A Phase II Study of Axitinib in Patients With Metastatic Renal Cell Cancer Unsuitable for Nephrectomy

Phase 2

Completed

• Conditions: Clear-cell Metastatic Renal Cell Carcinoma
• Interventions: Drug: Axitinib

• Registration Number: NCT01693822
• Lead Sponsor: Institute of Cancer Research, United Kingdom

Brief Summary

A-PREDICT is a study of axitinib in patients with metastatic renal cell carcinoma unsuitable for nephrectomy (as judged by the treating clinician) to evaluate efficacy, safety, toxicity and changes in biomarkers during therapy. Axitinib will given twice daily by mouth according to tolerability of treatment, for as long as patients are deriving clinical benefit. Blood and tumour tissue samples will be taken prior to and during therapy to evaluate biomarkers of treatment response. The primary clinical objective of this study is to define the activity of axitinib given to patients with metastatic renal cell carcinoma unsuitable for nephrectomy.

Detailed Description

A-PREDICT is a single arm, single agent, open label, multicentre, phase II study of axitinib in patients with metastatic renal cell carcinoma of predominant clear cell histology and unsuitable for debulking nephrectomy (as judged by the treating clinician). Patients who have provided consent and have satisfied the eligibility criteria will be registered into the trial.

The starting dose of axitinib will be 5 mg twice daily by mouth, escalating to a maximum of 10mg twice daily by mouth according to tolerability of treatment, for as long as patients are deriving clinical benefit. Treatment will be paused for one week prior to percutaneous biopsy of the primary on day 1 week 9. Disease progression will be evaluated according to RECIST v1.1 criteria 8 weeks after commencing treatment, at 8 weekly intervals to 6 months and 3 monthly thereafter. Blood and tumour tissue samples will be taken prior to and during therapy to evaluate biomarkers of treatment response. Nephrectomy will be carried out on any patient who becomes suitable in the opinion of the treating clinician during the course of the trial. Where possible, tissue samples will be taken from resected specimens. Response to axitinib in marker lesions will be correlated with changes in biomarkers.

Study Timeline

• Study First Submitted: 2012-08-06
• Study First Submitted QC: 2012-09-24
• Study First Posted: 2012-09-26
• Study Start: 2012-10
• Primary Completion: 2017-03
• Study Completion: 2022-02-28
• Results First Submitted: 2024-02-06
• Status Verified: 2024-11
• Results First Submitted QC: 2024-11-14
• Last Update Submitted: 2024-11-14
• Results First Posted: 2024-11-21
• Last Update Posted: 2024-11-21

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 65

Inclusion Criteria

1. Histologically confirmed metastatic renal cell carcinoma of predominant clear cell histology
2. Unsuitable for nephrectomy
3. Unsuitable for 'watch and wait' policy
4. No prior systemic therapy for renal cell carcinoma
5. Measurable metastatic disease using RECIST v1.1
6. Life expectancy 12 weeks or greater
7. ECOG performance status 0 or 1
8. Adequate organ function as defined by serum aspartate transaminase (AST) or serum alanine transaminase (ALT) ≤2.5 x upper limit of normal (ULN), or AST and ALT ≤5 x ULN if liver function abnormalities are due to liver metastases; total serum bilirubin ≤1.5 x ULN
9. Adequate haematological function as defined by absolute neutrophil count (ANC) ≥1500/μL, platelets ≥75,000/μL, haemoglobin ≥9.0 g/dL and prothrombin time (PT) ≤1.5 x ULN
10. Serum creatinine ≤1.5 x ULN or calculated creatinine clearance ≥ 60 mL/min;
11. Urinary protein <2+ by urine dipstick.
12. No evidence of pre-existing uncontrolled hypertension
13. Women of childbearing potential must have a negative serum or urine pregnancy test within 3 days prior to treatment.
14. Willingness and ability to comply with study procedures, including tumour biopsies.
15. Written informed consent

Exclusion Criteria

1. The presence of intracranial disease, unless stable >6 months. In the case of a solitary brain metastasis which has been resected, there must be evidence of a disease-free interval of at least 3 months post-surgery. All patients previously treated for brain metastases must be stable off corticosteroid therapy for at least 28 days.

2. The presence of active second malignancy.

3. Women who are pregnant or are breastfeeding. Female patients must be surgically sterile, be postmenopausal, or must agree to use effective contraception during the period of therapy.

4. Male patients must be surgically sterile or must agree to use effective contraception during the period of therapy.

5. Current signs or symptoms of severe progressive or uncontrolled hepatic, endocrine, pulmonary disease other than directly related to RCC.

