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Phase II Trial of XL184 (Cabozantinib) Plus Erlotinib in Patients With Advanced EGFR-Mutant Non-Small Cell Lung Cancer (NSCLC) Who Have Progressed on Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitor (TKI) Therapy

Phase 2
18 Years
Open (Enrolling)
Recurrent Non-small Cell Lung Cancer, Stage IV Non-small Cell Lung Cancer

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Trial Information

Phase II Trial of XL184 (Cabozantinib) Plus Erlotinib in Patients With Advanced EGFR-Mutant Non-Small Cell Lung Cancer (NSCLC) Who Have Progressed on Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitor (TKI) Therapy


I. To evaluate for efficacy by response rate (RR) when patients with advanced non-small cell
lung cancer (NSCLC) harboring an epidermal growth factor receptor (EGFR) mutation who have
progressed following EGFR tyrosine kinase inhibitor (TKI) therapy are treated with XL184
(cabozantinib [cabozantinib-s-malate]) and erlotinib (erlotinib hydrochloride).


I. Determine progression free survival (PFS) for combination XL184 (cabozantinib) and
erlotinib in EGFR mutation positive patients following progression on erlotinib.

II. Assess overall survival. III. Evaluate change in tumor growth rate on XL184
(cabozantinib) and erlotinib.

IV. Evaluate type, severity, duration and outcome of toxicities. V. Correlate outcome with
tumor biomarkers such as met proto-oncogene (MET) expression, T790M mutation, and serum
markers of the vascular endothelial growth factor (VEGF) and MET pathways in a preliminary


Patients receive cabozantinib-s-malate orally (PO) daily and erlotinib hydrochloride PO once
daily (QD) on days 1-28. Courses repeat every 28 days in the absence of disease progression
or unacceptable toxicity.

After completion of study treatment, patients are followed up every 12 weeks for 1 year and
then annually thereafter.

Inclusion Criteria:

- Patients must have histologically or cytologically confirmed non-small cell lung
cancer harboring an EGFR mutation; NOTE: EGFR mutational status will be known and
assays performed in Clinical Laboratory Improvement Amendments (CLIA) certified
laboratories will be accepted

- Patients should have tumor tissue available for retrieval; tissue blocks or unstained
slides from the time of original diagnosis are acceptable if repeat biopsy is not

- Patients must have measurable disease, defined as at least one lesion that can be
accurately measured in at least one dimension (longest diameter to be recorded for
non-nodal lesions and short axis for nodal lesions) as >= 20 mm with conventional
techniques or as >= 10 mm with spiral computed tomography (CT) scan, magnetic
resonance imaging (MRI), or calipers by clinical exam

- Patients must have received prior EGFR TKI therapy for metastatic disease and have
documented evidence of radiologic disease progression while on EGFR TKI as treatment
immediately prior to enrollment; (patients may have received prior chemotherapy, and
retreatment with erlotinib is allowed)

- Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 60%)

- Leukocytes >= 3,000/mcL

- Absolute neutrophil count >= 1,500/mcL

- Platelets >= 100,000/mcL

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

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 3.0 × institutional upper limit of normal

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

- Creatinine =< 1.5 × ULN OR creatinine clearance >= 50 mL/min/1.73 m^2 for patients
with creatinine levels above institutional normal

- Hemoglobin >= 9 g/dL

- Serum albumin >= 2.8 g/dL

- Urine protein/creatinine ratio (UPCR) =< 1

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

- Calcium >= LLN

- Magnesium >= LLN

- Potassium >= LLN

- Women of childbearing potential must have a negative pregnancy test at screening;
women of childbearing potential include women who have experienced menarche and who
have not undergone successful surgical sterilization (hysterectomy, bilateral tubal
ligation, or bilateral oophorectomy) or are not postmenopausal; postmenopause is
defined as amenorrhea >= 12 consecutive months; note: women who have been amenorrheic
for 12 or more months are still considered to be of childbearing potential if the
amenorrhea is possibly due to prior chemotherapy, antiestrogens, ovarian suppression
or any other reversible reason

