Erlotinib Hydrochloride and Quinacrine Dihydrochloride in Stage IIIB-IV Non-Small Cell Lung Cancer

PRIMARY OBJECTIVES:

I. To assess the safety and tolerability of the combination of erlotinib (erlotinib
hydrochloride) and quinacrine (quinacrine dihydrochloride) in patients with advanced
non-small-cell lung cancer.

II. To determine the recommended Maximum Tolerated Dose (MTD) of the combination of
erlotinib and quinacrine in patients with advanced non-small-cell lung cancer.

SECONDARY OBJECTIVES:

I. To describe the dose limiting toxicity of the erlotinib and quinacrine combination.

II. To determine the pharmacokinetic profile of the erlotinib and quinacrine combination.

III. To determine objective response rate (complete response [CR]+partial response [PR]) and
clinical benefit rate (CR+PR+ stable disease [SD]) of the erlotinib and quinacrine
combination.

IV. To estimate overall survival (OS)

OUTLINE: This is a phase I, dose escalation study of quinacrine dihydrochloride

Escalation Portion: Patients receive erlotinib hydrochloride orally (PO)daily on days 1-28
and quinacrine dihydrochloride PO thrice daily (TID) on days, 1-7 and PO daily from days
8-28.

After Maximum Tolerated Dose is established: Patients are randomized to 1 of 2 treatment
arms.

ARM I: Patients receive erlotinib hydrochloride PO daily on days 1-28.

ARM II: Patients receive erlotinib hydrochloride PO and quinacrine dihydrochloride PO daily
(TID) on days, 1-7 and PO daily from days 8-28.

In both arms, courses repeat every 28 days in the absence of disease progression or
unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days.

Inclusion Criteria:

- Patients must have histologically or cytologically confirmed incurable malignancy
that is surgically unresectable locally advanced, recurrent, or metastatic (stage
IIIB/IV) non-small cell lung cancer (NSCLC). Patients with adenocarcinoma, squamous
cell carcinoma, large cell carcinoma and sarcomatoid carcinoma will be eligible.

- Patients must have received at least one platinum-containing regimen for the
treatment of advanced or metastatic disease (except for EGFR-mutant patients). Prior
maintenance therapy is allowed and will be considered as the same line of therapy
when continued without discontinuation after initiation of a treatment regimen. NSCLC
with documented EGFR mutation will be eligible after progression on an EGFR-TKI
alone. NSCLC with other molecular targets, such as fusion gene involving the
anaplastic lymphoma kinase (ALK) gene (such as echinoderm microtubule associated
protein like 4 [EML4]-ALK) or ROS-1 will be eligible if they have progressed on
targeted agents (ALK inhibitor) and chemotherapy or are not a candidate for
chemotherapy. Adjuvant/neoadjuvant chemotherapy or chemoradiation is considered a
line of therapy if < 12 months have elapsed between the last dose and the date of
recurrence. Combined treatment with chemotherapy and radiation constitutes a single
regimen.

- Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2

- Life expectancy of ≥ 12 weeks, in the opinion of and as documented by the
investigator

- Hemoglobin ≥ 9.0 g/dl (transfusion and/or growth factor support allowed)

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

- Platelet count ≥ 100 x 10^9 L

- Alkaline phosphatase < 2.5 X institutional upper limit of normal (in subjects with no
liver metastasis and < 5.0 upper limit of normal [ULN] in subjects with liver
metastasis)

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and
alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) < 2.5 X
institutional upper limit of normal (in subjects with no liver metastasis and < 5.0
ULN in subjects with liver metastasis)

- Serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 50 mL/min

- Serum total bilirubin ≤ 1.5 x ULN OR total bilirubin ≤ 4.0 ULN with direct bilirubin
≤ 1.5 x ULN in patients with well documented Gilbert syndrome

- Patients who are receiving therapeutic anticoagulation with heparin are allowed to
participate provided that no prior evidence of underlying abnormality exists in these
parameters. Patients on warfarin are eligible provided they are on stable doses of
warfarin and there is close monitoring of INR.

