Erlotinib Hydrochloride and Cabozantinib-s-Malate Alone or in Combination as Second or Third Line Therapy in Treating Patients With Stage IV Non-small Cell Lung Cancer

PRIMARY OBJECTIVES:

I. To compare the progression-free survival (PFS) associated with patients treated with
erlotinib (erlotinib hydrochloride) versus (vs) erlotinib plus cabozantinib
(cabozantinib-s-malate).

II. To compare the PFS associated with patients treated with erlotinib vs cabozantinib.

SECONDARY OBJECTIVES:

I. To evaluate overall survival in the three treatment arms. II. To evaluate best objective
response rate in the three treatment arms. III. To define the toxicity associated with each
regimen. IV. To conduct correlative science studies that will help to select predictive
biomarkers of response to therapy, including hepatocyte growth factor receptor (MET)
expression and potentially other tissue biomarkers, plasma biomarkers, and bone scans.

OUTLINE: Patients are randomized to 1 of 3 treatment arms.

ARM A: Patients receive erlotinib hydrochloride orally (PO) daily on days 1-28. Courses
repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM B: Patients receive cabozantinib-s-malate PO daily on days 1-28. Courses repeat every 28
days in the absence of disease progression or unacceptable toxicity.

ARM C: Patients receive erlotinib hydrochloride as patients in Arm A and
cabozantinib-s-malate as patients in Arm B. Courses repeat every 28 days in the absence of
disease progression or unacceptable toxicity.

ARM Z: Patients achieving disease progression in Arm A or Arm B may receive erlotinib
hydrochloride and cabozantinib-s-malate as patients in Arm C. Courses repeat every 28 days
in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years and
then every 6 months for 3 years.

Inclusion Criteria:

- STEP 1:

- Cytologically or histologically confirmed non-small cell lung carcinoma (NSCLC)

- Predominant non-squamous histology (patients with NSCLC not otherwise specified [NOS]
are eligible); mixed tumors will be categorized by the predominant cell type; if
small cell elements are present the patient is ineligible

- Stage IV disease (includes M1a, M1b, or recurrent disease), according to the 7th
edition of the lung cancer TNM classification system

- The tumor must not have a sensitizing mutation in epidermal growth factor receptor
(EGFR), defined as follows:

- EGFR mutation testing of tumor has been performed and did not demonstrate an
EGFR tyrosine kinase inhibitor sensitizing mutation; at minimum, testing for
EGFR exon 19 deletion and exon 21 L858R mutations must have been included; OR

- EGFR mutation testing has been attempted and is inconclusive (for example, due
to lack of sufficient deoxyribonucleic acid [DNA] yield); OR

- EGFR mutation status is unknown but tumor is positive for at least one
alternative driver mutation, i.e: Kirsten rat sarcoma viral oncogene homolog
(KRAS) mutation, v-raf murine sarcoma viral oncogene homolog B (BRAF) mutation,
v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2 (HER2) mutation,
ret proto-oncogene (RET) rearrangement/fusion, or one not listed following
approval by the study chair prior to registration

- Patients must have measurable disease as defined by Response Evaluation Criteria in
Solid Tumors (RECIST) version (v) 1.1 criteria; baseline measurements and evaluation
of ALL sites of disease must be obtained within 4 weeks prior to registration

- Prior to registration, the investigator/site must confirm that sufficient pathology
material representative of patient's cancer is available for submission for MET
immunohistochemical testing; patients for whom there is not sufficient pathology
material representative of the patient's cancer (tumor block or 10 unstained slides)
are not eligible to participate in this study

- Patients must have received one or two lines of prior chemotherapy (first line
platinum-doublet based chemotherapy plus switch maintenance chemotherapy counts as
one line of therapy); prior adjuvant chemotherapy for early stage disease does not
count as one line of therapy if 12 months or greater elapsed between completion of
adjuvant therapy and initiation of first-line systemic therapy; if less than 12
months elapsed, adjuvant chemotherapy counts as one line of therapy

- No prior erlotinib, other EGFR tyrosine kinase inhibitor therapy, vascular
endothelial growth factor (VEGRF) tyrosine kinase inhibitor therapy, Met tyrosine
kinase inhibitor therapy, or Met monoclonal antibody (MetMAb); prior antibody therapy
such as bevacizumab or cetuximab is allowed with a washout period depending on dosing
interval and investigational nature

- Any prior chemotherapy (based on administration schedule) must have been completed in
greater than or equal to the following times prior to registration:

- Chemotherapy administered in a daily schedule must be completed >= 2 weeks prior
to registration

- Chemotherapy administered in a weekly schedule must be completed >= 2 weeks
prior to registration

- Chemotherapy administered in a 2-weekly schedule must be completed >= 3 weeks
prior to registration

- Chemotherapy administered in a 3-weekly schedule must be completed >= 4 weeks
prior to registration

- Patients must have discontinued treatment with any other type of investigational
agent >= 4 weeks prior to registration

- Patients must have recovered to baseline or Common Terminology Criteria for Adverse
Events (CTCAE) v 4.0 =< grade 1 from toxicity due to all prior therapies except
alopecia and other non-clinically significant adverse events (AEs)

