| General information |
| Database: | DB00345 |
| Objective: | The aim of thisphase I trial was to establish the maximum tolerated dose (MTD) for bortezomib plus cetuximab in patients with EGFRexpressing epithelial tumours. |
| Authors: | Dudek AZ, et al |
| Title: | Phase I study of bortezomib and cetuximab in patients with solid tumours expressing epidermal growth factor receptor. |
| Journal: | Br J Cancer. |
| Year: | 2009 |
| PMID: | 19401697 |
| Trial Design |
| Clinical Trial Id: | NCT00622674 |
| Agent: | cetuximab
|
| Target: | Epidermal growth factor receptor
|
| Cancer Type: | advanced solid tumors |
| Cancer Subtype: | advanced solid tumors |
| Therapy Type: | com |
| Therapeutic Combination Type: | 1 |
| Therapeutic Combination Content: | bortezomib and cetuximab |
| Study Type: | prospective, singlecenter, doseescalationphase I study |
| Key Patients Feature: | All patients were X18 years old with histologically confirmedadvanced solid cancer refractory to standard treatment and at leastone EGFRpositive tumour specimen determined by immunohistochemical staining. Expression of EGFR was assessed bypathologists at the University of Minnesota. An ECOG performance status of 0-1 and a life expectancy of at least 12 weeks wererequired. Earlier systemic chemotherapy, immunotherapy orbiological therapy was allowed, except for earlier treatment withbortezomib and/or cetuximab. patients were required to completeearlier radiation or systemic therapy at least 14 days before studyentry and at least 30 days for investigational agents. Any grade 41toxicity had to be resolved before study enrolment. Adequateorgan function within 14 days of study enrolment was required, including adequate bone marrow reserve: absolute neutrophilcount (ANC) X1.5 109 l 1, platelets 4100 109 l 1 and haemoglobin 49 g per 100 ml, and hepatic function: bilirubin o1.5 timeshe upper limit of normal ( ULN), alkaline phosphatase (ALP), aspartate transaminase (AST) and alanine transaminase (ALT)o3.0 ULN (ALP, AST and ALT o5 ULN was acceptable if liverhad tumour involvement). A calculated or measured creatinineclearance of 430 ml min 1 was required within 14 days beforeenrolment. Disease status had to be that of measurable or nonmeasurable disease, as defined by RECIST criteria. |
| Biomarker: | EGFR positive |
| Biomark Analysis: | The degree of EGFR staining did not correlate withresponse (P 0.562) |
| Control Group Info: | single arm |
| Treatment Info: | The 21day treatment cycle consisted of bortezomib administered on days 1 and 8 through dose escalation (1.32 mg m(2)). Cetuximab was delivered at a dose of 250 mg m(2) on days 1, 8 and 15 (400 mg m(2) day 1 cycle 1). A total of 37 patients were enroled and given a total 91 cycles. |
| Primary End Point: | the maximum tolerated dose (MTD) |
| Secondary End Point: | preliminary information regarding the antitumor activity of bortezomib and cetuximab, when given in combination. |
| Patients Number: | 37 |
| Trial Results |
| DLT_MTD: | No grade X3 haematological toxicity was noted. Nonhematological grade X3toxicities included fatigue (22% of patients), dyspnoea (16%) and infection (11%). The MTD was not reached at the highest tested bortezomib dose (2.0 mgm2). |
| Objective Response Rate: | Efficacy outcomes included disease progression in 21 patients (56.7%) and stable disease (SD) at 6 weeks in 16 patients (43.3%). Five of the six patients with SD at 12 weeks were diagnosed with cancers of the lungs or head and neck |
| Disease Control Rate: | NA |
| Median Time to Progression: | NA |
| Median PFS A vs. C: | NA |
| Median OS A vs. C: | NA |
| Adverse Event(agent arm): | The most common grade 1 and 2 haematological side effects were decreased haemoglobin (54% of patients) and lymphopenia (22% of patients). All grade 3 or 4 toxicities were nonhematological in origin, the most common of which were fatigue (22% of patients), dyspnoea (16%), infection (11%), dehydration (11%), constipation (8%), nausea (8%) and muscle theyakness (5%). Grade 3 cellulitis was observed at 1.3 mgm 2 in a 58yearold male patient with pyriform sinus cancer. Renal failure occurred in two patients at doses of 1.5 and 1.9 mgm 2. At the higher dose, renal failure was fatal for a 52yearold female with bladder cancer. The most commonly observed grade 1 and 2 nonhematological side effects were fatigue (81% of patients), skin rash (78%), anorexia (57%), vomiting (54%), nausea (51%), constipation (51%), diarrhoea (49%), peripheral neuropathy (35%), infection (22%) and dyspnoea (16%). |
| Conclusions: | This combination therapy was moderately effective in extensively pretreated patients with nonsmall cell lung or head and neck cancers and warrants further investigation. |