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A Phase I Study Investigating Everolimus and Dovitinib in Metastatic Clear Cell Renal Cancer

Phase 1
18 Years
Not Enrolling
Metastatic Clear Cell Renal Cancer

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Trial Information

A Phase I Study Investigating Everolimus and Dovitinib in Metastatic Clear Cell Renal Cancer

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. However the median time to progression with everolimus is 4 months in previously
treated patients, therefore further improvement in treating patients is required. The
optimal way of achieving this is to increase the efficacy of everolimus by adding agents
which directly target the cause of resistance to sunitinib.

dovitnib is a promising new drug the pharmacology data from a variety of in vitro and in
vivo studies with dovitnib provided preclinical rationale for clinical evaluation of
dovitinib in patients with metastatic clear cell renal cancer.

The combination of everolimus with dovitnib will target 3 major protagonists associated with
tumour growth The main risks and burdens to the patients participating in the study are the
potential for side effects of the trial medicines, these two drugs have not been used in
combination together and although there is safety data on each drug, there is no known
safety data on the drugs when used in combination. The first cohort of patients will receive
200mg of dovitnib and 5mg of everolimus. In previous studies these drugs have been
administered separately and at higher doses. The maximum tolerated dose (MTD) of dovitnib
for the 5-day on/ 2-day off dosing schedule has been defined as 500mg/day in a previous
Phase I studies. In the RECORD-1 study (a Phase III double blind randomised trial
investigating everolimus) a dose of 10mg was used.

Cohorts of three patients will be treated in each dose level. A minimum of 14 days will
elapse between the first patient being treated in each cohort and entering the next patient.
Further patients may be entered concurrently. Toxicity will be assessed according to NCI
CTCAE v4.0; if no dose limiting toxicity (DLT) occurs dose escalation will be undertaken for
the next cohort of patients.

In the event of DLT in 1out of the 3 patients the cohort will be expanded to a maximum of 6
patients. If more than or equal to 2 out of 6 patients experience DLT dose escalation will
be halted and the maximum administered dose (MAD) has been reached. If less than or equal
to 1 out of 6 patients had DLT dose escalation may continue.

Patients may not personally benefit from being in this study. However the information we
gain from this study might help to treat future patients who have metastatic kidney cancer.

Inclusion Criteria:

1. Histopathologically confirmed clear cell renal carcinoma with measurable metastases
on CT/MRI imaging (only a component of clear cell histology is required).

2. Patients must have progression on or after stopping treatment with a VEGF receptor
tyrosine kinase inhibitor (sunitinib and/or sorafenib)

3. Prior vaccine therapy or treatment with cytokines (ie IL-2, Interferon) and/ or VEGF
ligand inhibitors (bevacizumab) are permitted.

4. Minimum of 18 years of age (there is no upper age limit)

5. Radiological progressive disease.

6. ECOG performance status of 0 and 1.

7. Prior exposure to targeted therapy within the previous 4 months. Targeted therapy
consists of VEGF targeted agents or mTOR inhibitors. A gap of at least 2 week off
therapy is required prior to study entry (this gap should be at least 6 weeks for

8. 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 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.

9. Adequate organ function as defined by the following criteria:

- Total serum bilirubin ≤1.5 x ULN (patients with Gilbert's disease exempt),

- Serum transaminases <=3 x ULN (regardless of the presence or absence of liver

- Serum creatinine <=2 x ULN,

- Absolute neutrophil count (ANC) >= 1.5 x 109/L

- Platelets >= 100 x 109/L

10. Life expectance >12 weeks

11. Signed and dated informed consent document indicating that the patient (or legally
acceptable representative) has been informed of all the pertinent aspects of the
trial prior to enrolment.

12. Willingness and ability to comply with scheduled visits, treatment plans and
laboratory tests and other study procedures

Exclusion criteria

1. Congestive heart failure, myocardial infarction or coronary artery bypass graft in
the previous six months, ongoing severe heart disease.

2. Females of child-bearing potential, defined as all women physiologically capable of
becoming pregnant, without exceptions, Unless; They meet the following definition of
post-menopausal: 12 months of natural (spontaneous) amenorrhea or 6 months of
spontaneous amenorrhea with serum FSH levels >40 IU/l, OR; Have past 6 weeks from
surgical bilateral oophorectomy with or without hysterectomy OR;

Females are expected to use two forms of contraception. The following combinations
of contraception are acceptable:

- Surgical sterilization (e.g. bilateral tubal ligation)

- Diaphragm plus condom

- Intra-uterine device plus condom

- Intra-uterine device plus diaphragm Periodic abstinence (e.g. calendar,
ovulation, symptothermal, post-ovulation methods) and withdrawal are not
acceptable methods of contraception.

