Gefitinib and PEG-Interferon Alfa-2b in Treating Patients With Unresectable or Metastatic Kidney Cancer

• Sponsor: California Cancer Consortium (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00467077
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 21
• Locations: 3
• Arm: 1
• Duration (Months): 77.9
• Patients Per Site: 7
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

RATIONALE: Gefitinib may stop the growth of kidney cancer by blocking blood flow to the tumor and by blocking some of the enzymes needed for cell growth. PEG-interferon alfa-2b may interfere with the growth of tumor cells and slow the growth of kidney cancer. Giving gefitinib together with PEG-interferon alfa-2b may kill more tumor cells.

PURPOSE: This phase II trial is studying how well giving gefitinib together with PEG-interferon alfa-2b works in treating patients with unresectable or metastatic kidney cancer.

Condition or Disease	Intervention/Treatment	Phase
Kidney Cancer	Biological: PEG-interferon alfa-2b; Drug: gefitinib	Phase 2

Detailed Description

OBJECTIVES:

Primary

• Determine the 6-month progression-free survival of patients with unresectable or metastatic renal cell carcinoma treated with gefitinib and PEG-interferon alfa-2b.

Secondary

• Determine the response rate (by RECIST criteria), duration of response, time to treatment failure, and overall survival of patients treated with this regimen.

• Assess toxicity and tolerability of this regimen in these patients.

• Determine the pre-treatment expression of the von Hippel-Lindau (VHL) protein, the epidermal growth factor receptor (EGFR), and p27, and correlate with response to treatment.

• Determine post-treatment alteration of EGFR and p27 expression in patients with tumors accessible for serial biopsy.

• Assess changes in EGFR levels in buccal epithelial cells in patients treated with this regimen.

OUTLINE: This is a multicenter study.

Patients receive oral gefitinib once daily and PEG-interferon alfa-2b subcutaneously once weekly in weeks 1-6. Treatment repeats every 6 weeks for 2 courses in the absence of disease progression or unacceptable toxicity. Patients with a partial response or stable disease after completion of course 2 continue to receive gefitinib alone as above in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed periodically for up to 2 years.

PROJECTED ACCRUAL: A total of 39 patients will be accrued for this study.

Study Design

• Study Type: Interventional
• Actual Enrollment: 21 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Trial of ZD1839 (IRESSA®) and Pegylated Interferon Alfa 2b (PEG-Intron™) in Unresectable or Metastatic Renal Cell Carcinoma
• Study Start Date: Sep 1, 2004
• Actual Primary Completion Date: Mar 1, 2011
• Actual Study Completion Date: Mar 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Gefitinib and PEG-IFNa Treatment Gefitinib administered at a dose of 250 mg orally once daily for 12 weeks. PEG-IFNa at 4.0 µg/kg/wk administered subcutaneously once weekly for 6 weeks (cycle repeated once for a total of 2 cycles).	Biological: PEG-interferon alfa-2b; PEG-Interferon will be administered subcutaneously (sq) once weekly for 6 weeks; Drug: gefitinib; ZD1839 will be administered at a dose of 250 mg orally once daily,

Outcome Measures

Primary Outcome Measures

1. Six-month Progression-free Survival [From the date treatment started until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 6 months]

   Estimated using the product-limit method of Kaplan and Meier. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of LD of target lesions taking as references the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions or unequivocal progression of existing non-target lesions

Secondary Outcome Measures

1. Number of Participants With Overall Response as Measured by RECIST Criteria [After 2 cycles of treatment, up to 2 years.]

   Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) 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 = CR + PR

2. Progression-Free Survival [Until disease progression, up to 5 years.]

   Estimated using the product-limit method of Kaplan and Meier. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), 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.

