Sorafenib to Overcome Resistance to Systemic Chemotherapy in Androgen-independent Prostate Cancer

• Sponsor: Oncology Specialists, S.C. (Other)
• Overall Status: Completed
• CT.gov ID: NCT00414388
• Collaborator: (none)
• Enrollment: 22
• Locations: 2
• Arm: 1
• Duration (Months): 63
• Patients Per Site: 11
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The primary objective of this study is to evaluate the safety of combining Sorafenib and chemotherapy (mitoxantrone or docetaxel) in patients with AIPC.

Condition or Disease	Intervention/Treatment	Phase
Prostate Cancer	Drug: Sorafenib	Phase 1/Phase 2

Detailed Description

Patients who have AIPC and are progressing despite systemic chemotherapy will be offered participation in this study. Patients who relapse or progress shortly (within 12 weeks) after discontinuation of chemotherapy with either docetaxel/prednisone or mitoxantrone/prednisone will also be offered participation in this trial. Enrolled patients will receive sorafenib as per protocol define dose. Sorafenib will be administered in combination with the last chemotherapy utilized. If there is no disease progression after 6 cycles, chemotherapy will be stopped and Sorafenib may continue until disease progression.

Study Design

• Study Type: Interventional
• Actual Enrollment: 22 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase I/II Study to Evaluate the Ability of Sorafenib in Overcoming Resistance to Systemic Chemotherapy in Androgen-independent Prostate Cancer (AIPC)
• Study Start Date: Dec 1, 2006
• Actual Primary Completion Date: Sep 1, 2011
• Actual Study Completion Date: Mar 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Single agent Sorafenib Oral Single agent Sorafenib 400mg twice daily	Drug: Sorafenib; 400mg twice daily; Other Names: Nexavar

Outcome Measures

Primary Outcome Measures

1. Percentage of Patients Needing a Dose Reduction. [participants were followed for an average of 25 months]

   The actual percentage was determined by taking the number of patients requiring a dose reduction divided by the total number of patients multiplied by100%

Secondary Outcome Measures

1. Overall Clinical Benefit (OCB)of This Combination as Calculated by the Sum of Complete Response (CR), Partial Response (PR), and Stable Disease (SD). [3-10 months]

   Assessment of response was done per Response Evaluation Criteria in Solid Tumors (RECIST) criteria as outlined in the protocol. Complete Response (CR) defined as disappearance of all measurable lesions. Partial Response (PR) more than 30% decrease in the sum of longest diameter of measurable lesions compared to baseline. Stable Disease (SD) lesions should have no sufficient decrease for PR any sufficient increase to meet criteria for PD. Progressive Disease (PD) more than 20% increase in the sum of longest diameter of measurable lesions compared to baseline, and/or evidence of new lesions on imaging studies or the appearance of 2 or more new bony lesions. For patient with measurable disease,prostate-specific antigen (PSA), progression in the absence of measurable disease progression will not be considered progressive disease. Overall Clinical Benefit (OCB) (CR + PR+ SD)/#participants.

2. PSA -Biochemical Response [1-10 months]

   PSA Biochemical Response = PSA complete response + PSA partial response. A PSA complete response is defined as a non-detectable PSA (<4 ng/dl). A PSA partial response is defined as a PSA that decreases by greater than or equal to 50%.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 90 Years
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Age > 18 years old

• Eastern Cooperative Oncology Group (ECOG) Performance Status 0, 1, or 2.

• Patients with a known diagnosis of prostate cancer regardless of their Gleason grade.

• Patients have AIPC.

• Adequate bone marrow, liver and renal function as assessed by:

• Hemoglobin > 9.0 g/dl

• absolute neutrophil count (ANC) > 1,000/mm3

• Platelet count > 75,000/mm3

• Total bilirubin < 1.5 x upper limit of normal (ULN)

• Alanine transaminase (ALT) and aspartate aminotransferase (AST) < 2.5 x the ULN (< 5 x ULN for patients with liver involvement). international normalized ratio (INR) < 1.5 or a Prothrombin time (PT)/partial thromboplastin time (PTT) within normal limits. Patients receiving anti-coagulation treatment with an agent such as warfarin or heparin may be allowed to participate.

