Phase I/II Trial of Erlotinib and BKM120 in Patients With Advanced Non Small Cell Lung Cancer Previously Sensitive to Erlotinib

Inclusion Criteria:

PHASE I ONLY

- ECOG of 0 to 1

- Histologically or cytologically confirmed diagnosis of solid tumor malignancy with a
failure of at least 1, but not more than 3, prior chemotherapy regimens for advanced
disease

- Patient must be ≥4 weeks or ≥5 half lives from administration of last dose, whichever
is shorter, from administration of last dose of cancer therapy PHASE II ONLY

- One site of measurable disease by RECIST v1.1

- ECOGof 0 to 2

- Patients with progressive NSCLC (any histology).

- Archival tumor tissue available for correlative testing

- Failure of at least 1, and no more than 3, prior systemic treatments for advanced
disease with the last treatment being with erlotinib, gefitinib, or other EGFR TKI.

- Prior sensitivity to erlotinib or gefitinib or other EGFR TKI. Sensitivity is
defined as follows:

- Patients treated with erlotinib (or gefitinib or other EGFR TKI) for any
duration in the presence of a known activating mutation that confers sensitivity
to TKI treatment. These include, but are not limited to mutations in L858R
(Exon 21); Exon 19 deletion; G719S, G719A, G719C mutations (Exon 19);or L861Q.

- Prior treatment with erlotinib (or gefitinib, or other EGFR TKI), regardless of
mutation status, where there was ≥6 months of disease control (no disease
progression).

ALL PATIENTS

- Must be ≥18 years-of-age.

- Patients may have received radiation for palliation prior to starting trial drug if
they have recovered from the side effects of such therapy. Time from last palliative
radiation to beginning of trial treatment should be ≥1 week. Patients may have
received prior wide-field radiation prior to starting trial drug if they have
recovered from the side effects of such therapy. Time from last wide-field radiation
to beginning of trial treatment should be ≥4 weeks.

- Fasting plasma glucose (FPG) ≤120 mg/dL (6.7 mmol/L)

- Adequate hematologic function defined as:

- Absolute neutrophil count ≥1500/μL

- Hgb ≥9 g/dL

- Platelets ≥100,000/uL

- Adequate liver function defined as:

- ALT & AST WNL or ≤3.0 x ULN, if liver metastases are present.

- Serum bilirubin WNL (or ≤1.5 x the institutional ULN in patients with liver
metastases; or total bilirubin ≤3.0 x ULN with direct bilirubin WNL in patients
with well documented Gilbert Syndrome)

- Adequate renal function defined as:

• Serum creatinine ≤1.5 x institutional ULN or calculated 24-hour creatinine
clearance ≥50 mL/min

- Total calcium (corrected for serum albumin) WNL(biphosphonate use for malignant
hypercalcemia control is not allowed)

- Magnesium ≥ the LLN

- Potassium WNL.

- Serum amylase ≤ ULN.

- Serum lipase ≤ ULN.

- Ability to swallow oral medication.

- Fertile males, defined as all males physiologically capable of conceiving offspring,
must use condoms during treatment, for 5 T1/2 after stopping treatment, and for an
additional 12 weeks, and should not father a child in this period

- Female patients who are not of child-bearing potential, and female patients of
child-bearing potential who agree to use adequate contraceptive measures , who are
not breastfeeding, and who have a negative serum or urine pregnancy test performed
within 48 hours prior to start of treatment.

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

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

Exclusion Criteria:

- Prior treatment with a P13K inhibitor

- Known hypersensitivity to BKM120, and/or erlotinib/gefitinib.

- Patients who have not recovered to Grade 1 or better from any adverse events (except
alopecia) related to previous antineoplastic therapy before screening procedures are
initiated

- Patients with untreated brain metastases are excluded. Patients with treated brain
metastases may participate in this trial, if the patient is ≥4 weeks from therapy
completion , has recovered from all effects treatment, is clinically stable at the
time of trial entry, and is not receiving high-dose steroid therapy

- Acute or chronic liver or renal disease or pancreatitis.

- Patients with the following mood disorders, as judged by the Investigator or a
Psychiatrist, or as a result of patient's mood assessment questionnaire:

- Medically documented history of active major depressive episode, bipolar
disorder (I or II), obsessive-compulsive disorder, schizophrenia, a history of
suicidal attempt or ideation, or homicidal ideation (immediate risk of doing
harm to others).

- ≥ Grade 3 anxiety

- Meets the cut-off score of ≥10 in the PHQ-9 or a cut-off of ≥15 in the GAD-7
mood scale, respectively, or selects a positive response of "1, 2, or 3" to
question number 9 regarding potential for suicidal thoughts in the PHQ-9
(independent of the total score of the PHQ-9) will be excluded from the trial

- Active cardiac disease including any of the following:

- Angina pectoris that requires the use of anti-anginal medication

- Ventricular arrhythmias except for benign premature ventricular contractions

- Supraventricular and nodal arrhythmias requiring a pacemaker or not controlled
with medication

- Conduction abnormality requiring a pacemaker

- Valvular disease with documented compromise in cardiac function

- Symptomatic pericarditis

- History of cardiac dysfunction including any of the following:

- Myocardial infarction within the last 6 months

- History of documented congestive heart failure (New York Heart Association
functional classification III-IV) within the last 6 months

- Documented cardiomyopathy

- Stroke or transient ischemic attack within the past 6 months

- Poorly controlled diabetes mellitus (HbA1c >8%

- Patients who are currently taking therapeutic doses of warfarin sodium or any other
coumadin-derivative anticoagulant.

- Other concurrent severe and/or uncontrolled concomitant medical conditions that could
cause unacceptable safety risks or compromise compliance with the protocol.

- Diarrhea ≥ Grade 2.

- Impairment of GI function or GI disease that may significantly alter the absorption
of trial drugs

- Patients who have been treated with any hematopoietic colony-stimulating growth
factors (e.g., G-CSF, GM-CSF) ≤1 week prior to starting trial drug. Erythropoietin or
darbepoetin therapy, if initiated at least 1 week prior to enrollment, may be
continued.

- Patients who are currently receiving treatment with medication with a known risk to
prolong the QT interval or inducing Torsades de Pointes and the treatment cannot
either be discontinued or switched to a different medication prior to starting trial
drug.

- Patients who have taken herbal medications and certain fruits within 7 days prior to
starting trial drug. Herbal medications include, but are not limited to, St. John's
Wort, Kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA),
yohimbe, saw palmetto, and ginseng. Fruits include the CYP3A inhibitors: Seville
oranges, grapefruit, pummelos, or exotic citrus fruits.

- Patients who are currently treated with drugs known to be moderate and strong
inhibitors or inducers of isoenzyme CYP3A, and the treatment cannot be discontinued
or switched to a different medication prior to starting trial drug

- Patients who have received chemotherapy or targeted anticancer therapy ≤4 weeks (6
weeks for nitrosourea, antibodies or mitomycin-C) prior to starting study drug must
recover to a Grade 1 before starting the trial (with the exception of EGFR targeting
TKIs).

- Patients who have received any continuous or intermittent small molecule therapeutics
(excluding monoclonal antibodies or EGFR targeting TKIs) ≤5 effective half lives
prior to starting study drug or who have not recovered from side effects of such
therapy.

- Oral contraception, injected or implanted hormonal methods are not allowed as BKM120
potentially decreases the effectiveness of hormonal contraceptives.

- Any condition that would prevent patient comprehension of the investigative nature of
the trial and its associated risks or prevent the ability to comply with trial and/or
follow-up procedures