will receive the lowest dose level. Each new group will receive a
higher dose than the group before it, if no intolerable side effects were seen. This will
continue until the highest tolerable dose of ixazomib is found.

All participants will receive the same dose of erlotinib.

Once the highest tolerable dose is found, up to 18 participants will be enrolled at that dose
level as an expansion group.

The dose of the study drug combination that you receive may be lowered if you have
intolerable side effects.

Study Drug Administration Each study cycle is 28 days.

You will take ixazomib capsules by mouth on Days 1, 8, and 15 of each cycle.

You will take erlotinib tablets by mouth on Days 1-28 of each cycle.

You should swallow ixazomib capsules whole with 8 ounces (1 cup) of water. Each capsule
should be swallowed separately with a sip of water. You should also swallow erlotinib tablets
whole with water. You should take the ixazomib and erlotinib doses at the same time.

Do not break, chew, or open the capsules or tablets. Each dose should be taken on an empty
stomach, at least 1 hour before or 2 hours after a meal. If you miss a dose, take it as soon
as you remember, as long as the next scheduled dose is at least 72 hours (ixazomib) or 12
hours (erlotinib) away. You should not take a double dose to make up for a missed dose. If
you vomit after taking a dose, wait until the next scheduled dose. Do not take an additional
dose.

Your dose of study drug may be changed and/or you may be given drugs to help control the side
effects.

Study Visits:

Cycle 1:

Week 1:

- You will have a physical exam.

- Blood (about 6 teaspoons) will be drawn for routine tests and to check your liver and
kidney function.

- If you can become pregnant, leftover blood (about 1 teaspoon) and/or urine will be
collected for a pregnancy test.

- During Days 1, 2, 3, 5, and 8, blood (about 1-3 teaspoons) will be drawn for
pharmacokinetic (PK) testing. PK testing measures the amount of study drug in the body
at different time points.

Week 2:

°Blood (about 6 teaspoons) will be drawn for routine tests and to check your liver and kidney
function.

Week 3:

- You will have a physical exam.

- Blood (about 6 teaspoons) will be drawn for routine tests and to check your liver and
kidney function.

Cycle 2 and Beyond:

Week 1:

- You will have a physical exam.

- Blood (about 6 teaspoons) and urine will be collected for routine tests. The blood
sample will also be used for liver and kidney function tests.

- If you can become pregnant, part of the routine blood or urine test will be used for a
pregnancy test. To continue on this study, you must not be pregnant.

Week 4:

- You will have a physical exam.

- Blood (about 6 teaspoons) will be drawn for routine tests and to check your liver and
kidney function.

- On Day 28 of each cycle, if the doctor thinks it is needed, you will have an EKG.

- At the end of every other cycle (Cycles 2, 4, 6, and so on), you will have imaging scans
(either CT scans or MRI) performed to check the status of the disease.

If you have side effects or abnormal test results while on study, you may be asked to return
to the clinic for more tests until the side effects or abnormal test results improve.

Length of Study:

You may continue taking the study drugs for as long as the doctor thinks it is in your best
interest. You will no longer be able to take the study drug if the disease gets worse, if
intolerable side effects occur, if you develop new health problems, or if you are no longer
able to follow study directions.

Your participation on the study will be over after the end-of-study visit.

End of Study Visit:

Within 30 days after your last dose of the study drugs, the following tests and procedures
will be performed:

- You will have a physical exam.

- Blood (about 6 teaspoons) will be drawn for routine tests and to check your liver and
kidney function.

- Urine will be collected for routine tests.

Inclusion Criteria:

1. Patients with advanced or metastatic cancer that is refractory to standard therapy or
that has relapsed after standard therapy or has no standard therapy that increases
survival by at least three months.

2. All prior treatment- related toxicities must be CTCAE (Version 4.0) less than or equal
to Grade 2 (except alopecia) at the time of screening however clinically relevant AEs
that will impact on the ADE of the study drugs or safety of the subject must have
resolved to Grade 1 or better.

3. Adequate baseline organ function defined as following: Absolute neutrophil count
greater than or equal to 1.5 x 109 cells/L, hemoglobin greater than or equal to 8.0
g/dL, platelets greater than or equal to 75 x 109/L, creatinine less than or equal to
1.5 X upper limit of normal (ULN) with calculated creatinine clearance greater than 30
ml/min, total bilirubin less than or equal to 1.5 X ULN, AST(SGOT) and/or ALT(SGPT)
less than or equal to 3 XULN.

4. 18 years of age or older.

5. Life expectancy of at least 3 months in the opinion of investigator.

6. Able to swallow and retain orally administered medication and does not have any
clinically significant gastrointestinal abnormalities that may alter absorption such
as malabsorption syndrome or major resection of the stomach or bowels.

