-02341066 and PF-00299804 for Advanced Non-Small Cell Lung Cancer

BACKGROUND:

- Approximately 85% of lung cancer is defined histologically as NSCLC and the majority of
patients present with inoperable locally advanced (Stage IIIB) or metastatic (Stage IV)
disease for which no curative treatment is available.

- Patients with disease progression on or after first-line treatment with platinum-based
doublets may be candidates for second-line treatment.

- Recent evidence strongly implicates EGFR activating somatic mutations as a mechanism of
tumorigenesis and a determinant of sensitivity to EGFR TKIs in NSCLC.

- Despite the dramatic initial response to gefitinib and erlotinib, about 50% of NSCLC
tumors develop resistance due to secondary activating mutations in EGFR itself,
including the EGFR T790M gatekeeper mutation, and more than 20% of acquired resistance
is due to an increase in mesenchymal-epithelial transition factor (c-Met) signaling.

- There is evidence from a limited number of tumors from patients with acquired resistance
to EGFR-TKIs that both T790M and cMET resistance mechanisms can occur in the same
patient at different metastatic sites and even in different fractions of the same
lesion.

- Tumors with acquired resistance to erlotinib and gefitinib might be vulnerable to a
combination of PF-00299804 a second generation EGFR TKI which is also an inhibitor of
T790M mutation, and PF-02341066 which is an inhibitor of c- Met/Hepatocyte Growth Factor
Receptor (HGFR).

OBJECTIVES:

- To define the recommended Phase 2 dose (RP2D) of combined PF-02341066 plus

PF-00299804 in patients with advanced Non-Small Cell Lung Cancer (NSCLC).

- To assess the overall safety and tolerability, plasma pharmacokinetics (PK) and clinical
activity of combined PF-02341066 plus PF-00299804.

- To analyze potential predictive and pharmacodynamic biomarkers in tumor and blood in
patients with advanced NSCLC who have acquired resistance to erlotinib or gefitinib

ELIGIBILITY:

- Dose Escalation Phase: Adults with histologically documented diagnosis of NSCLC that is
locally advanced or metastatic, after failure of either at least one chemotherapy
regimen or treatment with erlotinib or gefitinib.

- Expansion Phase: Adults with histologically documented diagnosis of NSCLC that is
locally advanced or metastatic, with acquired resistance to erlotinib or gefitinib, and
must have one lesion amendable to biopsy.

- All pathology samples will be reviewed at the NCI.

DESIGN:

- Phase 1, multi-center, open-label, non-randomized trial of combined oral PF- 02341066
and oral PF-00299804 in patients with advanced NSCLC. Trial consists of two phases.

- Dose Escalation Phase: Patients will be treated with varying doses of combined PF-
02341066 plus PF-00299804. Tumor biopsy is not required.

- Expansion Phase: Two expansion cohorts will run concurrently following completion of the
Dose Escalation Phase. Both cohorts will enroll patients with locally advanced or
metastatic NSCLC with acquired resistance to erlotinib or gefitinib, which is defined as
progression following an initial response (complete or partial) or stable disease for at
least six months while on erlotinib or gefitinib.

- The dose escalation phase and the dose expansion phase can run concurrently insofar as
the dose expansion phase can enroll before completion of the dose escalation phase
provided that the dose used in the expansion phase has already been tested in the
escalation phase and has been declared safe; i.e., for each specific safe dose the
escalation phase is followed by the expansion phase.

- Tumor biopsy is mandatory for Expansion Phase entrance, however, all patients will be
treated with study drugs irrespective of the biomarker identified which will be analyzed
retrospectively. The mandatory biopsy in the Expansion Phase is necessary in order to
identify acquired mutations that change over time.

- Expansion cohort 1 will continue to evaluate safety, tolerability and PK of the drug
combination PF-02341066 plus PF-00299804.

- Expansion cohort 2 will enroll patients who are either untreated by prior PF- 00299804
or who have progressed on single agent PF-00299804 administered in an ongoing clinical
trial. Patients who are previously untreated with PF-00299804 will be treated
sequentially; i.e., first with single agent PF-00299804 until progression, then with the
combination of PF-02341066 plus PF-00299804. Those who progressed with single agent
PF-00299804 on another clinical trial will be treated with the combination PF-02341066
plus PF-00299804.

