A Phase 2 interventional study of cixutumumab and carboplatin in Recurrent Non-small Cell Lung Cancer, Stage IIIB Non-small Cell Lung Cancer and Stage IV Non-small Cell Lung Cancer, sponsored by National Cancer Institute (NCI). Completed at 249 sites in United States. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2014-09-26.
Sponsored by National Cancer Institute (NCI) · Phase 2, Interventional, and Treatment
This randomized phase II trial is studying how well giving carboplatin and paclitaxel together with cetuximab and/or cixutumumab (IMC-A12) works in treating patients with stage IIIB or stage IV non-small cell lung cancer. Drugs used in chemotherapy, such as carboplatin and paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as cetuximab and cixutumumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Giving chemotherapy together with monoclonal antibody therapy may kill more tumor cells. It is not yet known whether carboplatin and paclitaxel are more effective when given with cetuximab and/or cixutumumab in treating non-small cell lung cancer.
PRIMARY OBJECTIVES:
I. To evaluate the progression-free survival of patients with non-small cell lung cancer (NSCLC) randomized to carboplatin plus paclitaxel plus cetuximab or carboplatin plus paclitaxel plus cixutumumab (IMC-A12) or carboplatin plus paclitaxel plus cetuximab plus cixutumumab.
SECONDARY OBJECTIVES:
I. To evaluate the response rate, disease control rate (complete response plus partial response plus stable disease), and toxicities for each arm.
II. To evaluate epidermal growth factor receptor (EGFR) by Immunohistochemistry (IHC), mutation, and gene copy number, Insulin-like growth factor 1 receptor (IGF-1R) and Insulin-like growth factor 2 receptor (IGF-2R) expression (both phosphorylated and unphosphorylated states), expression of p-AKT (ie, Protein Kinase B) by IHC, and k-ras mutation.
III. Plasma-based biomarkers will be evaluated for total and free insulin-like growth factor 1 and 2, IGF-growth factor binding protein 3 (IGFBP3) and circulating levels of epidermal growth factor (EGF) and Transforming growth factor (TGF) alpha.
IV. To evaluate overall survival on each of the three arms.
OUTLINE: This is a multicenter study. Patients are stratified according to gender and histology (squamous cell vs non-squamous cell). Patients are randomized to 1 of 3 treatment arms.
ARM I: Patients receive carboplatin intravenously (IV) over 15-30 minutes and paclitaxel IV over 3 hours on days 1 and 22 and cetuximab IV over 1-2 hours on days 1, 8, 15, 22, 29, and 36. Treatment repeats every 42 days for 2 courses. Patients with stable or responding disease after 2 courses proceed to maintenance therapy with cetuximab alone on days 1, 8, 15, 22, 29, and 36. Treatment with cetuximab repeats every 42 days in the absence of disease progression or unacceptable toxicity.
ARM II: Patients receive carboplatin and paclitaxel as in arm I. Patients also receive cixutumumab IV over 1 hour on days 1, 15, and 29. Treatment repeats every 42 days for 2 courses. Patients with stable or responding disease after 2 courses proceed to maintenance therapy with cixutumumab alone on days 1, 15, and 29. Treatment with cixutumumab repeats every 42 days in the absence of disease progression or unacceptable toxicity.
ARM III: Patients receive carboplatin, paclitaxel, and cetuximab as in arm I. Patients also receive cixutumumab as in arm II. Treatment repeats every 42 days for 2 courses. Patients with stable or responding disease after 2 courses proceed to maintenance therapy with cetuximab as in arm I and cixutumumab as in arm II.
Tumor tissue samples are collected at baseline for analysis of EGFR expression by IHC, mutation, and gene copy number; IGF-1R and IGF-2R expression (both phosphorylated and unphosphorylated states); p-AKT expression by IHC; and k-ras mutation. Blood, serum, and plasma samples are collected periodically for biomarker analysis.
After completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 months for 1 year.
PROJECTED ACCRUAL: 200 patients
7,243 studies on the registry are indexed under Lung Neoplasms; 1,557 are open to participants now.
This study's enrollment of 140 is above the median of 60 across 5,295 interventional studies indexed under Lung Neoplasms.
Browse Lung Neoplasms studies →National Cancer Institute (NCI) is the lead sponsor of 3,506 studies on the registry; 334 are open to participants now.
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Histologically or cytologically confirmed non-small cell lung cancer (NSCLC)
Stage IIIB disease
No untreated or symptomatic central nervous system (CNS) metastases
Patients with a history of CNS metastases that are definitively treated, stable, and controlled are eligible provided the following criteria are met:
No poorly controlled diabetes mellitus
No other prior or concurrent malignancy, except for the following:
Exclusion criteria:
Significant uncontrolled cardiac disease within the past 6 months, including any of the following:
Patients receive carboplatin IV over 15-30 minutes and paclitaxel IV over 3 hours on days 1 and 22 and cetuximab IV over 1-2 hours on days 1, 8, 15, 22, 29, and 36. Treatment repeats every 42 days for 2 courses. Patients with stable or responding disease after 2 courses proceed to maintenance therapy with cetuximab alone on days 1, 8, 15, 22, 29, and 36. Treatment with cetuximab repeats every 42 days in the absence of disease progression or unacceptable toxicity.
