| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| unresectable, advanced Stage III or Stage IV 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 |
| To evaluate progression free survival (PFS) between subjects treated with sorafenib versus placebo in combination with paclitaxel and carboplatin. |
|
| E.2.2 | Secondary objectives of the trial |
| To evaluate overall survival (OS) between subjects treated with sorafenib versus placebo in combination with paclitaxel and carboplatin. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Histologically or cytologically confirmed unresectable (Stage III) or metastatic (Stage IV) melanoma
- Male and female subjects of > =18 years of age
- Measurable disease defined as at least one lesion that can be accurately and serially measured per the modified RECIST criteria. Cutaneous lesions measuring at least 1 cm will be considered measurable
- ECOG Performance Status of 0 or 1
- Life expectancy of at least 12 weeks
- Subjects must have progressed after receiving at least one cycle of DTIC (with a minimum total dose of 850 mg/m2) or TMZ (with a minimum total dose of 750 mg/m2) containing regimen in the advanced or metastatic setting. Subjects may not have received more than one prior regimen in the metastatic setting. Subjects must have evidence of progressive disease prior to study entry. Subjects may have received prior immunotherapy, cytokine, biological or vaccine regimen in the adjuvant setting.
- Previous chemotherapy, biologic therapy, or radiation treatment must have been discontinued at least 4 weeks prior to study entry and subjects must have recovered from adverse events due to those agents
- Signed informed consent must be obtained prior to any study specific procedures
- Adequate bone marrow, liver and renal function as assessed by the following laboratory requirements:
- Hemoglobin > 9.0 g/dl
- Absolute neutrophil count (ANC) >1,500/mm3
- Platelet count > = 100,000/mm3
- Total bilirubin < 1.5 times the ULN
- ALT and AST < = 2.5 x ULN (5.0 x ULN for subjects with hepatic involvement with tumor)
- 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 warfarin should have documentation of a normal PT/PTT prior to initiating that therapy.)
- Serum creatinine < 1.5 x ULN
- Serum amylase < = 1.5 ULN. Lipase will be assessed in case abnormal values of amylase. Subjects with lipase < = 1.5 x ULN will be eligible. |
|
| E.4 | Principal exclusion criteria |
- Primary ocular or mucosal melanoma
- Previous or concurrent cancer that is distinct in primary site or histology from the cancer being evaluated in this study except cervical carcinoma in situ, treated basal cell carcinoma, superficial bladder tumors (TA, Tis & Ti) or any cancer curatively treated < 5 years prior to study entry
- Excluded medical conditions:
a. Clinically evident congestive heart failure, as defined by New York Health Association (NYHA) > class 2
b. Cardiac arrhythmias including atrial fibrillation are excluded if not adequately controlled. Subjects on beta-blockers and digoxin must be monitored closely as sorafenib may affect metabolism of these agents
c. Active coronary artery disease or ischemia (myocardial infarction within the last 6 months prior to study entry)
d. Uncontrolled hypertension
e. Active clinically serious infections (> grade 2 NCI CTCAE Version 3.0). Subjects who have received parenteral antibiotics within 4 weeks of treatment are excluded
f. Subjects with seizure disorder requiring medication (such as anti-epileptics). The use of carbamazepine, phenytoin and phenobarbital (drugs that induce CYP450 3A4 activity) is prohibited as these may enhance the metabolism of sorafenib and decrease serum concentrations
g. History of or suspected HIV infection or chronic hepatitis B or C
h. Active CNS metastatic or meningeal tumors will be excluded. 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)
i. History of organ allograft or stem cell transplantation
j. Pregnant or breast-feeding subjects. Women of childbearing potential must have a negative pregnancy test result within 7 days prior to the first sorafenib/placebo administration. For the purposes of this study, post-menopausal >1 year without menses and females who are surgically sterilized will not be required to have pregnancy testing
k. Both men and women enrolled in this study must use at least one method of adequate barrier birth control measure from screening until at least 28 days into the active follow-up period of the study
l. Prior radiation therapy is allowed. However, if radiation has been administered to a lesion, there must be radiographic evidence of progression of that lesion in order for that lesion to constitute measurable disease or to be included in the measured target lesions.
- Excluded prior and concomitant therapies and medications:
a. Prior treatment with a Ras pathway inhibitor (including trastuzumab, farnesyl transferase inhibitors or MEK inhibitors), or treatment with a drug which targets VEGF will exclude subjects
b. Major surgery within 4 weeks of study entry
c. Subjects who have received more than one prior DTIC or TMZ containing regimen in the metastatic setting. Prior advanced or metastatic treatments include, additional anticancer therapy (biologics or chemotherapy), or investigational treatment in combination with DTIC or TMZ.
• Only one prior regimen is allowed in the metastatic setting. The regimen must have contained DTIC or TMZ and patients must have progressed on that regimen.
• DTIC + IFN would be considered one regimen, a patient who fails DTIC + IFN, and then receives a vaccine + IL-2 treatment in the metastatic setting would be ineligible.
• Patients who have received IFN in an adjuvant setting followed by DTIC + IL-2 + IFN in a metastatic setting would be eligible.
d. Biological response modifiers, such as Granulocyte Colony Stimulating Factor (G-CSF), within 3 weeks of study entry
e. Use of St John’s Wort and rifampicin during the study or within 3 weeks of the first dose of study entry
f. Subjects may not receive any investigational agent while participating on this study
g. Radiotherapy will not be allowed while participating on this study, except palliative radiotherapy during study participation as described in Permitted Concomitant Therapy/Medication, Section 4.9.
- Substance abuse, medical, psychological or social conditions that may interfere with the subject’s participation in the study or evaluation of the study results
- Known or suspected allergy to the investigational agent or any agent given in association with this trial
- Unresolved chronic toxicity (> grade 2 per NCI CTCAE Version 3.0) |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary efficacy variable was PFS based on the assessment by the independent oncologist. The final analysis for PFS was performed when approximately 173 progression events were observed. The treatment groups were compared with respoect to PFS using a log rank test.No adjustment for covariates was used in the primary analysis of PFS. A two-sided significance level of 0.01 (alfa = 0.01) was used for this analysis of PFS. The Kaplan-Meier estimates and distribution curves for PFS were determined for each treatment group. Two-sided 95% and 99% confidence intervals (CI) were calculated for median PFS, 25th %ile, 75th %ile, and the estimated probability of PFS at Days 90, 180, 270 and 360 for each treatment group and for the difference between groups. The hazard ratio for comparing the sorafenib +C/P and placebo +C/P groups was calculated along with two-sided 95% and 99% CI for the hazard ratio. The treatment groups were compared with respect to PFS using a log-rank test. No adjustment for co-variates was used in the primary analysis of PFS.
Final analysis of PFS- A total of 197 subjects had progressed or died as of the data cutoff date of 22 Sept 2006 based on the independent review (100 subjects, 74% in the placebo +C/P group and 97 subjects, 72% in the sorafenib +C/P group).
The median PFS was 125days (99% CI, 79,160) for the placebo +C/P group and 122days (99% CI, 83 162) for the sorafenib +C/P group (p-value for comparing the treatment groups based on PFS=0.492 [two-sided log-rank test]). The pre-specified significance level for this analysis was 0.01, thus the difference between the treatment groups is not significant.
The estimated hazard ratio (risk of progression with sorafenib +C/P versus placebo +C/P was 0.906 (99% CI, 0.627, 1.310), representing a 9.4% reduction in hazard with sorafenib +C/P versus placebo +C/P.
Following Final Analysis of PFS
Since the study did not demonstrate a statistically significant improvement in PFS as determined by blinded independent review, all ongoing subjects on randomised study treatment have been unblinded. Subjects identified as receiving sorafenib treatment were given the opportunity to continue on sorafenib treatment provided that the investigator's clinical judgement is that some patient benefit was being derived from sorafenib. Additionally, informed consent was obtained from patients who decided to continue treatment with sorafenib. Subjects randomised to placebo who elected not to continue with sorafenib treatment should be withdrawn from study treatment and transitioned into Post-study Follow-up once they have completed an End of Treatment visit. Treatment with sorafenib will continue until an unacceptable toxicity thought to be related to the study drug is found, until disease progression occurs, or until subject consent is withdrawn. |
|
| 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 | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| 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 | 9 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 30 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
|
| 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
|
| Since the secondary efficacy variable is overall survival and the analysis is scheduled when a specific number of "events" has occurred, the end of the trial is when these number of events have been achieved. The final analysis for overall survival will be performed when approximately 195 patients have died. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 31 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 31 |
Print