- Resolution of any toxic effects of prior therapy (including radiotherapy) according
to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI
CTCAE), version 4.0, grade ≤ 1 (with the exception of alopecia and ≤ grade 2
neuropathy); subject must have recovered from significant surgery-related
complications

- Women of childbearing potential must have a negative pregnancy test performed within
48 hours prior to the start of the study drug

- Women of child-bearing potential and men must agree to use adequate contraception
(double barrier method of birth control or abstinence) prior to study entry, for the
duration of study participation and for 90 days after completing the last
investigational drug dose; should a woman become pregnant or suspect that she is
pregnant while she or her partner is participating in this study, she should inform
the treating physician immediately

- Subjects must have the ability to understand and the willingness to sign a written
informed consent document

Exclusion Criteria:

- Patients with previous anti-cancer chemotherapy, immunotherapy or investigational
agents ≤ 3 weeks prior to the first day of study defined treatment. NSCLC patients
with EGFR mutation can enroll within 7 days of discontinuing EGFR-TKI. Palliative
radiation < 1 week before the start of treatment (lesions subjected to radiotherapy
may not be used as target lesions). Patients who receive gamma knife radiosurgery for
brain metastases within 1 week prior to treatment start.

- Patients with unknown status of EGFR mutation (only for patients with adenocarcinoma
histology)

- Patients that have had major surgery ≤ 3 weeks or minor surgery (e.g. talc
pleurodesis, excisional biopsy, etc) ≤ 1 week prior to the first day of study defined
treatment.

- History of cardiac disease: congestive heart failure defined as class II to IV per
New York Heart Association (NYHA) classification; active coronary artery disease
(CAD); previously diagnosed bradycardia or other cardiac arrhythmia defined as ≥
grade 2 according to NCI-CTCAE (version 4.0), or uncontrolled hypertension;
myocardial infarction occurred within 6 months prior to study entry (myocardial
infarction occurred > 6 months prior to study entry is permitted)

- Patients with clinically unstable central nervous system (CNS) metastasis (to be
enrolled in the study, subjects must have confirmation of stable disease by magnetic
resonance imaging [MRI] or computed tomography [CT] scan within 4 weeks of the first
day of study defined treatment and have CNS metastases well controlled by steroids,
anti-epileptics or other symptom-relieving medications)

- Patients with significant gastrointestinal disorder that, in the opinion of the
investigator, could interfere with absorption of quinacrine and/or erlotinib (eg,
Crohn's disease, small or large bowel resection, malabsorption syndrome)

- Patients with any known contraindication to treatment with, including
hypersensitivity to quinacrine or erlotinib

- Patients with active clinically serious infections defined as ≥ grade 2 according to
NCI CTCAE, version 4.0

- Patients with substance abuse, medical, psychological or social conditions that may,
in the opinion of the Investigator, interfere with the patient's participation in the
study or evaluation of the study results

- Any other condition that is unstable or which could jeopardize the safety of the
patient and his/her protocol compliance

- History of incurable malignancy other than NSCLC within the 5 years prior to start of
treatment, with the exceptions of adequately treated intraepithelial carcinoma of the
cervix uteri; prostate carcinoma with a prostate-specific antigen value <0.2 ng/mL;
or basal or squamous-cell carcinoma of the skin.

- Pregnant or breastfeeding women and adults of reproductive potential not employing an
effective method of birth control are excluded from this study because quinacrine is
category N agent with the potential for teratogenic or abortifacient effects; these
potential risks may also apply to other agents used in this study

- Patients with previously known infection with human immunodeficiency virus (HIV) or
active viral hepatitis are ineligible because of the potential for pharmacokinetic
interactions with quinacrine; (diagnostic testing for these infections will be done
only if clinically indicated)

- Patients with known Glucose-6-phosphate deficiency, psoriasis, porphyria and
psychosis (quinacrine may exacerbate the symptoms of these disorders)