| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| chemo-refractory metastatic melanoma |
|
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| clinical benefit rate defined as CR+PR+SD >=4 months duration (RECIST-criteria) |
|
| E.2.2 | Secondary objectives of the trial |
response rate
duration of response
duration of stable disease
progression free survival (PFS)
time to progressive disease (TTP)
effect on survival (one-year survival and overall survival)
toxicities |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Male and female patients aged 18 years and older.
Diagnosis of unresectable (Stage III) or metastatic (Stage IV), histologically or cytologically proven, melanoma without clinically meaningful surgical or radiotherapeutical options.
Subjects must have progressed after receiving at least one cycle of DTIC (with a minimum of total dose of 850 mg/m²). Other previous chemotherapeutic treatments are allowed as well.
Performance status of 0 to 2 on the ECOG scale
Life expectancy > 12 weeks.
Patients must be able to swallow Sunitinib capsules.
Evidence of measurable disease according to the RECIST criteria, which means:
Patients must have clinically and/or radiographically documented measurable disease. At least one site of disease must be unidimensionally measurable as follows:
X-ray, physical exam > 20 mm
Spiral CT scan > 10 mm
Non-spiral CT scan > 20 mm
All radiology studies must be performed within 21 days prior to registration (35 days if negative).
Cutaneous lesions measuring at least 1 cm will be considered measurable.
For radiated lesions there must be radiographic evidence of progression of that lesion in order for that lesion to be constituted measurable disease or to be included in the measured target lesions.
Prior radiation therapy allowed if completed at least 2 weeks and any major surgery allowed if completed at least 4 weeks prior to first dose of Sunitinib.
Resolution of all acute toxic side effects of prior therapy or surgical procedures to grade < 1 NCI-CTC (except for laboratory values).
Adequate organ function including the following:
Adequate bone marrow reserve: platelets > 100 x 109/L, hemoglobin > 8 g/dl without support of growth factors (previous administration of packed red cells is allowed), absolute neutrophils count (AGC) > 1.5 x 109/L.
Hepatic: bilirubin <=1.5 times upper limit of normal (ULN), aspartate transaminase (AST) and alanine transaminase (ALT) <=2.5 times normal (AST and ALT <=5.0 times normal is acceptable if liver function abnormalities are due to underlying malignancy).
INR < 1.5 or a PTT within normal limits. Subjects must not have any evidence of a bleeding diathesis. (Subjects who are on therapeutic anticoagulation with an oral anticoagulation should have a documentation of a normal PT/PTT prior to initiating that therapy).
Renal: Serum creatinine < 1.5 x ULN, serum calcium < 12 mg/dl.
Pancreatic: Serum lipase and amylase within normal range (in case of a tumor-related elevation of amylase and/or lipase the possibility of study participation should be discussed with the principle investigator).
All other laboratory values specified in chapter 6.1, resolution of all side effects of prior therapy or surgical procedure to grade < 3 NCI-CTC.
Signed and dated informed consent given according to ICH/GCP guidelines, and national/ local regulations before the start of specific protocol procedures.
Patients who understand the nature of the trial and are willing and able to comply with scheduled visits, treatment plans, laboratory tests and other trial procedures.
Female patients who are capable of bearing children must have a negative pregnancy test result (serum or urine) at trial entry. All women included in the trial must be surgically sterile or postmenopausal or agree to employ adequate birth control measures for the duration of the trial and six months post-dosing. Male patients must be surgical sterile or must agree to use effective contraception during the trial and six months post-dosing |
|
| E.4 | Principal exclusion criteria |
Prior treatment with ras-raf-MEK-ERK signaling pathway inhibitors (including trastuzumab, sorafenib, farnesyl transferase inhibitors or MEK inhibitors), or treatment with drugs which target VEGF (such as bevacizumab).
Radiotherapy, except palliative radiotherapy during study participation as described in permitted prior and concomitant therapy
Known active infection (i.e. HIV, chronic hepatitis B or C, at the discretion of the investigator)
History of organ allograft or stem cell transplantation.
