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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

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01708954
First received: October 15, 2012
Last updated: October 6, 2016
Last verified: October 2016

October 15, 2012
October 6, 2016
February 2013
August 2015   (final data collection date for primary outcome measure)
Progression-free Survival (PFS) [ Time Frame: Assessed every 3 months if patient is < 2 years from study entry; every 6 months if patient is 2 - 5 years from study entry ] [ Designated as safety issue: No ]
PFS is defined as the time from randomization to documented disease progression or death from any cause, whichever occurred first. Patients who had not experienced an event of interest by the time of analysis were censored at the date of last disease assessment.
PFS [ Time Frame: Time from randomization to documented disease progression or death from any cause, whichever occurs first, assessed to up to 5 years ] [ Designated as safety issue: No ]
PFS distributions will be estimated using the Kaplan-Meier method, and Cox proportional hazards models will be used to estimate the treatment hazard ratios. The two primary comparisons of PFS will each use a log rank test stratified on the randomization stratification factors with a one-sided type I error rate of 10%. Subset analyses of PFS by treatment arm will be estimated and compared within subsets. Point estimates of all endpoints will be accompanied by the corresponding 90% confidence intervals.
Complete list of historical versions of study NCT01708954 on ClinicalTrials.gov Archive Site
  • Overall Survival (OS) [ Time Frame: Assessed every 3 months if patient is < 2 years from study entry; every 6 months if patient is 2 - 5 years from study entry ] [ Designated as safety issue: No ]
    OS is defined as the time from randomization to death from any cause or date of last known alive.
  • Proportion of Patients With Objective Response [ Time Frame: Assessed every 3 months if patient is < 2 years from study entry; every 6 months if patient is 2 - 5 years from study entry ] [ Designated as safety issue: No ]
    Objective response is defined as complete response (CR) or partial response (PR) evaluated using RECIST v 1.1. CR is defined as disappearance of all lesions and any pathological lymph nodes must have reduction in short axis to < 10 mm. PR is defined as at least a 30% decrease in the sum of the diameters of target lesions and persistence of one or more non-target lesion(s).
  • Proportion of Patients With MET Positivity [ Time Frame: Assessed at baseline ] [ Designated as safety issue: No ]
    Submission of archival tissue for central MET IHC testing was required for this study, and total MET IHC testing was conducted at the Brigham and Women's Hospital using the c-Met clone CVD13 (arabbit polyclonal). Membranous and cytoplasmic staining were individually scored, and positivity was declared if MET was expressed in either the membrane or cytoplasm.
  • Proportion of Patients With Worst Grade Toxicities of Grade 3 or Higher [ Time Frame: Assessed every 4 weeks while on treatment and for 30 days after the end of treatment ] [ Designated as safety issue: Yes ]
  • Overall Survival (OS) [ Time Frame: Time from randomization to death from any cause, assessed up to 3 years ] [ Designated as safety issue: No ]
    OS distributions will be estimated using the Kaplan-Meier method, and Cox proportional hazards models will be used to estimate the treatment hazard ratios. Point estimates of all endpoints will be accompanied by the corresponding 90% confidence intervals.
  • Best objective response according to RECIST v 1.1 [ Time Frame: Up to 5 years ] [ Designated as safety issue: No ]
    Response rates (complete response [CR] + partial response [PR]) will be compared using Fisher's exact tests with a one-sided type I error rate of 10%; multivariable logistic regression modeling will be used to adjust for the effect of any covariates that are associated with these categorical outcomes.
  • Incidence of adverse events as assessed by the National Cancer Institute (NCI) CTCAE version 4.0 [ Time Frame: Up to 5 years ] [ Designated as safety issue: Yes ]
    Compared using Fisher's exact tests with a one-sided type I error rate of 10%; multivariable logistic regression modeling will be used to adjust for the effect of any covariates that are associated with these categorical outcomes. Point estimates of all endpoints will be accompanied by the corresponding 90% confidence intervals.
Not Provided
Not Provided
 
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
A Randomized Phase II Trial of Erlotinib, Cabozantinib, or Erlotinib Plus Cabozantinib as 2nd or 3rd Line Therapy in Patients With EGFR Wild-Type NSCLC
This randomized phase II trial studies how well giving erlotinib hydrochloride and cabozantinib-s-malate alone or in combination works as second or third line therapy in treating patient with stage IV non-small cell lung cancer. Erlotinib hydrochloride and cabozantinib-s-malate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether giving erlotinib hydrochloride together with cabozantinib-s-malate is more effective than erlotinib hydrochloride or cabozantinib-s-malate alone in treating 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 mesenchymal-epidermal transition (MET) expression and potentially other tissue biomarkers, plasma biomarkers, and bone scans.

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

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

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

ARM C (erlotinib+cabozantinib): Patients receive erlotinib as patients in Arm A and cabozantinib 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 and cabozantinib 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.

