Kidney Cancer
Conditions
Keywords
stage III renal cell cancer, stage IV renal cell cancer, clear cell renal cell carcinoma, recurrent renal cell cancer
Brief summary
RATIONALE: Sunitinib and erlotinib may stop the growth of tumor cell by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. Giving sunitinib together with erlotinib may kill more tumor cells. PURPOSE: This phase II trial is studying the best dose of erlotinib when given together with sunitinib and to see how well they work in treating patients with unresectable or metastatic kidney cancer.
Detailed description
OBJECTIVES: Primary * Determine the maximum tolerated dose of erlotinib hydrochloride when administered with sunitinib malate in patients with unresectable or metastatic renal cell carcinoma. * Determine the 8-month progression-free survival of patients treated with this regimen. Secondary * Determine the safety of sunitinib malate and erlotinib hydrochloride in these patients. * Determine the duration of response in these patients. * Determine the proportion of patients whose best overall response is complete response, partial response, stable disease, or progressive disease. * Determine the overall survival of patients treated with this regimen. * Determine the maximum percent reduction in tumor measurement in patients treated with this regimen. * Collect blood and tissue from these patients for future correlative studies. OUTLINE: This is an open-label, multicenter, dose-escalation study of erlotinib hydrochloride. Patients receive oral sunitinib malate once daily on days 1-28 and oral erlotinib hydrochloride once daily on days 1-42. Treatment repeats every 6 weeks in the absence of disease progression or unacceptable toxicity. Cohorts of 3-6 patients receive escalating doses of erlotinib hydrochloride until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose at which 33% of patients experience dose-limiting toxicity. Once the MTD is determined, patients are treated with erlotinib hydrochloride at the MTD and sunitinib malate. Patients undergo blood and tumor specimen collection periodically during study for future correlative studies. PROJECTED ACCRUAL: A total of 49 patients will be accrued for this study.
Interventions
DRUGerlotinib hydrochloride
Dose Level 0 = 50 mg/day, continuous daily; 0.5= 75 mg/day, continuous daily; 1. 100 mg/day, continuous daily; 1.5= 125 mg/day, continuous daily; 2. 150 mg/day, continuous daily
DRUGsunitinib malate
Will be administered at 50 mg daily, 4 weeks on, 2 weeks off
PROCEDUREbiopsy
Paraffin block (or unstained slides) of the primary tumor and/or metastatic lesions (as available) and a plasma sample for future correlative studies will be collected. A paraffin block (or at least 10 unstained slides, each of 10 micromillimeter thickness) from the original paraffin-embedded biopsy material taken at the diagnosis will be stored at 4 degrees Celsius.
Sponsors
National Cancer Institute (NCI)
OHSU Knight Cancer Institute
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
DISEASE CHARACTERISTICS: * Histologically confirmed renal cell carcinoma with a component of clear cell or papillary carcinoma * Unresectable or metastatic disease (radiologically or clinically confirmed) * Measurable disease (≥ 1 site) * No known brain metastasis that has not been adequately treated with radiotherapy and/or surgery PATIENT CHARACTERISTICS: * Eastern Cooperative Oncology Group (ECOG) performance status 0-2 * Absolute neutrophil count ≥ 1,500/mm³ * Platelet count ≥ 100,000/mm³ * No grade 3 hemorrhage within the past 4 weeks * Bilirubin ≤ 1.5 times upper limit of normal (ULN) * Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) ≤ 2.5 times ULN (\< 5 times ULN if due to underlying disease) * No chronic liver disease (i.e., chronic active hepatitis or cirrhosis) * Creatinine ≤ 1.5 times ULN * None of the following cardiovascular conditions within the past 12 months: * Myocardial infarction * Severe/unstable angina * Coronary/peripheral artery bypass graft * Symptomatic congestive heart failure * Cerebrovascular accident or transient ischemic attack * Pulmonary embolism * Ongoing cardiac dysrhythmia ≥ grade 2 * Atrial fibrillation of any grade * Prolongation of the corrected QT (QTc) interval to \> 450 msec for males or to \> 470 msec for females * Left Ventricular Ejection Fraction (LVEF) normal by Multigated Acquisition (MUGA) or echocardiogram * No hypertension uncontrolled with medical therapy * No other active malignancy within the past 5 years except basal cell skin cancer or cervical carcinoma in situ * No uncontrolled adrenal insufficiency * No uncontrolled hypothyroidism * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective contraception during and for 3 months after completion of study treatment * No severe and/or uncontrolled medical disease (i.e., uncontrolled diabetes, chronic renal disease, or active uncontrolled infection) * No impaired gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study drugs * No other severe acute or chronic medical or psychiatric condition or laboratory abnormality that would preclude study participation PRIOR CONCURRENT THERAPY: * See Disease Characteristics * More than 4 weeks since prior major surgery * More than 4 weeks since prior cytotoxic chemotherapy (6 weeks for nitrosoureas or mitomycin C) * More than 4 weeks since prior radiotherapy * No prior radiotherapy to \> 25% of the bone marrow * More than 28 days since prior investigational agents * No prior sunitinib malate * No prior anti-epidermal growth factor receptor therapy (e.g., erlotinib hydrochloride, panitumumab, cetuximab, or gefitinib) * No concurrent therapeutic warfarin * Low-dose oral warfarin ≤ 2 mg daily for deep vein thrombosis prophylaxis is allowed after the maximum tolerated dose of erlotinib hydrochloride is determined * No concurrent Hypericum perforatum (St. John's wort) * No concurrent chemotherapy or biologic therapy * No other concurrent anticancer therapy * No other concurrent investigational agents