• Creatinine < 1.5 x ULN

• Transfusions and the use of growth factors (for red and white cells) are allowed

• Patients must have received either docetaxel or mitoxantrone as the chemotherapy regimen

• Ability to understand and willingness to sign a written informed consent. A signed informed consent must be obtained prior to any study specific procedures.

• Patients must have progressed while receiving systemic chemotherapy for AIPC. Patients could have progressed within 12 weeks of their last systemic chemotherapy administration. The definition of progression is defined as follows:

• 1-For patients who are receiving systemic chemotherapy (one criteria is sufficient):

• Increase in prostate-specific antigen (PSA) by 25% or more than the previous value. This should be repeated within 3 weeks (while patient is off chemotherapy) to confirm that the PSA did not decrease.

• For patients with visceral disease, radiographic evidence of progression by standard Response Evaluation Criteria in Solid Tumors (RECIST) criteria (regardless of the PSA value).

• For patients with bone only disease, progression on a whole body bone scan (2 or more new lesions) is sufficient to fulfill the definition of progressive disease, regardless of PSA value or the visceral disease status.

• 2-For patients who have received chemotherapy previously (Both criteria are needed):

• Not more than 12 weeks have elapsed since last chemotherapy administration

• Either biochemical progression (25% increase in PSA that is confirmed with a repeat analysis within 3 weeks), OR radiographic progression (RECIST criteria for visceral disease patients OR 2 or more lesions on a whole body bone scan)

Exclusion Criteria:

• Cardiac disease: Congestive heart failure > class II New York Heart Association 9NYHA). Patients must not have unstable angina or new onset angina or myocardial infarction within the past 6 months.

• Known brain metastasis. Patients with neurological symptoms must undergo a CT scan or MRI of brain to exclude brain metastasis.

• Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy. Patients with history of chronic and well controlled atrial fibrillation are allowed. Beta-blockers, calcium channel blockers, or digoxin are not considered anti-arrhythmics.

• Uncontrolled hypertension defined as systolic blood pressure > 150 mmHg or diastolic pressure > 90 mmHg, despite optimal medical management.

• Sorafenib is contraindicated in patients with known severe hypersensitivity to sorafenib or any of the excipients.

• Known human immunodeficiency virus (HIV) infection or chronic Hepatitis B or C.

• Active clinically serious infection > Common Toxicity Criteria for Adverse Effects (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 uncontrolled coagulopathy.

• Major surgery, open biopsy or significant traumatic injury within 4 weeks of first study drug.

• Use of St. John's Wort or rifampin (rifampicin).

• 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Onocology Specialists, S.C	Niles	Illinois	United States	60714
2	Oncology Specialists, S.C	Park Ridge	Illinois	United States	60068

Sponsors and Collaborators

• Oncology Specialists, S.C.

Investigators

• Principal Investigator: Chadi Nabhan, MD, Oncology Specialists, SC

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Dr. Sigrun Hallmeyer, Director of Research, Oncology Specialists, S.C.
• ClinicalTrials.gov Identifier: NCT00414388
• Other Study ID Numbers: 0603
• First Posted: Dec 21, 2006
• Last Update Posted: Apr 7, 2014
• Last Verified: Feb 1, 2014

• Keywords provided by Dr. Sigrun Hallmeyer, Director of Research, Oncology Specialists, S.C.: AIPC
• Additional relevant MeSH terms: Prostatic Neoplasms; Sorafenib

Study Results

Participant Flow

Recruitment Details	Recruitment was from our clinic population.
Pre-assignment Detail	Eligible patients were those who progressed while receiving chemotherapy (docetaxel or mitoxantrone)or within 12 weeks of stopping chemo.

