Pemetrexed and/or Sunitinib as Second-Line Therapy in Treating Patients With Stage IIIB or 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:
NCT00698815
First received: June 14, 2008
Last updated: October 7, 2013
Last verified: October 2013
  Purpose

This randomized phase II trial is studying pemetrexed and sunitinib to compare how well they work when given alone or together as second-line therapy in treating patients with stage IIIB or stage IV non-small cell lung cancer. Drugs used in chemotherapy, such as pemetrexed, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Sunitinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. Giving pemetrexed together with sunitinib may kill more tumor cells. It is not yet known whether pemetrexed and sunitinib are more effective when given alone or together in treating non-small cell lung cancer.


Condition Intervention Phase
Recurrent Non-small Cell Lung Cancer
Stage IIIB Non-small Cell Lung Cancer
Stage IV Non-small Cell Lung Cancer
Drug: sunitinib malate
Drug: pemetrexed disodium
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Randomized Phase II Study to Assess the Efficacy of Pemetrexed or Sunitinib (NSC # 736511, IND # 74019) or Pemetrexed Plus Sunitinib in the Second-Line Treatment of Advanced Non-Small Cell Lung Cancer

Resource links provided by NLM:


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

Primary Outcome Measures:
  • Progression-free survival (PFS) rate defined as proportion of patients who remain alive and progression free after initial administration of the treatment. [ Time Frame: At 18 weeks ] [ Designated as safety issue: No ]
    All patients will be followed up for the 18-week PFS regardless of whether they have completed the protocol treatment. Comparisons of treatment effects in terms of 18-week PFS rate will be conducted using a one-sided Fisher's exact test. The comparisons will follow the multiple testing procedure as described above. As a supplementary analysis, stratified comparisons of 18-week PFS rates between the experimental arms versus the control arm will be done using the Mantel-Haenszel chi-square test.


Secondary Outcome Measures:
  • Progression-free survival (PFS) [ Time Frame: Time from registration to disease progression and death of any cause, whichever comes first, assessed every 6 weeks during follow up ] [ Designated as safety issue: No ]
    PFS rates between the experimental arms versus the control arm will be done using the Mantel-Haenszel chi-square test.

  • Best overall response rate (complete or partial response) and duration of response rate [ Time Frame: Every 6 weeks until disease progression ] [ Designated as safety issue: No ]
    The proportion of patients who respond (completely or partially) to each treatment regimen will be estimated as well as their 95% confidence intervals. Response rates (including complete and partial response) will be tested using Fisher's exact test and multivariately using a logistic regression model.

  • Rate of stable disease due to the subsequent therapy [ Time Frame: Assessed every 6 weeks until disease progression ] [ Designated as safety issue: No ]
  • Toxicity profile as assessed by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 [ Time Frame: During course 1 ] [ Designated as safety issue: Yes ]
    The toxicity associated with each treatment regimen will be summarized.

  • Degree of change in VEGF concentrations induced by sunitinib is haplotype dependent [ Time Frame: From baseline to up to 3 and 6 weeks of therapy ] [ Designated as safety issue: No ]
    This hypothesis will be formally investigated in the framework of a two-way ANOVA model where the interaction term will be the primary statistical parameter of interest. Other clinical endpoints will be considered for this analysis by using two-way Cox's proportional hazard models for censored endpoints and two-way logistic models for binary endpoints.

  • Association between mean change in tumor size and PFS [ Time Frame: At 6 weeks ] [ Designated as safety issue: No ]
    This association will be using the rank-covariance statistic discussed in Jung et al (37) which is a nonparametric counterpart to the Cox association statistic.


