Metastatic Clear Cell Renal Carcinoma Clinical Trial
— ZEBRAOfficial title:
An Open Label, Randomised Phase II Study, Comparing AZD2014 Versus Everolimus With Advanced Metastatic Renal Cancer and Progression on VEGF Targeted Therapy
When kidney cancer spreads beyond the kidney, it is known as metastatic kidney cancer. This
is very difficult to treat and almost all patients will die of their disease within 2 years
of the diagnosis.
Sunitinib and other related drugs (e.g. pazopanib) have become standard therapy for
untreated patients with metastatic kidney cancer. They target a growth factor known as VEGF
which is important in treating kidney cancer. Although the results with this drug are
impressive, patients develop resistance to the drug and stop therapy. It is currently
standard practice is to give everolimus when resistance to sunitinib occurs; this is
associated with clear clinical benefit.
However the average time to cancer regrowth with everolimus is only 5 months. It is thought
this might be because, everolimus only partially inhibits its target (TORC 1 and TORC 2).
Therefore further improvement in treating patients is required. AZD2014 is a promising new
drug which does inhibit both TORC 1 and TORC 2 and is therefore worthy of investigation in
renal cancer as it theoretically could may have advantages over everolimus. Therefore study
compares AZD2014 to everolimus in the setting where everolimus is used as standard of care.
(e.g. in patients who have failed drug like sunitinib). The study is a randomised trial
allowing us to quantify the benefit and potential for further development of AZD2014. Repeat
Xrays (CT scans) will be used to assess if the new drug delays tumour growth. Patients will
be closely followed up in clinic to ensure safety. A maximum of 122 patients will be
recruited into this multi centre national trial. The primary goal of the study is to
investigate if AZ2014 delays the time for cancer regrowth (time to progression) compared to
everolimus.
| Status | Terminated |
| Enrollment | 49 |
| Est. completion date | November 2015 |
| Est. primary completion date | May 2014 |
| Accepts healthy volunteers | No |
| Gender | Both |
| Age group | 18 Years and older |
| Eligibility |
Inclusion Criteria: 1. Histopathologically confirmed renal cell carcinoma with measurable metastases on CT/MRI imaging. Only a component of clear cell is required. 2. Radiological progressive disease on VEGF targeted therapy (RECIST v1.1). Exposure to more than one line of VEGF targeted therapy is acceptable. Previous treatment with initial interferon or IL-2 or other experimental agent is acceptable (with the exception of drugs specifically targeting mTOR). 3. Evidence of measurable disease (ie, =1 malignant tumour mass that can be accurately measured in at least 1 dimension = 20 mm with conventional computerized tomography [CT] scan or Magnetic Resonance Imaging [MRI], or =10 mm (except lymph nodes which must have short axis = 15 mm) with spiral CT scan using a 5 mm or smaller contiguous reconstruction algorithm). Bone lesions, ascites, peritoneal carcinomatosis or miliary lesions, pleural or pericardial effusions, lymphangitis of the skin or lung, cystic lesions, or irradiated lesions are not considered measurable. 4. Adequate organ function as defined by the following criteria: 1. Total serum bilirubin =1.5 x ULN (patients with Gilbert's disease exempt), 2. Serum transaminases =3.0 x ULN (x5 in the presence of liver metastasis). 3. Serum creatinine = 2 x ULN or Cockcroft and Gault >30ml/min 4. Absolute neutrophil count (ANC) =1.5 x 109/L without growth factor support, 5. Platelets = 100 x 109/L 5. Signed and dated informed consent document indicating that the patient has been informed of all the pertinent aspects of the trial prior to enrolment. 6. Willingness and ability to comply with scheduled visits, treatment plans and laboratory tests and other study procedures 7. ECOG performance status of 0, 1 or 2. 8. Life expectance >12 weeks 9. At least 14 days since the end of prior systemic treatment (sunitinib, pazopanib, sorafenib), radiotherapy, or surgical procedure with resolution of all treatment-related toxicity to NCI CTCAE Version 4.0 grade =1 or back to baseline except for alopecia or hypothyroidism. A 21 day gap between bevacizumab and interferon therapy should exist. 10. Fasting blood sugar =8mmol/l and HbA1C =7% 11. Age =18 years Exclusion Criteria: 1. Previous exposure to mTOR inhibitors for metastatic renal cancer. 