| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| local advanced or metastatic melanoma |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10027481 |
| E.1.2 | Term | Metastatic melanoma |
|
| 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 |
The primary objectives of this study are to determine the maximum tolerated dose (MTD) and/or recommended phase II dose (RPTD), dose limiting toxicities (DLTs), and the safety profile of RAF265 when administered orally to patients with locally advanced or metastatic melanoma; to determine the plasma pharmacokinetics (PK) of orally administered RAF265; and to evaluate potential pharmacodynamic effects of RAF265 using tumor/nevus biopsies, peripheral blood samples, and imaging.
The primary objective of Arm 4 is to confirm the safety and tolerability of the tablet formulation of RAF265 when dosed daily at its MTD, and to confirm that exposure with the tablet is comparable to that of the liquid formulation under steady-state conditions. |
|
| E.2.2 | Secondary objectives of the trial |
| Secondary objectives are to evaluate the effect of somatic BRAF and NRAS mutations of pharmacodynamic markers and with clinical response; to determine the response rate for BRAF mutant patients at the MTD and/or recommended phase II dose (RPTD); and to determine the RPTD, based on safety, PK and pharmacodynamic data and clinical tumor response. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Age ≥ 18 years.
2. Histologically confirmed diagnosis of locally advanced or metastatic melanoma (for cutaneous melanoma American Joint Committee on Cancer [AJCC] Stage IIIB to IV, pathologic Stage III and IV for noncutaneous melanoma), (see Appendix 1 for the AJCC Staging System for Cutaneous Melanoma).
3. Confirmed BRAF mutation status:
• Phase I: Patients must have either archival tumor tissue or tumor that can be biopsied in order to determine whether it contains mutated or wild-type BRAF. A minimum of 6 patients with tumor accessible to pretreatment and on-treatment biopsies at the MTD will be required before starting the dose expansion (phase II) of the study. The study will retain the option of enrolling patients with tumor that can be biopsied for the purpose of PD assessment at any dose level, if it is needed to inform dose selection for the dose expansion (phase II) or any subsequent study.
• Phase II: Patients must have documented presence of somatic BRAF mutation in
tumor tissue. Acceptable documentation includes:
1. Results of mutation analysis performed by Novartis on pre-treatment tumor
biopsy tissue or archival tumor tissue received and analyzed during the prescreening
period.
Results of mutation analysis documented by a non-Novartis laboratory prior to
the study. In this case pre-treatment tumor biopsy tissue or archival tumor tissue
should still be sent to Novartis for confirmation of BRAF mutation status and to
enable other exploratory analyses to be considered eligible.
4. Evidence of measurable disease, defined as at least one lesion that can accurately be measured in at least one dimension as ≥ 20 mm with conventional techniques or ≥ 10 mm with spiral CT scan; cutaneous lesions must have clearly defined margins and measure ≥ 5 mm in at least one diameter.
5. Patients scheduled for FDG-PET should have uptake of the tracer in at least one lesion (tumor-to-muscle ratio >2) in the baseline PET/CT scan in order to be eligible for the follow-up FDG PET scans. Patients who do not have uptake will be excluded from having additional FDG-PET scans, but can continue in the trial.
6. ECOG Performance Status of 0 or 1.
7. Required baseline laboratory data include:
Absolute neutrophil count (ANC) ≥ 1,500/mm3 [SI units 109/L];
Platelets ≥ 100,000/mm3 [SI units 109/L];
Hemoglobin ≥ 9.0 gm/dL [SI units gm/L];
Serum creatinine ≤ 1.5 x upper limit of normal (ULN);
Bilirubin ≤ 1.5 x ULN;
Lipase/Amylase ≤ ULN
Aspartate transaminase (AST) ≤ 2.5 x ULN, except for patients with tumor
Alanine transaminase (ALT) involvement of the liver who must have AST and ALT ≤ 5 x ULN;
8. At least 4 weeks must have elapsed since any major surgery.
9. For women of childbearing potential, negative serum pregnancy test within 72 hours of treatment and use of physician-approved method of birth control throughout the study.
10. No concurrent anticancer or investigational therapy for at least 4 weeks before study entry, with full recovery (NCI CTCAE Grade 1) from the toxic effects of that treatment.