- The effects of XL184 (cabozantinib) on the developing human fetus are unknown; for
this reason and because tyrosine kinase inhibitors agents as well as other
therapeutic agents used in this trial are known to be teratogenic, women of
child-bearing potential and men must agree to use adequate contraception 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, she should inform her treating physician immediately; men treated or enrolled
on this protocol must also agree to use adequate contraception prior to the study,
for the duration of study participation, and 4 months after completion of XL184
(cabozantinib) administration; 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 subjects of reproductive 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)

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

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

Exclusion Criteria:

- The subject has received cytotoxic chemotherapy (including investigational cytotoxic
chemotherapy) or biologic agents (e.g., cytokines or antibodies) within 3 weeks, or
nitrosoureas/ mitomycin C within 6 weeks before the first dose of study treatment

- Prior treatment with XL184 (cabozantinib) or other MET/hepatocyte growth factor (HGF)

- The subject has received radiation therapy:

- To the thoracic cavity, abdomen, or pelvis within 2 weeks before the first dose
of study treatment, or has ongoing complications, or is without complete
recovery and healing from prior radiation therapy

- To bone or brain metastasis within 14 days before the first dose of study

- To any other site(s) within 28 days before the first dose of study treatment

- The subject has received prior treatment with a small molecule kinase inhibitor or a
hormonal therapy (including investigational kinase inhibitors or hormones) within 14
days or five half-lives of the compound or active metabolites, whichever is longer,
before the first dose of study treatment

- The subject has received any other type of investigational agent within 28 days
before the first dose of study treatment

- The subject has not recovered to baseline or Common Terminology Criteria for Adverse
Events (CTCAE) =< grade 1 from toxicity due to all prior therapies except alopecia
and other non-clinically significant adverse events (AEs)

- The subject has a primary brain tumor

- The subject has active brain metastases or epidural disease; subjects with brain
metastases previously treated with whole brain radiation or radiosurgery or subjects
with epidural disease previously treated with radiation or surgery who are
asymptomatic and do not require steroid treatment for at least 2 weeks before
starting study treatment are eligible; baseline brain imaging with contrast-enhanced
CT or MRI scans for subjects with known brain metastases is required to confirm

- The subject has prothrombin time (PT)/international normalized ratio (INR) or partial
thromboplastin time (PTT) test >= 1.3 x the laboratory ULN within 7 days before the
first dose of study treatment

- The subject requires concomitant treatment, in therapeutic doses, with anticoagulants
such as warfarin or warfarin-related agents, heparin, thrombin or Factor Xa
inhibitors, or antiplatelet agents (e.g., clopidogrel); low dose aspirin (=< 81
mg/day), low-dose warfarin (=< 1 mg/day), and prophylactic low molecular weight
heparin (LMWH) are permitted

- Strong cytochrome P450 (CYP)3A4 inducers and inhibitors should be avoided; selection
of alternate concomitant medications with no or minimal CYP3A4 enzyme inhibition
potential is recommended; because the lists of these agents are constantly changing,
it is important to regularly consult a frequently-updated list such as; medical reference texts such as
the Physicians' Desk Reference may also provide this information; as part of the
enrollment/informed consent procedures, the patient will be counseled on the risk of
interactions with other agents, and what to do if new medications need to be
prescribed or if the patient is considering a new over-the-counter medicine or herbal

- The subject has experienced any of the following:

- Clinically-significant gastrointestinal bleeding within 6 months before the
first dose of study treatment

- Hemoptysis of >= 0.5 teaspoon (2.5 mL) of red blood within 3 months before the
first dose of study treatment

- Any other signs indicative of pulmonary hemorrhage within 3 months before the
first dose of study treatment

- Patients with active bleeding or pathologic conditions that carry high risk of
bleeding, such as known bleeding disorder or coagulopathy

- The subject has radiographic evidence of cavitating pulmonary lesion(s)

- The subject has tumor in contact with, invading or encasing any major blood vessels

