Carcinoma, Renal Cell
Conditions
Brief summary
Pazopanib is an orally administered multi-kinase inhibitor targeting VEGFR (vascular endothelial growth factor receptor), PDGFR (platelet derived growth factor) and c-kit, which are critical to growth and proliferation of neoplastic cells. Pazopanib has been FDA approved for advanced renal cell carcinoma (RCC) with a clear cell component. Conventional Pazopanib dosing WITHOUT FOOD is with an initial dose of 800 mg by mouth daily. Investigators hypothesize that administration of pazopanib with low fat meal would be safe and feasible with secondary implications of higher pazopanib levels; potentially translating into greater anti-tumor efficacy in advanced renal cell cancer, with significant cost savings. In the proposed pilot study, investigators seek to test the feasibility and practicality of this approach and gather preliminary data on adverse effects and the safety profile. Investigators hope to ameliorate any potential for greater toxicities with a dynamic dosing design that incorporates adverse events from each cycle into dosing for the next cycle and a structured symptom specific plan.
Interventions
DRUGPazopanib
OTHERLow Fat Diet
Registered subjects will take pazopanib by mouth with a low-fat meal (containing less than 400 calories and less than 10% fat or 10 grams per meal.
Sponsors
University of Michigan Rogel Cancer Center
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
* Adult (\>18 years of age) with unresectable locally advanced or metastatic renal cell carcinoma with a clear cell component. * Subjects must have measurable disease per RECIST 1.1 criteria. * Subjects must not have had prior pazopanib therapy. * Subjects must have an ECOG (Eastern Cooperative Oncology Group scoring system used to quantify general well-being and activities of daily life; scores range from 0 to 5 where 0 represents perfect health and 5 represents death.) performance status of less than or equal to 2. * Up to 3 lines of prior VEGF (vascular endothelial growth factor) or VEGFR (vascular endothelial growth factor receptor) targeted therapy are permitted. Any prior therapy should have been completed ≥ 2 weeks prior to start of study therapy. * Subjects may have received any number of the following therapies: cytokine therapy (e.g. high dose interleukin-2) or checkpoint inhibitor therapy (e.g. anti-PD1/PDL1, anti-CTLA4) or mTOR inhibitor therapy (e.g. everolimus, temsirolimus). * Adequate organ and marrow function (Absolute neutrophil count \> 1000/mm3, platelets \> 100,000/mm3, aspartate aminotransferase/ alanine aminotransferase/ total bilirubin \< 1.5 X ULN (upper limit of normal). Patients with Gilbert's disease are exempt. * Subject must be willing and able to take pazopanib with a low-fat meal every day as specified in the protocol. * Subjects must be willing and able to come off any PPI(proton pump inhibitor)/other strong CYP3A4 inhibitors or inducers/simvastatin. * Ability to understand and the willingness to sign a written informed consent. * All subjects, including those who are surgically sterilized, must be willing to use an effective method of contraception.
Exclusion criteria
* Any concurrent health condition that in the view of the treating physician would pose excessive risk to the patient if enrolled in the study. * Subjects with a history of hemoptysis, cerebral hemorrhage, clinically significant GI hemorrhage, myocardial infarction within the past 6 months. * Patients at significant risk for GI (gastrointestinal) perforation or fistula. * Pregnant or nursing mothers. * Untreated CNS (central nervous system) metastasis. If treated CNS metastasis/es, treatment of CNS disease (surgery or radiation) must have been completed at least 30 days prior to registration. Patients could still be on steroids. * Subjects with known history of Cirrhosis, HIV, Hepatitis B or C. * Averaged QTc baseline in 3 ECGs (electrocardiograms) at least 5 minutes apart of ≥450 ms. * Congestive Heart Failure (NYHA Class III/IV) or LVEF (left ventricular ejection fraction) \<50% at baseline. * Uncontrolled hypertension (HTN) despite medical management (blood pressure (BP) ≥ 160/100.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Grade 3 or 4 Adverse Events | Through 12 weeks of treatment to 30 days post-treatment | Number of grade 3 or 4 adverse events associated with pazopanib administered with a low fat meal by CTCAE version 4.0. |
| Number of Participants With Dose Reductions | 12 weeks | — |
| Duration of Treatment | 12 weeks | The median duration of treatment will be reported. |
| Median Total Dose | 12 weeks | Median total dose given. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Complete Response | 12 Weeks after start of study treatment | Complete response is defined as the disappearance of all target lesions, determined by two separate observations conducted not less than 4 weeks apart. There can be no appearance of new lesions. |
| Number of Patients With Partial Response | 12 Weeks after start of study treatment | Partial response is defined as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD. There can be no appearance of new lesions. |
| Percentage of Patients That Respond to Treatment (Overall Response) With Pazopanib Administered Along With a Low Fat Diet | 12 Weeks after start of study treatment | To estimate the overall response proportion to pazopanib administered with a low fat meal by RECIST 1.1 criteria. Overall response is defined as the number patients that experience Partial Response (PR) or Complete Response (CR). CR is defined as the disappearance of all target lesions, determined by two separate observations conducted not less than 4 weeks apart. There can be no appearance of new lesions. PR is defined as At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD. There can be no appearance of new lesions. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Pazopanib Registered subjects will take pazopanib by mouth with a low-fat meal (containing less than 400 calories and less than 10% fat or 10 grams per meal) every day in 14 day cycles, with a starting dose of 400 mg and adjusted for the next cycle (dose level +1:600 mg; dose level +2: 800 mg; dose level -1: 200 mg) based on toxicity assessment during or at the end of each cycle. | 16 |
