Alimta® Versus Its Combination With Carboplatin in Advanced Non-small-cell Lung Cancer in Patients Performance Status 2

NCT ID: NCT01836575

Last Updated: 2013-04-22

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 228 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2008-04-30
• Study Completion Date: 2012-12-31

Brief Summary

Optimal management of patients with advanced NSCLC and with PS 2 remains controversial and underrepresented in clinical trials, typically accounting for 5 to 10% of enrolled patients. Patient PS 2 proportion in population-based studies is considerably higher than that included in clinical trials. Management of patients with PS of 2 in clinical practice is empirical and inconsistent. Patients have median overall survival of 3 to 5 months in randomized trials, and treatment options include best supportive care, single-agent and combination chemotherapy. Retrospective studies have suggested that patients PS 2 may benefit from first-line chemotherapy in terms of symptom improvement and overall survival. In many of these studies, single-agent chemotherapy was compared with best supportive care alone. Data on the role of cisplatin-based combinations for patients with PS 2 is more scant, with one study questioning its benefit, and another interrupting accrual because of undue toxicity. With regards to carboplatin, the Cancer and Leukemia Group B (CALGB) study 9730 compared paclitaxel plus carboplatin versus paclitaxel alone in a subgroup of 107 patients with PS 2; the median overall survival was significantly longer in group treated with combination chemotherapy (4.7 versus 2.4 months). Combination chemotherapy with carboplatin and paclitaxel also produced a statistically significantly higher incidence of severe hematological and non-hematological toxicities. On the basis of aforementioned results, a recent European panel stated that carboplatin-based or low-dose cisplatin-based doublets might represent alternative options to single-agent chemoterapy in patients PS 2. Outside clinical trials, single-agent chemotherapy with a 3rd generation agent remains valid option for patients PS2. Results demonstrate that pemetrexed is an agent with established single-agent activity in NSCLC, and suggest it is a potential candidate for combinations with platinum and other agents currently utilized for patients with advanced NSCLC. Favorable toxicity profile of pemetrexed suggests that this agent is an ideal candidate for single agent testing and in combination among patients with PS 2. Substantial doubt remains in the comparative benefit from monotherapy versus combination. Starting dose and schedule of pemetrexed were set for this study based on its current labeling in the 2nd line treatment of metastatic NSCLC and 1st line treatment of malignant pleural mesothelioma.

Detailed Description

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.

Conditions

Non Small Cell Lung Carcinoma

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Arm B

Pemetrexed, 500mg/m2 + appropriate vitamin supplementation + Carboplatin \[Target AUC 5 IV infusion,based on Calvert formula,GFR estimated using estimated creatinine clearance per Cockcroft and Gault formula, obtained prior to each cycle\] + Antiemetic therapy at investigator's discretion.

Group Type: EXPERIMENTAL

Pemetrexed

Intervention Type: DRUG

Pemetrexed, 500 mg/m2 + Pretreatment \[dexamethasone + vitamin B12 + folic acid, as per pemetrexed label\] + Antiemetic therapy at investigator's discretion.

Carboplatin

Intervention Type: DRUG

Carboplatin \[Target AUC 5 IV infusion,based on Calvert formula,GFR estimated using estimated creatinine clearance per Cockcroft and Gault formula, obtained prior to each cycle\].

Arm A:

Pemetrexed, 500mg/m2 + appropriate vitamin supplementation + Antiemetic therapy at investigator's discretion.

Group Type: ACTIVE_COMPARATOR

Pemetrexed

Intervention Type: DRUG

Pemetrexed, 500 mg/m2 + Pretreatment \[dexamethasone + vitamin B12 + folic acid, as per pemetrexed label\] + Antiemetic therapy at investigator's discretion.

Interventions

Pemetrexed

Pemetrexed, 500 mg/m2 + Pretreatment \[dexamethasone + vitamin B12 + folic acid, as per pemetrexed label\] + Antiemetic therapy at investigator's discretion.

Intervention Type: DRUG

Carboplatin

Carboplatin \[Target AUC 5 IV infusion,based on Calvert formula,GFR estimated using estimated creatinine clearance per Cockcroft and Gault formula, obtained prior to each cycle\].

