Clinical Trial of Dovitinib in First-line Metastatic or Locally Advanced Non-resectable Adrenocortical Carcinoma

* Design: non-randomized, open label, phase II clinical trial.
* Study population and disease: adult patients with metastatic or locally advanced non-resectable adrenocortical carcinoma, confirmed histologically.
* Estimated number of patients: 15.
* Study drug: dovitinib (TKI-258), dosed on a flat scale of 500mg/day on a 5 days on / 2 days off.
* Treatment duration: study treatment period will be continued until disease progression, unacceptable toxicity, death or premature withdrawal from study. An average of 6 months treatment period is expected.
* Study duration: expected recruitment period will be 18 months, and patients will be followed for 6 additional months after last patient is included in the trial.Study total expected duration is 24 months.
* Sites: the study is planned to be conducted in 7 Spanish centers.

Non applicable

Eligibility Criteria:
Inclusion Criteria:

* Male or female patients aged ≥ 18 years old
* A performance status of 0, 1, or 2, according to the Eastern Cooperative Oncology Group (ECOG) scale.
* Histologically confirmed adrenocortical carcinoma.
* Metastatic or locally advanced non-resectable disease.
* At least one radiologically measurable lesion, according to RECIST 1.1.
* Adequate liver function as shown by: serum or plasma ALT and AST ≤ 3.0 x ULN (regardless of the presence or absence of metastases)and serum or plasma total bilirubin: ≤ 1.5 x ULN.
* Adequate bone marrow function as shown by: blood absolute neutrophil count (ANC) ≥ 1.5 x 109/L, platelets ≥ 100 x 109/L and hemoglobin (Hb) \> 9g/dL.
* Adequate renal function as shown by serum creatinine ≤ 1.5 x ULN.
* Patients give a written informed consent obtained according to local guidelines.

Exclusion Criteria:

* Prior chemotherapy other than mitotane (Patients who have previously received mitotane will only be eligible if drig has been withdrawn at least two weeks earlier than dovitinib first dose is administered).
* Patients with another primary malignancy within 3 years prior to starting the study drug, with the exception of adequately treated in-situ carcinoma of the uterine cervix, or completely excised basal or squamous cell carcinoma of the skin.
* Patients who have received radical radiotherapy ≤4 weeks prior to starting the study treatment or who have not recovered from radiotherapy-related toxicities. Palliative radiotherapy for bone lesions ≤2 weeks prior to starting study treatment is allowed.
* Patients who have undergone any major surgery (i.e., intra-thoracic, intrabdominal, or intra-pelvic) ≤4 weeks prior to starting study treatment or who have not recovered from side effects of such therapy.
* Patients with a history of pulmonary embolism (PE) within the past 6 months or untreated deep-venous-thrombosis (DVT) within the past 6 months. Adequately treated DVT will be permitted providing that patient has been on anticoagulation for at least 2 weeks.
* Patients with impaired cardiac function or clinically significant cardiac diseases, including any of the following:

  * History or presence of serious uncontrolled ventricular arrhythmias.
  * Clinically significant resting bradycardia.
  * LVEF \<45% when assessed by 2-D echocardiogram (ECHO) or multiple gated acquisition scan (MUGA). (No basal cardiac test is mandatory other than ECG)
  * Any of the following within 6 months prior to starting study treatment: Myocardial infarction (MI), severe/unstable angina, Coronary Artery Bypass Graft (CABG), Congestive Heart Failure (CHF),Cerebrovascular Accident (CVA), Transient Ischemic Attack TIA).
  * Uncontrolled hypertension defined by a SBP ≥160 mm Hg and/or DBP ≥100 mm Hg, with or without anti-hypertensive medication. Initiation or adjustment of antihypertensive medication (s) is allowed prior to study entry.
* Patients with impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of Dovitinib (TKI258) (i.e., severe ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or extensive (\>1m) small bowel resection, inability to swallow oral medications). Prior partial or total gastrectomy is not an exclusion criterion.
* Known diagnosis of human immunodeficiency virus (HIV) infection. HIV testing is not mandatory.
* Patients who are currently receiving full dose of anticoagulation treatment with therapeutic doses of dicumarinical drugs as warfarin/acenocoumarol or anti-platelet therapy (i.e.,clopidogrel bisulfate). Treatment with acetylsalicyclic acid 100mg daily is allowed, as well as prophylactic or therapeutic low-weight-heparin.
* Pregnant or breast-feeding women.
* Women of child-bearing potential not employing an effective method of birth control. Effective contraception (e.g. condom with spermicidal jelly, foam suppository or film; diaphragm with spermicide; male condom and diaphragm with spermicide) must be used throughout the trial and 8 weeks after the end of Dovitinib treatment. Oral, implantable, or injectable contraceptives may be affected by cytochrome P450 interactions, and are therefore not considered effective for this study. Women of child-bearing potential defined as sexually mature women who have not undergone a hysterectomy or who have not been naturally postmenopausal for at least 12 consecutive months (i.e., who has had menses any time in the preceding 12 consecutive months), must have a negative serum pregnancy test ≤ 14 days prior to starting study drug. Women of child-bearing potential not employing and not willing to use an effective method of birth control. Post-menopausal women must have been amenorrheic for at least 12 months to be considered of non-childbearing potential.
* Fertile males not willing to use contraception as stated above.
* Patients unwilling or unable to comply with the protocol.