- Patients with no known brain metastasis at baseline must have baseline brain imaging
within 12 weeks prior to study registration not demonstrating brain metastases;
patients with brain metastases at baseline must have baseline brain imagining within
4 weeks prior to study registration and meet all of the following criteria:

- Have completed treatment to all active brain metastases (with whole brain
radiation or radiosurgery) >= 2 weeks prior to registration, or have undergone
complete neurosurgical resection >= 3 months prior to registration;

- Be asymptomatic from brain metastases at time of screening;

- Not require steroid treatment or enzyme inducing anticonvulsant drugs for at
least 2 weeks prior to registration; non-enzyme inducing anti-epileptic drugs
(NEIAED) such as levetiracetam are allowed;

- Known leptomeningeal disease or epidural disease is not allowed

- Patients must not have received radiation therapy to the thoracic cavity, abdomen, or
pelvis within 3 months prior to registration, to bone or brain metastasis within 14
days prior to registration, or to any other site within 28 days prior to registration

- Radiation related toxicities must have resolved to =< grade 1 prior to registration

- Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status
between 0-2

- Patients must have an anticipated life expectancy greater than 3 months

- Leukocytes >= 3,000/mm^3

- Absolute neutrophil count >= 1,500/ mm^3

- Platelets >= 100,000/mm^3

- Hemoglobin >= 9 g/dL

- Total bilirubin =< 1.5 institutional upper limit of normal (ULN)

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and
alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x
ULN

- Serum albumin >= 2.8 g/dL

- Lipase =< 2.0 x ULN and no radiologic or clinical evidence of pancreatitis

- Serum phosphorus* >= institutional lower limit of normal (LLN)

- Serum calcium* (absolute or albumin corrected) >= LLN

- Serum magnesium* >= LLN

- Serum potassium* >= LLN

- * Note: Serum phosphorus, calcium, magnesium and potassium can be replaced if values
are below LLN

- Creatinine =< 1.5 x ULN or calculated or measured creatinine clearance >= 50
mL/min/1.73 m^2 (normalized to body surface area [BSA]) for patients with creatinine
levels greater than 1.5 times the institutional normal

- Screening urine dipstick must equal 0 or "trace"; if urine dipstick results are >=
1+, calculation of urine protein creatinine (UPC) is required and patients must have
a UPC ratio =< 1 to participate in the study

- Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin
time (PTT) test =< 1.3 x ULN

- No history of the following:

- Clinically-significant gastrointestinal bleeding within 6 months prior to
registration

- Hemoptysis of >= 0.5 teaspoon (2.5 mL) of red blood within 3 months prior to
registration

- Any other signs indicative of pulmonary hemorrhage within 3 months prior to
registration

- No radiographic or other evidence of within 28 days prior to registration:

- Tumor invading the gastrointestinal (GI) tract (esophagus, stomach, small or
large bowel, rectum or anus), or any evidence of endotracheal or endobronchial
tumor

- Cavitating pulmonary lesion(s)

- Tumor in contact with, invading or encasing any major blood vessels

- No patients with psychiatric illness/social situations that would limit compliance
with study requirements

- No history of major thrombotic events (deep vein thrombosis [DVT] or pulmonary
embolism [PE]) within 6 months prior to registration; NOTE: subjects with a venous
filter (e.g. vena cava filter) are not eligible for this study

- No concomitant treatment, in therapeutic doses, with anticoagulants such as warfarin
or warfarin-related agents, heparin, low molecular weight heparin (LMWH), thrombin or
Factor Xa inhibitors, or antiplatelet agents (e.g., clopidogrel [clopidogrel
bisulfate]); (low dose aspirin [=< 81 mg/day] and prophylactic LMWH are permitted)

- No concomitant treatment of strong cytochrome P450 family 3, subfamily A, polypeptide
4 (CYP3A4) inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin,
rifabutin, rifapentine, phenobarbital, and St. John's wort)

- No cardiovascular disorders including:

- Congestive heart failure (CHF): New York Heart Association (NYHA) class III
(moderate) or class IV (severe) at the time of screening

- Concurrent uncontrolled hypertension defined as sustained blood pressure (BP) >
150 mm Hg systolic, or > 100 mm Hg diastolic despite optimal antihypertensive
treatment within 7 days prior to registration

- Any history of congenital long QT syndrome

- Any of the following within 6 months prior to registration:

- Unstable angina pectoris

- Clinically-significant cardiac arrhythmias

- Stroke (including transient ischemic attack [TIA], or other ischemic event)

- Myocardial infarction

- No gastrointestinal disorders particularly those associated with a high risk of
perforation or fistula formation including:

- Any of the following within 28 days prior to registration

- Intra-abdominal tumor/metastases invading GI mucosa

- Active peptic ulcer disease

- Inflammatory bowel disease (including ulcerative colitis and Crohn's
disease), diverticulitis, cholecystitis, symptomatic cholangitis or
appendicitis

- Malabsorption syndrome

- Any of the following within 6 months prior to registration:

- Abdominal fistula

- Gastrointestinal perforation

- Bowel obstruction or gastric outlet obstruction

- Intra-abdominal abscess; Note: complete resolution of an intra-abdominal
abscess must be confirmed prior to initiating treatment with cabozantinib
even if the abscess occurred more than 6 months prior to registration

- No other disorders associated with a high risk of fistula formation including
percutaneous endoscopic gastrostomy (PEG) tube placement within 3 months prior to
registration

- No uncontrolled, significant, intercurrent or recent illness including, but not
limited to, the following conditions:

- Grade 3 or greater infection, or infection requiring intravenous systemic
treatment within 28 days prior to registration; patients should be off
antibiotics at the time of registration

- Serious non-healing wound/ulcer/bone fracture within 28 days prior to
registration

- History of organ transplant

- Concurrent uncompensated hypothyroidism or thyroid dysfunction within 7 days
prior to registration

- History of surgery as follows:

- Major surgery (as an example, surgery requiring anesthesia and a > 24 hour
hospital stay) within 3 months prior to registration if there were no wound
healing complications or within 6 months prior to registration if there
were wound complications

- Minor surgery (such as chest tube placement, but not including
thoracentesis or paracentesis) within 28 days prior to registration if
there were no wound healing complications or within 3 months prior to
registration if there were wound complications

- In addition, complete wound healing from prior surgery and procedures must
be confirmed prior to registration

- Patients must have corrected QT interval calculated by the Fridericia formula (QTcF)
=< 500 ms within 28 days before registration

- Patients must be able to swallow tablets

- No prior malignancy within 2 years prior to registration which required systemic
treatment or is currently active

- Women must not be pregnant or breast-feeding; for this reason, all females of
childbearing potential must have a blood test or urine study within 2 weeks prior to
registration to rule out pregnancy; a female of childbearing potential is any woman,
regardless of sexual orientation or whether they have undergone tubal ligation, who
meets the following criteria:

- Has not undergone a hysterectomy or bilateral oophorectomy; or

- Has not been naturally postmenopausal for at least 24 consecutive months (i.e.,
has had menses at any time in the preceding 24 consecutive months)

- Sexually active subjects (men and women) must agree to use medically accepted barrier
methods of contraception (e.g. male or female condom) during the course of the study
and for 4 months after the last dose of study drug(s), even if oral contraceptives
are also used; all sexually active subjects of reproduction potential must agree to
use both a barrier method and a second method of birth control during the course of
the study and for 4 months after the last dose of study drug(s)

- Patients with known human immunodeficiency virus (HIV) disease taking antiretroviral
therapy are excluded

- Patients with known chronic active hepatitis B (defined as a positive hepatitis B
surface antigen and/or hepatitis B viral load in the last 12 months) are excluded,
regardless of antiviral treatment

- STEP 2: Patients must have met all eligibility requirements for Step 1 at time of
registration to Step 1 to be eligible for Step 2

- STEP 2: Patients must have radiographic progressive disease per RECIST criteria after
>= 2 courses of therapy on Arm A or Arm B

- STEP 2: Patients must not have intervening anticancer treatment or major surgical
procedure(s) between Step 1 and Step 2, except palliative radiation to the bone
finishing >= 2 weeks prior to registration to Step 2

- STEP 2: Patients may not have central nervous system progression but patients with
stable central nervous system (CNS) disease are allowed

- STEP 2: Patients must be registered to Step 2 within 4 weeks of the last dose of
treatment administration from Step 1

- STEP 2: Patients must have an ECOG performance status between 0-2

- STEP 2: Patients must have recovered to baseline (pre-Step 1) or CTCAE =< grade 1
from toxicity due to all prior therapies except alopecia and other non-clinically
significant AEs

- STEP 2: Leukocytes >= 3,000/mm^3

- STEP 2: Absolute neutrophil count >= 1,500/mm^3

- STEP 2: Platelets >= 100,000/mm^3

- STEP 2: Hemoglobin >= 9 g/dL

- STEP 2: Total bilirubin =< 1.5 x ULN

- STEP 2: AST(SGOT) and ALT(SGPT) =< 3 x ULN

- STEP 2: Serum albumin >= 2.8 g/dL

- STEP 2: Lipase =< 2.0 x ULN and no radiologic or clinical evidence of pancreatitis

- STEP 2: Serum phosphorus* >= LLN

- STEP 2: Serum calcium* (absolute or albumin corrected) >= LLN

- STEP 2: Serum magnesium* >= LLN

- STEP 2: Serum potassium* >= LLN

- * NOTE: serum phosphorus, calcium, magnesium and potassium can be replaced if values
are below LLN

- STEP 2: Creatinine =< 1.5 x ULN or calculated or measured creatinine clearance >= 50
mL/min/1.73 m^2 (normalized to BSA) for patients with creatinine levels greater than
1.5 times the institutional normal

- STEP 2: Screening urine dipstick must equal 0; if urine dipstick results are >= 1+,
calculation of UPC is required and patients must have a UPC ratio =< 1 to participate
in the study

- STEP 2: Patients must have corrected QT interval calculated by the Fridericia formula
(QTcF) =< 500 ms within 28 days before registration

- STEP 2: No intercurren