3. Overall Survival [Up to 5 years.]

   Estimated using the product-limit method of Kaplan and Meier.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 120 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed renal cell carcinoma

• Metastatic or advanced/unresectable disease

• Measurable or nonmeasurable disease as defined by RECIST criteria

• No uncontrolled brain metastases

• Patients with adequately treated brain metastases who are not taking anticonvulsants and corticosteroids may be eligible

PATIENT CHARACTERISTICS:

• Karnofsky performance status 60-100%

• Life expectancy ≥ 12 weeks

• WBC ≥ 3,500/mm³

• Platelet count ≥ 100,000/mm³

• Absolute granulocyte count ≥ 1,500/mm³

• Creatinine ≤ 2.0 mg/dL OR creatinine clearance ≥ 50 mL/min

• Bilirubin ≤ 1.5 mg/dL

• AST ≤ 2 times upper limit of normal (ULN)

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective contraception

• No other malignancy within the past 5 years except adequately treated basal cell or squamous cell carcinoma of the skin, carcinoma in situ of the cervix, or adequately treated stage I or II cancer from which the patient is currently in complete remission

• No known severe hypersensitivity to gefitinib or its excipients

• No incomplete healing from previous oncologic or other major surgery

• No unresolved chronic toxicity > grade 2 from previous anticancer therapy (except alopecia and anemia)

• No evidence of clinically active interstitial lung disease

• Patients with chronic stable radiographic changes who are asymptomatic are eligible

• No evidence of severe or uncontrolled systemic disease (e.g., unstable or uncompensated respiratory, cardiac, hepatic, or renal disease)

• No other significant clinical disorder or laboratory finding that would preclude study participation

PRIOR CONCURRENT THERAPY:

• More than 30 days since prior nonapproved or investigational drugs

• More than 6 weeks since prior aldesleukin or interferon and recovered

• At least 3 weeks since prior radiotherapy

• No prior gefitinib

• Prior chemotherapy or biological therapy allowed

• Prior or concurrent bisphosphonate therapy for bone metastases allowed

• No concurrent phenytoin, carbamazepine, rifampin, barbiturates, phenobarbital, or Hypericum perforatum (St. John's wort)

• No other concurrent agents specifically designed to inhibit the epidermal growth factor receptor (EGFR)

• No concurrent radiotherapy to measurable lesions

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	City of Hope Comprehensive Cancer Center	Duarte	California	United States	91010-3000
2	USC/Norris Comprehensive Cancer Center and Hospital	Los Angeles	California	United States	90089-9181
3	University of California Davis Cancer Center	Sacramento	California	United States	95817

Sponsors and Collaborators

• California Cancer Consortium
• National Cancer Institute (NCI)

Investigators

• Study Chair: Primo N. Lara, MD, University of California, Davis

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: California Cancer Consortium
• ClinicalTrials.gov Identifier: NCT00467077
• Other Study ID Numbers: CDR0000540598; P30CA093373; CCC-PHII-40; ZENECA-AZ1839US/0227; UCD-200412338-4; UCD-ZD1839
• First Posted: Apr 27, 2007
• Last Update Posted: Mar 17, 2017
• Last Verified: Jan 1, 2017

• Keywords provided by California Cancer Consortium: recurrent renal cell cancer; stage IV renal cell cancer; stage III renal cell cancer
• Additional relevant MeSH terms: Kidney Neoplasms; Carcinoma, Renal Cell; Interferons; Interferon-alpha; Interferon alpha-2; Peginterferon alfa-2b; Gefitinib

Study Results

Participant Flow

Arm/Group Title	Gefitinib and PEG-IFNa Treatment
Arm/Group Description	Gefitinib administered at a dose of 250 mg orally once daily for 12 weeks. PEG-IFNa at 4.0 µg/kg/wk administered subcutaneously once weekly for 6 weeks (cycle repeated once for a total of 2 cycles).
Period Title: Overall Study
STARTED	21
COMPLETED	21
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Gefitinib and PEG-IFNa Treatment
Arm/Group Description	Gefitinib administered at a dose of 250 mg orally once daily for 12 weeks. PEG-IFNa at 4.0 µg/kg/wk administered subcutaneously once weekly for 6 weeks (cycle repeated once for a total of 2 cycles).
Overall Participants	21
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	60
Sex: Female, Male (Count of Participants)
Female	6 28.6%
Male	15 71.4%
Region of Enrollment (participants) [Number]
United States	21 100%

