Prior Axitinib as a Determinant of Outcome of Renal Surgery

Study Overview
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Brief Summary
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This is a single arm phase II study of axitinib in patients with clear cell renal cell carcinoma (RCC) with strong indications for partial nephrectomy (PN) for whom PN is not currently possible due to anatomic considerations and residual renal function concerns. Evaluation of tumor downsizing will be performed including changes of tumor complexity by nephrometry score. A total of 50 participants will be enrolled. It is hypothesized that pretreatment with axitinib will be safe and improve the feasibility of complex nephron sparing surgery in select patients with localized clear cell RCC and imperative indications for partial nephrectomy.

Detailed Description
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The primary objective of the study is to prospectively assess utility of axitinib in facilitation of partial nephrectomy where partial nephrectomy was not thought to be safe/possible in the setting of imperative indication for complex renal masses in renal cell cancer. Secondary objectives: To determine the safety, tumor diameter (per RECIST v1.1) volume change, surgical morbidity and renal functional outcomes following neoadjuvant axitinib for RCC. Anatomical/morphometric: tumor diameter/volume change, conversion of hilar to non-hilar tumors, reduction in RENAL morphometric score. Functional Considerations: Requirement of acute dialysis Change in Glomerular Filtration Rate (GFR) Whether or not GFR crosses 30 threshold, or decline by GFR to >50% of baseline. Safety indices: Incidence of Clavien >3 complications Avoidance of need for multiple blood transfusions

Official Title
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PADRES (Prior Axitinib as a Determinant of Outcome of REnal Surgery)

Conditions
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Clear Cell Renal Cell Carcinoma

Intervention / Treatment
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* Drug: Axitinib Oral Tablet [Inlyta]


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Localized clear cell renal carcinoma without evidence of distant metastases Imperative indication for nephron sparing surgery Baseline chronic kidney disease (CKD) (stage 3, GFR <60 ml/min/1.73m2), or anatomically or functional solitary kidney (defined by renal scintigraphy of contralateral renal unit with <15% function) or bilateral synchronous disease); and RENAL score ≥10 or proximity to renal hilum (defined as <2 mm away from at least 2 renal hilar vessels-the main artery/vein or first order branches); and Radical nephrectomy would lead to severe CKD (stage 3b, GFR <45 ml/min/1.73m2). Male or female, age ≥ 18 years 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 ≤1.5 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: Presence of metastatic disease on radiographic imaging. Elective indication for nephron sparing surgery Non-clear cell histology Prior systemic treatment of any kind or radiotherapy for RCC NCI CTCAE Version 5.0 grade 3 hemorrhage within 4 weeks of starting the study treatment Ongoing cardiac dysrhythmias of NCI CTCAE Version 5.0 grade ≥2. Controlled atrial fibrillation is permitted. Prolonged corrected QT interval by the Fridericia correction formula (QTcF) on screening EKG >480 msec. 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 hypertension (HTN): systolic blood pressure ≥150 or diastolic blood pressure ≥ 100 mmHg or both despite appropriate therapy. HTN with need for greater than three anti-hypertensive agents at baseline. Drug formulations containing two or more anti-hypertensive agents will be counted based on the number of active agents in each formulation. New York Heart Association (NYHA) class III or greater congestive heart failure (CHF) Uncontrolled hyper- or hypothyroidism. Subjects with arterial thrombotic events in the prior 12 months (axitinib has never been studied in this population) Subjects who have had venous thrombotic events in the prior 6 months (axitinib has never been studied in this population)

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 Oral Tablet [Inlyta]<br>Axitinib 5 mg PO BID for 8-10 weeks | Drug: Axitinib Oral Tablet [Inlyta]<br>* Axitinib 5 milligrams (mg) administered orally (po) twice daily (BID) for 8 weeks (with titration to 7 mg BID as tolerated at 4 weeks)<br>* Other names: Inlyta;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent reduction of longest diameter of tumor in millimeters |  | 90 days | 
| Objective Tumor Response Rate (by RECIST criteria) | Percentage of patients achieving partial response (reduction in tumor diameter by at least 30% of maximum diameter) as defined by RECIST criteria | 90 days | 
| Effect on tumor morphometry, as measured by RENAL score [(R)adius, (E)xophytic/endophytic components, (N)earness to the collecting system or sinus, (A)neterior/posterior, and (L)ocation relative to polar lines] | The RENAL nephrometry score quantifies tumor size and location relative to the major blood vessel and collecting system supply of the kidney according to 5 domains (tumor radius, exophytic/endophytic appearance, proximity to urinary collecting system, anterior/posterior location, and location with respect to renal poles). Four of these domains have a score of 1-3, with 3 indicating a more complex score within the domain. The total score is the sum of all of the domains (total minimum score being 4 and the maximum score being 12, and with more complex tumors having a higher score). The study will record effect of the medication on tumor complexity as measured by total RENAL nephrometry score. | 90 days | 
| Feasibility of partial nephrectomy surgery | Percentage of Successful partial nephrectomy perfomed (as opposed to radical nephrectomy) with negative surgical margins determined by pathological assessment of resection margins. | 90 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Renal Cell Carcinoma, Axitinib, Nephrectomy, Neoadjuvant, Clear Cell Renal Carcinoma