Intervention Type: DRUG

Other Intervention Names

Arm A - active comparator Pemetrexed (Alimta).; Carboplatin AUC 5 IV in 5% dextrose or 0.9% sodium chloride.

Eligibility Criteria

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 of NSCLC;
• 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 thereafter;
• 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 included;
• 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 recurrence);
• 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.

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Eli Lilly and Company

INDUSTRY

Sponsor Role: collaborator

Instituto Nacional de Cancer, Brazil

OTHER_GOV

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Carlos G Ferreira, PhD

Role: PRINCIPAL_INVESTIGATOR

National Cancer Institute, France

Rogerio Lilenbaum, MD

Role: PRINCIPAL_INVESTIGATOR

The Mount Sinai Comprehensive Cancer Center

Carlos Henrique E Barrios, MD

Role: PRINCIPAL_INVESTIGATOR

Pontifícia Universidade Católica do RS

Carlos Augusto M. Beato, MD

Role: PRINCIPAL_INVESTIGATOR

Hospital Amaral Carvalho

José Rodrigues, MD

Role: PRINCIPAL_INVESTIGATOR

Instituto do Câncer Arnaldo Vieira Carvalho - ICAVC

Yeni Neron, MD

Role: PRINCIPAL_INVESTIGATOR

Centro de Pesquisas Oncológicas - CEPON

André Murad, PhD

Role: PRINCIPAL_INVESTIGATOR

Lifecenter Hospital

Ronaldo A Ribeiro, PhD

Role: PRINCIPAL_INVESTIGATOR

Instituto do Câncer do Ceará - ICC

Fábio Franke, MD

Role: PRINCIPAL_INVESTIGATOR

Hospital de Caridade de Ijuí - CACON

Mauro Zukin, MD

Role: PRINCIPAL_INVESTIGATOR

National Cancer Institute, France

Locations

The Mount Sinai Comprehensive Cancer Center

Miami Beach, Florida, United States

Instituto do Câncer do Ceará - ICC

Fortaleza, Ceará, Brazil

Hospital Lifecenter

Belo Horizonte, Minas Gerais, Brazil

INCA

Rio de Janeiro, Rio de Janeiro, Brazil

Hospital Caridade de Ijuí - CACON

Ijuí, Rio Grande do Sul, Brazil

Hospital São Lucas

Porto Alegre, Rio Grande do Sul, Brazil

Centro de Pesquisas Oncológicas - CEPON

Florianópolis, Santa Catarina, Brazil

Hospital Amaral Carvalho

Jaú, São Paulo, Brazil

Instituto do Câncer Arnaldo Vieira de Carvalho

São Paulo, São Paulo, Brazil

Countries

United States; Brazil

References

Gijtenbeek RG, de Jong K, Venmans BJ, van Vollenhoven FH, Ten Brinke A, Van der Wekken AJ, van Geffen WH. Best first-line therapy for people with advanced non-small cell lung cancer, performance status 2 without a targetable mutation or with an unknown mutation status. Cochrane Database Syst Rev. 2023 Jul 7;7(7):CD013382. doi: 10.1002/14651858.CD013382.pub2.

Reference Type: DERIVED

PMID: 37419867 (View on PubMed)

Zukin M, Barrios CH, Pereira JR, Ribeiro Rde A, Beato CA, do Nascimento YN, Murad A, Franke FA, Precivale M, Araujo LH, Baldotto CS, Vieira FM, Small IA, Ferreira CG, Lilenbaum RC. Randomized phase III trial of single-agent pemetrexed versus carboplatin and pemetrexed in patients with advanced non-small-cell lung cancer and Eastern Cooperative Oncology Group performance status of 2. J Clin Oncol. 2013 Aug 10;31(23):2849-53. doi: 10.1200/JCO.2012.48.1911. Epub 2013 Jun 17.

Reference Type: DERIVED

PMID: 23775961 (View on PubMed)

Other Identifiers

H3E - US -I023

Identifier Type: OTHER

Identifier Source: secondary_id

INCA-Lung001

Identifier Type: OTHER

Identifier Source: secondary_id

H3E-BL-O027-PS2

Identifier Type: -

Identifier Source: org_study_id