Drug: carboplatin · Drug: paclitaxel · Biological: cetuximab
Patients receive carboplatin and paclitaxel as in arm I. Patients also receive cixutumumab IV over 1 hour on days 1, 15, and 29. Treatment repeats every 42 days for 2 courses. Patients with stable or responding disease after 2 courses proceed to maintenance therapy with cixutumumab alone on days 1, 15, and 29. Treatment with cixutumumab repeats every 42 days in the absence of disease progression or unacceptable toxicity.
Biological: cixutumumab · Drug: carboplatin · Drug: paclitaxel
Patients receive carboplatin, paclitaxel, and cetuximab as in arm I. Patients also receive cixutumumab as in arm II. Treatment repeats every 42 days for 2 courses. Patients with stable or responding disease after 2 courses proceed to maintenance therapy with cetuximab as in arm I and cixutumumab as in arm II.
Biological: cixutumumab · Drug: carboplatin · Drug: paclitaxel · Biological: cetuximab
Given IV
Also known as: anti-IGF-1R recombinant monoclonal antibody IMC-A12, IMC-A12
Given IV
Also known as: Carboplat, CBDCA, JM-8, Paraplat, Paraplatin
Given IV
Also known as: Anzatax, Asotax, TAX, Taxol
Given IV
Also known as: C225, C225 monoclonal antibody, IMC-C225, MOAB C225, monoclonal antibody C225
Progression Free Survival
Progression free survival is defined as time from registration to disease progression or death from any cause, whichever occurred earlier. Disease progression was assessed via Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0, and defined as at least a 20% increase in the sum of the longest diameters of target lesions, taking as reference the smallest sum longest diameter recorded since the baseline measurements, and/or the appearance of one or more new lesion(s), and/or unequivocal progression of existing nontarget lesions . All eligible and treated patients were included in the analysis.
Time frame: Tumor measurements are repeated every 6 weeks while on treatment. After off treatment, assessed every 3 months if patient is < 2 years from study entry and every 6 months in year 3
Overall Survival
Overall survival is defined as time from registration to death from any cause.
Time frame: assessed every 3 months if patient is < 2 years from study entry and every 6 months in year 3
Response Rate
Tumor response was assessed via Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0. Complete response (CR) was defined disappearance of all tumor lesions. Partial response (PR) was defined as as at least a 30% decrease in the sum of the longest diameters of target lesions, taking as reference the baseline sum longest diameter. Overall response rate= CR+PR.
Time frame: Tumor measurements are repeated every 6 weeks while on treatment. After off treatment, assessed every 3 months if patient is < 2 years from study entry and every 6 months in year 3
This study was activated on September 11, 2009. The trial was suspended to accrual on December 17, 2010 after accruing 140 patients and accrual was subsequently terminated on April 19, 2011 due to excessive grade 5 events within 30 days of study registration.
| Milestone | Arm I (Carboplatin, Paclitaxel, Cetuximab) | Arm II (Carboplatin, Paclitaxel, Cixutumumab) | Arm III (Carboplatin, Paclitaxel, Cetuximab, Cixutumumab) |
|---|---|---|---|
| Started | 47 | 45 | 48 |
| Treated | 43 | 42 | 47 |
| Eligible and treated | 39 | 41 | 47 |
| Completed | 0 | 0 | 0 |
| Not completed | 47 | 45 | 48 |
| Withdrew: Lack of efficacy | 28 | 25 | 23 |
| Withdrew: Adverse event | 4 | 8 | 9 |
| Withdrew: Death | 5 | 0 | 4 |
| Withdrew: Withdrawal by subject | 6 | 2 | 1 |
| Withdrew: Alternative therapy | 0 | 0 | 1 |
| Withdrew: Not start protocol therapy | 4 | 3 | 1 |
| Withdrew: Unknown/not specify | 0 | 7 | 9 |
Progression free survival is defined as time from registration to disease progression or death from any cause, whichever occurred earlier. Disease progression was assessed via Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0, and defined as at least a 20% increase in the sum of the longest diameters of target lesions, taking as reference the smallest sum longest diameter recorded since the baseline measurements, and/or the appearance of one or more new lesion(s), and/or unequivocal progression of existing nontarget lesions . All eligible and treated patients were included in the analysis.
| months | Arm I (Carboplatin, Paclitaxel, Cetuximab) | Arm II (Carboplatin, Paclitaxel, Cixutumumab) | Arm III (Carboplatin, Paclitaxel, Cetuximab, Cixutumumab) |
|---|---|---|---|
| Progression Free Survival | 3.4 (2.6 to 5.8) | 4.2 (3.5 to 5.3) | 4.0 (3.2 to 5.4) |
Overall survival is defined as time from registration to death from any cause.
