Sorafenib in Treating Patients With Advanced Malignant Solid Tumors

Single Agent Sorafenib in Advanced Solid Tumors: Phase II Evaluation of Dose Re-Escalation Following a Dose Reduction (IST000375)

RATIONALE: Sorafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor.

PURPOSE: This phase II trial is studying the side effects and best dose of sorafenib and to see how well it works in treating patients with advanced malignant solid tumors.

Study Overview

• Status: Completed
• Conditions: Unspecified Adult Solid Tumor, Protocol Specific
• Intervention / Treatment: Drug: Sorafenib

Detailed Description

OBJECTIVES:

Primary

• To evaluate the feasibility of re-escalating the dose of sorafenib tosylate in patients with advanced malignant solid tumors who initially required a dose reduction for toxicity, and dose escalation in those patients who are able to tolerate the initial dose.

Secondary

• To evaluate the efficacy of this drug in these patients who are able to tolerate a dose escalation initially or after a dose reduction compared to those who are unable to tolerate a dose escalation.

Tertiary

• To evaluate the percentage and demographic characteristics of patients who are able to tolerate 2 dose escalations without a dose reduction.

OUTLINE: This is a dose-finding study.

• Course 1: Patients receive oral sorafenib tosylate twice daily at dose level 0 on weeks 1-4.
• Course 2: Patients experiencing no dose-limiting or intolerable toxicities receive oral sorafenib tosylate at dose level +1 twice daily on weeks 5-8; while patients experiencing dose-limiting or intolerable toxicities receive oral sorafenib tosylate at dose level -1 once daily on weeks 5-8.
• Course 3: Depending on whether or not patients are experiencing dose-limiting or intolerable toxicities, they are escalated to dose level 0 or dose level +2 (patients in both dose levels receive oral sorafenib tosylate twice daily) in weeks 9-12, or de-escalated to dose level 0 or dose level -2 (patients in dose level -2 receives oral sorafenib tosylate once every other day) in weeks 9-12.
• Maintenance therapy: Patients receive oral sorafenib tosylate at the dose level* attained at the end of course 3. Treatment continues in the absence of unacceptable toxicity.
• Dose level de-escalation for toxicity or dose re-escalation after a toxicity-related dose reduction allowed to a maximum level of the initial dose level of the maintenance therapy.

After completion of study therapy, patients are followed for up to 1 year.

• Study Type: Interventional
• Enrollment (Actual): 50
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Sacramento, California, United States, 95817
      • University of California Davis Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria

• Histologically or cytologically confirmed metastatic or unresectable solid tumor for which standard curative or palliative measures do not exist or are no longer effective or solid tumor for which sorafenib is considered acceptable therapy
• Age > 18 years old
• Performance Status 0 - 2
• Measurable or non-measurable disease.
• Adequate bone marrow, liver and renal function
• Any number of prior chemotherapy regimens are allowed.
• Any prior chemotherapy, immunotherapy or targeted therapy must have been completed at least 2 weeks prior to start of this protocol and all side effects resolved to grade 1 or less. Any prior radiation must have been completed at least 2 weeks prior to start of therapy.
• Women of childbearing potential must have a negative pregnancy test performed within 7 days prior to the start of treatment
• Women of childbearing potential and men must agree to use adequate contraception prior to study entry and for the duration of study participation. Men should use adequate birth control for at least three months after the last administration of sorafenib.
• Ability to understand and the willingness to sign a written informed consent.
• International normalized ratio < 1.5 or a Prothrombin Time/Partial thromboplastin time within normal limits.

Exclusion Criteria

• Prior therapy with sorafenib or sunitinib.
• Cardiac disease: Congestive heart failure > class II New York Heart Association.
• Symptomatic or uncontrolled brain metastasis.
• No component of squamous carcinoma can be present in any patient with non-small cell lung cancer
• Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy.
• Uncontrolled hypertension defined as systolic blood pressure > 150 mmHg or diastolic pressure > 90 mmHg, despite optimal medical management.
• Known HIV infection or chronic Hepatitis B or C.
• Active clinically serious infection > CTCAE Grade 2.
• Thrombolic or embolic events such as a cerebrovascular accident including transient ischemic attacks within the past 6 months.
• Pulmonary hemorrhage/bleeding event > CTCAE Grade 2 within 4 weeks of first dose of study drug.
• Any other hemorrhage/bleeding event > CTCAE Grade 3 within 4 weeks of first dose of study drug.
• Serious non-healing wound, ulcer, or bone fracture.
• Evidence or history of bleeding diathesis or coagulopathy
• Major surgery, open biopsy or significant traumatic injury within 4 weeks of first dose of study drug.
• Use of St. John's Wort or rifampin
• Known or suspected allergy to sorafenib or any agent given in the course of this trial.
• Any condition that impairs patient's ability to swallow whole pills.
• Any significant malabsorption problem.
• Therapy with bevacizumab < 3 months prior to first dose of study drug.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Sorafenib; Dose Re-Escalation Following a Dose Reduction	Drug: Sorafenib; Patients will be registered and started on the standard recommended dose-schedule for sorafenib (400 mg tablet by mouth twice a day continuously). Dose reductions will be instituted in the event of grade 3 or higher hematologic or non-hematologic toxicity or for any toxicity that is considered by the patient or physician as intolerable.; Other Names: Nexavar

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Patients Tolerating Re-escalated Dose of Sorafenib for 28 Days Without Dose Interruption or De-escalation for Toxicity	Overall percentage of patients tolerating a dose escalation to 600 mg twice daily for 28 days plus the percentage tolerating a re-escalation to 400 mg twice daily in Cycle 3.	At least 3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response Rate	Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR).	At least 3 months
Time to Disease Progression	Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.	Up to 2 years

Collaborators and Investigators

• Sponsor: University of California, Davis
• Collaborators: Bayer
• Investigators: Principal Investigator: Primo N. Lara, MD, University of California, Davis

Publications and helpful links

General Publications

• Semrad TJ, Eddings C, Pan CX, Lau DH, Gandara D, Beckett L, Lara PN Jr. Feasibility study of intra-patient sorafenib dose-escalation or re-escalation in patients with previously treated advanced solid tumors. Invest New Drugs. 2012 Oct;30(5):2001-7. doi: 10.1007/s10637-011-9761-y. Epub 2011 Oct 21.

Study record dates

Study Major Dates

• Study Start: December 1, 2008
• Primary Completion (Actual): October 1, 2011
• Study Completion (Actual): March 1, 2012

Study Registration Dates

• First Submitted: December 17, 2008
• First Submitted That Met QC Criteria: December 17, 2008
• First Posted (Estimate): December 18, 2008

Study Record Updates

• Last Update Posted (Actual): January 10, 2018
• Last Update Submitted That Met QC Criteria: January 5, 2018
• Last Verified: March 1, 2017

More Information

Terms related to this study

• Keywords: unspecified adult solid tumor, protocol specific
• Additional Relevant MeSH Terms: Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Sorafenib
• Other Study ID Numbers: UCDCC#213; 236614 (Other Identifier: University of California Davis); IST000375 (Other Grant/Funding Number: Bayer); UCDCC-213 (Other Identifier: University of California Davis)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No