| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Advanced or metastatic BRAF V600E/K mutation-positive melanoma |
|
| E.1.1.1 | Medical condition in easily understood language |
| Advanced or metastatic melanoma |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 16.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10027481 |
| E.1.2 | Term | Metastatic melanoma |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 objective for this study is to establish the superiority of TRAMETINIB over chemotherapy with respect to progression-free survival for subjects with advanced/metastatic BRAF V600E mutation-positive melanoma without a history of prior brain metastases. |
|
| E.2.2 | Secondary objectives of the trial |
Secondary efficacy objectives:
• characterize PFS in subgroup of subjects from primary population (subjects with BRAF V600E mutation-positive melanoma without prior history of brain metastases) that have received no prior chemotherapy in the advanced or metastatic setting and the subgroup who have received one prior chemotherapy in the advanced or metastatic setting;
•further characterize efficacy in the primary population
•further characterize efficacy in the overall study population
•To characterize ORR and duration of response in subjects with BRAF V600 K mutation-positive melanoma regardless of prior history of brain metastases or prior chemotherapy;
•To characterize ORR and duration of response in subjects with BRAF V600E mutation-positive melanoma regardless of prior history of brain metastases or prior chemotherapy; and
•To characterize efficacy (PFS, ORR, and duration of response) in subjects following crossover from chemotherapy to TRAMETINIB. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects eligible for enrolment in the study must meet all of the following criteria:
1. Signed written informed consent.
2. ≥18 years of age.
3. Histologically confirmed, Stage III unresectable (Stage IIIc) or metastatic (Stage IV) cutaneous melanoma which is also determined to be BRAF V600E/K mutation-positive by the central laboratory.
4. Subjects may have received no prior treatment or up to one prior regimen of chemotherapy for advanced or metastatic melanoma. Subjects having received
one prior regimen of chemotherapy must have had documented disease
progression prior to randomization.
Prior treatment with immunotherapy (with the exception of prior ipilimumab, which is only allowed if given in the adjuvant setting), cytokine therapy, biological or vaccine regimen is permitted. Prior use of sorafenib is allowed. Disease progression must be documented for any anti-cancer therapy
(i.e., immunotherapy or biologic therapy), if given as a most recent treatment
prior to randomization.
5. Measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1) [Eisenhauer, 2009].
6. All prior treatment- related toxicities must be CTCAE (Version 4.0) ≤ Grade 1 (except alopecia) at the time of randomization.
7. Able to swallow and retain oral medication and does not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels.
8. Women of childbearing potential and men with reproductive potential must agree to use effective contraception during the study. Additionally women of childbearing potential must have a negative serum pregnancy test within 14 days prior to randomization.
9. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1 [Oken, 1982].
10. Adequate screening organ function
11. French subjects: In France, a subject will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category |
|
| E.4 | Principal exclusion criteria |
Subjects meeting any of the following criteria must not be enrolled in the study:
1. Any prior use of:
• BRAF inhibitors or MEK inhibitors.
• Ipilimumab in the advanced or metastatic setting.
2. Subjects who have received dacarbazine or paclitaxel prior to randomization will not be eligible to receive the same chemotherapy as study medication (i.e. a subject who received prior dacarbazine cannot receive dacarbazine on this trial and would thus receive paclitaxel if randomized to the control arm).
3. Any major surgery, extensive radiotherapy, chemotherapy with delayed toxicity, biologic therapy or immunotherapy within the last 21 days. Chemotherapy given daily or weekly without the potential for delayed toxicity within the last 14 days.
4. Administration of an investigational drug within 28 days or 5 half-lives, (whichever is shorter), prior to randomization – at least 14 days must have passed between the last dose of the prior investigational anti-cancer drug and randomization.
5. Current use of any prohibited medication (see Section 6).
• Use of anticoagulants such as warfarin and low molecular weight heparin is permitted, however INR must be monitored in accordance with local institutional practice.
6. History of another malignancy.
Exception: Subjects disease-free for 3 years i.e., subjects with
second malignancies that are indolent or definitively treated at least 3 years
ago), or subjects with history of completely resected non-melanoma skin cancer. Subjects with second malignancies that are indolent or definitely treated may be enrolled. Consultation with GSK Medical monitor is possible.
7. Any serious and/or unstable pre-existing medical (aside from malignancy exception above), psychiatric disorder, or other conditions that could interfere with subject’s safety, obtaining informed consent or compliance to the study procedures.
8. Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection (with the exception of chronic or cleared HBV and HCV infection which will be allowed).
9. Brain metastases with the following exceptions that are ALL confirmed by the GSK Medical Monitor: All known lesions must be previously treated with surgery or stereotactic radiosurgery (prior whole brain radiotherapy is not allowed, and Brain lesion(s), if still present, must be confirmed stable (i.e. no increase in lesion size) or if no longer present, must be confirmed as no evidence of
disease for ≥90 days prior to randomization (must be documented with two consecutive MRI or CT scans at least 60 days apart using contrast), and asymptomatic with no corticosteroids requirement for ≥ 30 days prior to randomization, and no enzyme-inducing anticonvulsants for ≥ 30 days prior to randomization.
10. History or evidence of cardiovascular risk including any of the following: QTcB ≥ 480 msec, or history or evidence of current clinically significant uncontrolled arrhythmias (exception: subjects with controlled Atrial Fibrillation for > 30 days prior to randomisation), or history of (within 6 months prior to randomization)acute coronay syndromes, coronary angioplasty, or stenting within 6 months prior to randomisation, or history/evidence of current ≥Class II congestive heart failure as defined by NYHA.
11. History of interstitial lung disease or pneumonitis.
12. History or current evidence / risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR) - see protocol for details
13. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study drug, or excipients or to dimethyl sulfoxide (DMSO) or to Cremophor EL (polyoxyethylated castor oil).
14. Lactating female.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint of this study will be progression free survival in subjects with BRAF V600E mutation positive melanoma without a prior history of brain metastases and will be based on investigator assessments. PFS is defined as the time from randomization until the earliest date of disease progression or death due to any cause. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Week 6, Week 12, Week 21 and Week 30 and then every 12 weeks (± 7 days) |
|
| E.5.2 | Secondary end point(s) |
Overall survival defined as the time from randomization until death due to any cause, evaluated in the primary population (i.e. subjects with BRAF V600E mutation positive melanoma without a prior history of brain metastases). Overall survival will also be evaluated in the overall study population (i.e. regardless of BRAF mutation, prior history of brain metastases, or prior chemotherapy).
Best overall response defined as the percentage of subjects with evidence of CR or PR RECIST 1.1 [Eisenhauer, 2009], evaluated in all subjects, V600E subjects, V600K subjects, as well as the primary population of subjects with BRAF V600E mutation positive melanoma without a prior history of brain metastases. Response rate following crossover to GSK1120212 will also be evaluated.
Per RECIST 1.1 best overall response will be based on confirmed or unconfirmed responses as OS/PFS are the primary endpoints.
Duration of Response
For subjects who demonstrate CR or PR, duration of response is defined to be the time from first documented evidence of CR or PR until disease progression or death due to any cause. Duration of response for subjects who have not progressed or died at the time of analysis will be censored at the date of their last tumor assessment. Duration of Response will be evaluated in the primary population (i.e. subjects with BRAF V600E mutation positive melanoma without a prior history of brain metastases), all subjects regardless of BRAF mutation or history of brain metastases, V600E subjects, and V600K subjects.
Duration of response following crossover to GSK1120212 will also be evaluated.
PFS will be evaluated in the subset of subjects from the primary population (i.e. subjects with BRAF V600E mutation-positive melanoma without a prior history of brain metastases) without prior chemotherapy in the advanced or metastatic setting as well as the subgroup with prior chemotherapy in the advanced or metastatic setting.
Additionally PFS will be evaluated in all subjects regardless of BRAF mutation or prior history of brain metastases.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | Yes |
| 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) | 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 | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | Yes |
| 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 | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 60 |
| 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 |
| Belgium |
| Canada |
| Denmark |
| France |
| Greece |
| Ireland |
| Italy |
| Austria |
| Netherlands |
| New Zealand |
| Norway |
| Sweden |
| Australia |
| Czech Republic |
| Finland |
| Germany |
| Hungary |
| Spain |
| Poland |
| United Kingdom |
| United States |
|
| 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
|
| End of trial = LPLV. Survival follow-up will continue until all subjects have either died, been followed for a minimum of 5 years (measured from the date of randomization), or have otherwise been lost follow-up. At this time the study objectives will have been met and the study will be closed |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 0 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
Print