Coexisting second malignancy (excluding basal or squamous cell carcinoma of the skin, superficial bladder cancer and in situ carcinoma of the cervix with no evidence of recurrence) or history of prior malignancy (patients curatively treated and disease free for at least 5 years will be discussed with the sponsor before inclusion).
Bowel obstruction, history or presence of inflammatory enteropathy or extensive intestinal resection (> hemicolectomie or extensive small intestine resection with chronic diarrhea), Crohn’s disease, ulcerative colitis.
Current history of chronic diarrhea.
Any of the following events (in any grade) prior to starting the trial treatment:
clinically evident congestive heart failure, as defined by New York Health Association (NYHA) > class II
Ongoing cardiac dysrhythmias of NCI CTCAE grade ≥2, artrial fibrillation of any grade, or prolongation of the QTc interval to >450 msec for males or >470 msec for females. Subjects on beta-blockers and digoxin must be monitored closely.
Active coronary artery disease or ischemia (myocardial infarction within the last 6 months prior to study entry).
coronary/peripheral artery bypass graft.
cerebrovascular accident or transient ischemic attack.
Active disseminated intravascular coagulation, or history of clinically significant bleeding within the past 6 months, including gross hemoptysis or haematuria, or underlying coagulopathy
Hypertension that cannot be controlled by medications (>150/100 mmHg despite optimal medical therapy).
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 trial participation or trial drug administration, or which, in the judgment of the investigator, would make the patient inappropriate for entry into the trial.
Participation in any other clinical trial within the last 3 weeks.
Pregnant or lactating women.
Known allergic/hypersensitivity reaction to any of the components of the treatment, or known drug abuse/alcohol abuse.
Active CNS metastatic or meningeal tumors. Patients with prior disease must be at least 3 months off definitive therapy. They must have a negative imaging study (MRI or CT) within 4 weeks of study entry (if imaging study indicates residual scarring, the lesion must be stable for at least 3 months prior to study entry).
Intake of non-permitted concomitant drugs (the coordinating investigator should be contacted to discuss the individual case)
Concomitant treatment with antiarrhythmics and drugs with dysrhythmic potential (i.e. terfenadine, quinidine, procainamide, disopyramidine, sotalol, probucol, bepridil, haloperidol, risperidone, and indapamide)
Administration of potent CYP3A4 inhibitors during and within 7 days before start of Sunitinib-treatment (e.g. ketoconazole, itraconazole, clarithromycin, erythromycin, diltiazem, verapamil, delavirdine, indinavir, saquinavir, ritonavir, atazanavir, nelfinavir, grapefruit juice)
Administration of potent CYP3A4 inducers during or within 12 days before the start of Sunitinib-treatment (e.g. dexamethason, rifampicin, rifabutin, carbamazepine, phenobarbital, phenytion, St.John’s worth, efavirenz, tipranavir)
Ongoing treatment with therapeutic doses of anticoagulans such as Coumadin or heparins (however, low dose Coumadin or low dose heparin for deep vein thrombosis prophylaxis is allowed).
Any other medical anticancer therapy during the treatment phase except treatment with non-conventional therapies (e.g. herbs or acupuncture) and vitamin/mineral supplements, provided that they do not interfere with the trial endpoint, in the opinion of the investigator.
Concurrent systemic immune therapy, chemo- or hormone therapy.
Concomitant or within a 3-week period administration (from the first dose of Sunitinib) of any other experimental drug under investigation or any other form of chemotherapy.
Patients with seizure disorders requiring medication (such as antiepileptics, the use of carbamazepine, phenytion an phenobarbital is prohibited). |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| clinical benefit rate defined as a CR + PR + SD > 4 months duration (RECIST-Criteria). |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | Information not present in EudraCT |
| E.8.1.2 | Open | Information not present in EudraCT |
| E.8.1.3 | Single blind | Information not present in EudraCT |
| E.8.1.4 | Double blind | Information not present in EudraCT |
| E.8.1.5 | Parallel group | Information not present in EudraCT |
| E.8.1.6 | Cross over | Information not present in EudraCT |
| E.8.1.7 | Other | Information not present in EudraCT |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| Last visit is the end of the study |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
Print