- The subject has evidence of tumor invading the gastrointestinal (GI) tract
(esophagus, stomach, small or large bowel, rectum or anus), or any evidence of
endotracheal or endobronchial tumor within 28 days before the first dose of

- The subject has uncontrolled, significant intercurrent or recent illness including,
but not limited to, the following conditions:

- 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) > 140 mm Hg systolic, or > 90 mm Hg diastolic despite optimal
antihypertensive treatment within 7 days of the first dose of study

- Any history of congenital long QT syndrome

- Any of the following within 6 months before the first dose of study

- Unstable angina pectoris

- Clinically-significant cardiac arrhythmias

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

- Myocardial infarction

- Thromboembolic event requiring therapeutic anticoagulation (Note:
subjects with a venous filter [e.g. vena cava filter] are not eligible
for this study)

- Gastrointestinal disorders particularly those associated with a high risk of
perforation or fistula formation including:

- Any of the following within 28 days before the first dose of study

- 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

- Malabsorption syndrome

- Any of the following within 6 months before the first dose of study

- 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 before the first dose of study treatment

- Other disorders associated with a high risk of fistula formation including
percutaneous endoscopic gastrostomy (PEG) tube placement within 3 months before
the first dose of study therapy

- Other clinically significant disorders such as:

- Active infection requiring systemic treatment within 28 days before the
first dose of study treatment

- Serious non-healing wound/ulcer/bone fracture within 28 days before the
first dose of study treatment

- History of organ transplant

- Concurrent uncompensated hypothyroidism or thyroid dysfunction within 7
days before the first dose of study treatment

- History of major surgery as follows:

- Major surgery within 8 weeks of the first dose of cabozantinib, with
complete wound healing; (patients with ongoing wound healing or other
complications will be excluded)

- Minor surgery within 4 weeks of the first dose of cabozantinib; Pleurx
catheter placement within 7 days of the first dose of cabozantinib

- The subject is unable to swallow tablets

- The subject has a corrected QT interval calculated by the Fridericia formula (QTcF) >
500 ms within 28 days before randomization; note: if initial QTcF is found to be >
500 ms, two additional electrocardiograms (EKGs) separated by at least 3 minutes
should be performed; if the average of these three consecutive results for QTcF is =<
500 ms, the subject meets eligibility in this regard

- The subject is unable or unwilling to abide by the study protocol or cooperate fully
with the investigator or designee

- The subject has had evidence within 2 years of the start of study treatment of
another malignancy which required systemic treatment

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to XL184 (cabozantinib) or erlotinib

- Pregnant women are excluded from this study because XL184 (cabozantinib) is a
tyrosine kinase inhibitor 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 XL184 (cabozantinib), breastfeeding
should be discontinued if the mother is treated with XL184 (cabozantinib); these
potential risks may also apply to other agents used in this study

- Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
therapy are ineligible because of the potential for pharmacokinetic interactions with
XL184 (cabozantinib); 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

Type of Study:


Study Design:

Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Objective response defined by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1

Outcome Description:

All radiographic responses will be presented as waterfall plots.

Outcome Time Frame:

Up to 2 years

Safety Issue:


Principal Investigator

Karen Reckamp

Investigator Role:

Principal Investigator

Investigator Affiliation:

Beckman Research Institute


United States: Food and Drug Administration

Study ID:




Start Date:

May 2013

Completion Date:

Related Keywords:

  • Recurrent Non-Small Cell Lung Cancer
  • Stage IV Non-Small Cell Lung Cancer
  • Carcinoma, Non-Small-Cell Lung
  • Lung Neoplasms



University of Pittsburgh Cancer Institute Pittsburgh, Pennsylvania  15213
City of Hope Duarte, California  91010
Wayne State University Detroit, Michigan  48202
UC Davis Comprehensive Cancer Center Sacramento, California  95817
University of Southern California Los Angeles, California  90033
Penn State Milton S Hershey Medical Center Hershey, Pennsylvania  17033
City of Hope- South Pasadena Cancer Center South Pasadena, California  91030