Pharmacokinetic and Phase I Study of Sorafenib (BAY 43-9006, NSC 724772, IND 69896) for Solid Tumors and Hematologic Malignancies in Patients With Hepatic or Renal Dysfunction
Overview
- Phase
- Phase 1
- Intervention
- sorafenib tosylate
- Conditions
- Extranodal Marginal Zone B-cell Lymphoma of Mucosa-associated Lymphoid Tissue
- Sponsor
- National Cancer Institute (NCI)
- Enrollment
- 150
- Locations
- 1
- Primary Endpoint
- Relationship between the pharmacokinetics and measures of renal dysfunction categorized by creatinine clearance as estimated by the Cockcroft and Gault formula (Part 1)
- Status
- Completed
- Last Updated
- 13 years ago
Overview
Brief Summary
This phase I trial is studying the side effects and best dose of sorafenib in treating patients with metastatic or unresectable solid tumors, multiple myeloma, or non-Hodgkin's lymphoma with or without impaired liver or kidney function. Sorafenib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the cancer. Sorafenib may have different effects in patients who have changes in their liver or kidney function
Detailed Description
PRIMARY OBJECTIVES: I. To characterize the pharmacokinetics of BAY 43-9006 in patients with hepatic or renal dysfunction (part 1 of the study). II. To determine a tolerable starting dose of BAY 43-9006 in patients with varying degrees of hepatic or renal dysfunction (part 2 of the study). OUTLINE: This is a dose-escalation, multicenter study. Patients are assigned to 1 of 9 treatment cohorts according to hepatic or renal function. Patients receive oral sorafenib once on day 1 and then once daily, twice daily, or every other day beginning on day 8 and continuing for 3 months. Patients are re-evaluated at 3 months. Patients with responding disease may continue study treatment in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients (per treatment cohort) receive escalating doses of sorafenib until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. At least 6 patients are treated at the MTD. PROJECTED ACCRUAL: A total of 120 patients will be accrued for this study.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Patients must have cytologically or histologically confirmed tumors that are metastatic or unresectable and for which standard curative or palliative measures do not exist or are no longer effective; Patients with solid tumors, multiple myeloma, or non-Hodgkin's lymphoma are eligible
- •Lesions that can be accurately measured in at least one dimension (longest diameter to be recorded) as ≥ 20 mm with conventional techniques or as ≥ 10 mm with spiral CT scan
- •All other lesions, including small lesions (longest diameter \< 20 mm with conventional techniques or \< 10 mm with spiral CT scan) and truly nonmeasurable lesions; Lesions that are considered non-measurable include the following:
- •Bone lesions
- •Pleural/pericardial effusion
- •Lymphangitis cutis/pulmonis
- •Abdominal masses that are not confirmed and followed by imaging techniques
- •Cystic lesions
- •≥ 4 weeks since major surgery
- •≥ 4 weeks since completion of radiation or chemotherapy except for ≥ 6 weeks for nitrosoureas, L-PAM or mitomycin-C
Exclusion Criteria
- Not provided
Arms & Interventions
Treatment (sorafenib tosylate)
Patients receive oral sorafenib once on day 1 and then once daily, twice daily, or every other day beginning on day 8 and continuing for 3 months. Patients are re-evaluated at 3 months. Patients with responding disease may continue study treatment in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients (per treatment cohort) receive escalating doses of sorafenib until the MTD is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. At least 6 patients are treated at the MTD.
Intervention: sorafenib tosylate
Treatment (sorafenib tosylate)
Patients receive oral sorafenib once on day 1 and then once daily, twice daily, or every other day beginning on day 8 and continuing for 3 months. Patients are re-evaluated at 3 months. Patients with responding disease may continue study treatment in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients (per treatment cohort) receive escalating doses of sorafenib until the MTD is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. At least 6 patients are treated at the MTD.
Intervention: pharmacological study
Outcomes
Primary Outcomes
Relationship between the pharmacokinetics and measures of renal dysfunction categorized by creatinine clearance as estimated by the Cockcroft and Gault formula (Part 1)
Time Frame: Prior to and at 1, 2, 3, 4, 6, and 24 hours post-dose on day 1
Explored using standard parametric and non-parametric methods for one- and two-way analysis of variance (ANOVA) layouts (the dysfunction factor (hepatic/renal) and the severity factor (mild, moderate, severe, very severe).
Distribution of and association patterns between the Child-Pugh score and that of patient's risk of toxicity beyond each dose or cohort, assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v3.0
Time Frame: Up to 5 years
Mean levels of area under the curve (AUC) using the ANOVA model
Time Frame: Up to 12 weeks
90% confidence intervals for the relative change (from mild to moderate and from moderate to severe) of the mean AUC levels will be calculated.
Maximum tolerated dose (MTD) of sorafenib tosylate, assessed using the NCI CTCAE v3.0 (Part 2)
Time Frame: Up to 4 weeks
Dose-limiting toxicities (DLT), defined as any grade 3 or greater non-hematologic toxicity, assessed using the NCI CTCAE v3.0
Time Frame: Up to 7 weeks
Severity of hepatic disease as assessed by the Child-Pugh criteria
Time Frame: Up to 3 months
Non-parametric measures of association for ordinal data will be employed.