Outcome Measures

1. Primary Outcome

Title	Six-month Progression-free Survival
Description	Estimated using the product-limit method of Kaplan and Meier. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of LD of target lesions taking as references the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions or unequivocal progression of existing non-target lesions
Time Frame	From the date treatment started until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Gefitinib and PEG-IFNa Treatment
Arm/Group Description	Gefitinib administered at a dose of 250 mg orally once daily for 12 weeks. PEG-IFNa at 4.0 µg/kg/wk administered subcutaneously once weekly for 6 weeks (cycle repeated once for a total of 2 cycles).
Measure Participants	21
Number (95% Confidence Interval) [percentage of participants]	29 138.1%

2. Secondary Outcome

Title	Number of Participants With Overall Response as Measured by RECIST Criteria
Description	Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) 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 = CR + PR
Time Frame	After 2 cycles of treatment, up to 2 years.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Gefitinib and PEG-IFNa Treatment
Arm/Group Description	Gefitinib administered at a dose of 250 mg orally once daily for 12 weeks. PEG-IFNa at 4.0 µg/kg/wk administered subcutaneously once weekly for 6 weeks (cycle repeated once for a total of 2 cycles).
Measure Participants	21
Number [participants]	2 9.5%

3. Secondary Outcome

Title	Progression-Free Survival
Description	Estimated using the product-limit method of Kaplan and Meier. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), 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	Until disease progression, up to 5 years.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Gefitinib and PEG-IFNa Treatment
Arm/Group Description	Gefitinib administered at a dose of 250 mg orally once daily for 12 weeks. PEG-IFNa at 4.0 µg/kg/wk administered subcutaneously once weekly for 6 weeks (cycle repeated once for a total of 2 cycles).
Measure Participants	21
Median (95% Confidence Interval) [Months]	5.2

4. Secondary Outcome

Title	Overall Survival
Description	Estimated using the product-limit method of Kaplan and Meier.
Time Frame	Up to 5 years.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Gefitinib and PEG-IFNa Treatment
Arm/Group Description	Gefitinib administered at a dose of 250 mg orally once daily for 12 weeks. PEG-IFNa at 4.0 µg/kg/wk administered subcutaneously once weekly for 6 weeks (cycle repeated once for a total of 2 cycles).
Measure Participants	21
Median (95% Confidence Interval) [Months]	13.6