11. Written informed consent, willingness, and ability to comply with all study procedures.
|
|
| E.4 | Principal exclusion criteria |
Patients with the following characteristics are excluded:
1. Previous therapy with the following molecularly-targeted agents:
• MEK inhibitors (such as PD0325901)
• VEGF or VEGFR inhibitors (such as Bevacizumab and small molecule inhibitors with activity against any of the VEGF receptor isoforms)
• Raf inhibitors (such as sorafenib, PLX4032)
2. Patients with a history of primary central nervous system tumors or brain metastases or who have signs/symptoms attributable to brain metastases and have not been assessed with radiologic imaging to rule out the presence of brain metastases.
3. Clinically significant cardiac disease including congestive heart failure (New York Heart Association Class III or IV), arrhythmia or conduction abnormality requiring medication, or cardiomyopathy; or clinically uncontrolled hypertension (blood pressure > 160/110 mmHg).
• Impaired cardiac function or clinically significant cardiac diseases, including any one
of the following:
1. LVEF < 45% as determined by MUGA scan or echocardiogram
2. Complete left bundle branch block
3. Obligate use of a cardiac pacemaker
4. Congenital long QT syndrome
5. History or presence of ventricular tachyarrhythmia
6. Presence of unstable atrial fibrillation (ventricular response > 100 bpm). Patients
with stable atrial fibrillation are eligible, provided they do not meet any of the
other exclusion criteria.
7. Clinically significant resting bradycardia (< 50 bpm)
8. QTc > 480 msec on screening ECG
9. Right bundle branch block + left anterior hemiblock (bifasicular block)
10. Angina pectoris ≤ 3 months prior to starting study drug
11. Acute MI ≤ 3 months prior to starting study drug
4. Previous or concurrent malignancy. Exceptions to this exclusion criteria include: adequately treated basal cell or squamous cell skin cancer; in situ carcinoma of the cervix, treated curatively and without evidence of recurrence for at least 3 years prior to study entry, or other solid tumor treated curatively, and without evidence of recurrence for at least 3 years prior to study entry.
5. Active, and uncontrolled clinically significant infection.
6. Breastfeeding women.
7. Chronic anticoagulation therapy with full strength acetylsalicylic acid (ASA), warfarin sodium, or heparin (low dose ASA ≤ 100 mg, or low dose warfarin ≤ 1 mg to maintain indwelling venous access device patency is allowed).
8. History of thromboembolic or cerebrovascular events within the last 12 months, including transient ischemic attack, cerebrovascular accident, deep vein thrombosis, or pulmonary embolism.
9. History of melena, hematemesis, or hemoptysis within the last 3 months.
10. Prior acute or chronic pancreatitis of any etiology.
11. Prior intra or extrahepatic biliary obstruction within the previous 12 months, or history of malignant obstruction requiring a biliary stent, unless stably treated with no prior obstruction or blockage of the stent.
12. History or current evidence of retinal disease, confirmed by ophtalmologic examination.
13.Other severe, acute, or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration or that may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for the study.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
• Determine the MTD and/or recommended phase II dose (RPTD), DLTs and safety profile (AEs and abnormal laboratory parameters) of orally administered RAF265
• Determine the plasma PK (including but not limited to area under the concentration versus time curve (AUC), half-life [t1/2], observed maximum plasma concentration [Cmax], time at which maximum concentration is observed [tmax])
• Single dose (run-in patients only)
• Repeat-dose (all patients)
• Evaluate the potential pharmacodynamic effects of RAF265 using tumor/nevi biopsies, peripheral blood, and tumor imaging:
• Tumor and nevi biopsies (nevi, if available): signaling molecules, apoptosis, proliferation and microvessel density
• Peripheral blood: levels of soluble growth factors and melanoma-related markers (e.g. MIA)
• Tumor imaging:
• Tumor metabolic activity relative to baseline as measured by FDG-PET (dose escalation and dose expansion)
• Changes in tumor vascular perfusion and permeability relative to baseline as measured by DCE MRI (at the dose expansion). |
|
| 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 | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| 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) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| 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 | 2 |
| 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 | 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 | No |
| 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
|
|
| 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 | 2 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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