| months | Arm I (Carboplatin, Paclitaxel, Cetuximab) | Arm II (Carboplatin, Paclitaxel, Cixutumumab) | Arm III (Carboplatin, Paclitaxel, Cetuximab, Cixutumumab) |
|---|---|---|---|
| Overall Survival | 9.8 (7.4 to 17.2) | 7.7 (5.8 to 11.5) | 8.8 (7.2 to 14.9) |
Tumor response was assessed via Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0. Complete response (CR) was defined disappearance of all tumor lesions. Partial response (PR) was defined as as at least a 30% decrease in the sum of the longest diameters of target lesions, taking as reference the baseline sum longest diameter. Overall response rate= CR+PR.
| percentage of participants | Arm I (Carboplatin, Paclitaxel, Cetuximab) | Arm II (Carboplatin, Paclitaxel, Cixutumumab) | Arm III (Carboplatin, Paclitaxel, Cetuximab, Cixutumumab) |
|---|---|---|---|
| Response Rate | 11.1 (3.1 to 26.1) | 22.0 (10.6 to 37.6) | 21.7 (10.9 to 36.4) |
Collected over Assessed every cycle (6 weeks) while on treatment and for 30 days after the end of treatment.. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Arm I (Carboplatin, Paclitaxel, Cetuximab) | — | 27/44 (61.4%) | 43/44 (97.7%) |
| Arm II (Carboplatin, Paclitaxel, Cixutumumab) | — | 27/42 (64.3%) | 40/42 (95.2%) |
| Arm III (Carboplatin, Paclitaxel, Cetuximab, Cixutumumab) | — | 36/48 (75%) | 46/48 (95.8%) |
| Event | Arm I (Carboplatin, Paclitaxel, Cetuximab) | Arm II (Carboplatin, Paclitaxel, Cixutumumab) | Arm III (Carboplatin, Paclitaxel, Cetuximab, Cixutumumab) |
|---|---|---|---|
| Neutrophil count decreasedInvestigations | 12/44 | 13/42 | 20/48 |
| White blood cell decreasedInvestigations | 8/44 | 6/42 | 8/48 |
| FatigueGeneral disorders | 5/44 | 7/42 | 5/48 |
| HyperglycemiaMetabolism and nutrition disorders | 0/44 | 4/42 | 7/48 |
| AnemiaBlood and lymphatic system disorders | 6/44 | 3/42 | 6/48 |
| Platelet count decreasedInvestigations | 3/44 | 5/42 | 4/48 |
| NauseaGastrointestinal disorders | 5/44 | 3/42 | 4/48 |
| AnorexiaMetabolism and nutrition disorders | 2/44 | 4/42 | 2/48 |
| Lung infectionInfections and infestations | 4/44 | 0/42 | 1/48 |
| Rash acneiformSkin and subcutaneous tissue disorders | 2/44 | 0/42 | 4/48 |
| Event | Arm I (Carboplatin, Paclitaxel, Cetuximab) | Arm II (Carboplatin, Paclitaxel, Cixutumumab) | Arm III (Carboplatin, Paclitaxel, Cetuximab, Cixutumumab) |
|---|---|---|---|
| FatigueGeneral disorders | 31/44 | 30/42 | 37/48 |
| Rash acneiformSkin and subcutaneous tissue disorders | 30/44 | 6/42 | 29/48 |
| AnemiaBlood and lymphatic system disorders | 29/44 | 28/42 | 29/48 |
| NauseaGastrointestinal disorders | 20/44 | 27/42 | 20/48 |
| AnorexiaMetabolism and nutrition disorders | 17/44 | 23/42 | 25/48 |
| AlopeciaSkin and subcutaneous tissue disorders | 16/44 | 22/42 | 13/48 |
| Peripheral sensory neuropathyNervous system disorders | 19/44 | 20/42 | 18/48 |
| Mucositis oralGastrointestinal disorders | 16/44 | 11/42 | 21/48 |
| DiarrheaGastrointestinal disorders | 17/44 | 15/42 | 19/48 |
| Platelet count decreasedInvestigations | 13/44 | 14/42 | 19/48 |
The primary population is eligible and treated patients in the study. Both baseline analysis and efficacy outcomes are based on this primary population.
| Age, Continuous(years) | Arm I (Carboplatin, Paclitaxel, Cetuximab) | Arm II (Carboplatin, Paclitaxel, Cixutumumab) | Arm III (Carboplatin, Paclitaxel, Cetuximab, Cixutumumab) | Total |
|---|---|---|---|---|
| Median | 60 (42 to 89) | 60 (43 to 81) | 60 (44 to 76) | 60 (42 to 89) |
| Sex: Female, Male(Participants) | Arm I (Carboplatin, Paclitaxel, Cetuximab) | Arm II (Carboplatin, Paclitaxel, Cixutumumab) | Arm III (Carboplatin, Paclitaxel, Cetuximab, Cixutumumab) | Total |
|---|---|---|---|---|
| Female | 19 | 17 | 22 | 58 |
| Male | 20 | 24 | 25 | 69 |
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