Sorafenib in Treating Patients With Advanced Malignant Solid Tumors

• Sponsor: University of California, Davis (Other)
• Overall Status: Completed
• CT.gov ID: NCT00810394
• Collaborator: Bayer (Industry)
• Enrollment: 50
• Location: 1
• Arm: 1
• Duration (Months): 39
• Patients Per Site Per Month: 1.3

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Unspecified Adult Solid Tumor, Protocol Specific	Drug: Sorafenib	Phase 2

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 Design

• Study Type: Interventional
• Actual Enrollment: 50 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Single Agent Sorafenib in Advanced Solid Tumors: Phase II Evaluation of Dose Re-Escalation Following a Dose Reduction (IST000375)
• Study Start Date: Dec 1, 2008
• Actual Primary Completion Date: Oct 1, 2011
• Actual Study Completion Date: Mar 1, 2012

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Percentage of Patients Tolerating Re-escalated Dose of Sorafenib for 28 Days Without Dose Interruption or De-escalation for Toxicity [At least 3 months]

   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.

Secondary Outcome Measures

1. Overall Response Rate [At least 3 months]

   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).

2. Time to Disease Progression [Up to 2 years]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California Davis Cancer Center	Sacramento	California	United States	95817

Sponsors and Collaborators

• University of California, Davis
• Bayer

Investigators

• Principal Investigator: Primo N. Lara, MD, University of California, Davis

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: University of California, Davis
• ClinicalTrials.gov Identifier: NCT00810394
• Other Study ID Numbers: UCDCC#213; 236614; IST000375; UCDCC-213
• First Posted: Dec 18, 2008
• Last Update Posted: Jan 10, 2018
• Last Verified: Mar 1, 2017

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by University of California, Davis: unspecified adult solid tumor, protocol specific
• Additional relevant MeSH terms: Neoplasms; Sorafenib

Study Results

Participant Flow

Arm/Group Title	Sorafenib
Arm/Group Description	Dose Re-Escalation Following a Dose Reduction 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.
Period Title: Overall Study
STARTED	50
Cycle 2 600mg Twice Daily	13
Cycle 2 400mg Once Daily	22
Cycle 3 800 mg Twice Daily	4
Cycle 3 400mg Twice Daily	5
COMPLETED	47
NOT COMPLETED	3

Baseline Characteristics

Arm/Group Title	Sorafenib
Arm/Group Description	Dose Re-Escalation Following a Dose Reduction 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.
Overall Participants	50
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	61
Sex: Female, Male (Count of Participants)
Female	31 62%
Male	19 38%
Region of Enrollment (participants) [Number]
United States	50 100%

Outcome Measures

1. Primary Outcome

Title	Percentage of Patients Tolerating Re-escalated Dose of Sorafenib for 28 Days Without Dose Interruption or De-escalation for Toxicity
Description	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.
Time Frame	At least 3 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sorafenib
Arm/Group Description	Dose Re-Escalation Following a Dose Reduction 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.
Measure Participants	50
Count of Participants [Participants]	11 22%

2. Secondary Outcome

Title	Overall Response Rate
Description	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).
Time Frame	At least 3 months

Outcome Measure Data

Analysis Population Description

Of the 34 patients who were evaluable for treatment response by RECIST, no responses were observed.

Arm/Group Title	Sorafenib
Arm/Group Description	Dose Re-Escalation Following a Dose Reduction 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.
Measure Participants	34
Count of Participants [Participants]	0 0%

3. Secondary Outcome

Title	Time to Disease Progression
Description	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.
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sorafenib
Arm/Group Description	Dose Re-Escalation Following a Dose Reduction 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.
Measure Participants	34
Median (95% Confidence Interval) [months]	4.7

Adverse Events

Time Frame	Up to 2 years
Arm/Group Title	Sorafenib
Arm/Group Description	Dose Re-Escalation Following a Dose Reduction 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.
All Cause Mortality
	Sorafenib
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Sorafenib
	Affected / at Risk (%)	# Events
Total	19/50 (38%)
Blood and lymphatic system disorders
INR	1/50 (2%)
Neutropenia	1/50 (2%)
Gastrointestinal disorders
Nausea	1/50 (2%)
Constipation	1/50 (2%)
Lower Gastrointestinal Hemorrhage	1/50 (2%)
General disorders
Fever	2/50 (4%)
Musculoskeletal and connective tissue disorders
Ataxia	1/50 (2%)
Osteonecrosis	1/50 (2%)
Muscle Weakness	2/50 (4%)
Respiratory, thoracic and mediastinal disorders
Bronchopulmonary Hemorrhage	2/50 (4%)
Pneumonia	1/50 (2%)
Cough	1/50 (2%)
Skin and subcutaneous tissue disorders
Rash	2/50 (4%)
Skin Reaction	1/50 (2%)
Hand and Foot Syndrome	1/50 (2%)
Other (Not Including Serious) Adverse Events
	Sorafenib
	Affected / at Risk (%)	# Events
Total	42/50 (84%)
Blood and lymphatic system disorders
Hemoglobin	10/50 (20%)
Leukopenia	7/50 (14%)
Lymphopenia	11/50 (22%)
Thrombocytopenia	3/50 (6%)
Edema	3/50 (6%)
Hypoalbuminemia	4/50 (8%)
Alkaline Phosphatase	7/50 (14%)
AST	5/50 (10%)
Bicarbonate, Serum	4/50 (8%)
Hyperbilirubinemia	3/50 (6%)
Hyperkalemia	3/50 (6%)
Hypokalemia	7/50 (14%)
Hyponatremia	5/50 (10%)
Hypophosphatemia	9/50 (18%)
Cardiac disorders
Hypertension	13/50 (26%)
General disorders
Fever	5/50 (10%)
Fatigue	17/50 (34%)
Weight Loss	7/50 (14%)
Pain	18/50 (36%)
Voice Changes	3/50 (6%)
Musculoskeletal and connective tissue disorders
Muscle Weakness	2/50 (4%)
Psychiatric disorders
Mood Alteration	4/50 (8%)
Respiratory, thoracic and mediastinal disorders
Pulmonary Hemorrhage	2/50 (4%)
Skin and subcutaneous tissue disorders
Dry Skin	5/50 (10%)
Hand Foot Skin Reaction	16/50 (32%)
Pruritis	3/50 (6%)
Rash	14/50 (28%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.