Interventional
Phase 2
Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Non-Small Cell Lung Cancer
  • Drug: Cabozantinib
    Given PO
    Other Names:
    • EXEL-7184
    • Cabozantinib-s-malate
    • EXEL-02977184
    • XL184
  • Drug: Erlotinib
    Given PO
    Other Names:
    • Tarceva
    • Erlotinib Hydrochloride
    • OSI-774
  • Active Comparator: Arm A (erlotinib)
    Patients receive erlotinib PO daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
    Intervention: Drug: Erlotinib
  • Experimental: Arm B (cabozantinib)
    Patients receive cabozantinib PO daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
    Intervention: Drug: Cabozantinib
  • Experimental: Arm C (erlotinib+cabozantinib)
    Patients receive erlotinib as patients in Arm A and cabozantinib as patients in Arm B. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
    Interventions:
    • Drug: Cabozantinib
    • Drug: Erlotinib
  • Experimental: Arm Z (erlotinib+cabozantinib; step II)
    Patients achieving disease progression in Arm A or Arm B may receive erlotinib and cabozantinib as patients in Arm C. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
    Interventions:
    • Drug: Cabozantinib
    • Drug: Erlotinib
  • Neal, J.W., Dahlberg, S.E., Wakelee, H.A., Aisner, J., Bowden, M., Carbone, D.P., Ramalingam, S.S.: A randomized phase 2 trial of cabozantinib, erlotinib or the combination as 2nd or 3rd line therapy in EGFR wild-type NSCLC: ECOG-ACRIN E1512. J Thorac Oncol 2015;10(9)(2):S373. Abstract 30.04.
  • Neal, J.W., Dahlberg, S.E., Wakelee, H.A., Aisner, S., Bowden, M., Carbone, D.P., Ramalingam, S.S.: Cabozantinib (C), erlotinib (E) or the combination (E+C) as second- or third-line therapy in patients with EGFR wild-type (wt) non-small cell lung cancer (NSCL): A randomized phase 2 trial of the ECOG-ACRIN Cancer Research Group (E1512). J Clin Oncol 2015;33(15s). Abstract 8003.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Active, not recruiting
125
Not Provided
August 2015   (final data collection date for primary outcome measure)

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
  • 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 (IHC) testing
  • 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
  • Any prior chemotherapy (based on administration schedule) must have been completed in greater than or equal to the time frames specified in the protocol
  • 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 specific criteria for brain mets listed in the protocol
  • 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
  • Acceptable bone marrow, renal and hepatic function within 2 weeks prior to registration as defined in the protocol
  • 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

Exclusion Criteria (Step 1):

  • Tumor with 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, human epidermal growth factor receptor 2 (HER2) mutation, ret proto-oncogene (RET) rearrangement/fusion, or one not listed following approval by the study chair prior to registration
  • Patients without sufficient pathology material representative of the patient's cancer (tumor block or 10 unstained slides)
  • Prior erlotinib, other EGFR tyrosine kinase inhibitor therapy, vascular endothelial growth factor receptor (VEGFR) 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
  • Prior 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
  • History of the following: Clinically-significant gastrointestinal (GI) 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
  • Radiographic or other evidence of the following within 28 days prior to registration: Tumor invading the 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
  • Psychiatric illness/social situations that would limit compliance with study requirements
  • History of major thrombotic events (deep vein thrombosis [DVT] or pulmonary embolism [PE]) within 6 months prior to registration
  • 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). (low dose aspirin [=< 81 mg/day] and prophylactic LMWH are permitted)
  • Concomitant treatment of strong cytochrome P450 3A4 (CYP3A4) inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, and St. John's wort)
  • 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; 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
  • GI disorders particularly those associated with a high risk of perforation or fistula formation specified in the protocol
  • Other disorders associated with a high risk of fistula formation including percutaneous endoscopic gastrostomy (PEG) tube placement within 3 months prior to registration
  • Uncontrolled, significant, intercurrent or recent illness
  • Prior malignancy within 2 years prior to registration which required systemic treatment or is currently active
  • Pregnant or breast-feeding
  • Patients with known human immunodeficiency virus (HIV) disease taking antiretroviral therapy
  • Known chronic active hepatitis B

Inclusion Criteria (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
  • Patients must have radiographic progressive disease per RECIST v1.1 criteria after >= 2 courses of therapy on Arm A or Arm B
  • Patients must be registered to Step 2 within 4 weeks of the last dose of treatment administration from Step 1
  • ECOG performance status between 0-2
  • Patients must have recovered to baseline (pre-Step 1) or CTCAE version 4.0 <= grade 1 from toxicity due to all prior therapies except alopecia and other non-clinically significant AEs
  • Acceptable bone marrow, renal and hepatic function within 2 weeks prior to registration as defined in the protocol
  • Patients must have corrected QT interval calculated by the Fridericia formula (QTcF) =< 500 ms within 28 days before registration

Exclusion Criteria: (Step 2):

  • 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
  • Central nervous system (CNS) progression; patients with stable CNS disease are allowed
  • Intercurrent illness or disease complication that the investigator believes would limit the ability to safely tolerate the combination of erlotinib and cabozantinib
Both
18 Years and older   (Adult, Senior)
No
Contact information is only displayed when the study is recruiting subjects
United States
 
NCT01708954
NCI-2012-01938, NCI-2012-01938, E1512, U10CA180820, U10CA021115
Yes
Yes
Individual participant data may be made available upon request as per the ECOG-ACRIN Data Sharing Policy.
National Cancer Institute (NCI)
National Cancer Institute (NCI)
Not Provided
Study Chair: Joel Neal, M.D., Ph.D. Stanford University/Stanford Cancer Institute
National Cancer Institute (NCI)
October 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP