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Phase III Trial of Single-Agent Pemetrexed (Alimta®) Versus the Combination of Carboplatin and Pemetrexed in Patients With Advanced Non-small-cell Lung Cancer and Performance Status of 2

Phase 3
18 Years
Not Enrolling
Non Small Cell Lung Carcinoma

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Trial Information

Phase III Trial of Single-Agent Pemetrexed (Alimta®) Versus the Combination of Carboplatin and Pemetrexed in Patients With Advanced Non-small-cell Lung Cancer and Performance Status of 2

This is a Phase III, open label, randomized study to enroll 228 patients with advanced in a
1:1 ratio at the time of registration. Patients in Arm A will receive pemetrexed, 500 mg/m2,
with appropriate vitamin supplementation; patients in Arm B will receive the same dose and
schedule of pemetrexed as in Arm A, in combination with carboplatin, AUC of 5. For the
purpose of the study, treatment (Arm A or Arm B) will consist of up to four cycles of
therapy (repeated every 21 days). Primary endpoint of the study is overall survival;
secondary endpoints include toxicity, response rate, and progression-free survival. At the
time of analysis, patients will be stratified according to age (≥ 70 versus < 70 years),
disease stage (IIIB versus IV), site, and weight loss (≥ 5 Kg versus < 5 Kg).

The dose of carboplatin will be determined according to the formula developed by Calvert et
al., which is shown in equation [1] below and uses the estimated creatinine clearance
according to the method of Cockcroft and Gault for estimation of the glomerular filtration
rate (GFR) (equation [2] below):

1. Dose of carboplatin (mg) = Target AUC x (GFR + 25)

2. GFR = (140 - Age) x Weight/(72 x serum creatinine) (multiply by 0.85 in women) Sample
Size and Expected Accrual In the CALGB 9730 study of advanced NSCLC, first-line
treatment with paclitaxel plus carboplatin resulted in a median overall survival of 4.7
months among patients with a performance status of 2. In the ECOG 1594 study, the
median overall survival of patients with a performance status of 2 who were treated
with platinum-based doublets was 4.1 months. Approximately 208 eligible patients are
needed to provide 80% power to detect a difference between the two treatment arms with
a two-sided type I error of 0.05, assuming that pemetrexed plus carboplatin will result
in a median survival of at least 4.3 months, and pemetrexed alone 2.9 months. An
additional 20 patients will be accrued to account for an early dropout rate of 10%, for
a total of 228 patients. It is anticipated that the accrual time will be approximately
22 months and patients will be followed for 1 year after completion of treatment;
therefore, 2 years and 10 months will be needed to complete the study.

Inclusion Criteria:

- Newly diagnosed NSCLC in stage IIIB (with a cytologically positive pleural or
pericardial effusion) or stage IV, according to the sixth edition of the American
Joint Committee on Cancer (AJCC) Cancer Staging Manual37;

- Age > 18 years;

- No prior chemotherapy, including adjuvant or neoadjuvant therapy, for the treatment

- Histological confirmation of any non-squamous histological type of NSCLC, given the
recent findings of treatment benefit in this population44;

- ECOG performance status of 2;

- At least 3 weeks must have elapsed since major surgery, and at least 1 week since
mediastinoscopy, pleuroscopy, or thoracostomy;

- Patients must have measurable disease, defined as lesions that can be accurately
measured in at least 1 dimension (longest diameter to be recorded) as ≥ 20 mm with
conventional techniques (computed tomography [CT] or magnetic resonance imaging [MRI]
scan) or as ≥ 10 mm with spiral CT scan;

- Adequate organ function as indicated by the following:

- White blood cell (WBC) count ≥ 3500/mm3

- Absolute neutrophil count (ANC) ≥1500/mm3

- Hemoglobin ≥ 9.0 g/dL

- Platelet count ≥ 100,000/ mm3

- Total bilirubin ≤ 2 times the upper limit of normal (ULN)

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 times
the ULN, unless liver metastases present, in which case AST and ALT have to be ≤
5 times the ULN

- Estimated glomerular filtration rate (GFR) ≥ 45 mL/min

- Female patients of childbearing potential must have a negative serum pregnancy test
within 7 days prior to registration;

- Fertile patients (male or female) must agree to use an acceptable method of
contraception to avoid pregnancy for the duration of the study and for 3 months

- Patients must sign an Informed Consent Form;

- Have the ability to take folic acid, Vitamin B12, and dexamethasone according to
protocol requirements;

Exclusion Criteria:

- ECOG performance status other than 2;

- Prior chemotherapy for the treatment of NSCLC;

- Lesions that have been irradiated cannot be included as sites of measurable disease.
If the only measurable lesion was previously irradiated the patient cannot be

- Symptomatic central nervous system (CNS) metastases. Prior CNS metastases are allowed
if the patient is neurologically stable and not receiving corticosteroids;

- Serious uncontrolled intercurrent medical or psychiatric illness;

- Active and ongoing systemic infection;

- Second primary malignancy (except in situ carcinoma of the cervix, in situ carcinoma
of the bladder, adequately treated basal-cell carcinoma of the skin, adequately
treated squamous-cell carcinoma of the skin, T1 vocal cord cancer in remission, or
prior malignancy treated more than 5 years prior to enrollment and without

- Known hypersensitivity to pemetrexed;

- known hypersensitivity to carboplatin;

- Pregnancy or lactation;

- Use of any investigational agent within 30 days prior to enrollment into the study;

- Unable to discontinue administration of non-steroidal anti-inflammatory (NSAIDSs)
agents for 2 days before, the day of and 2 days after the dose of pemetrexed, in the
case of NSAIDs with short half-life, such as ibuprofen (total of 5 days), in patients
with a GFR between 45 and 79 mL/min; and for 5 days before, the day of and 2 days
after the dose of pemetrexed, in the case of NSAIDs with long half-life (total of 8
days, see 7.4.2) in all patients; patients with a GFR ≥ 80 mL/min may receive
concomitant study treatment and ibuprofen or aspirin (≤ 1.3 g/day);

- Inability to comply with requirements and procedures of study.

Type of Study:


Study Design:

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

Outcome Measure:

Overall survival

Outcome Description:

Each patient will be followed from inclusion date in the study (ICF signature) until the death date for any cause, whichever came first, assessed up to one year after completion of study treatment. Primary objective of this study is to determine and compare the overall survival produced by pemetrexed as a single-agent and by the combination of pemetrexed plus carboplatin in a patient with previously untreated, advanced non-squamous NSCLC and an ECOG Performance status of 2.

Outcome Time Frame:

From ICF signature date until e until death date for any cause

Safety Issue:


Principal Investigator

Carlos G Ferreira, PhD

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Institute, France


Brazil: National Committee of Ethics in Research

Study ID:




Start Date:

April 2008

Completion Date:

December 2012

Related Keywords:

  • Non Small Cell Lung Carcinoma
  • Advanced NSCLC
  • PS2
  • Pemetrexed
  • First line
  • non squamous
  • Carcinoma
  • Carcinoma, Non-Small-Cell Lung
  • Lung Neoplasms



The Mount Sinai Comprehensive Cancer Center Miami Beach, Florida  33140