Estimated Enrollment: 225
Study Start Date: April 2008
Estimated Primary Completion Date: December 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Arm I (chemotherapy)
Patients receive pemetrexed disodium IV over 10 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients with documented disease progression may then receive sunitinib malate as in arm II as third-line therapy.
Drug: pemetrexed disodium
Given IV
Experimental: Arm II (enzyme inhibitor therapy)
Patients receive oral sunitinib malate once daily on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients with documented disease progression may then receive pemetrexed disodium as in arm I as third-line therapy.
Drug: sunitinib malate
Given orally
Experimental: Arm III (chemotherapy, enzyme inhibitor therapy)
Patients receive pemetrexed disodium IV over 10 minutes on day 1 and oral sunitinib malate once daily on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients with documented disease progression may then receive third-line therapy at the discretion of the treating physician.
Drug: sunitinib malate
Given orally
Drug: pemetrexed disodium
Given IV

Detailed Description:

PRIMARY OBJECTIVES:

I. To compare the 18-week progression-free survival rate in patients with stage IIIB or IV non-small cell lung cancer treated with pemetrexed disodium alone vs sunitinib malate alone vs pemetrexed disodium in combination with sunitinib malate as second-line therapy.

SECONDARY OBJECTIVES:

I. To compare the progression-free survival of patients treated with these regimens.

II. To compare the response rate, duration of response, rate of stable disease, and overall survival of patients treated with these regimens.

III. To characterize the toxicity profiles of these regimens in these patients. IV. To determine the response rate, duration of response, rate of stable disease, and overall survival of patients who receive sunitinib malate in the third-line setting.

V. To assess the toxicity of sunitinib malate when administered in the third-line setting in these patients.

VI. To test changes in tumor size at 6 weeks as an early predictor of therapeutic activity of these second-line treatment regimens.

OUTLINE: This is a multicenter study. Patients are stratified according to ECOG performance status (0 vs 1), disease stage (IIIB vs IV), and gender. Patients are randomized to 1 of 3 treatment arms.

ARM I: Patients receive pemetrexed disodium IV over 10 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients with documented disease progression may then receive sunitinib malate as in arm II as third-line therapy.

ARM II: Patients receive oral sunitinib malate once daily on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients with documented disease progression may then receive pemetrexed disodium as in arm I as third-line therapy.

ARM III: Patients receive pemetrexed disodium IV over 10 minutes on day 1 and oral sunitinib malate once daily on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients with documented disease progression may then receive third-line therapy at the discretion of the treating physician.

After completion of study therapy, patients are followed every 6 weeks until disease progression and then every 6 months for 2 years.

  Eligibility

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

Inclusion Criteria:

  • Histologically or cytologically confirmed non-small cell lung cancer (NSCLC)

    • Stage IIIB or IV disease
  • Must have evidence of disease progression after first-line therapy
  • Measurable or non-measurable disease

    • Measurable disease is defined as lesions that can be accurately measured in ≥ 1 dimension as ≥ 2 cm by conventional techniques or ≥ 1 cm by spiral CT scan
    • Non-measurable disease is defined as all other lesions, including small lesions (i.e., longest diameter < 20 mm by conventional techniques or < 10 mm by spiral CT scan) and truly non-measurable lesions, including any of the following:

      • Bone lesions
      • Leptomeningeal disease
      • Ascites
      • Pleural or pericardial effusion
      • Lymphangitis cutis or pulmonis
      • Abdominal mass that are not confirmed and followed by imaging techniques
      • Cystic lesions
  • No cavitary lesions
  • No pleural effusions or ascites detectable on physical exam
  • No symptomatic or untreated CNS metastases

    • Patients with CNS metastases are eligible provided the metastases were definitively treated with surgery or radiotherapy AND patient is asymptomatic and off steroids or on a stable dose of steroids for 2 weeks prior to study entry
  • Concurrent enrollment on CALGB-580702 (imaging study) required
  • ECOG performance status 0-1
  • Granulocytes ≥ 1,500/μL
  • Platelet count ≥ 100,000/μL
  • Magnesium ≥ lower limit of normal
  • Bilirubin ≤ 1.5 times upper limit of normal (ULN)
  • AST and ALT ≤ 2.5 times ULN
  • PTT ≤ 1.5 times ULN
  • INR ≤ 1.5
  • Creatinine clearance ≥ 45 mL/min
  • Quantitative urine protein < 30 mg/dL OR ≤ 1+ on dipstick
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception during and for 6 months after completion of study therapy
  • QTc interval ≤ 500 msec within the past 2 years
  • No ongoing cardiac dysrhythmias
  • No atrial fibrillation
  • No symptomatic congestive heart failure within the past 12 months

    • NYHA class I heart failure allowed
    • Patients with a history of NYHA class II heart failure are eligible provided at least 1 of the following criteria is met:

      • Asymptomatic on treatment
      • Previously treated with anthracycline
      • Previously treated with central thoracic radiotherapy that included the heart in the radiotherapy port
  • No myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft or stenting, cerebrovascular accident, or transient ischemic attack within the past year
  • No hypertension that cannot be controlled by medications (i.e., blood pressure > 150/100 mm Hg despite optimal medical therapy)
  • No history of venous thrombosis, pulmonary embolism, or hypercoagulopathy syndrome
  • No history of pulmonary hemorrhage, bleeding diathesis, or evidence of hemoptysis

    • Patients with blood-tinged or blood-streaked sputum are eligible provided the hemoptysis is < 5 mL of blood per episode and < 10 mL of blood per 24-hour period, in the best estimate of the investigator
  • No abdominal fistula, gastrointestinal perforation, intra-abdominal abscess, or serious or non-healing wound, ulcer, or bone fracture within the past 28 days
  • History of hypothyroidism allowed provided patient is currently euthyroid
  • At least 28 days since prior first-line therapy

    • No more than one prior chemotherapy regimen (platinum or non-platinum based) in the first-line setting for NSCLC
  • Prior adjuvant therapy allowed provided the patient received one regimen in the advanced setting
  • At least 4 weeks since prior EGFR inhibitors or bevacizumab
  • At least 28 days since prior major surgery (6 weeks since resection of brain metastases)
  • At least 14 days since prior radiotherapy
  • More than 7 days since prior and no concurrent CYP3A4 inhibitors, including any of the following:

    • Azole antifungals (e.g., ketoconazole or itraconazole)
    • Diltiazem
    • Clarithromycin
    • Erythromycin
    • Verapamil
    • Delavirdine
    • HIV protease inhibitors (e.g., indinavir, saquinavir, ritonavir, atazanavir, or nelfinavir)
  • More than 12 days since prior and no concurrent CYP3A4 inducers, including any of the following:

    • Rifampin
    • Rifabutin
    • Carbamazepine
    • Phenobarbital
    • Phenytoin
    • St. John's wort
    • Efavirenz
    • Tipranavir
  • No prior pemetrexed disodium
  • No prior VEGFR inhibitors (e.g., semaxanib, SU6668, AZ6474, sunitinib malate, vatalanib, cediranib, AEE-788, or sorafenib)
  • No concurrent chronic daily treatment with aspirin (> 325 mg/day) or non-steroidal anti-inflammatory agents known to inhibit platelet function
  • No concurrent dipyridamole (Persantine), ticlopidine (Ticlid), clopidogrel (Plavix), and/or cilostazol (Pletal)
  • No concurrent therapeutic anticoagulation for thromboembolic disease

    • Concurrent low-dose warfarin (≤ 2 mg/day) allowed for prophylaxis of thrombosis
  • No concurrent agents with proarrhythmic potential (e.g., quinidine, procainamide, disopyramide, sotalol, probucol, bepridil, haloperidol, risperidone, indapamide, or flecainide)
  • No concurrent hormonal therapy, except steroids for adrenal failure, hormones for non-disease-related conditions (e.g., insulin for diabetes), or dexamethasone used intermittently as an antiemetic or as premedication for pemetrexed disodium
  • No other concurrent chemotherapy
  • No concurrent palliative radiotherapy
  • No concurrent G-CSF (filgrastim), GM-CSF (sargramostim), and/or pegfilgrastim
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00698815

  Show 104 Study Locations
Sponsors and Collaborators
Investigators
Principal Investigator: Rebecca Suk Heist Cancer and Leukemia Group B
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT00698815     History of Changes
Other Study ID Numbers: NCI-2009-00471, NCI-2009-00471, CALGB-30704, CDR0000589102, CALGB 30704, CALGB-30704, U10CA031946
Study First Received: June 14, 2008
Last Updated: October 7, 2013
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
Enzyme Inhibitors
Pemetrexed
Sunitinib
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Folic Acid Antagonists
Antimetabolites, Antineoplastic
Antimetabolites
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Physiological Effects of Drugs
Growth Inhibitors

ClinicalTrials.gov processed this record on April 17, 2014