- INCLUSION CRITERIA:

- Subject eligibility should be reviewed and documented by an appropriately qualified
member of the investigator s study team before subjects are included in the study.

- Evidence of a personally signed and dated informed consent document indicating that
the subject (or a legally acceptable representative) has been informed of all
pertinent aspects of the study.

- Subjects must be willing and able to comply with scheduled visits, treatment plan,
laboratory tests, and other study procedures.

- Subjects must meet all of the following inclusion criteria to be eligible for
enrollment into the study:

- Disease Criteria:

- Dose Escalation Phase: Histologically proven diagnosis of NSCLC that is locally
advanced or metastatic, after failure of either at least one prior chemotherapy
regimen or targeted therapy.

- Expansion Phase: Histologically proven diagnosis of NSCLC that is locally advanced or
metastatic and with acquired resistance to erlotinib or gefitinib. Acquired resistance
is defined as progression following either an initial response (complete or partial),
or stable disease for at least six months, while on single agent erlotinib or single
agent gefitinib. In addition to these patients, Cohort 2 will also enroll patients
from ongoing trials, including A7471017 and A7471028, who have progressed on single
agent PF-00299804.

- For the dose escalation phase, any prior treatment (chemotherapy, targeted therapy,
radiation or surgery) must have been completed at least 2 weeks prior to initiation of
study medication, except patients being treated with single agent PF-02341066 will
have the option of continuing single agent PF-02341066 until the combination of PF-
02341066 and PF-00299804 is given. For the expansion phase, patients must not have had
any intervening treatmen (chemotherapy, targeted therapy, radiation or surgery)
between single agent erlotinib or single agent gefitinib treatment, and biopsy and
dosing with study drug, unless agreed by the sponsor. In Expansion Cohort 2, patients
who have received PF-00299804 as part of an ongoing clinical trial will continue with
single agent therapy with PF-00299804 at their current dose after documentation of
progression until the combination is given.

- Any acute toxicity from prior treatment must have been recovered to less than or equal
to Grade 1 (except alopecia).

- At least 1 target lesion used for assessment of antitumor activity must be measurable
by RECIST (version 1.1), or considered evaluable by agreement between the investigator
and the sponsor.

- Target lesions can be chosen from a previous irradiated area if lesions in those areas
have documented progression.

- Female or male, 18 years of age or older.

- ECOG (Zubrod) performance status 0-2.

- Adequate organ function as defined by the following criteria measured within 7 days
prior to enrollment.

- Serum aspartate transaminase (AST) and serum alanine transaminase (ALT) less than or
equal to 2.5 times upper limit of normal (ULN), or AST and ALT less than or equal to 5
times ULN if liver function abnormalities are due to underlying malignancy;

- Total serum bilirubin less than or equal to 1.5 times ULN (except patients with
documented Gilbert s syndrome);

- Absolute neutrophil count (ANC) greater than or equal to1000/microL;

- Platelets greater than or equal to 30,000/microL;

- Hemoglobin greater than or equal to 8.0 g/dl;

- Serum creatinine <2 times institution ULN.

- Adequate cardiac function, including:

- 12-Lead electrocardiogram (ECG) with normal tracing or non-clinically significant
changes that do not require medical intervention;

- QTc interval less than or equal to 470 msec and without history of Torsades de Pointes
or other symptomatic QTc abnormality;

- LVEF (by MUGA or echocardiogram) of greater than or equal to 50%.

- All female patients of child-bearing potential are required to have a negative
pregnancy test at screening. The test should be repeated whenever one menstrual cycle
is missed during treatment or a potential pregnancy is otherwise suspected.

- Willingness and ability to comply with scheduled visits, treatment plans, laboratory
tests, other study procedures and, for enrollment into the Expansion Phase, must be
willing to undergo a tumor biopsy.

EXCLUSION CRITERIA:

Subjects presenting with any of the following will not be included in the study:

- Participation in other studies or treatment within 2 weeks before the current study
begins and/or during study participation (with the exception of patients who are
receiving single agent PF-00299804 and who enroll into Expansion Cohort 2 from ongoing
trials including A7471017 and A7471028, and with the exception of patients being
treated with single agent PF-02341066 treatment who enroll during the dose escalation
phase and exercise the option of continuing single agent PF-02341066 treatment until
the combination of PF-02341066 and PF-00299804 is given) to allow for recovery and
drug wash-out.

- Known interstitial fibrosis or interstitial lung disease.

- Patients with known brain metastases who are neurologically stable (asymptomatic) for
at least 2 weeks and with no ongoing requirement for corticosteroids may enroll on
study before treatment of brain metastases.

- History of carcinomatous meningitis, or leptomeningeal disease.

- Any of the following within 6 months prior to starting study treatment: myocardial
infarction, severe/unstable angina pectoris, coronary/peripheral artery bypass graft,
congestive heart failure, cerebrovascular accident including transient ischemic
attack.

- Any history of clinically significant ventricular arrhythmias (such as ventricular
tachycardia, ventricular fibrillation or Torsades de Pointes). Diagnosed or suspected
congenital long QT syndrome. Ongoing cardiac dysrhythmias of Grade greater than or
equal to 2 (CTCAE version 4.02), uncontrolled atrial fibrillation of any grade, or QTc
interval >470 msec.

- Hypertension that cannot be controlled by medications (>150/100 mmHg despite optimal
medical therapy).

- Patient must not have had major surgery or trauma within 28 days prior to enrollment.

- Active uncontrolled infection.

- Pregnant or lactating females.

- Significant gastrointestinal condition that may impair intake, transit, absorption or
ability to tolerate investigational drugs.

- Prior malignancy (other than NSCLC): patients will not be eligible if they have
evidence of active malignancy (other than non-melanoma skin cancer or in situ cervical
cancer, or localized and presumed cured prostate cancer with PSA < ULN) within the
last 3 years.

- Other severe acute or chronic medical or psychiatric condition or laboratory
abnormality that may increase the risk associated with study participation or
investigational product administration or may interfere with the interpretation of
study results and, in the judgment of the investigator, would make the subject
inappropriate for entry into this study.

- Use of drugs or foods that are known potent CYP3A4 inhibitors within 7 days prior to
the first dose of study medication, including but not limited to itraconazole,
ketoconazole, miconazole, clarithromycin, erythromycin, indinavir, nefazodone,
amprenavir, delavirdine, nelfinavir, ritonavir, saquinavir, diltiazem, verapamil and
grapefruit juice.

- Use of drugs that are known potent CYP3A4 inducers within 12 days prior to the first
dose of study medication, including but not limited to carbamazepine, phenobarbital,
phenytoin, rifabutin, rifabutin, rifampin, tipranavir, ritonavir, and St. John s wort.

- Concurrent use of drugs that are CYP3A4 substrates with narrow therapeutic indices,
including but not limited to pimozide, aripiprazole, triazolam, ergotamine and
halofantrine.

- Concurrent use of drug that are highly dependent on CYP2D6 metabolism including
S-metoprolol, propafenone, timolol, amitriptyline, clomipramine, desipramine,
imipramine, paroxetine, haloperidol, risperidone, thioridazine, codeine, flecainide,
mexilletine, tamoxifen, venlafaxine.

Dextromethorphan, a CYP2D6, substrate is allowed if medically indicated and no suitable
alternative anti-tussive medication is available. However, the dose of dextromethorphan may
need to be modified. In a clinical study in healthy volunteers who were extensive
metabolizers (A7471039) PF-00299804 increased mean total exposure (AUC(last) and C(max)) of
dextromethorphan 855% and 874%, respectively, following concomitant administration with
PF-00299804 45 mg compared to exposure of administration of dextromethorphan alone.
Extensive metabolizers comprise approximately 80% of the population, with ultra-,
intermediate-, and poor-metabolizers accounting for the remaining portion of the general
population. Therefore, if no alternative is available dextromethorphan dosing should be
initiated at a lower dose (approx 25%) with close monitoring of patient clinical status.
Dose increases or decreases of dextromethorphan may be considered based upon individual
patient tolerability.

Lidocaine may be used systemically with clinical monitoring (including telemetry).

Opiates such as morphine, oxycodone, dihydrocodeine, hydrocodone, and tramadol can be used
as substitutes to replace codeine. Use of these opiates should be monitored for altered
analgesic effect during treatment as they may be partly metabolized by CYP2D6.