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose (MTD) of Erlotinib Hydrochloride When Used in Combination With Sunitinib. | Participants assessed for DLTs weekly during the first cycle of treatment and every 3 weeks in subsequent cycles until at least one DLT occurs in 33% or more of participants at that dose; participants assessed for the duration of the study, up to 7 years | The MTD is defined as the dose that produces dose limiting toxicity (DLT) in 33% of the patients. |
| Progression-free Survival at 8 Months | 8 months after initiating treatment with sunitinib in combination with erlotinib in patients with metastatic or unresectable clear cell or papillary carcinoma of the kidney | Defined as the proportion of patients who are progression free (CR, PR and SD) at 8 months after initiating treatment with sunitinib in combination with erlotinib in patients with metastatic or unresectable clear cell or papillary carcinoma of the kidney. Complete Response (CR)= disappearance of all target lesions, Partial Response (PR)= At least a 30% decrease in the sum of the longest diameter of target lesions, and Stable Disease (SD)= Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (20% increase in the sum). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| To Determine the Safety of Sunitinib in Combination With Erlotinib | For the duration of the study, up to 7 years | — |
| Median Time to Progression | For the duration of the study, up to 7 years | The Kaplan-Meier method will be used to estimate the median time to progression. |
| Proportion of Patients Whose Best Overall Response is Complete Response, Partial Response, Stable Disease, or Progressive Disease | From the start of treatment until the criteria for response is met. | — |
| Maximum Percent Change in Tumor Measurement | Baseline through end of study, up to 7 years | The maximum percent change in Tumor Measurement is the greatest percent change in longest diameter (LD) for the target lesions from the baseline LD. For patients with no change in LD, the maximum percent change is the lowest increase in LD from the baseline LD. |
Countries
United States
Participant flow
Pre-assignment details
The discrepancy between the number of participants enrolled (60) and the number of participants Started in the Participant Flow module (46) is due to screen failures and consent withdrawals.
Participants by arm
| Arm | Count |
|---|---|
| Sunitinib and Erlotinib Erlotinib: Dose Level 0 = 50 mg/day, continuous daily; 0.5= 75 mg/day, continuous daily;
1. 100 mg/day, continuous daily; 1.5= 125 mg/day, continuous daily;
2. 150 mg/day, continuous daily
Sunitinib: 50 mg daily, 4 weeks on, 2 weeks off | 46 |
| Total | 46 |
Baseline characteristics
| Characteristic | Sunitinib and Erlotinib |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 13 Participants |
| Age, Categorical Between 18 and 65 years | 33 Participants |
| Age, Continuous | 58 years |
| Region of Enrollment United States | 46 participants |
| Sex: Female, Male Female | 9 Participants |
| Sex: Female, Male Male | 37 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 46 / 46 |
| serious Total, serious adverse events | 7 / 46 |
Outcome results
Primary
Maximum Tolerated Dose (MTD) of Erlotinib Hydrochloride When Used in Combination With Sunitinib.
The MTD is defined as the dose that produces dose limiting toxicity (DLT) in 33% of the patients.
Time frame: Participants assessed for DLTs weekly during the first cycle of treatment and every 3 weeks in subsequent cycles until at least one DLT occurs in 33% or more of participants at that dose; participants assessed for the duration of the study, up to 7 years
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sunitinib and Erlotinib | Maximum Tolerated Dose (MTD) of Erlotinib Hydrochloride When Used in Combination With Sunitinib. | Sunitinib | 50 milligrams |
| Sunitinib and Erlotinib | Maximum Tolerated Dose (MTD) of Erlotinib Hydrochloride When Used in Combination With Sunitinib. | Erlotinib | 150 milligrams |
Primary
Progression-free Survival at 8 Months
Defined as the proportion of patients who are progression free (CR, PR and SD) at 8 months after initiating treatment with sunitinib in combination with erlotinib in patients with metastatic or unresectable clear cell or papillary carcinoma of the kidney. Complete Response (CR)= disappearance of all target lesions, Partial Response (PR)= At least a 30% decrease in the sum of the longest diameter of target lesions, and Stable Disease (SD)= Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (20% increase in the sum).
