Axitinib Given on an Individualized Schedule for Metastatic Renal Cell Cancer

Study Overview
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Brief Summary
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Axitinib is a drug which is approved by the FDA for patients with advanced kidney cancer who have already received some treatment. It works by reducing blood flow to a tumor. Axitinib is normally give at 5mg twice per day and sometimes this dose is increased if patients tolerate it. The purpose of this study is to figure out a different way to decide which dose of axitinib each patient should receive based on the side effects they experience.

Detailed Description
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Primary objective To determine whether axitinib given on an individualized dose/schedule for metastatic renal cell carcinoma following immunotherapy with PD-1 and PD-L1 Inhibitors leads to improved progression-free survival (PFS). Secondary objectives: To characterize the objective response rates in patients given axitinib on an individualized dose/schedule. To evaluate the tolerability and safety of an alternative method of axitinib titration. To characterize the anti-tumor effect, as measured by change in tumor burden per RECIST 1.1, of axitinib titration performed after initial RECIST PD on axitinib.

Official Title
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A Phase II Study of the Efficacy and Safety of Axitinib Given on an Individualized Schedule for Metastatic Renal Cell Cancer After Treatment With Pd-1 or Pd-L1 Inhibitors

Conditions
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Metastatic Renal Cell Cancer

Intervention / Treatment
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* Drug: Axitinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed, locally recurrent or metastatic clear cell renal cell carcinoma Has received one prior systemic therapy regimen for Metastatic Renal Cell Carcinoma (mRCC) directed against PD-1 and/or PD-L1 which must have been the most recent regimen Prior high-dose interleukin-2 therapy is permitted in addition to anti-PD(L)1 therapy, but is not required Prior bevacizumab or Vascular Endothelial Growth Factor (VEGF) Tyrosine Kinas Inhibitor (TKI) is permitted either in combination with anti-PD(L)1 therapy OR as monotherapy when given PRIOR to anti-PD(L)1 therapy Prior treatment with combined ipilimumab and nivolumab is permitted Prior axitinib in any setting is not permitted A minimum of two weeks since last dose of most recent renal cell cancer therapy assuming resolution of clinically significant treatment-related toxicities to grade 1, baseline, or controlled with supportive medications Evidence of measurable disease per RECIST 1.1. Karnofsky performance status ≥ 70 %. Adequate organ function as defined by: Absolute neutrophil count (ANC) ≥1,000/μL Platelets ≥100,000/μL Hemoglobin ≥9.0 g/dL Serum calcium ≤12.0 mg/dL Serum creatinine ≤2.0 x Upper Limit of Normal (ULN) Total serum bilirubin ≤1.5 x ULN SGOT≤2.5 x ULN and Serum Glutamic Pyruvic Transaminase (SGPT) ≤2.5x ULN Signed informed consent and willingness/ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures Exclusion Criteria: Non clear cell Renal Cell Carcinoma (RCC) Major surgery within 4 weeks of starting the study treatment. Radiation therapy within 2 weeks of starting the study treatment. Prior palliative radiotherapy to metastatic lesion(s) is permitted, provided there is at least one measurable lesion that has not been irradiated. NCI CTCAE Version 4.03 grade 3 hemorrhage within 4 weeks of starting the study treatment. Any of the following within the 6 months prior to study drug administration: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack. Ongoing cardiac dysrhythmias of NCI CTCAE Version 4.03 grade ≥2. Controlled atrial fibrillation is permitted. Uncontrolled hypertension (>160/100 mm Hg despite optimal medical therapy) Concurrent treatment on another clinical trial. Supportive care trials or non-treatment trials, e.g. QOL, and imaging trials, are allowed. Pregnancy or breastfeeding. Female subjects must be surgically sterile or be postmenopausal, or must agree to use effective contraception during the period of therapy. All female subjects with reproductive potential must have a negative pregnancy test (serum) prior to enrollment. Male subjects must be surgically sterile or must agree to use effective contraception during the period of therapy. The definition of effective contraception will be based on the judgment of the principal investigator or a designated associate Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, and in the judgment of the investigator would make the subject inappropriate for entry into this study. Uncontrolled Central Nervous System (CNS) metastases. Patients are considered to have controlled CNS metastases (and thus eligible) if they have completed local therapy (XRT and/or surgery) and are off steroids with clinical and radiographic stability 3 months from the end of CNS-directed therapy.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Axitinib<br>All subjects will be given axitinib on an individualized dosing schedule. Axitinib will be administered orally beginning with 5mg twice a day and can be escalated or reduced if specific grade 2 or greater toxicity develops. Axitinib will continue until progression. At progressive disease, dose escalation above current dose is allowed based on investigator discretion of clinical benefit. However, axitinib should be discontinued if a subject experiences a second RECIST progressive disease following dose escalation, patient intolerability, or at provider discretion. | Drug: Axitinib<br>* The intent is to maximize sustained dose intensity of axitinib based on individual tolerability using dose modification criteria<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Progression-free Survival | The primary endpoint of progression-free survival in months (per per RECIST v1.1 criteria) will be estimated using the Kaplan-Meier method. Summary statistics will be provided along with 95% confidence intervals. | Up to 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Patients With Complete Response | Tumor Response, defined as overall confirmed objective response, is confirmed complete response (CR) according to the RECIST 1.1 criteria. RECIST 1.1: Complete response (CR) is defined as the disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. | Up to 4 months of treatment and approximately 1 year of follow-up | 
| Patients With Partial Response | Tumor Response, defined as overall confirmed objective response, is confirmed complete response (CR) according to the RECIST 1.1 criteria. RECIST 1.1: Partial response (PR) is defined as a >=30% decrease in the sum of the longest dimensions of the target lesions taking as a reference the baseline sum longest dimensions. | Up to 4 months of treatment and approximately 1 year of follow-up | 
| Objective Response Rate (ORR) | ORR as defined by Recist V. 1.1. ORR = (CR + PR) | Up to 4 months of treatment and approximately 1 year of follow-up | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Kidney, Cancer, Axitinib, Pd-1 inhibitor, Pd-L1 inhibitor