Adverse Events

Time Frame	Adverse events were collected over a period of 38 months.
Adverse Event Reporting Description	"Other Adverse Events" include all events that were not severe adverse events regardless of grade or relation to treatment.
Arm/Group Title	Arm 1
Arm/Group Description	Gefitinib administered at a dose of 250 mg orally once daily for 12 weeks. PEG-IFNa at 4.0 µg/kg/wk administered subcutaneously once weekly for 6 weeks (cycle repeated once for a total of 2 cycles).
All Cause Mortality
	Arm 1
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Arm 1
	Affected / at Risk (%)	# Events
Total	11/21 (52.4%)
Cardiac disorders
Atrial fibrillation	1/21 (4.8%)	1
Gastrointestinal disorders
Nausea	2/21 (9.5%)	2
General disorders
Edema limbs	1/21 (4.8%)	1
Fatigue	2/21 (9.5%)	2
Injury, poisoning and procedural complications
Fracture	1/21 (4.8%)	1
Investigations
Aspartate aminotransferase increased	1/21 (4.8%)	1
Creatinine increased	1/21 (4.8%)	1
INR increased	1/21 (4.8%)	1
Leukopenia	1/21 (4.8%)	1
Lymphopenia	1/21 (4.8%)	1
Neutrophil count decreased	1/21 (4.8%)	1
Metabolism and nutrition disorders
Anorexia	1/21 (4.8%)	1
Dehydration	2/21 (9.5%)	2
Hypokalemia	1/21 (4.8%)	1
Hyponatremia	2/21 (9.5%)	2
Musculoskeletal and connective tissue disorders
Muscle weakness	1/21 (4.8%)	1
Nervous system disorders
Syncope	1/21 (4.8%)	1
Renal and urinary disorders
Renal failure	1/21 (4.8%)	2
Respiratory, thoracic and mediastinal disorders
Dyspnea	3/21 (14.3%)	3
Hypoxia	1/21 (4.8%)	1
Skin and subcutaneous tissue disorders
Acne	1/21 (4.8%)	1
Vascular disorders
Hypotension	3/21 (14.3%)	3
Thrombosis	1/21 (4.8%)	1
Other (Not Including Serious) Adverse Events
	Arm 1
	Affected / at Risk (%)	# Events
Total	20/21 (95.2%)
Blood and lymphatic system disorders
Hemoglobin decreased	17/21 (81%)	63
Cardiac disorders
Cardiac disorder	1/21 (4.8%)	3
Palpitations	1/21 (4.8%)	1
Eye disorders
Conjunctival disorder	1/21 (4.8%)	6
Dry eye syndrome	1/21 (4.8%)	3
Eye disorder	1/21 (4.8%)	1
Eyelid function disorder	2/21 (9.5%)	11
Retinopathy	1/21 (4.8%)	3
Vision blurred	2/21 (9.5%)	3
Watering eyes	1/21 (4.8%)	2
Gastrointestinal disorders
Abdominal pain	3/21 (14.3%)	9
Constipation	1/21 (4.8%)	1
Diarrhea	13/21 (61.9%)	28
Dry mouth	3/21 (14.3%)	4
Dyspepsia	1/21 (4.8%)	1
Dysphagia	2/21 (9.5%)	2
Ear, nose and throat examination abnormal	2/21 (9.5%)	3
Hemorrhoids	1/21 (4.8%)	1
Mucositis oral	1/21 (4.8%)	1
Nausea	13/21 (61.9%)	21
Vomiting	8/21 (38.1%)	10
General disorders
Chills	1/21 (4.8%)	1
Disease progression	7/21 (33.3%)	7
Edema limbs	2/21 (9.5%)	12
Fatigue	17/21 (81%)	48
Fever	2/21 (9.5%)	2
Flu-like symptoms	1/21 (4.8%)	1
Gait abnormal	1/21 (4.8%)	2
General symptom	1/21 (4.8%)	2
Injection site reaction	1/21 (4.8%)	1
Pain	2/21 (9.5%)	3
Infections and infestations
Eye infection	1/21 (4.8%)	2
Infection	2/21 (9.5%)	2
Nail infection	1/21 (4.8%)	3
Pneumonia	1/21 (4.8%)	1
Rhinitis infective	1/21 (4.8%)	3
Scrotal infection	1/21 (4.8%)	1
Upper respiratory infection	2/21 (9.5%)	3
Urinary tract infection	1/21 (4.8%)	1
Injury, poisoning and procedural complications
Bruising	1/21 (4.8%)	2
Fracture	1/21 (4.8%)	1
Investigations