Arm/Group Title	Single Agent Sorafenib
Arm/Group Description	Eligible patients were continued on the same chemotherapeutic regimen they had progressed on prior on entry into the study (docetaxel or mitoxantrone) with the addition of Sorafenib at 400mg twice daily. Docetaxel was given at 75 mg/m^2 and mitoxantrone was given at 12 mg/m^2, both once every 21 days and both combined with prednisone at 5mg twice daily. A maximum of 6 cycles of sorafenib plus chemotherapy were allowed. Patients without objective disease progression after combination therapy was complete were allowed to receive sorafenib monotherapy until disease progression.
Period Title: Overall Study
STARTED	22
COMPLETED	21
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	Single Agent Sorafenib
Arm/Group Description	Oral Single agent Sorafenib 400mg twice daily
Overall Participants	22
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	5 22.7%
>=65 years	17 77.3%
Sex: Female, Male (Count of Participants)
Female	0 0%
Male	22 100%
Region of Enrollment (participants) [Number]
United States	22 100%

Outcome Measures

1. Primary Outcome

Title	Percentage of Patients Needing a Dose Reduction.
Description	The actual percentage was determined by taking the number of patients requiring a dose reduction divided by the total number of patients multiplied by100%
Time Frame	participants were followed for an average of 25 months

Outcome Measure Data

Analysis Population Description

15 patients required dose reductions.

Arm/Group Title	Single Agent Sorafenib
Arm/Group Description	Oral Single agent Sorafenib 400mg twice daily
Measure Participants	21
Number [percentage of participants]	71 322.7%

2. Secondary Outcome

Title	Overall Clinical Benefit (OCB)of This Combination as Calculated by the Sum of Complete Response (CR), Partial Response (PR), and Stable Disease (SD).
Description	Assessment of response was done per Response Evaluation Criteria in Solid Tumors (RECIST) criteria as outlined in the protocol. Complete Response (CR) defined as disappearance of all measurable lesions. Partial Response (PR) more than 30% decrease in the sum of longest diameter of measurable lesions compared to baseline. Stable Disease (SD) lesions should have no sufficient decrease for PR any sufficient increase to meet criteria for PD. Progressive Disease (PD) more than 20% increase in the sum of longest diameter of measurable lesions compared to baseline, and/or evidence of new lesions on imaging studies or the appearance of 2 or more new bony lesions. For patient with measurable disease,prostate-specific antigen (PSA), progression in the absence of measurable disease progression will not be considered progressive disease. Overall Clinical Benefit (OCB) (CR + PR+ SD)/#participants.
Time Frame	3-10 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Single Agent Sorafenib
Arm/Group Description	Oral Single agent Sorafenib 400mg twice daily
Measure Participants	21
Number [percentage of patients]	76

3. Secondary Outcome

Title	PSA -Biochemical Response
Description	PSA Biochemical Response = PSA complete response + PSA partial response. A PSA complete response is defined as a non-detectable PSA (<4 ng/dl). A PSA partial response is defined as a PSA that decreases by greater than or equal to 50%.
Time Frame	1-10 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Sorafenib
Arm/Group Description	Eligible patients were continued on the same chemotherapeutic regimen they had progressed on prior on entry into the study (Docetaxel or Mitoxantrone) with the addition of Sorafenib at 400mg twice daily. Docetaxel was given at 75 mg/m2 and Mitoxantrone was given at 12 mg/m2, both once every 21 days and both combined with Prednisone at 5mg twice daily. A maximum of 6 cycles of Sorafenib plus chemotherapy were allowed. Patients without objective disease progression after combination therapy was complete were allowed to receive Sorafenib monotherapy until disease progression.
Measure Participants	21
Number [percentage of participants]	45 204.5%

