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: September 12, 2014
Last verified: June 2014
  Purpose

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.


Condition Intervention Phase
Recurrent Non-small Cell Lung Cancer
Stage IV Non-small Cell Lung Cancer
Drug: erlotinib hydrochloride
Drug: cabozantinib-s-malate
Other: laboratory biomarker analysis
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Crossover Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • 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.


Secondary Outcome Measures:
  • Overall survival (OS) [ Time Frame: Time from randomization to death from any cause, assessed up to 5 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 + partial response) 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 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.


Estimated Enrollment: 117
Study Start Date: February 2013
Estimated Primary Completion Date: June 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm A (erlotinib hydrochloride)
Patients receive erlotinib hydrochloride PO daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Drug: erlotinib hydrochloride
Given PO
Other Names:
  • CP-358,774
  • erlotinib
  • OSI-774
Other: laboratory biomarker analysis
Correlative studies
Experimental: Arm B (cabozantinib-s-malate)
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.
Drug: cabozantinib-s-malate
Given PO
Other Names:
  • BMS-907351
  • Cometriq
  • XL184
Other: laboratory biomarker analysis
Correlative studies
Experimental: Arm C (erlotinib hydrochloride, cabozantinib-s-malate)
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.
Drug: erlotinib hydrochloride
Given PO
Other Names:
  • CP-358,774
  • erlotinib
  • OSI-774
Drug: cabozantinib-s-malate
Given PO
Other Names:
  • BMS-907351
  • Cometriq
  • XL184
Other: laboratory biomarker analysis
Correlative studies
Experimental: Arm Z (erlotinib hydrochloride, cabozantinib-s-malate)
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.
Drug: erlotinib hydrochloride
Given PO
Other Names:
  • CP-358,774
  • erlotinib
  • OSI-774
Drug: cabozantinib-s-malate
Given PO
Other Names:
  • BMS-907351
  • Cometriq
  • XL184
Other: laboratory biomarker analysis
Correlative studies

Detailed Description:

PRIMARY OBJECTIVES:

I. To compare the progression-free survival (PFS) associated with patients treated with erlotinib (erlotinib hydrochloride) 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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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) 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) =< 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 above 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 above 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 ration =< 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 intercurrent illness or disease complication that the investigator b
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01708954

  Show 371 Study Locations
Sponsors and Collaborators
Investigators
Principal Investigator: Joel Neal ECOG-ACRIN Cancer Research Group
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01708954     History of Changes
Other Study ID Numbers: NCI-2012-01938, NCI-2012-01938, CDR0000741879, ECOG-E1512, E1512, E1512, U10CA021115, U10CA180820
Study First Received: October 15, 2012
Last Updated: September 12, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Carcinoma, Non-Small-Cell Lung
Lung Neoplasms
Carcinoma, Bronchogenic
Bronchial Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Erlotinib
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions

ClinicalTrials.gov processed this record on September 16, 2014