Phase II Trial of the Akt Inhibitor MK-2206 Plus Erlotinib (OSI-774) in Patients With Advanced Non-Small Cell Lung Cancer Who Have Progressed After Previous Response (Including Stable Disease) With Erlotinib Therapy

Inclusion Criteria:

- Patients must have histologically or cytologically confirmed non-small cell lung
cancer (NSCLC) of any histologic subtype

- Epidermal growth factor receptor (EGFR) mutational status (either wild-type or
positive for an activating mutation)will be determined for all patients on this
study

- Commercial assays for EGFR mutation status are allowed

- Knowledge of EGFR mutational status is not required at the time of protocol
entry but should be determined or known before the end of course 2

- If one of the strata is temporarily closed to accrual, knowledge of EGFR
mutational status will be required prior to protocol entry

- Patients may have measurable or non-measurable disease; x-rays and/or scans for
disease assessment of measurable disease must have been completed within 28 days
prior to registration

- Patients must have radiological or clinical progressive disease following prior
benefit(response or stable disease) to EGFR-TKI therapy (e.g., erlotinib
hydrochloride) administered either as a single agent or in combination with other
agents for at least 12 weeks prior to progression

- Patients may have received intervening systemic therapy after EGFR-TKI
progression

- Patients must have radiologic or clinical progressive disease following prior benefit
(response or stable disease) to EGFR-TKI therapy (e.g., erlotinib) administered
either as a single agent or in combination with other agents for at least 12 weeks
prior to progression; (Note: patients may have received intervening systemic therapy
after EGFR-TKI progression); additionally, patients must have documentation of
radiographic progression within the preceding three months prior to study entry

- Prior cytotoxic chemotherapy is allowed; any number of prior chemotherapy regimens is
also allowed; prior cetuximab therapy is also allowed; NOTE: a patient with an EGFR
activating mutation who has received EGFR-TKI therapy as first line therapy, but has
not received platinum-based chemotherapy, would be considered eligible for this trial

- Karnofsky performance status >= 60%

- Absolute neutrophil count (ANC) >= 1,500/mcL

- Platelet count >= 100,000/mcL

- Total bilirubin =< upper institutional normal limits

- Aspartate aminotrnasferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvate transaminase [SGPT])
=< 2.5 x institutional upper limit of normal

- Creatinine =< upper institutional normal limits OR creatinine clearance >= 60
mL/min/1.73 m^2 for patients with creatinine levels above institutional normal

- Prior to the first patient registration, this study must be institutional review
board approved; a copy of the institutional review board (IRB) approval for each site
involved must be given to the Data Coordinating Center at City of Hope

- The effects of MK-2206 on the developing human fetus at the recommended therapeutic
dose are unknown; for this reason and because MK-2206 or erlotinib have the potential
to be teratogenic, women of childbearing potential and men must use two forms of
contraception (hormonal or barrier method of birth control; abstinence) prior to
study entry and for the duration of study participation; should a woman become
pregnant or suspect she is pregnant while she or her partner is participating in this
study, the patient should inform the treating physician immediately

- Patients on coumadin should have their International Normalized Ratio (INR) monitored
at least once per week or more frequently depending on the investigator's judgment;
there have been some case reports of increased INR when coumadin is co-administered
with erlotinib

- Ability to understand and the willingness to sign a written informed consent document

- Patients should have tumor tissue (either fresh frozen tumor tissue or
paraffin-embedded tumor tissue) available for retrieval; if an endobronchial lesion
is present or suspected, bronchoscopy is recommended as a source of fresh tissue;
tissue blocks or unstained slides from the time of original diagnosis are acceptable
if repeat biopsy is not feasible

Exclusion Criteria:

- Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study or those who have any
ongoing Grade 2 or greater toxicity from a prior treatment

- Patients may not be receiving any other investigational agents

- 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; patients with asymptomatic controlled or treated (e.g., with
radiation and/or surgery) brain metastases are otherwise eligible as long as
corticosteroids given expressly for brain mets have been stopped for at least 14 days

- Caution must be observed for patients receiving any medications or substances that
are strong inhibitors or inducers of CYP 450 3A4; although these patients are still
potentially eligible, close monitoring is required for toxicity

- Preclinical studies demonstrated the potential of MK-2206 for induction of
hyperglycemia in all preclinical species tested; patients with diabetes or in risk
for hyperglycemia should not be excluded from trials with MK-2206, but the
hyperglycemia should be well controlled on oral agents before the patient enters the
trial

- Preclinical studies indicated transient changes in QTc interval during MK-2206
treatment; prolongation of QTc interval is potentially a safety concern while on
MK-2206 therapy; cardiovascular: baseline QTcF > 450 msec (male) or QTcF > 470 msec
(female) will exclude patients from entry on study

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements

- Pregnant women are excluded from this study because MK-2206 and erlotinib are
anti-cancer agents with 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 MK-2206 and erlotinib, breastfeeding should
be discontinued if the mother is treated with this combination

- Human immunodeficiency (HIV)-positive patients on combination antiretroviral therapy
are ineligible because of the potential for pharmacokinetic interactions with MK-2206
plus erlotinib; in addition, these patients are at increased risk of lethal
infections when treated with marrow-suppressive therapy; appropriate studies will be
undertaken in patients receiving combination antiretroviral therapy when indicated

- Prior MK-2206 therapy is not allowed

- Patients unable to swallow MK-2206 tablets and erlotinib tables whole are ineligible;
(the tablets cannot be crushed or broken)