Phase 1/2 Study of X-396, an Oral ALK Inhibitor, in Patients With ALK-positive Non-Small Cell Lung Cancer

This is the first study of X-396 (ensartinib) in humans and the investigational drug will be
given as a once or twice daily oral dose in 28 day cycles until there is disease progression
or unacceptable safety issues. X-396 will be given to small groups of patients (1 - 6) at
each dose level and the patients will be observed to see if there are any adverse safety
effects. As long as there are no unacceptable safety issues after 28 days, the dose of X-396
will be increased for the next group of patients. This process will continue until the
maximum tolerated dose (MTD) of X-396 is reached. Once the MTD is reached, up to 170
additional patients will also be given X-396 to further determine the activity of X-396 in
patients with ALK-positive non-small cell lung cancer. These additional patients will be
enrolled in the following expansion cohorts: ALK TKI-naïve patients, patients that progressed
on crizotinib, patients that progressed on one or more 2nd generation ALK TKIs (patients may
or may not have also received prior crizotinib), including patients with asymptomatic CNS
metastases.

Inclusion Criteria:

1. Histologically or cytologically confirmed diagnosis of advanced solid tumor
malignancy. Patients may be ALK TKI-naive or may have received prior crizotinib and/or
second generation ALK TKIs. In addition, patients with a known ALK 1198 mutation will
be allowed.

-For the expanded cohort portion of the study, patients must have NSCLC with ALK
genomic alterations; however, patients will be allowed to enroll based on local
FDA-approved ALK results.

2. Eastern Cooperative Group ECOG) Performance Status score of 0 or 1.

3. Ability to swallow and retain oral medication.

4. Adequate organ system function.

5. Patients with treated or untreated asymptomatic CNS metastases may be allowed to
enroll.

6. Male patients willing to use adequate contraceptive measures.

7. Female patients who are not of child-bearing potential, and female patients of
child-bearing potential who agree to use adequate contraceptive measures.

8. Patients must be ≥ 18 years of age.

9. Patients must have measurable or evaluable disease for the dose escalation portion of
the study and measurable disease for the expanded cohort portion of the study (except
for patients in the CNS metastases and leptomeningeal cohorts).

10. Willingness and ability to comply with the trial and follow-up procedures.

11. Ability to understand the nature of this trial and give written informed consent.

Exclusion Criteria:

1. Patients currently receiving cancer therapy.

2. Use of an investigational drug within 21 days or 5 half-lives (whichever is shorter)
prior to the first dose of X-396. A minimum of 10 days between treatment and X-396 and
2 days between ALK TKI and X-396.

3. Any major surgery, radiotherapy, or immunotherapy within the last 21 days (focal
radiation does not require a washout period; ≥4 weeks for WBRT). Chemotherapy regimens
with delayed toxicity within the last 4 weeks. Chemotherapy regimens given
continuously or on a weekly basis with limited potential for delayed toxicity within
the last 2 weeks.

4. Prior stem cell transplant.

5. Patients with a known allergy or delayed hypersensitivity reaction to drugs chemically
related to X-396 (e.g., crizotinib) or to the active ingredient of X-396.

6. Patients with primary CNS tumors are ineligible.

7. Patients receiving CYP3A substrates with narrow therapeutic indices, strong CYP3A
inhibitors, and strong CYP3A inducers.

8. Concomitant use of herbal medications at least 7 days prior to the first dose of study
drug and throughout participation in the trial.

9. Females who are pregnant or breastfeeding.

10. Presence of active gastrointestinal (GI) disease or other condition that will
interfere significantly with the absorption, distribution, metabolism, or excretion of
X-396.

11. Clinically significant cardiovascular disease.

12. Patients who are immunosuppressed (including known HIV infection), have a serious
active infection at the time of treatment, have known hepatitis C, or have any serious
underlying medical condition that would impair the ability of the patient to receive
protocol treatment.

13. Psychological, familial, sociological, or geographical conditions that do not permit
compliance with the protocol.

14. Concurrent condition that in the investigator's opinion would jeopardize compliance
with the protocol or would impart excessive risk associated with study participation
that would make it inappropriate for the patient to be enrolled.

15. Inability or unwillingness to comply with study and/or follow-up procedures outlined
in the protocol.