| General information |
| Database: | DB00326 |
| Objective: | They studied the combination of pemetrexed, a multitargeted antifolate, and cetuximab, an mAb against the epidermal growth factor receptor, with radiotherapy in poor prognosis head and neck cancer. |
| Authors: | Argiris A, et al |
| Title: | Phase I trial of pemetrexed in combination with cetuximab and concurrent radiotherapy in patients with head and neck cancer. |
| Journal: | Ann Oncol. |
| Year: | 2011 |
| PMID: | 21363880 |
| Trial Design |
| Clinical Trial Id: | NCT00291707 |
| Agent: | cetuximab
|
| Target: | Epidermal growth factor receptor
|
| Cancer Type: | head and neck cancer |
| Cancer Subtype: | advanced head and neck squamous cell carcinoma |
| Therapy Type: | com |
| Therapeutic Combination Type: | 3 |
| Therapeutic Combination Content: | pemetrexed + cetuximab and concurrent radiotherapy |
| Study Type: | Phase I trial |
| Key Patients Feature: | Patients 18 years with advanced head and neck squamous cell carcinoma who required radiotherapy to thehead and neck were eligible. Other key eligibility criteria includedperformance status of zero to two, according to the Eastern CooperativeOncology Group scale, absolute neutrophil count (ANC) 1500/mm3, hemoglobin >8 g/dl, platelet count 100 000/mm3, total bilirubin levelswithin normal limits, liver transaminases not exceeding three times theupper limit of normal, and creatinine clearance 45 ml/min. Any numberof prior systemic therapies was allowed, except prior treatment with EGFRinhibitors or pemetrexed. Patients with metastatic disease were eligible ifthey had predominant symptoms from locoregional disease and requiredradiotherapy; patients with newly diagnosed SCCHN were eligible if theyhad stage IV disease and poor expected survival |
| Biomarker: | The MTHFR (rs1801133, rs1801131 and rs2274976);The TS gene promoter repeat and SNP |
| Biomark Analysis: | No association of gene polymorphisms with toxicity or efficacy was evident. |
| Control Group Info: | A:not previously irradiated B:previously irradiated |
| Treatment Info: | Patients received pemetrexed on days 1, 22, and 43 on a doseescalation scheme with starting level (0) 350 mg/m(2) (level 1, 200 mg/m(2); level +1, 500 mg/m(2)) with concurrent radiotherapy (2 Gy/day) and cetuximab in two separate cohorts, not previously irradiated (A) and previously irradiated (B), who received 70 and 6066 Gy, respectively. Genetic polymorphisms of thymidylate synthase and methylenetetrahydrofolate reductase were evaluated. |
| Primary End Point: | the DLTs and determine the maximum tolerated dose (MTD) |
| Secondary End Point: | the objective response rate, locoregional control, overall survival (OS) and progression free survival (PFS). |
| Patients Number: | 32 |
| Trial Results |
| DLT_MTD: | The maximum tolerated dose of pemetrexed was 500 mg/m2 in cohort Aand 350 mg/m2 in cohort B. Prophylactic antibiotics were required. In cohort A, two doselimiting toxicities (DLTs)occurred (febrile neutropenia), one each at levels 0 and +1. In cohort B, two DLTs occurred at level +1 (febrileneutropenia; death from perforated duodenal ulcer and sepsis). Grade 3 mucositis was common. No association ofgene polymorphisms with toxicity or efficacy was evident |
| Objective Response Rate: | Of 21 patients assessable for response in cohort A, 12 patients(4 on each dose level) achieved a complete response and 7a partial response (4 at dose level +1; 2 at dose level 0; 1 at dose level 21). Of seven assessable patients in cohort B, four patientsachieved a complete response (three at dose level 0; one at doselevel +1) and three a partial response (two at dose level 0; oneat dose level +1). |
| Disease Control Rate: | in cohort A: 90.47%; in cohort B: 100% |
| Median Time to Progression: | NA |
| Median PFS A vs. C: | the 3year PFS was 41% in cohort A and 22% in cohort B |
| Median OS A vs. C: | the 3year OS was 55% and 37%, in cohorts A and B, respectively. |
| Adverse Event(agent arm): | Five patients experienced a DLT. Dose level +1 (500 mg/m2) was determined as the MTD of pemetrexed for not previously irradiated patients. In cohort B, two patients, both at pemetrexed dose level +1, experienced a DLT. One had febrile neutropenia, whereas the other presented with perforated duodenal bleeding and subsequent grade 5 sepsis with grade 4 thrombocytopenia and neutropenia. Hence, the MTD of pemetrexed for previously irradiated patients was determined at 350 mg/m2. In cohort A, six patients developed grade 3 and five patients grade 4 neutropenia. In cohort B, three patients experienced grade 4 neutropenia. Serious thrombocytopenia was rare; one patient in group A and two patients in group B developed grade 3-4 thrombocytopenia. Mucositis, dysphagia, rash and dermatitis were the most common nonhematologic toxic effects. |
| Conclusions: | The addition of pemetrexed 500 mg/m(2) to cetuximab and radiotherapy is recommended for further study in not previously irradiated patients. |