Alanine aminotransferase increased	8/21 (38.1%)	15
Alkaline phosphatase increased	6/21 (28.6%)	8
Aspartate aminotransferase increased	10/21 (47.6%)	22
Bilirubin increased	2/21 (9.5%)	9
Creatinine increased	8/21 (38.1%)	34
Hyperbilirubinemia	3/21 (14.3%)	4
INR increased	1/21 (4.8%)	2
Leukocyte count decreased	5/21 (23.8%)	10
Leukopenia	11/21 (52.4%)	18
Lymphocyte count decreased	4/21 (19%)	10
Lymphopenia	3/21 (14.3%)	5
Neutrophil count decreased	10/21 (47.6%)	16
Platelet count decreased	6/21 (28.6%)	9
Weight loss	6/21 (28.6%)	18
Metabolism and nutrition disorders
Anorexia	13/21 (61.9%)	29
Blood glucose increased	2/21 (9.5%)	11
Dehydration	5/21 (23.8%)	5
Hypercalcemia	3/21 (14.3%)	5
Hyperglycemia	11/21 (52.4%)	36
Hyperkalemia	2/21 (9.5%)	3
Hypernatremia	1/21 (4.8%)	1
Hypoalbuminemia	12/21 (57.1%)	28
Hypocalcemia	5/21 (23.8%)	6
Hypoglycemia	2/21 (9.5%)	3
Hypokalemia	3/21 (14.3%)	3
Hyponatremia	6/21 (28.6%)	7
Serum albumin decreased	4/21 (19%)	7
Serum calcium decreased	2/21 (9.5%)	3
Serum glucose decreased	1/21 (4.8%)	1
Serum potassium decreased	1/21 (4.8%)	1
Serum potassium increased	1/21 (4.8%)	1
Musculoskeletal and connective tissue disorders
Back pain	5/21 (23.8%)	9
Bone pain	1/21 (4.8%)	1
Joint pain	3/21 (14.3%)	16
Muscle weakness	3/21 (14.3%)	10
Muscle weakness lower limb	1/21 (4.8%)	2
Muscle weakness trunk	1/21 (4.8%)	1
Myalgia	5/21 (23.8%)	8
Pain in extremity	4/21 (19%)	9
Nervous system disorders
Dizziness	5/21 (23.8%)	9
Headache	2/21 (9.5%)	8
Memory impairment	2/21 (9.5%)	14
Peripheral motor neuropathy	1/21 (4.8%)	3
Sinus pain	1/21 (4.8%)	1
Syncope	1/21 (4.8%)	1
Taste alteration	1/21 (4.8%)	1
Tremor	1/21 (4.8%)	19
Psychiatric disorders
Agitation	2/21 (9.5%)	3
Anxiety	4/21 (19%)	7
Depression	5/21 (23.8%)	26
Euphoria	1/21 (4.8%)	3
Insomnia	3/21 (14.3%)	4
Renal and urinary disorders
Bladder hemorrhage	1/21 (4.8%)	1
Bladder pain	1/21 (4.8%)	2
Hemorrhage urinary tract	2/21 (9.5%)	3
Proteinuria	2/21 (9.5%)	2
Urethral pain	1/21 (4.8%)	1
Urinary frequency	2/21 (9.5%)	4
Urinary retention	1/21 (4.8%)	3
Urine discoloration	1/21 (4.8%)	1
Respiratory, thoracic and mediastinal disorders
Allergic rhinitis	3/21 (14.3%)	16
Cough	2/21 (9.5%)	16
Dyspnea	6/21 (28.6%)	8
Hemorrhage nasal	1/21 (4.8%)	5
Laryngeal mucositis	1/21 (4.8%)	1
Nasal congestion	1/21 (4.8%)	1
Pharyngolaryngeal pain	1/21 (4.8%)	1
Pleuritic pain	1/21 (4.8%)	1
Respiratory disorder	1/21 (4.8%)	4
Voice alteration	2/21 (9.5%)	16
Skin and subcutaneous tissue disorders
Acne	5/21 (23.8%)	23
Alopecia	2/21 (9.5%)	4
Dry skin	7/21 (33.3%)	19
Nail disorder	3/21 (14.3%)	5
Petechiae	1/21 (4.8%)	1
Pruritus	2/21 (9.5%)	3
Rash acneiform	4/21 (19%)	19
Rash desquamating	7/21 (33.3%)	28
Skin disorder	1/21 (4.8%)	2
Skin ulceration	1/21 (4.8%)	1
Sweating	1/21 (4.8%)	2
Vascular disorders
Hypertension	2/21 (9.5%)	2

Limitations/Caveats

Protocol was closed prior to the second stage of accrual (pegged at n = 24) due to slow accrual. The reason for the slow accrual was likely the availability of several new Food and Drug Administration approved targeted agents during the study period.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.