Note: Reliable contraception must be maintained throughout the study.

3. Females of child bearing potential must have a negative pregnancy test prior to
starting the study. Females must not be pregnant or lactating.

4. Male subjects and their partners who are not using two highly effective methods of
contraception, comprising a barrier method (e.g. condom with spermicidal gel) plus
use by the female partner of a second method of contraception (e.g. hormonal, IUD,
barrier method such as occlusive cap with spermicide). These measures should be in
place for the entire duration of the study up the Study Completion visit, and males
should refrain from fathering a child in the 12 months following the last dose of
study medication.

5. Other severe acute or chronic medical or psychiatric condition, or laboratory
abnormality that would impart, in the judgment of the investigator, excess risk
associated with study participation or study drug administration, or which, in the
judgment of the investigator, would make the patient inappropriate for entry into
this study

6. Patients with a recent history(in the previous 3 months) of poorly controlled
hypertension with resting blood pressure >150/100 mmHg in the presence or absence of
a stable regimen of anti-hypertensive therapy, or patients who are requiring maximal
doses of calcium channel blockers to stabilize blood pressure

7. Mean QTc with Bazetts correction >480msec in screening ECG or history of familial
long QT syndrome

8. Any evidence of interstitial lung disease (bilateral, diffuse, parenchymal lung
disease), especially pulmonary fibrosis.

9. Significant haemorrhage (>30mL bleeding/episode in previous 3 months) or haemoptysis
(>5mL fresh blood in previous 4 weeks)

10. Recent (<14 days) major thoracic or abdominal surgery prior to entry into the study,
or a surgical incision that is not fully healed

11. Unresolved toxicity ≥ CTC grade 2 (except alopecia) from previous anti-cancer

12. History of other malignancies (except for adequately treated basal or squamous cell
carcinoma of the skin or carcinoma in situ or localised controlled prostate cancer or
cervical cancer) within 2 years.

13. Known inherited or acquired immunodeficiency

14. Other concomitant anti-cancer therapy (excluding LHRH agonists).

15. Current steroid use. Concomitant use of steroids on study should be considered an
adverse event and the clinical trials unit should be contacted.

16. Previous bone marrow transplant

17. Uncontrolled diabetes (fasting glucose 2x ULN.)

18. Patients with any severe and /or uncontrolled medical conditions such as serious
uncontrolled cardiac arrhythmia, uncontrolled hyperlipidemia, active or uncontrolled
serve infection, cirrhosis or persistent active hepatitis (where hepatitis is
suspected, investigations must be undertaken) or severely impaired lung function.

19. Impairment of gastrointestinal (GI) function or GI disease that may significantly
alter the absorption of dovitinib or everolimus (e.g. ulcerative diseases,
uncontrolled nausea, vomiting, diarrhoea, malabsorption syndrome, or small bowel

20. Patients who are currently receiving anticoagulation treatment with therapeutic doses
of warfarin.

21. Patient on strong or moderate inhibitors of cytochrome P450 3A4 include ketoconazole,
itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin,
ritonavir, amprenavir, indinavir, nelfinavir, delavirdine, fosamprenavir,
voriconazole, aprepitant, erythromycin, fluconazole, grapefruit juice, verapamil, or

22. Presence of brain metastases

Type of Study:


Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

To determine and establish the safety profile of everolimus and dovitinib and define the dose limiting toxicity (DLT)

Outcome Description:

Determining causality of each adverse (AE) to everolimus and dovitinib and grading severity according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0

Outcome Time Frame:

6 Months after all patients have come off study

Safety Issue:


Principal Investigator

Thomas Powles, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Queen Mary Unviersity of London, UK


United Kingdom: 'Ministry of Health and Regulatory Authority'

Study ID:




Start Date:

April 2011

Completion Date:

October 2012

Related Keywords:

  • Metastatic Clear Cell Renal Cancer
  • Metastatic Clear Cell Renal Cancer Dovitinib Everolimus Cohort Maximum administered dose maximum tolerated dose
  • Carcinoma, Renal Cell
  • Kidney Neoplasms