Time frame: 8 months after initiating treatment with sunitinib in combination with erlotinib in patients with metastatic or unresectable clear cell or papillary carcinoma of the kidney
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sunitinib and Erlotinib | Progression-free Survival at 8 Months | 40 percentage of participants |
Secondary
Maximum Percent Change in Tumor Measurement
The maximum percent change in Tumor Measurement is the greatest percent change in longest diameter (LD) for the target lesions from the baseline LD. For patients with no change in LD, the maximum percent change is the lowest increase in LD from the baseline LD.
Time frame: Baseline through end of study, up to 7 years
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Sunitinib and Erlotinib | Maximum Percent Change in Tumor Measurement | 18 percent change in size |
Secondary
Median Time to Progression
The Kaplan-Meier method will be used to estimate the median time to progression.
Time frame: For the duration of the study, up to 7 years
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Sunitinib and Erlotinib | Median Time to Progression | 5.8 months |
Secondary
Proportion of Patients Whose Best Overall Response is Complete Response, Partial Response, Stable Disease, or Progressive Disease
Time frame: From the start of treatment until the criteria for response is met.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sunitinib and Erlotinib | Proportion of Patients Whose Best Overall Response is Complete Response, Partial Response, Stable Disease, or Progressive Disease | Partial Response | 22 percentage of participants |
| Sunitinib and Erlotinib | Proportion of Patients Whose Best Overall Response is Complete Response, Partial Response, Stable Disease, or Progressive Disease | Stable Disease | 59 percentage of participants |
| Sunitinib and Erlotinib | Proportion of Patients Whose Best Overall Response is Complete Response, Partial Response, Stable Disease, or Progressive Disease | Progressive Disease | 11 percentage of participants |
Secondary
To Determine the Safety of Sunitinib in Combination With Erlotinib
Time frame: For the duration of the study, up to 7 years
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sunitinib and Erlotinib | To Determine the Safety of Sunitinib in Combination With Erlotinib | Diarrhea | 35 participants |
| Sunitinib and Erlotinib | To Determine the Safety of Sunitinib in Combination With Erlotinib | Rash | 35 participants |
| Sunitinib and Erlotinib | To Determine the Safety of Sunitinib in Combination With Erlotinib | Fatigue | 30 participants |
| Sunitinib and Erlotinib | To Determine the Safety of Sunitinib in Combination With Erlotinib | Dysguesia | 29 participants |
| Sunitinib and Erlotinib | To Determine the Safety of Sunitinib in Combination With Erlotinib | Nausea | 21 participants |
| Sunitinib and Erlotinib | To Determine the Safety of Sunitinib in Combination With Erlotinib | Anorexia | 15 participants |
| Sunitinib and Erlotinib | To Determine the Safety of Sunitinib in Combination With Erlotinib | Vomitting | 14 participants |
| Sunitinib and Erlotinib | To Determine the Safety of Sunitinib in Combination With Erlotinib | Hand-foot syndrome | 13 participants |
| Sunitinib and Erlotinib | To Determine the Safety of Sunitinib in Combination With Erlotinib | Stomatitis | 13 participants |
| Sunitinib and Erlotinib | To Determine the Safety of Sunitinib in Combination With Erlotinib | Weight loss | 13 participants |
| Sunitinib and Erlotinib | To Determine the Safety of Sunitinib in Combination With Erlotinib | Constipation | 12 participants |
| Sunitinib and Erlotinib | To Determine the Safety of Sunitinib in Combination With Erlotinib | Dyspepsia | 12 participants |
| Sunitinib and Erlotinib | To Determine the Safety of Sunitinib in Combination With Erlotinib | Dry skin | 10 participants |
| Sunitinib and Erlotinib | To Determine the Safety of Sunitinib in Combination With Erlotinib | Alopecia | 9 participants |
| Sunitinib and Erlotinib | To Determine the Safety of Sunitinib in Combination With Erlotinib | Pruritus | 9 participants |
| Sunitinib and Erlotinib | To Determine the Safety of Sunitinib in Combination With Erlotinib | Other skin/hair changes | 8 participants |
| Sunitinib and Erlotinib | To Determine the Safety of Sunitinib in Combination With Erlotinib | Dehydration | 5 participants |