2. Females of child-bearing potential. The definition of child-bearing potential: women between menarche and menopause who have not been permanently or surgically sterilised and capable of procreation. Female patients must be surgically sterile or be postmenopausal, 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. Male patients must be surgically sterile or agree to use effective contraception. 3. Pregnant and Breast feeding women. 4. Other severe acute or chronic medical or psychiatric condition, or laboratory abnormally that would impart, in the judgment of the investigator, excess risk associated with study participation or study drug administration, or which, in the judgement of the investigator, would make the patient inappropriate for entry into this study. Specifically the following indications are contraindicated: Hereditary galacto-intolerance, glucose/galactose malabsorption and lactose deficiency 5. Untreated clinically symptomatic brain or meningeal metastases. Patients with evidence of clinically stable brain metastases are eligible providing that they do not require corticosteroids. 6. Any evidence of severe or uncontrolled diseases e.g., unstable or uncompensated respiratory, hepatic or renal disease. 7. Evidence of interstitial fibrotic lung disease (bilateral, diffuse, parenchymal lung disease). 8. Unresolved toxicity = CTCAE v.4.0 grade 2 (except alopecia and hypothyroidism) from previous anti-cancer therapy. 9. History of other malignancies (except for adequately treated basal or squamous cell carcinoma or carcinoma in situ or localised controlled prostate cancer) within 5 years, unless the patient has been disease free for 2 years and there is a tissue diagnosis of the primary cancer of interest from a target lesion. 10. Uncontrolled diabetes mellitus or hyperlipidaemia (> grade 1) 11. Treatment with an investigational drug (not including VEGF TKIs such as pazopanib/ tivozanib) within 21 days prior to the first dose of therapy. If investigational drug is a VEGF TKI then with 14 days prior to the first dose of therapy 12. Patients who have experienced any of the following procedures or conditions currently or in the preceding 12 months: 1. Coronary artery bypass graft 2. Angioplasty 3. Vascular stent 4. Myocardial infarction 5. Angina pectoris 6. Congestive heart failure new york heart association grade =2 7. Ventricular arrhythmias requiring continuous therapy 8. Supraventricular arrhythmias including atrial fibrillation, which are uncontrolled 9. Haemorrhagic or thrombotic stroke, including transient ischaemic attacks or 10. Any other central nervous system bleeding 13. Mean resting QTcF =470 msec as per local reading 14. Abnormal ECHO at baseline (left ventricular ejection fraction [LVEF] <50% 15. Known inherited or acquired immunodeficiency 16. Known active hepatitis B or C infection or Known HIV. 17. Other concomitant anti-cancer therapy (including LHRH agonists) except steroids 18. Previous bone marrow transplant 19. Age <18 years 20. Any haemopoietic growth factors (eg, G-CSF, GM-CSF) within 2 weeks prior to receiving study drug |
Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
| Country | Name | City | State |
|---|---|---|---|
| United Kingdom | Royal Bournemouth Hospital | Bournemouth | |
| United Kingdom | Royal Sussex County Hospital | Brighton | |
| United Kingdom | University Hospitals Coventry & Warwickshire NHS Trust | Coventry | |
| United Kingdom | Beatson West of Scotland Cancer Center | Glasgow | |
| United Kingdom | St. James' Hospital | Leeds | |
| United Kingdom | Barts Health NHS Trust | London | |
| United Kingdom | Royal Free London Hospital | London | |
| United Kingdom | Southampton General Hospital | Southampton | |
| United Kingdom | Southend University Hospital NHS Foundation Trust | Westcliff-On-Sea |
| Lead Sponsor | Collaborator |
|---|---|
| Queen Mary University of London | AstraZeneca, Cancer Research UK |
United Kingdom,
| Type | Measure | Description | Time frame | Safety issue |
|---|---|---|---|---|
| Other | To compare overall survival of the two group of patients. | 3 years | No | |
| Primary | To investigate if single agent AZD2014 delays progression free survival compared to everolimus using RESIST v1.1 | Completion of study- approx 3 years | No | |
| Secondary | To evaluate tumour response rate after at least 8 weeks of treatment with the study drugs. | 3 years | No |
| Status | Clinical Trial | Phase | |
|---|---|---|---|
| Recruiting |
NCT05782400 -
Multiomics Approach in Metastatic Clear Renal Cell Carcnoma
|