A Study Comparing AZD2014 vs Everolimus in Patients With Metastatic Renal Cancer
Information source: Queen Mary University of London
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Metastatic Clear Cell Renal Carcinoma
Intervention: AZD2014 (Drug); Everolimus (Drug)
Phase: Phase 2
Status: Terminated
Sponsored by: Queen Mary University of London Official(s) and/or principal investigator(s): Thomas Powles, Principal Investigator, Affiliation: Queen Mary University of London, UK
Summary
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.
Clinical Details
Official title: An Open Label, Randomised Phase II Study, Comparing AZD2014 Versus Everolimus With Advanced Metastatic Renal Cancer and Progression on VEGF Targeted Therapy
Study design: Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Primary outcome: To investigate if single agent AZD2014 delays progression free survival compared to everolimus using RESIST v1.1
Secondary outcome: To evaluate tumour response rate after at least 8 weeks of treatment with the study drugs.
Detailed description:
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, patients develop 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
benefit.
POTENTIAL RISKS FOR PATIENTS RECEIVING AZD2014:
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
POTENTIAL RISKS FOR PATIENTS RECEIVING EVEROLIMUS:
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.
POTENTIAL RISKS FOR ALL PATIENTS:
SIDE EFFECTS:
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.
Eligibility
Minimum age: 18 Years.
Maximum age: N/A.
Gender(s): Both.
Criteria:
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
Locations and Contacts
Royal Bournemouth Hospital, Bournemouth BH7 7DW, United Kingdom
Royal Sussex County Hospital, Brighton BN2 5BE, United Kingdom
University Hospitals Coventry & Warwickshire NHS Trust, Coventry CV2 2DX, United Kingdom
Beatson West of Scotland Cancer Center, Glasgow G12 0YN, United Kingdom
St. James' Hospital, Leeds LS9 7TF, United Kingdom
Barts Health NHS Trust, London EC1A 6BE, United Kingdom
Royal Free London Hospital, London NW3 2QG, United Kingdom
Southampton General Hospital, Southampton SO16 6YD, United Kingdom
Southend University Hospital NHS Foundation Trust, Westcliff-On-Sea SS0 0RY, United Kingdom
Additional Information
Starting date: February 2013
Last updated: June 23, 2014
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