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

Overview

  • Study type

    Interventional
  • Study phase

    II
  • Study IDs

  • Describes the nature of a clinical study. Types include:

    • Observational study — observes people and measures outcomes without affecting results.
    • Interventional study (clinical trial) — studies new tests, treatments, drugs, surgical procedures or devices.
    • Medical records research — uses historical information collected from medical records of large groups of people to study how diseases progress and which treatments and surgeries work best.
  • During the early phases (phases 1 and 2), researchers assess safety, side effects, optimal dosages and risks/benefits. In the later phase (phase 3), researchers study whether the treatment works better than the current standard therapy. They also compare the safety of the new treatment with that of current treatments. Phase 3 trials include large numbers of people to make sure that the result is valid. There are also less common very early (phase 0) and later (phase 4) phases. Phase 0 trials are small trials that help researchers decide if a new agent should be tested in a phase 1 trial. Phase 4 trials look at long-term safety and effectiveness, after a new treatment has been approved and is on the market.

  • Site IRB
    • Scottsdale/Phoenix, Arizona: 13-002537
    NCT ID: NCT01708954
    Sponsor Protocol Number: E1512

About this study

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.

Participation eligibility

Participant eligibility includes age, gender, type and stage of disease, and previous treatments or health concerns. Guidelines differ from study to study, and identify who can or cannot participate. If you need assistance understanding the eligibility criteria, please contact the study team.

See eligibility 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
  • Patients must have radiographic progressive disease per RECIST criteria after ≥ 2 courses of therapy on Arm A or Arm B
  • 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
  • Patients may not have central nervous system progression but patients with stable central nervous system (CNS) disease are allowed
  • Patients must be registered to Step 2 within 4 weeks of the last dose of treatment administration from Step 1
  • Patients must have an ECOG performance status between 0-2
  • 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
  • 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 x ULN
  • AST(SGOT) and ALT(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* ≥ 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 BSA) for patients with creatinine levels above institutional normal
  • 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
  • Patients must have corrected QT interval calculated by the Fridericia formula (QTcF) ≤ 500 ms within 28 days before registration
  • No intercurrent illness or disease complication that the investigator believes would limit the ability to safely tolerate the combination of erlotinib and cabozantinib.

Participating Mayo Clinic locations

Study statuses change often. Please contact us for help.

Mayo Clinic Location Status Contact

Scottsdale/Phoenix, Ariz.

Mayo Clinic principal investigator

Helen Ross, M.D.

Closed for enrollment

Contact information:

Research Information Center

800-664-4542

.
CLS-20111946

Mayo Clinic Footer