| General information |
| Database: | DB00689 |
| Objective: | They undertook thisphase I trial to assess the safety, the recommended dose forphase II trials (RPTD), pharmacokinetics (PK), pharmacodynamics (PD), and the preliminary antitumour activity of the combination of lapatinib and sorafenib in patients with advanced refractory solid tumours. |
| Authors: | Simonelli M, et al |
| Title: | Phase I pharmacokinetic and pharmacodynamic study of lapatinib in combination with sorafenib in patients with advanced refractory solid tumors. |
| Journal: | Eur J Cancer. |
| Year: | 2013 |
| PMID: | 23146956 |
| Trial Design |
| Clinical Trial Id: | NCT00984425 |
| Agent: | lapatinib, sorafenib
|
| Target: | NA
|
| Cancer Type: | advanced solid tumors |
| Cancer Subtype: | advanced solid tumors |
| Therapy Type: | com |
| Therapeutic Combination Type: | 1 |
| Therapeutic Combination Content: | lapatinib+sorafenib |
| Study Type: | Phase I pharmacokinetic and pharmacodynamic study |
| Key Patients Feature: | the Italian National Health Institute and the institutional review board approved this study, which was conducted in accordance with the 1996 Declaration of Helsinki. Signed informed consent was obtained from all patients before trial participation. Patients enrolled in this study were men or women more than and equal to 18 years of age with recurrent or metastatic histologically confirmed solid tumors refractory to available standard treatment. Eligibility requirements included at least one measurable lesion according to Response Evaluation Criteria in Solid Tumor (RECIST) version 1.035; Eastern Cooperative Oncology Group (ECOG) performance status less than and equal to 1; patients were required to have the following laboratory values: hemoglobin more than and equal to 9 g/dL, absolute neutrophil count more than and equal to 1, 500/mm3, platelet count more than and equal to 100 000/¦ÌL, total bilirubin < 1.5 times the upper limit of normal (ULN), alanine aminotransferase and aspartate aminotransferase < 2.5 ULN, alkaline phosphatase < 4 ULN, prothrombin timeinternational normalized ratio/partial thromboplastin time < 1.5 ULN, and serum creatinine < 1.5 ULN. Baseline left ventricular ejection fraction had to be more than and equal to 50% in the absence of a documented history of congestive heart failure. A representative tissue specimen for the analysis of tumor molecular status was required. All major surgery, hormonal therapy, biologic therapy, chemotherapy, or radiotherapy was discontinued at least 4 weeks before study entry.Patients with active serious infections, seizures, or arrhythmias requiring medication, congestive heart failure, angina pectoris, uncontrolled brain or leptomeningeal metastases, and a history of bleeding diathesis were excluded. Any previous treatment targeting EGFR, human epidermal growth factor receptor 2, or VEGFR, except for trastuzumab, cetuximab, and bevacizumab, was not allowed. |
| Biomarker: | NA |
| Biomark Analysis: | NA |
| Control Group Info: | single arm |
| Treatment Info: | Four cohorts of at least three patients each received lapatinib once daily and sorafenib twice daily together on a continuous schedule. Doses of lapatinib and sorafenib were escalated based on doselimiting toxicities (DLTs) in the first treatment cycle following a traditional 3+3 design until the RPTD was reached. Additional patients were treated at the RPTD to characterise PK profiles of this combination and to investigate the potential interaction between lapatinib and sorafenib. Serum samples were collected at baseline and then prospectively every two cycles to assess changes in PD parameters. |
| Primary End Point: | the recommended dose for phase II trials (RPTD), safety/tolerability, pharmacokinetics (PK), pharmacodynamics(PD), and antitumour activity |
| Secondary End Point: | NA |
| Patients Number: | 30 |
| Trial Results |
| DLT_MTD: | DLTs were grade three fatigue and grade 3 atypical skin rash observed at dose levels 3 and 4, respectively. The higher dose level explored (lapatinib 1250mg/day and sorafenib 400mg twice daily) represented the RPTD of the combination. |
| Objective Response Rate: | Of the 27 assessable patients for clinical activity, one achieved a confirmed complete response, four (15%) had a partial response, and 12 (44%) achieved disease stabilisation. The disease control rate overall was 63%. |
| Disease Control Rate: | 0.63 |
| Median Time to Progression: | NA |
| Median PFS A vs. C: | NA |
| Median OS A vs. C: | NA |
| Adverse Event(agent arm): | The most common drugrelated adverse events were fatigue (68%), hypocalcemia (61%), diarrhoea (57%), lymphopaenia (54%), anorexia (50%), rash (50%), and hypophosphatemia (46%). |
| Conclusions: | Combination treatment with lapatinib and sorafenib was feasible with promising clinical activity and without significant PK interactions. Long term tolerability seems to be challenging. |