7. Measurable disease as defined by RECIST criteria (Version 1.1).

8. Patients with Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or
1.

9. Having archival paraffin tissue is ideal for the correlative study but it is not
mandatory.

10. 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 patient at any time without prejudice to future medical care.

11. Female patients 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 form through 90 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 subject. (Periodic abstinence [eg, calendar, ovulation,
symptothermal, post-ovulation methods]), And latex or non-latex condom with or without
a spermicidal agent, Diaphragm with spermicide; Cervical cap with a spermicide; Sponge
with a spermicide

12. Male patients, even if surgically sterilized (ie, status post-vasectomy), must agree
to one of the following: a) Agree to practice effective barrier contraception during
the entire study treatment period and through 90 days after the last dose of study
drug, OR b) Latex or non-latex condom with or without a spermicidal agent, Diaphragm
with spermicide; Cervical cap with a spermicide; Sponge with a spermicide.

13. Inclusion Criteria for dose expansion cohort: Non-small cell lung cancer: 1) We will
enroll non-small cell lung cancer patients with documented EGFR mutation who failed
treatment with anti-EGFR therapy (e.g. erlotinib or afatinib) and tested negative for
EGFR T790M mutation. We will allow patients with positive EGFR T790M mutation if they
have progressed on third generation anti-EGFR therapy (e.g. CO-1686 or AZD9291) or
medically not suitable/candidate for the third generation anti-EGFR therapy. Failure
from anti-EGFR therapy will be defined as progressive disease by RECIST (Version 1.1)
after at least two months of therapy. We plan to enroll up to 9 patients in this
cohort.

14. Pancreatic ductal adenocarcinoma: 1) Pancreatic ductal adenocarcinoma patient with
KRAS point mutation at codon G12 or G13. Since KRAS mutation is present in more than
90% of pancreatic cancer with 98% of the mutation found at codon 12, we expect
majority of patients with pancreatic ductal adenocarcinoma will be eligible for the
study. We plan to enroll up to 9 patients in this cohort. In addition to the above
inclusion criteria, first 5 patients from both non-small cell lung cancer and
pancreatic ductal adenocarcinoma patients will need to agree to mandatory pre- and
post-treatment tumor biopsies.

Exclusion Criteria:

1. Any serious and/or unstable pre-existing medical disorder (aside from malignancy
exception above), psychiatric disorder, or other conditions that could interfere with
subject's safety, obtaining informed consent or compliance to the study procedures, in
the opinion of the Investigator.

2. Radiotherapy completed within 2 weeks prior to treatment initiation. Radiotherapy
completed >2 weeks prior to treatment initiation is allowed if all procedure-related
toxicities resolved per inclusion #2.

3. Patient who were receiving prior therapy will require wash out period of either more
than 2 weeks or more than 5 half-lives whichever shorter.

4. Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
chemically related to study drug, or excipients or to dimethyl sulfoxide (DMSO).

5. Current use of a prohibited medication.

6. Symptomatic or untreated leptomeningeal or brain metastases or spinal cord
compression. If these were treated and clinically stable for 4 weeks, patient can be
considered for the trial.

7. Patient who is on strong inducer/inhibitor of CYP3A needs to be off the medication
prior to treatment initiation unless it is medically necessary for the patient.

8. Female patients who are lactating or have a positive serum pregnancy test suggestive
of pregnancy and not as a tumor marker during the screening period. If pregnancy is
tested positive, treating physician will further investigate if the patient is
pregnant or not. Treating physician may consider repeating the serum beta-hCG at next
follow up visit or refer patient to OB/GYN for further evaluation.

9. Major surgery within 14 days before enrollment.

10. Infection requiring systemic antibiotic therapy or other serious infection within 14
days before study enrollment.

11. Evidence of current uncontrolled cardiovascular conditions, including uncontrolled
hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure,
unstable angina, or myocardial infarction within the past 6 months.

12. Ongoing or active systemic infection, active hepatitis B or C virus infection, or
known human immunodeficiency virus (HIV) positive.

13. Diagnosed or treated for another malignancy within 2 years before study enrollment or
previously diagnosed with another malignancy and have any evidence of residual
disease. Patients with nonmelanoma skin cancer or carcinoma in situ of any type are
not excluded if they have undergone complete resection.

14. Patient has greater than or equal than Grade 2 peripheral neuropathy, or Grade 1 with
pain on clinical examination during the screening period.

15. Patients that have previously been treated with ixazomib, or participated in a study
with ixazomib whether treated with ixazomib or not.