| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Histologically confirmed cutaneous melanoma that is either Stage IIIc (unresectable) or Stage IV (metastatic), and determined to be BRAF V600 mutation-positive |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10025671 |
| E.1.2 | Term | Malignant melanoma stage IV |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10025670 |
| E.1.2 | Term | Malignant melanoma stage III |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | HLT |
| E.1.2 | Classification code | 10027156 |
| E.1.2 | Term | Skin melanomas (excl ocular) |
| E.1.2 | System Organ Class | 100000004858 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10040891 |
| E.1.2 | Term | Skin melanoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 broaden the understanding of molecular characterization of the melanoma in correlation to the clinical response (defined as partial response according to RECIST) at week 8 of targeted therapy in differently pre-treated patients with advanced/metastatic BRAF V600 mutation-positive cutaneous melanoma |
|
| E.2.2 | Secondary objectives of the trial |
To correlate the tumor´s molecular composition to metabolic responses and biological effects on the downstream signaling cascade in order to get first insights into an adaptive mechanism in the downstream signaling of an oncogenic driver mutation upon its selective inhibition.
Further secondary objectives are
- Safety / toxicity according to the CTC Criteria (Version 4.0)
- Efficacy according to RECIST criteria
- Progression free survival rate at 6 and 12 months
- Exploration of effects of rechallenge |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. ≥ 18 years of age.
2. Signed written informed consent.
3. Histologically confirmed cutaneous melanoma that is either Stage IIIc (unresectable) or Stage IV (metastatic), and determined to be BRAF V600 mutation-positive by the central laboratory. Subjects with ocular or mucosal melanoma are not eligible.
4. Assessable lesion for biopsy at week 2 not inferring with RECIST measurements
(Biopsies for genetic/biomarker analyses must be taken from lesions not required for disease assessment)
5. Measurable disease, i.e., present with at least one measurable lesion per RECIST, version 1.1 for the definition of a measureable lesion.
6. For Cohort A: Must NOT have received prior treatment with BRAF or MEK inhibitor.
If a prior systemic therapy (such as but not limited to chemotherapy, immunotherapy, biologic, vaccine and/or investigational treatment) in metastatic disease has been administered, four weeks or more since last systemic treatment must have passed. Must have recovered from any acute toxicity associated with prior therapy.
7. For Cohort B: Must have shown PR/CR during treatment with selective BRAF/MEK combination treatment that was discontinued due to tumor progression and received subsequent alternative treatment (such as but not limited to surgery, chemotherapy,
immunotherapy, biologic, vaccine and/or investigational treatment), with a period of at least 3 months since last intake of BRAF/MEK inhibitor.
8. All prior treatment-related toxicities (except alopecia) must be ≤ Grade 1 according to the CTCAE (version 4.0) at the time of registration.
9. Able to swallow and retain oral medication and must not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels.
10. Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to registration and agree to use effective contraception, as defined in Section 9.8 throughout the treatment period, and for 4 months after the last dose of study treatment.
Men with a female partner of childbearing potential must have either had a prior vasectomy or agree to use effective contraception as described in Section 9.8 throughout the treatment period, and for 4 months after the last dose of study treatment.
11. An ECOG performance status of 0 or 1.
12. Adequate baseline organ function as defined:
- ANC: >= 1.2 × 109/L
- Hemoglobin: >= 9 g/dL
- Platelet count: >= 100 x 109/L
- PT/INR and PTT: <= 1.3 x ULN
- Albumin: >= 2.5 g/dL
- Total bilirubin: <= 1.5 x ULN
- AST and ALT: <= 2.5 x ULN
- Serum creatinine: <= 1.5 mg/dL
13. A left ventricular ejection fraction (LVEF) ≥ the institutional lower limit of normal as measured by ECHO |
|
| E.4 | Principal exclusion criteria |
1. Any major surgery, extensive radiotherapy, chemotherapy with delayed toxicity, biologic therapy, or immunotherapy within 21 days prior to registration and/or daily or weekly chemotherapy without the potential for delayed toxicity within 14 days prior to registration.
2. Taken an investigational drug within 28 days or 5 half-lives (minimum 14 days), whichever is shorter, prior to registration.