Adverse Events

Arm/Group Title	Single Agent Sorafenib
Arm/Group Description	Oral Single agent Sorafenib 400mg twice daily
All Cause Mortality
	Single Agent Sorafenib
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Single Agent Sorafenib
	Affected / at Risk (%)	# Events
Total	12/22 (54.5%)
Blood and lymphatic system disorders
Anemia	1/22 (4.5%)
Electrolyte imbalance	1/22 (4.5%)
Neutropenic Fever	1/22 (4.5%)
Diverticular Bleed	1/22 (4.5%)
Cardiac disorders
Atrial Fibrillation	1/22 (4.5%)
Gastrointestinal disorders
constipation	2/22 (9.1%)
Dehydration	1/22 (4.5%)
C-diff	1/22 (4.5%)
General disorders
Hypoglycemia	1/22 (4.5%)
Back Pain	1/22 (4.5%)
Fatigue	1/22 (4.5%)
Adominal Pain	2/22 (9.1%)
Renal and urinary disorders
urinary retention	2/22 (9.1%)
Urinary Tract Infection	1/22 (4.5%)
Respiratory, thoracic and mediastinal disorders
Pneumonia	2/22 (9.1%)
Other (Not Including Serious) Adverse Events
	Single Agent Sorafenib
	Affected / at Risk (%)	# Events
Total	22/22 (100%)
Blood and lymphatic system disorders
Leukopenia	14/22 (63.6%)
Neutropenia	9/22 (40.9%)
Thrombocytopenia	17/22 (77.3%)
Anemia	17/22 (77.3%)
Lymphopenia	19/22 (86.4%)
Hypocalcemia	11/22 (50%)
Bruises Easily	8/22 (36.4%)
Cardiac disorders
Atrial Fibrillation	2/22 (9.1%)
Tachycardia	9/22 (40.9%)
Ear and labyrinth disorders
Ear Pain	3/22 (13.6%)
Hard of hearing	3/22 (13.6%)
Eye disorders
Eyes dry	3/22 (13.6%)
Eyes tearing	3/22 (13.6%)
Vision Problems	4/22 (18.2%)
Gastrointestinal disorders
Anorexia	15/22 (68.2%)
Albumin decreased	15/22 (68.2%)
AST increased	6/22 (27.3%)
Alkaline Phosphatase Increased	11/22 (50%)
Constipation	8/22 (36.4%)
Dehydration	4/22 (18.2%)
Diarrhea	18/22 (81.8%)
Globulin decreased	6/22 (27.3%)
Hypokalemia	8/22 (36.4%)
Heartburn	2/22 (9.1%)
Hyponatremia	8/22 (36.4%)
Hyperkalemia	4/22 (18.2%)
Mouth Dry	11/22 (50%)
Mouth Sores	2/22 (9.1%)
Nausea	8/22 (36.4%)
Protein Decreased	14/22 (63.6%)
Stomatitis	3/22 (13.6%)
Taste Changes	7/22 (31.8%)
Throat sore	9/22 (40.9%)
Vomiting	2/22 (9.1%)
General disorders
Fatigue	16/22 (72.7%)
Hypoglycemia	2/22 (9.1%)
Hyperglycemia	10/22 (45.5%)
Alopecia	12/22 (54.5%)
Back Pain	2/22 (9.1%)
Chills	5/22 (22.7%)
Concentration Difficulty	4/22 (18.2%)
Dizziness	5/22 (22.7%)
Edema	4/22 (18.2%)
Fall	2/22 (9.1%)
Fever	4/22 (18.2%)
Foot pain	2/22 (9.1%)
Facial swelling	2/22 (9.1%)
Hypotension	2/22 (9.1%)
Headache	7/22 (31.8%)
Hypertension	2/22 (9.1%)
Insomnia	3/22 (13.6%)
Neuropathy	14/22 (63.6%)
Pain	7/22 (31.8%)
Sweats	3/22 (13.6%)
Weight decreased	8/22 (36.4%)
Infections and infestations
Pneumonia	3/22 (13.6%)
Musculoskeletal and connective tissue disorders
Chest pain non cardiac	3/22 (13.6%)
Jaw Pain	5/22 (22.7%)
Nervous system disorders
Arthralgia	3/22 (13.6%)
Psychiatric disorders
Anxiety	4/22 (18.2%)
Depression	5/22 (22.7%)
Renal and urinary disorders
Bilirubin Increased	3/22 (13.6%)
Creatinine Increased	3/22 (13.6%)
Urinary retention	2/22 (9.1%)
Urination Problems	3/22 (13.6%)
Reproductive system and breast disorders
Gynecomastia	3/22 (13.6%)
Hot flashes	2/22 (9.1%)
Libido decreased	3/22 (13.6%)
Respiratory, thoracic and mediastinal disorders
Cough	8/22 (36.4%)
Dyspnea on Exertion	3/22 (13.6%)
Shortness of Breath	4/22 (18.2%)
Wheezing	3/22 (13.6%)
Skin and subcutaneous tissue disorders
hand/foot syndrome	10/22 (45.5%)
Itching	5/22 (22.7%)
Nail changes	7/22 (31.8%)
Rash	15/22 (68.2%)
Skin peeling	2/22 (9.1%)
Ulcer pressure	3/22 (13.6%)

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.