Cabozantinib-S-Malate and Erlotinib Hydrochloride in Treating Patients With Previously Treated Metastatic Non-Small Cell Lung Cancer



Status:Completed
Conditions:Lung Cancer, Cancer, Cancer
Therapuetic Areas:Oncology
Healthy:No
Age Range:18 - Any
Updated:4/17/2018
Start Date:May 20, 2013
End Date:March 30, 2018

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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

This phase II trial studies how well cabozantinib-s-malate and erlotinib hydrochloride works
in treating patients with previously treated metastatic non-small cell lung cancer.
Cabozantinib-s-malate and erlotinib hydrochloride may stop the growth of tumor cells by
blocking some of the enzymes needed for cell growth. Cabozantinib-s-malate may also stop the
growth of non-small cell lung cancer by blocking blood flow to the tumor. Giving
cabozantinib-s-malate together with erlotinib hydrochloride may be an effective treatment for
non-small cell lung cancer.

PRIMARY OBJECTIVES:

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).

SECONDARY OBJECTIVES:

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) amplification, T790M mutation, and serum
markers of the vascular endothelial growth factor (VEGF) and MET pathways in a preliminary
manner.

OUTLINE:

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
indicated

- 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

- 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)
inhibitor

- 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
treatment

- 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; prior erlotinib is required and does not
require a 14-day wash out

- 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 eligibility

- The subject has prothrombin time (PT)/ International Normalized Ratio (INR) or partial
thromboplastin time (PTT) test >= 1.3 x the laboratory ULN within 14 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
http://medicine.iupui.edu/clinpharm/ddis/table.aspx; 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
product

- 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 cabozantinib

- 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
treatment

- Any history of congenital long QT syndrome

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

- Unstable angina pectoris

- Clinically-significant cardiac arrhythmias

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

- 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 treatment

- 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 before the first dose of study
treatment:

- 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 14
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 treatment; 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; 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; appropriate studies will be undertaken in patients receiving
combination antiretroviral therapy when indicated
We found this trial at
7
sites
1500 E Duarte Rd
Duarte, California 91010
(626) 256-4673
City of Hope Comprehensive Cancer Center City of Hope is a leading research and treatment...
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4160 John R St #2122
Detroit, Michigan 48201
(313) 833-1785
Wayne State University/Karmanos Cancer Institute Karmanos is based in southeast Michigan, in midtown Detroit, and...
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500 University Dr
Hershey, Pennsylvania 17033
(717) 531-6955
Penn State Milton S. Hershey Medical Center Penn State Milton S. Hershey Medical Center, Penn...
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1441 Eastlake Ave
Los Angeles, California 90033
(323) 865-3000
U.S.C./Norris Comprehensive Cancer Center The USC Norris Comprehensive Cancer Center, located in Los Angeles, is...
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Los Angeles, CA
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Pittsburgh, Pennsylvania 15232
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Sacramento, CA
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South Pasadena, California 91030
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South Pasadena, CA
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