| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Subjects with advanced, metastatic, histologically confirmed melanoma, for whom treatment with dacarbazine is considered medically acceptable. Subjects should have measurable and evaluable disease (as per the RECIST criteria), and not have received prior cytotoxic chemotherapy. |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Classification code | 10027481 |
|
| 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 the overall tumour response rate (including complete responses (CR) and partial responses (PR)) of oral BAY 43-9006 given continuously in combination with repeated 21-day cycles of dacarbazine, in subjects with advanced, metastatic melanoma. The response rate will be determined using the RECIST criteria |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate:
Progression-free survival;
Overall survival;
Duration of response for those subjects who exhibit an objective response (PR or CR);
Disease control rate (PR+CR+SD);
Duration of stable disease for those subjects who exhibit SD as their best response;
Time to response for those subjects who exhibit an objective response (PR or CR);
Evaluate the safety and toxicity profile of the combination study treatment;
Explore possible BRAF and RAS mutations in melanoma biopsy samples that may correspond with a better response rate to the combination therapy of BAY 43-9006 and dacarbazine;
Analyse pERK and pVEGFR2 levels in melanoma biopsy samples to determine whether increased phosphorylation corresponds with a better response rate to the combination therapy of BAY 43-9006 and dacarbazine, and whether levels are modulated by the combination therapy. Other markers associated with these pathways may also be analysed. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Subjects with advanced, metastatic, histologically confirmed melanoma, for whom treatment with dacarbazine is considered medically acceptable.
2. Age >/=18 years.
3. Subject has measurable and evaluable disease defined as at least one metastatic lesion that can be accurately and serially measured by CT or MRI scan as per the RECIST criteria (see Section 10.5, Appendix 5). Cutaneous lesions measuring at least 20mm in longest diameter can be considered measurable (and therefore target lesions) via color photography including a ruler.
4. Subject has biopsiable disease at baseline and is willing to provide biopsy samples, or does not have biopsiable disease at baseline.
5. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.
6. Life expectancy of at least 12 weeks.
7. Adequate bone marrow, liver and renal function as assessed by the following laboratory requirements. These should be conducted at screening, within 7 days prior to the first dose of study drug:
* Haemoglobin > 9.0 g/dl.
* Absolute neutrophil count (ANC) >1,500/mm3.
* Platelet count ≥ 100,000/mm3.
* Total bilirubin < 1.5 x ULN.
* Alanine transaminase (ALT) and aspartate transaminase (AST) </= 2.5 x ULN (5.0 x ULN for subjects with hepatic metastases).
* Serum creatinine < 1.5 x ULN.
8. Prothrombin time (PT) or the International Normalized Ratio of PT (PT-INR), and partial thromboplastin time (PTT) < 1.5 x ULN. Subjects who are being therapeutically anticoagulated with an agent such as coumadin or heparin will be allowed to participate provided that no prior evidence of underlying abnormality in these parameters exists. For subjects on warfarin, close monitoring of at least weekly evaluations will be performed until INR is stable based on a measurement at pre-dose, as defined by the local standard of care.
9. Serum amylase and lipase must not be above the ULN at screening.
10. Signed informed consent must be obtained prior to any study specific procedures being performed, including per protocol biopsies. |
|
| E.4 | Principal exclusion criteria |
1. Primary ocular or mucosal melanoma (cutaneous vulval melanoma is permitted).
2. 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 & T1] or any cancer curatively treated > 3 years prior to study entry.
3. Presence of:
* Clinically evident congestive heart failure, NYHA > class 2. NYHA class II states; Patients have cardiac disease resulting in slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnoea or anginal pain.
* Cardiac arrhythmias requiring antiarrythmics, other than beta blockers or digoxin.
* Active coronary artery disease or ischaemia (myocardial infarction more than 6 months prior to study entry is allowed).
* Uncontrolled hypertension (> grade 2 NCI-CTCAE v3).
* Active clinically serious infections (> grade 2 NCI-CTCAE v3).
* Subjects with seizure disorder requiring medication are excluded.
* History of or suspected HIV infection, or chronic hepatitis B or C.
* Symptomatic metastatic brain or meningeal tumours unless the subject is > 6 months from definitive therapy, has a negative imaging study within 4 weeks prior to study entry and is clinically stable with respect to the tumor at the time of study entry. Also the subject must not be undergoing acute steroid therapy or taper (chronic steroid therapy is acceptable provided that the dose is stable for one month prior to and following screening radiographic studies).
* History of organ allograft.
* Pregnant or breast-feeding subjects. Women of childbearing potential must have a negative serum pregnancy test result within 7 days prior to the first study drug administration. Both men and women enrolled in this trial must use adequate barrier birth control measures from screening until the end of the active follow-up period of the trial. For the purposes of this study, post-menopausal will be considered to be 1 year without menses.
4. Excluded prior and concomitant therapies and medications, such as:
* Subjects who have received prior anticancer chemotherapy, or prior treatment with a Ras pathway inhibitor (including trastuzumab, EGFR inhibitors, farnesyl transferase inhibitors or MEK inhibitors), or treatment with a drug which targets VEGF (such as bevacizumab) will be excluded. Anticancer chemotherapy is defined as any agent or combination of agents with clinically proven anticancer activity administered by any route with the purpose of affecting the cancer, either directly or indirectly, including palliative and therapeutic endpoints. This includes anticancer chemotherapy given by isolated limb perfusion.Prior immunotherapy, cytokine or biological therapy is permitted, as long as there is at least 4 weeks’ recovery following the last dose of therapy prior to study entry. Prior vaccine therapy is also permitted, as long as there is at least 3 months’ recovery following the last administration of therapy prior to study entry.
* Radiotherapy during the study or within 3 weeks prior to first dose of study drug. Palliative radiotherapy will be allowed as described in Prior and concomitant therapy.
* Major surgery within 4 weeks prior to study entry.
* Bone marrow transplant or stem cell rescue within 4 months prior to the first dose of study drug.
* Biological response modifiers, such as G-CSF, within 3 weeks prior to study entry. G-CSF and other hematopoietic growth factors may be used in the management of acute toxicity such as febrile neutropaenia when clinically indicated or at the discretion of the investigator, however they may not be substituted for a required dose reduction. Erythropoietin given as secondary prophylaxis when clinically indicated is permitted, although use as primary prophylaxis is excluded. Again, this should not be substituted for a required dose reduction.
* Use of cyclo-oxygenase-2 inhibitors during the study or within 2-weeks prior to the first dose of study drug.
* Investigational drug therapy outside of this trial during or within 4 weeks prior to study entry.
5. Substance abuse, medical, psychological or social conditions that may interfere with the subject’s participation in the study or evaluation of the study results.
6. Known or suspected allergy to the investigational agent or any agent given in association with this trial, including subjects who are known to be hypersensitive to dacarbazine.
7. Any condition that is unstable or could jeopardize the safety of the subject and their compliance in the study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Overall tumour response rate. This will be calculated by dividing the total number of complete and partial responses seen by the total number of subjects enrolled. |
|
| 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 | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | Yes |
| 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 | No |
| 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) | No |
| E.8.2.2 | Placebo | No |
| 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 | 11 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 17 |
| 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
|
| The end of the study for regulatory purposes will be when the last subject finishes active study follow-up and moves into post-study follow-up. The justification for this is that only survival information will be collected in the post-study follow-up, and the contacts can either be to the subject or to their GP if more appropriate. The subject is not required to attend the clinic or to undergo any physical assessments during this period. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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