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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

Phase 2
18 Years
Open (Enrolling)
Recurrent Non-small Cell Lung Cancer, Stage IIIB Non-small Cell Lung Cancer, Stage IV Non-small Cell Lung Cancer

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Trial Information

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


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.


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

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.

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

- 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

- 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

- More than 12 days since prior and no concurrent CYP3A4 inducers, including any of the

- 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

- 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

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Progression-free survival (PFS) rate defined as proportion of patients who remain alive and progression free after initial administration of the treatment.

Outcome Description:

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.

Outcome Time Frame:

At 18 weeks

Safety Issue:


Principal Investigator

Rebecca Suk Heist

Investigator Role:

Principal Investigator

Investigator Affiliation:

Cancer and Leukemia Group B


United States: Food and Drug Administration

Study ID:




Start Date:

April 2008

Completion Date:

Related Keywords:

  • Recurrent Non-Small Cell Lung Cancer
  • Stage IIIB Non-Small Cell Lung Cancer
  • Stage IV Non-Small Cell Lung Cancer
  • Carcinoma, Non-Small-Cell Lung
  • Lung Neoplasms



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