6. Gastrointestinal abnormalities including:

   1. inability to take oral medication;
   2. requirement for intravenous alimentation;
   3. prior surgical procedures affecting absorption including total gastric resection;
   4. treatment for active peptic ulcer disease in the past 6 months;
   5. active gastrointestinal bleeding, unrelated to cancer, as evidenced by hematemesis, hematochezia or melena in the past 3 months without evidence of resolution documented by endoscopy or colonoscopy;
   6. malabsorption syndromes.

7. Current use or anticipated need for treatment with drugs that are known potent CYP3A4 inhibitors (see section 8.12, concomitant therapy).

8. Current use or anticipated need for treatment with drugs that are known CYP3A4 or CYP1A2 inducers (see section 8.12, concomitant therapy).

9. Requirement of anticoagulant therapy with oral vitamin K antagonists. Low-dose anticoagulants for maintenance of patency of central venous access device or prevention of deep venous thrombosis is allowed. Therapeutic use of low molecular weight heparin is allowed.

10. Active seizure disorder, spinal cord compression, or carcinomatous meningitis.

11. Any of the following within 12 months prior to study entry: myocardial infarction, uncontrolled angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack.

12. Deep vein thrombosis or pulmonary embolism within 6 months prior to study entry.

13. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness.

14. Known galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Axitinib	Axitinib	Axitinib - oral tablet twice daily until disease progression. Starting dose 5mg.

Primary Outcome Measures

Name	Time	Method
Freedom From Progression at 6 Months	6 months	The proportion of study participants alive and progression free at 6 months (day 1 week 25 visit). Progression will be measured from the date of study entry (registration date) until the first date of either death or confirmed progressive disease according to RECIST v1.1 (https://recist.eortc.org/recist-1-1-2/). Patients alive and free from progression will be censored at the date of last follow-up. The proportion of patients progression free at 6 months will be reported with 95% confidence interval. In addition, progression free survival will be presented using the Kaplan Meier product limit method with median progression free survival reported. A blinded central review of CT scans will be conducted for verification purposes.

Secondary Outcome Measures

Name	Time	Method
Best Overall Response	From registration, during treatment and up to 30 days after treatment discontinuation. Patients remain on treatment until disease progression assessed up to 106 months.	Best overall response (one of Complete Response (CR), Partial Response (PR), Stable Disease (SD), or Progressive Disease (PD) throughout the treatment period according to RECIST v1.1 (https://recist.eortc.org/recist-1-1-2/).
Progression Free Survival	From the date of registration until first date of either death or confirmed progressive disease from any cause, whichever came first, assessed up to 106 months.	Progression-free survival (PFS) will be measured from the date of registration until first date of either death or confirmed progressive disease according to RECIST 1.1. Time to last follow-up will be used if patient has not progressed or died and PFS time for the patient will be considered censored. A Kaplan Meier graph and median survival time will be presented.
Overall Survival	From the date of registration until the date of death due to any cause, up to 106 months.	Overall survival will be measured from the date of registration until the date of death due to any cause. Time to last follow-up will be used if patient has not died and survival time for the patient will be considered censored.
Safety and Toxicity of Axitinib (by NCI CTC Grading Version 4)	Treatment duration (at least 4 weekly, and again at disease progression), up to 106 months.	Progression of the malignancy was not reported as a serious adverse event. Hospitalisation due to signs and symptoms of malignancy progression was not reported as a serious adverse event. Occurrences are counted as any subject reporting a particular AE at a visit where toxicity was assessed.
Number of Patients Who Become Suitable for Nephrectomy as a Consequence of Therapy With Axitinib	Study duration (assessed by clinician over treatment duration), up to 106 months.	The proportion of patients who undergo nephrectomy following registration as a result of treatment with axitinib will be reported with 95% confidence intervals.

Trial Locations

Locations (11)

Royal Free Hospital; 🇬🇧 London, United Kingdom

Royal Surrey County Hospital; 🇬🇧 Guildford, Surrey, United Kingdom

The Clatterbridge Cancer Centre NHS Foundation Trust; 🇬🇧 Wirral, United Kingdom

Royal Marsden Hospital - Sutton; 🇬🇧 London, Sutton, United Kingdom

Addenbrooke's Hospital; 🇬🇧 Cambridge, United Kingdom

Derriford Hospital; 🇬🇧 Plymouth, United Kingdom

Leeds Teaching Hospitals NHS Trust; 🇬🇧 Leeds, United Kingdom

Western General Hospital; 🇬🇧 Edinburgh, United Kingdom

Royal Marsden Hospital; 🇬🇧 London, United Kingdom

Christie Hospital; 🇬🇧 Manchester, United Kingdom

Guy's Hospital; 🇬🇧 London, United Kingdom