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An Open Label, Randomised Phase II Study, Comparing AZD2014 Versus Everolimus With Advanced Metastatic Renal Cancer and Progression on VEGF Targeted Therapy

Phase 2
18 Years
Open (Enrolling)
Metastatic Clear Cell Renal Carcinoma

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Trial Information

An Open Label, Randomised Phase II Study, Comparing AZD2014 Versus Everolimus With Advanced Metastatic Renal Cancer and Progression on VEGF Targeted Therapy

Renal cell cancer, also referred to as kidney cancer, is diagnosed in approximately 170,000
people worldwide annually, resulting in 82,000 deaths. Treatment for metastatic kidney
cancer is difficult. Almost all of the patients die from their disease.

In 2006 a new drug called sunitinib, a tyrosine kinase inhibitor, transformed treatment
options. It targets the development of new blood vessels within the cancer. Although the
results with this drug are impressive, patientsdevelop resistance a median after 11 months
to the drug, relapse and die of renal cancer. It is currently standard practice to switch to
everolimus when resistance to sunitinib occurs; this is associated with clear clinical


The main risks and burdens to the patients participating in the study are the potential for
side effects of the AZD2014 drug. The phase I study using this drug has been completed,
therefore we know it is safe to administer to patients and we have a good idea of what side
effects the drug causes. But as the drug is given to larger numbers, additional side effects
may be discovered. The activity of the drug has not been evaluated in kidney cancer.
Therefore we are not sure if AZD2014 will work


Everolimus is the current standard therapy for these patients so the risks associated with
study drug for these patients are the same as standard of care.



Side effects will be closely monitored during and after the study. Patients are required to
attend clinic weekly for the first four weeks and then every 4 weeks whilst they are on
study medication where adverse events will be recorded.

The patient information sheet includes details on expected adverse events for patients to
look out for and also details that unexpected events may occur. Patients are provided with
the research nurse and principal investigator contact details should any adverse events
occur during the course of the study.

Other medical professionals are informed that patients are receiving an experimental drug
(through GP letter and labelling of hospital records). There will be an independent data
monitoring committee for the trial which will closely assess the side effects of the drugs
on a regular basis and the trial results to make sure there are no risk excess to patients.

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

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 malabsorbtion 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 hyperlipideamia (> grade 1)

11. Treatment with an investigational drug (not including VEGF TKIs such as
pazopanib/ tivozinib) 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

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

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

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

Type of Study:


Study Design:

Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

To investigate if single agent AZD2014 delays progression free survival compared to everolimus using RESIST v1.1

Outcome Time Frame:

Completion of study- approx 3 years

Safety Issue:


Principal Investigator

Thomas Powles

Investigator Role:

Principal Investigator

Investigator Affiliation:

Queen Mary University of London, UK


United Kingdom: Medicines and Healthcare Products Regulatory Agency

Study ID:

008424 QM



Start Date:

February 2013

Completion Date:

December 2015

Related Keywords:

  • Metastatic Clear Cell Renal Carcinoma
  • Carcinoma
  • Carcinoma, Renal Cell
  • Kidney Neoplasms