Dose Escalation Study Investigating Everolimus and Dovitinib in Metastatic Clear Cell Renal 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 bevacizumab).
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 metastases).
   * 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 therapy.
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 resection).
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 diltiazem
22. Presence of brain metastases