Pazopanib or Pemetrexed and Crizotinib in Advanced Cancer

Study groups:

Dose escalation:

If you are found to be eligible to take part in this study, your doctor will decide if you
will receive one of the following drug combinations:

- If you are in Group A, you will receive crizotinib and pazopanib.

- If you are in Group B, you will receive crizotinib and pemetrexed.

- If you are in Group C, you will receive pazopanib and pemetrexed.

- If you are in Group D, you will receive crizotinib, pazopanib, and pemetrexed.

Once it is decided which combination you will receive, you will be assigned to a dose level
based on when you join the study.

Up to 8 dose levels of crizotinib with pazopanib will be tested. Up to 6 dose levels of
crizotinib with pemetrexed will be tested. Up to 6 dose levels of pazopanib with pemetrexed
will be tested. Up to 8 dose levels of pazopanib with pemetrexed and crizotinib will be
tested. Up to 6 participants will 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 combination is found.

Dose expansion:

Once the highest tolerable dose of each study drug combination is found, up to 14 more
participants may be enrolled to further study the safety of each combination of drugs at that
dose.

Study Drug Administration:

Each study cycle is 21 days. Drugs should be taken and/or administered simultaneously. On
days of pharmacokinetic testing (if you agree) you should take the drugs at least 1 hour
before or 2 hours after a meal.

If you are taking crizotinib, you will take it by mouth at the same time every day
consistently either with or without food. It should be swallowed whole with a glass of water.
You will take the drug every other day, 1 or 2 times a day. You will be told how often to
take this drug.

If you are taking pazopanib, you will take it by mouth at the same time every day with a
glass of water. You should take it at least 1 hour before or 2 hours after a meal.

If you receive pemetrexed:

- You will receive it by vein on Day 1 of each cycle over about 10 minutes.

- The day before your first dose of pemetrexed, you will start taking folic acid to help
lower the risk of side effects. Although the study drug is designed to prevent the body
from making folic acid that could help cancer grow and spread, some folic acid is needed
to prevent side effects in non-cancerous tissue. You will take folic acid by mouth 1
time every day until at least 30 days after you received the last dose of pemetrexed.

- The day before your first dose of pemetrexed, you will receive a vitamin B12 injection.
You will receive an injection of Vitamin B12 about every 9 weeks after that. Vitamin B12
is given to help reduce the risks of side effects.

- You will take dexamethasone by mouth 2 times a day on the day before, the day of, and
the day after you receive pemetrexed.

Study Visits:

At every study visit, you will be asked about any other drugs or herbal supplements you are
taking and about any side effects you may have.

During Cycles 1 and 2, you will have weekly blood (about 1 tablespoon) collected for routine
tests.

During Week 1 of Cycles 2 and beyond:

- Your medical history will be recorded, including any cancer symptoms.

- You will have a physical exam, including measurement of your weight and vital signs.

- Your performance status will be recorded.

- Blood (about 1 tablespoon) and urine will be collected for routine tests.

- If your doctor thinks it is needed, you will have an ECG to check your heart function.

Every 6 weeks, or earlier if needed, blood (about 1 tablespoon) will be drawn for tumor
marker testing.

After about 6 weeks and then every 2-3 cycles after that, you will have a CT scan, x-ray, MRI
scan, and/or PET scan to check the status of the disease. It may be done more often if your
study doctor thinks it is needed.

If you are able to become pregnant, you will have a blood (about 1 teaspoon) or urine
pregnancy test every 2 cycles or at any time the study doctor thinks it is needed.

Length of Study Participation:

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 drugs if the disease gets worse, if
intolerable side effects occur, or if you are unable to follow study directions.

Your participation on the study will be over once you have completed the end-of-dosing and/or
follow-up visits.

End-of-Dosing Visit:

Within 30 days after your last dose of study drugs, you will have an end-of-study visit. If
you are having side effects at the time of this visit, you may have follow-up for a longer
period of time. At this visit, the following tests or procedures may be performed:

- Your medical history will be recorded, including any cancer symptoms.

- You will be asked if you have had any side effects.

- You will have a physical exam, including measurement of your weight and vital signs.

- Your performance status will be recorded.

- Blood (about 1 tablespoon) and urine will be collected for routine tests.

- Blood (about 1 tablespoon) will be drawn for tumor marker testing.

- If the doctor thinks it is needed, you will have an x-ray, CT scan, MRI scan, and/or
PET/CT scan to check the status of the disease.

- If your doctor thinks it is needed, you will have an ECG to check your heart function.

Inclusion Criteria:

1. Patients with advanced cancer, either refractory to standard therapy or for which no
effective standard therapy that increases survival for at least 3 months is available.

