| General information |
| Database: | DB00321 |
| Objective: | a phase I clinical trial and molecular correlative studies were conducted to evaluate preclinical evidence for combinatorial activity of the proteasome inhibitor bortezomib, the epidermal growth factor receptor (EGFR) inhibitor cetuximab, and radiation therapy. |
| Authors: | Argiris A, et al |
| Title: | Early tumor progression associated with enhanced EGFR signaling with bortezomib, cetuximab, and radiotherapy for head and neck cancer. |
| Journal: | Clin Cancer Res. |
| Year: | 2011 |
| PMID: | 21750205 |
| Trial Design |
| Clinical Trial Id: | NA |
| Agent: | bortezomib, cetuximab
|
| Target: | NA
|
| 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: | bortezomib+cetuximab+radiotherapy |
| Study Type: | phase I clinical trial |
| Key Patients Feature: | agemore than and equal to 18 years; pathologically confirmedSCCHN or poorly/undifferentiated carcinoma of any head/neck site except the nasopharynx;previously untreated stage IV disease, residual disease or regional recurrence, without orwith distant metastatic disease <3cm; ECOG performance status 01; adequate organfunction; recovery from any prior surgery or chemotherapy including prior cisplatin >3months; and no prior systemic EGFR inhibitors, bortezomib, head and neck radiation, uncontrolled intercurrent illness; or grade more than and equal to 2 peripheral sensory neuropath |
| Biomarker: | EGFR, MAPK, AKT, STAT3 and NF¦ÊB signal pathways, tumor cell survival, and levels of proinflammatory and angiogenic cytokines regulated by these pathways and detectable in serum |
| Biomark Analysis: | Bortezomib antagonized cetuximab and radiationinduced cytotoxicity, degradation of EGFR, and enhanced prosurvival signal pathway activation in SCCHN tumor biopsies and UMSCC1. |
| Control Group Info: | single arm |
| Treatment Info: | Escalating doses of bortezomib (0.7, 1.0, and 1.3 mg/m2) were given intravenously twice weekly on days 1, 4, 8, and 11, every 21 days, with weekly cetuximab beginning 1 week prior and concurrently with intensitymodulated radiotherapy, delivered in 2 Gy fractions to 70 to 74 Gy. Molecular effects were examined in serial serum and SCCHN tumor specimens and the cell line UMSCC1. |
| Primary End Point: | the toxicities and the maximum tolerated dose (MTD); clinical response, progression free and overall survival. |
| Secondary End Point: | the effects of combined bortezomib and cetuximab to inhibit those biomarkers. |
| Patients Number: | 7 |
| Trial Results |
| DLT_MTD: | expected grade 3 toxicities for the treatment combination, such as mucositis (4), dysphagia (3), xerostomia (1), and dermatitis (1); cetuximabassociatedacneiform rash (1); and bortezomibassociated peripheral neuropathy (1). One Grade 3 infection occurred in a patient without neutropenia. |
| Objective Response Rate: | Only 3 of 7 patients achieved a complete response (CR) within 2 to 5 months(patients 1, 4, 6). Of these, patient 4 developed a solitary pulmonary metastasis at 11 months |
| Disease Control Rate: | NA |
| Median Time to Progression: | NA |
| Median PFS A vs. C: | 4.8 months; 95% CI, 2.66.9 |
| Median OS A vs. C: | NA |
| Adverse Event(agent arm): | Toxicities included expected grade 3 toxicities for the treatment combination, such as mucositis (n = 4), dysphagia (n = 3), xerostomia (n = 1), and dermatitis (n = 1); cetuximabassociated acneiform rash (n = 1); and bortezomibassociated peripheral neuropathy (n = 1). One grade 3 infection occurred in a patient without neutropenia. |
| Conclusions: | Combining bortezomib with cetuximab and radiation therapy showed unexpected early progression, evidence for EGFR stabilization, increased prosurvival signaling, and SCCHN cytokine expression, warranting avoidance of this combination. |