Molecular Profiling and Targeted Therapy for Advanced Non-Small Cell Lung Cancer, Small Cell Lung Cancer, and Thymic Malignancies

BACKGROUND:

- A better understanding of the genetic make-up of the individual tumor may offer
potentially improved therapies. This approach may also give rapid access to response
data in patients with sometimes rare genetic abnormalities.

- In addition, it will allow us to test targeted therapies in a select population of
patients that is more likely to have a favorable response based on their molecular
profile and the specific mechanism of action of the drug being tested.

- This approach will also speed up drug development and potentially approval, and rescue
an otherwise ineffective drug candidate for the specific subgroup that can benefit.

Primary Objectives:

- To determine the feasibility of the use of tumor s molecular profiling and targeted
therapies in the treatment of advanced stage non-small cell lung cancer (NSCLC), small
cell lung cancer (SCLC) and thymic malignancies.

- To estimate the response rate of molecular-profile directed treatments in NSCLC, SCLC
and thymic malignancies patients.

ELIGIBILITY:

- Patients with histologically confirmed advanced lung cancer or thymic malignancies for
whom surgical resection with curative intent is not feasible.

- Patients must either have biopsiable disease and be willing to undergo biopsy for

molecular profiling or have paraffin embedded tissue blocks suitable for molecular

profiling analysis.

- Individuals are eligible for EGFR germline mutation testing if they have:

- a personal history of invasive lung cancer or one of the pre-invasive histologies

associated with the development of lung cancer and more than two affected family

DESIGN:

- All patients will have their tumors undergo molecular profiling. Based on these results
and on other eligibility criteria, the patients will be offered enrollment into
different targeted therapy arms.

- At the NCI site only, individuals eligible for EGFR germline mutation will undergo
testing for germline mutations affecting the EGFR gene; if a mutation is detected, their
first-degree relatives would be invited to undergo testing for the index germline
mutation found in the proband and appropriate follow-up on trial.

- Effective with Amendment I, the participating site, OHSU, will discontinue new
enrollments and data entry for existing patients on the NOS arm on this protocol in
favor of the OHSU protocol L8639, Personalized Cancer Medicine Registry. The data from
these patients will be included with the data from 11-C-0096 (8639) NCI patients at the
time of publication. Any OHSU patients who are eligible for a treatment arm will
continue to be enrolled and followed per protocol.

- ELIGIBILITY CRITERIA FOR INITIAL ENROLLMENT:

- Patients with histologically confirmed advanced NSCLC, SCLC and thymic malignancies
for whom surgical resection or multimodality therapy with curative intent is not
feasible. For patients with Stage III NSCLC, who can be encompassed by a radiation
port, definitive XRT should have been performed first when possible.

- Individuals who meet the eligibility criteria for EGFR germline mutation testing but
who do not have advanced cancer as defined in 3.1.1 may enroll for EGFR germline
mutation testing only and will not be eligible for the treatment or NOS arms.

- Patients with advanced cancer must meet one of the following criteria (does not apply
to firstdegree relatives or individuals with pre-invasive histology enrolling only for
EGFR germline mutation testing):

- Patients must have biopsiable disease and be willing to undergo biopsy for
molecular profiling

OR

-Patients must have enough and adequate archival material from a previous biopsy to perform
molecular profiling analyses. The adequacy of the material provided will be determined by
the principal investigator in conjunction with the laboratories performing the molecular
profiling analyses

OR

- Patients must have previously undergone a successful molecular profiling of their
tumor with mutation analysis of the genes described in section 5.2, as part of this
protocol (crossover patients) or other molecular profiling protocols such as the Lung
Cancer Mutation Consortium protocol among others.

- Age greater than or equal to18 years.

EXCLUSION CRITERIA:

1. Patients who have had major surgery, chemotherapy or radiotherapy within 2 weeks prior
to entering the study or those who have not recovered from adverse events due to
agents administered more than 2 weeks earlier.

2. Patients may not be receiving any other investigational agents or other medications
for the treatment of their malignancy.

3. Patients with symptomatic brain metastases should be excluded from this clinical trial
because of their poor prognosis and because they often develop progressive neurologic
dysfunction that would confound the evaluation of neurologic and other adverse events.
However, patients who have had treatment for their brain metastases and whose brain
metastatic disease status has remained stable for at least 1 week after the end of
brain radiation may be enrolled to undergo molecular profiling at the discretion of
the principal investigator. In addition, brain metastatic disease should be stable for
at least 4 weeks, before the patients can be enrolled in any of the experimental
treatment arms.

4. Patients with any condition (e.g., gastrointestinal tract disease resulting in an
inability to take oral medication or a requirement for IV alimentation, prior surgical
procedures affecting absorption, or active peptic ulcer disease) that impairs their
ability to swallow and retain tablets are excluded.

5. Any uncontrolled medical illness that precludes the patient from undergoing a biopsy
for molecular profiling and / or receiving treatment under one of the experimental
arms of the study should be excluded. These conditions include but are not limited to:

- Ongoing or uncontrolled, symptomatic congestive heart failure (Class III or IV as
defined by the NYHA functional classification system (see Appendix D).

- Uncontrolled hypertension

- Unstable angina pectoris

- Cardiac arrhythmia

- Uncontrolled diabetes

- Uncontrolled psychiatric illness/social situations that would limit compliance
with study requirements.

6. Patients with QTc prolongation (defined as a QTc interval equal to or greater than 500
msec) or other significant ECG abnormalities are excluded.

7. Caution should be used if patients are required to use a concomitant medication that
can prolong the QT interval and efforts should be made to switch to a different
medication before the patient begins treatment under an experimental arm. See Appendix
E for a table of medications with the potential to prolong the QTc interval. A
comprehensive list of agents with the potential to cause QTc prolongation can be found
at: http://www.azcert.org/medical-pros/drug-lists/bycategory.cfm

8. The eligibility of patients taking medications that are potent inducers or inhibitors
of that enzyme will be determined following a review of their case by the Principal
Investigator. (A list of potent CYP3A4 inducers or inhibitors can be found in Appendix
F). Every effort should be made to switch patients taking such agents or substances to
other medications before they begin treatment with one of the experimental drug
included in this protocol, particularly patients with gliomas or brain metastases who
are taking enzyme-inducing anticonvulsant agents. A comprehensive list of medications
and substances known or with the potential to alter the pharmacokinetics of sunitinib
through CYP3A4 is provided in Appendix F.

9. Patients with tumor amenable to potentially curative therapy as assessed by the
investigator.

10. Pregnant women are excluded from this study because many of the FDA approved agents
and investigational agents in this trial have the potential for teratogenic or
abortifacient effects. Because there is an unknown but potential risk for adverse
events in nursing infants secondary to treatment of the mother with these agents,
breastfeeding should be discontinued if the mother is treated in this protocol. These
potential risks may also apply to other agents used in this study.