2. Patients must have measurable or evaluable disease, as defined by RECIST 1.1.

3. Women of child-bearing potential and men must agree to use adequate contraception.

4. ECOG performance status of 0 to 2.

5. Adequate organ functions: (Crizotinib plus Pazopanib arm A): Neutrophils > 1000/uL;
Platelets ≥ 75,000/uL; Total bilirubin < or= 2 x ULN (upper limit of normal); ALT < or
= 2.5 x ULN or < o r= 5 x ULN if liver metastases persist; Serum creatinine < 2 x ULN
(Crizotinib plus Pemetrexed arm B, Pazopanib plus Pemetrexed arm C, Crizotinib plus
Pazopanib plus Pemetrexed arm D) Neutrophils > 1500/uL; Platelets > or = 100,000/uL;
Total bilirubin < or = 2 x ULN (upper limit of normal); ALT < or = 2.5 x ULN or < or =
5 x ULN if liver metastases persist; Calculated GFR > 45 mL/min.

6. Creatinine Clearance: The standard Cockcroft and Gault formula must be used to
calculate CrCl for enrollment or dosing. Also include in the pre-treatment or baseline
text portion of the protocol, the 'On Study Evaluations or During Treatment' for every
Pemetrexed treatment day, and also capture in the study Schedule of Events. No dosage
adjustment is needed in patients with creatinine clearance > 45 mL/min. Insufficient
numbers of patients have been studied with creatinine clearance <45 mL/min to give a
dose recommendation. Therefore, Pemetrexed should not be administered to patients
whose creatinine clearance is <45 mL/min.

7. For pemetrexed arms: The ability to interrupt NSAIDs 2 days before (5 days for
long-acting NSAIDs), the day of, and 2 days following administration of Pemetrexed.

8. The ability to take folic acid, Vitamin B12, and dexamethasone according to protocol
for all pemetrexed arms.

9. Expansion cohort only for arms containing crizotinib: arm A (Crizotinib plus
Pazopanib) and arm B (Crizotinib plus Pemetrexed) and arm D (Crizotinib plus Pazopanib
Plus Pemetrexed) but not arm C (Pazopanib plus Pemetrexed). Patients must have ALK
abnormality including: translocation, ALK amplification, mutation and overexpression
as determined by FISH, IHC, qPCR, qRT-PCR, array Comparative Genomic Hybridization or
direct sequencing (aCGH). Or patients must have a c-Met abnormality; either c-Met
amplification or c-Met mutation or patients must have the ROS1 translocation as
determined by FISH.

Exclusion Criteria:

1. Patient receiving any concurrent chemotherapy.

2. Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection requiring intravenous antibiotics.

3. Symptomatic congestive heart failure (NYHA Class III or IV), unstable angina pectoris
or congenital long QT syndrome.

4. Medical and/or psychiatric problems of sufficient severity to limit full compliance
with the study or expose patients to undue risk.

5. Known anaphylactic or severe hypersensitivity to study drugs or their analogs.

6. Patient has failed to recover from any prior surgery within 4 weeks of study entry.

7. Patient is pregnant or lactating.

8. Patient has had any treatment specific for tumor control within 3 weeks of dosing with
investigational drugs and cytotoxic agents, or within 2 weeks of cytotoxic agent given
weekly, or within 6 weeks of nitrosoureas or mitomycin C, or within 5 half-lives of
biological targeted agents with half-lives and pharmacodynamic effects lasting less
than 5 days (that includes, but is not limited to, erlotinib, sorafenib, sunitinib,
bortezomib, and other similar agents).

9. Patient has any signs of intestinal obstruction.

10. Patient is not able to swallow oral medication.

11. Patients receiving whole brain radiation within 14 days prior to the first dose of
study drugs will be excluded. NOTE: Patients receiving palliative radiation (other
than whole brain) before or during treatment may still be eligible as long as there
are evaluable lesions that are not being irradiated.

12. Pemetrexed arms only: Presence of third space fluid which cannot be controlled by
drainage.

13. Additional Exclusions for the 3 pazopanib containing arms (Crizotinib plus Pazopanib)
and (Pazopanib plus Pemetrexed) and (Crizotinib plus Pazopanib plus Pemetrexed). 1.
History of stroke or transient ischemic attack within 6 months prior to study
enrollment. 2. History of abdominal fistula, gastrointestinal perforation, or
intra-abdominal abscess within 6 months prior to study enrollment. 3. Urine for
proteinuria > or = 2+ (patients discovered to have > or = 2+ proteinuria on urinalysis
at baseline should undergo a 24 hour urine collection and must demonstrate < or = 1g
of protein in 24 hours to be eligible).