3. Current use of a prohibited medication as described in Section 5.4.1.
4. History of another malignancy.
Exception: Subjects who have been disease-free for 3 years, subjects with a history of completely resected non-melanoma skin cancer, and/or subjects with successfully treated in situ carcinoma are eligible. Subjects with second malignancies that are indolent or definitively treated may be enrolled.
5. Any serious or unstable pre-existing medical conditions (aside from malignancy exceptions specified above), psychiatric disorders, or other conditions that could interfere with the subject’s safety, obtaining informed consent, or compliance with study procedures.
6. Known Human Immunodeficiency Virus (HIV), active Hepatitis B Virus (HBV), or active Hepatitis C Virus (HCV). Subjects with chronic or cleared HBV and/or HCV are eligible.
7. A history of glucose-6-phosphate dehydrogenase (G6PD) deficiency.
8. Subjects with brain metastases are excluded, unless:
• All known lesions must be previously treated with surgery or stereotactic radiosurgery, and
• Brain lesion(s), if present, must be confirmed stable (ie, no increase in lesion size) for 90 days prior to first dose of study drug(s). This must be documented with two consecutive MRI or CT scans using contrast, and
• Asymptomatic with no corticosteroids requirement for 30 days prior to first dose of study drug(s), and
• No enzyme-inducing anticonvulsants for 30 days prior to first dose of study drug(s).
In addition, even in cases of no evidence of disease (NED), confirmation on two consecutive MRI or CT scans using contrast will be required. Enrollment of a subject with brain metastases who meet the above criteria requires approval of the sponsor
9. A history or evidence of cardiovascular risk including any of the following:
a. A QT interval corrected for heart rate using the Bazett’s formula (QTcB; >= 480 msec;
b. A history or evidence of current clinically significant uncontrolled arrhythmias;
Exception: Subjects with controlled atrial fibrillation for > 30 days prior to registration are eligible.
c. A history of acute coronary syndromes (including myocardial infarction or unstable angina), coronary angioplasty, or stenting within 6 months prior to registration; or
d. A history or evidence of current >= Class II congestive heart failure as defined by the New York Heart Association (NYHA) guidelines.
10. A history or current evidence/risk of RVO or CSR including:
Presence of predisposing factors to RVO or CSR (e.g., uncontrolled glaucoma or ocular hypertension, uncontrolled hypertension, uncontrolled diabetes mellitus, or a history of hyperviscosity or hypercoagulability syndromes); or
Visible retinal pathology as assessed by ophthalmic examination that is considered a risk factor for RVO or CSR such as:
i. Evidence of new optic disc cupping;
ii. Evidence of new visual field defects on automated perimetry;
iii. Intraocular pressure > 21 mmHg as measured by tonography.
11. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study treatments, their excipients, and/or dimethyl sulfoxide (DMSO).
12. Interstitial lung disease or pneumonitis
13. Pregnant or breast-feeding lactating females
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Correlation of clinical response at week 8 of targeted therapy, defined as the rate of patients with PR and CR according to RECIST with molecular results of the biopsies |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Week 8 after start of therapy |
|
| E.5.2 | Secondary end point(s) |
• All adverse events ≥ Grade 3 according to CTCAE, Version 4.0 criteria, that are definitely, probably, or possibly related to the administration of the investigational agents will be assessed.
• Overall response rate (PR+CR) according to RECIST Criteria at any time in the study.
• Disease control rate (DCR = rate of CR or PR or SD) according to RECIST Criteria at any time in the study.
• Progression free survival rate at 6 months, PFS is defined as the time from the first study treatment date until the first documented tumor progression date (as defined by RECIST criteria) or date of death, whichever occurs first.
• Overall survival rate at 12 months defined as the rate of patients alive 12 months after the date from the first study treatment.
• Clinical efficacy parameter (1-year OS, ORR, DCR, PFS at 6 months) according to molecular composition of tumor
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| During study treatment, 6 months from the date of first study treatment, 12 months from the date of first study treatment |
|
| 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 | No |
| 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 | No |
| E.8.1.7 | Other | No |
| 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.8.2.4 | 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 | 12 |
| 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 | No |
| 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 | 4 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | |
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