| Total | 16 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Withdrawal by Subject | 3 |
Baseline characteristics
| Characteristic | Pazopanib |
|---|---|
| Age, Continuous | 60 years |
| Baseline Disease Site Adrenal | 6 Participants |
| Baseline Disease Site Bone | 1 Participants |
| Baseline Disease Site Liver | 3 Participants |
| Baseline Disease Site Lung | 10 Participants |
| Baseline Disease Site Nephrectomy bed | 2 Participants |
| Baseline Disease Site Pancreas | 1 Participants |
| Baseline Disease Site Retroperitoneal and perisplenic nodule | 1 Participants |
| Baseline Performance Status 0 | 11 Participants |
| Baseline Performance Status 1 | 5 Participants |
| Heng Criteria Score Favorable | 3 Participants |
| Heng Criteria Score Intermediate | 13 Participants |
| Heng Criteria Score Poor | 0 Participants |
| Histology Mixed Histology | 5 Participants |
| Histology Pure Clear Cell | 11 Participants |
| Number of Prior Therapies 1 Prior Therapy | 3 Participants |
| Number of Prior Therapies 3 Prior Therapies | 1 Participants |
| Number of Prior Therapies No Prior Therapy | 12 Participants |
| Prior Therapy Type Everolimus | 1 Participants |
| Prior Therapy Type High-dose IL-2 | 3 Participants |
| Prior Therapy Type Nivolumab | 1 Participants |
| Prior Therapy Type Sunitinib | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 15 Participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 16 |
| other Total, other adverse events | 15 / 16 |
| serious Total, serious adverse events | 1 / 16 |
Outcome results
Primary
Duration of Treatment
The median duration of treatment will be reported.
Time frame: 12 weeks
Population: 16 participants were enrolled. 13 of the 16 enrolled participants completed the 12 weeks of pazopanib therapy on study protocol.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pazopanib | Duration of Treatment | 12 weeks |
Primary
Median Total Dose
Median total dose given.
Time frame: 12 weeks
Population: 16 participants were enrolled. 13 of the 16 enrolled participants completed the 12 weeks of pazopanib therapy on study protocol.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pazopanib | Median Total Dose | 42,700 mg |
Primary
Number of Grade 3 or 4 Adverse Events
Number of grade 3 or 4 adverse events associated with pazopanib administered with a low fat meal by CTCAE version 4.0.
Time frame: Through 12 weeks of treatment to 30 days post-treatment
Population: 16 participants were enrolled and treated.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pazopanib | Number of Grade 3 or 4 Adverse Events | Grade 3 adverse events associated with treatment | 5 adverse events |
| Pazopanib | Number of Grade 3 or 4 Adverse Events | Grade 4 adverse events associated with treatment | 0 adverse events |
Primary
Number of Participants With Dose Reductions
Time frame: 12 weeks
Population: 16 participants were enrolled. 13 of the 16 enrolled participants completed the 12 weeks of pazopanib therapy on study protocol.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pazopanib | Number of Participants With Dose Reductions | 3 Participants |
Secondary
Number of Participants With Complete Response
Complete response is defined as the disappearance of all target lesions, determined by two separate observations conducted not less than 4 weeks apart. There can be no appearance of new lesions.
Time frame: 12 Weeks after start of study treatment
Population: 16 participants were enrolled. 13 of the 16 enrolled participants completed the 12 weeks of pazopanib therapy on study protocol.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pazopanib | Number of Participants With Complete Response | 0 Participants |
Secondary
Number of Patients With Partial Response
Partial response is defined as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD. There can be no appearance of new lesions.
Time frame: 12 Weeks after start of study treatment
Population: 16 participants were enrolled. 13 of the 16 enrolled participants completed the 12 weeks of pazopanib therapy on study protocol.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Pazopanib | Number of Patients With Partial Response | 5 Participants |
Secondary
Percentage of Patients That Respond to Treatment (Overall Response) With Pazopanib Administered Along With a Low Fat Diet
To estimate the overall response proportion to pazopanib administered with a low fat meal by RECIST 1.1 criteria. Overall response is defined as the number patients that experience Partial Response (PR) or Complete Response (CR). CR is defined as the disappearance of all target lesions, determined by two separate observations conducted not less than 4 weeks apart. There can be no appearance of new lesions. PR is defined as At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD. There can be no appearance of new lesions.
Time frame: 12 Weeks after start of study treatment
Population: 16 participants were enrolled. 13 of the 16 enrolled participants completed the 12 weeks of pazopanib therapy on study protocol.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pazopanib | Percentage of Patients That Respond to Treatment (Overall Response) With Pazopanib Administered Along With a Low Fat Diet | 38.46 percentage of participants |