Study to Determine the Safety, Maximum Tolerated Dose, Pharmacokinetics of Sorafenib (BAY43-9006)

Study Overview
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Brief Summary
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The primary objective of the study was to define the safety profile and maximum tolerated dose (MTD) of sorafenib tablets in combination with carboplatin and paclitaxel chemotherapy in patients with advanced, refractory solid tumors. The secondary objectives were evaluation of pharmacokinetics (PK) and tumor response of these patients being treated with sorafenib in combination with paclitaxel and carboplatin.

Official Title
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Phase I Study to Determine the Safety, Maximum Tolerated Dose, PK of BAY43-9006 in Repeated Cycles of 18 Days On/3 Days Off in Combination With Paclitaxel and Carboplatin Chemotherapy in Patients With Advanced, Refractory Solid Tumors

Conditions
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Carcinoma

Intervention / Treatment
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* Drug: Sorafenib 100 mg (50-mg tablet)
* Drug: Sorafenib 200 mg (50-mg tablet)
* Drug: Sorafenib 400 mg (50-mg tablet)
* Drug: Sorafenib 400 mg (200-mg tablet)
* Drug: Sorafenib 400 mg (Expansion)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed solid tumors Evaluable disease Eastern Cooperative Oncology Group (ECOG) 0 or 1 Life expectancy minimum 12 weeks Exclusion Criteria: Congestive heart failure Serious arrhythmias Coronary artery disease (CAD) or ischemia HIV (human immunodeficiency virus) Hepatitis B or C Serious active infection Metastatic brain or meningeal tumors

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sorafenib 100 mg (50-mg tablet)<br>Dose-escalation cohort 1: Sorafenib (Nexavar, BAY43-9006) 100 mg twice daily (50-mg tablet). Treatment were planned until primary completion date (PCD). | Drug: Sorafenib 100 mg (50-mg tablet)<br>* Sorafenib (Nexavar, BAY43-9006) 100 mg twice daily (50-mg tablet)<br>|
| Experimental: Sorafenib 200 mg (50-mg tablet)<br>Dose-escalation cohort 2: Sorafenib (Nexavar, BAY43-9006) 200 mg twice daily (50-mg tablet). Treatment were planned until primary completion date (PCD). | Drug: Sorafenib 200 mg (50-mg tablet)<br>* Sorafenib (Nexavar, BAY43-9006) 200 mg twice daily (50-mg tablet)<br>|
| Experimental: Sorafenib 400 mg (50-mg tablet)<br>Dose-escalation cohort 3: Sorafenib (Nexavar, BAY43-9006) 400 mg twice daily (50-mg tablet). Treatment were planned until primary completion date (PCD). | Drug: Sorafenib 400 mg (50-mg tablet)<br>* Sorafenib (Nexavar, BAY43-9006) 400 mg twice daily (50-mg tablet)<br>|
| Experimental: Sorafenib 400 mg (200-mg tablet)<br>Dose-escalation cohort 4: Sorafenib (Nexavar, BAY43-9006) 400 mg twice daily (200-mg tablet). Treatment were planned until primary completion date (PCD). | Drug: Sorafenib 400 mg (200-mg tablet)<br>* Sorafenib (Nexavar, BAY43-9006) 400 mg twice daily (200-mg tablet)<br>|
| Experimental: Sorafenib 400 mg (Expansion)<br>Dose-expansion cohort: Sorafenib (Nexavar, BAY43-9006) 400 mg twice daily (200-mg tablet) expansion. Treatment were planned until primary completion date (PCD). 25 of 119 participants from the Expansion Phase, were still on the treatment as of 31 May 2005. Of these, 6 subjects were continuing to receive sorafenib in combination with carboplatin and/or paclitaxel and 19 subjects were receiving single-agent sorafenib until 18 Sep 2008. | Drug: Sorafenib 400 mg (Expansion)<br>* Sorafenib (Nexavar, BAY43-9006) 400 mg twice daily (200-mg tablet) expansion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) of Sorafenib in Combination With Paclitaxel and Carboplatin | MTD was determined by testing increasing doses up to 400 mg twice daily (bid) on dose escalation cohorts 1 to 3 with 3 patients each. MTD reflects highest dose of drug that did not cause an unacceptable side effect (= Dose Limiting Toxicity (DLT) in more than 30% of patients; e.g., hematologic toxicities like Common Toxicity Criteria (CTC) Grade 4 Neutropenia in specific conditions, platelets < 25,000 cells/mL; specific non-hematologic/biochemical toxicities CTC Grade 3 or 4; additionally, any toxicity considered by the investigator severe enough was designated a DLT); CTC Version 2 were used. | 21 days | 
| Participants With Hematological and Biochemical Toxicities | Participants are considered at risk for toxicity if participants had a lab measurement for the toxicity >= National Cancer Institute Common Toxicity Criteria (NCI CTC) Grade 3 as defined by the NCI CTC version 2; SGOT: Serum Glutamic-Oxaloacetic Transaminase, SGPT: Serum Glutamic-Pyruvic Transaminase, AST: Aspartate Aminotransferase, ALT: Alanine Aminotransferase. | Start of treatment until death or within 14 days last study drug intake | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Tumor Response | Tumor Response (= Best Overall Response) of a subject was defined as the best tumor response (confirmed Complete Response (CR), confirmed Partial Response (PR), Stable Disease (SD), or Progressive Disease (PD)) observed during trial period assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. CR was defined as disappearance of tumor lesions, PR was defined as a decrease of at least 30% in the sum of tumor lesion sizes, SD was defined as steady state of disease, PD was defined as an increase of at least 20% in the sum of tumor lesions sizes. | From start of treatment until progression or death occurs assessed every 6 weeks. | 
| Area Under the Curve From Time 0 to 12 Hours Post-dose (AUC 0-12) Start From Day 2 of Cycle 1 | The AUC is a measure of systemic drug exposure, which is obtained by collecting a series of blood samples and measuring the concentrations of drug in each sample. A plot of concentration vs time after dosing is created, and the area under this curve is calculated by standard methods (eg, trapezoidal rule) to provide a measure of how much drug was in the bloodstream following dosing. | At day 2 in study | 
| Maximum Concentration (CMAX) Start From Day 2 of Cycle 1 | Cmax refers to the highest plasma concentration of drug reached after dosing. It is obtained by collecting a series of blood samples after dosing, and analyzing them for drug content by a sensitive and specific analytical method. The highest measured concentration is referred to as the Cmax. | At day 2 in study | 
| Time of Maximum Concentration (TMAX) Start From Day 2 of Cycle 1 | Tmax refers to the time after dosing when a drug attains its maximum concentration in the blood. It is obtained by collecting a series of blood samples at various times after dosing, and measuring them for drug content. The time corresponding to the highest measurable concentration (Cmax) is referred to as Tmax. | At day 2 in study | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sorafenib, Advanced Solid Tumors, Maximum tolerated dose, Carboplatin and paclitaxel chemotherapy combination