E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
N-RAS mutated locally advanced or metastatic malignant cutaneous melanoma |
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E.1.1.1 | Medical condition in easily understood language |
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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 | 18.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10025655 |
E.1.2 | Term | Malignant melanoma of skin |
E.1.2 | System Organ Class | 100000004864 |
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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 compare the progression-free survival (PFS) of previously untreated subjects with N-Ras mutated locally advanced or metastatic malignant cutaneous melanoma treated with either pimasertib or dacarbazine. |
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E.2.2 | Secondary objectives of the trial |
Efficacy
- Compare the objective response of subjects treated with either pimasertib or dacarbazine.
- Compare the disease control of subjects treated with either pimasertib or dacarbazine.
- Evaluate the overall survival of subjects treated with either pimasertib or dacarbazine.
- Compare the Quality of Life of subjects treated with either pimasertib or dacarbazine.
Safety
- Compare the safety profile of subjects treated with pimasertib or dacarbazine.
Pharmacokinetics
- Assess the pharmacokinetics of pimasertib in melanoma subjects and to evaluate relationships between exposure and response as well as exposure and AEs.
Pharmacogenetics and Biomarkers
- Describe the relationship between basal tumor characteristics and circulating markers and pimasertib anti-tumor activity.
Explore genes that are important in the drug metabolizing enzymes and transporters of pimasertib and identify potential genetic variations that may account for differences in PK profile. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Subjects with measurable, histologically or cytologically confirmed, unresectable locally advanced or metastatic cutaneous melanoma (stage III c or M1a-c) N-Ras mutated. If N-Ras mutational status is unknown at screening, it must be prospectively defined before inclusion. If N-Ras mutational status is already known before screening, it must be retrospectively confirmed after inclusion by the sponsor.
2. Tumor lesions amenable to biopsy or available tumor tissue as archival samples.
3. Age ≥ 18 years.
4. Has read and understood the informed consent form and is willing and able to give informed consent. Fully understands requirements of the trial and willing to comply with all trial visits and assessments.
5. Women of childbearing potential must have a negative blood pregnancy test at the screening visit. For the purposes of this trial, women of childbearing potential are defined as: “All female subjects after puberty unless they are post-menopausal for at least two years, or are surgically sterile”.
6. Female subjects of childbearing potential and male subjects with female partners of childbearing potential must be willing to avoid pregnancy by using an adequate method of contraception for 2 weeks prior to, during and four weeks after the last dose of trial medication. Effective contraception is defined as the method of contraception with a failure rate of less than 1% per year. Adequate contraception for female
subjects or female partners of male subjects is defined as follows: two barrier methods or one barrier method in combination with an intrauterine device or oral contraception. |
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E.4 | Principal exclusion criteria |
1. Has previous systemic treatment for locally advanced or metastatic cutaneous melanoma (excluding adjuvant treatment).
2. Has non-measurable lesions, disease not evaluable by RECIST v. 1.1
3. Has an Eastern Cooperative Oncology Group performance status (ECOG PS) >1.
4. Has bone marrow impairment as evidenced by Hemoglobin < 10.0 g/dL, Neutrophil count <1.5 x 10^9/L, platelets < 100 x 10^9/L.
5. Has renal impairment as evidenced by calculated creatinine clearance <60 mL/min (according to the Cockcroft-Gault formula).
6. Has liver function abnormality as defined by total bilirubin > 1.5 x ULN, or AST/ALT >2.5 x ULN, for subjects with liver involvement AST/ALT >5 x ULN.
7. Has significant cardiac conduction abnormalities, including QTc prolongation of >480 ms and/or pacemaker or clinically relevant impaired cardiovascular function (NYHA Class III/IV).
8. Has hypertension uncontrolled by medication
9. Has retinal degenerative disease (hereditary retinal degeneration or age-related macular degeneration), history of uveitis, or history of retinal vein occlusion (RVO) or any eye condition that would be considered a risk factor for RVO (e.g., uncontrolled glaucoma or ocular hypertension).
10. Has known active CNS metastases unless previously radiotherapy treated, stable by CT scan for at least 3 months without evidence of cerebral edema and no requirements for corticosteroids or anticonvulsants.
11. History of difficulty swallowing, malabsorption or other chronic gastro-intestinal disease, or conditions that may hamper compliance and/or absorption of the tested product.
12. Known HIV positivity, active hepatitis C, or active hepatitis B.
13. Has undergone surgical intervention within 28 days from Day 1 of trial drug treatment.
14. Has received extensive prior radiotherapy on more than 30% of bone marrow reserves, or prior bone marrow/stem cell transplantation within 5 years from Day 1 of trial drug treatment.
15. Has history of any other significant medical disease such as major gastric or small bowel surgery, recent drainage of significant volumes of ascites or pleural effusion or has a psychiatric condition that might impair the subject well-being or preclude full participation in the trial.
16. Has known hypersensitivity to dacarbazine.
17. Is a pregnant or nursing female.
18. Participated in another clinical trial within the past 28 days.
19. Has CPK level at baseline NCI CTCAE Grade ≥2 (i.e., > 2.5 x ULN), and/or has a previous history of myositis or rhabdomyolysis. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Progression-free survival, defined as the time from randomization to the first documentation of objective disease progression (according to RECIST v. 1.1) as determined by the investigator or death, whichever comes first. Death will be considered as an event only if it is reported within 12 weeks after the last tumor assessment without progression. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Baseline; Day 1 of cycles 3, 5, 7, 9, 11, 13 and every 4 cycles thereafter; EoT |
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E.5.2 | Secondary end point(s) |
*Efficacy
All efficacy endpoints involving RECIST v. 1.1 criteria will be based upon investigator assessment. Independent central review of scans will be performed retrospectively for the purpose of sensitivity analyses.
- Objective response defined as complete or partial tumor response according to RECIST v. 1.1 criteria.
- Disease control defined as the proportion of subjects with complete response, partial response, or stable disease for > 3 months, according to RECIST v. 1.1 criteria.
- Progression-free survival rate at six months from the time of randomization based upon objective disease progression (according to RECIST v. 1.1 as defined for PFS above.
- Overall survival defined as the time from randomization to death from any cause.
- Overall survival rate at 12 months from the time of randomization.
- Change in patient-reported QoL (assessed by FACT-Melanoma) from baseline assessment to last assessment prior to objective disease progression (according to RECIST v. 1.1).
*Safety
- Treatment-emergent adverse events (TEAEs), SAEs, deaths.
- Clinically significant changes in safety-related laboratory parameters according to NCI-CTC v 4.0 and abnormal vital signs.
*Pharmacokinetics
- Plasma PK parameters estimates of pimasertib
* Pharmacogenetics and Biomarkers
- Gene products and genetic alterations in tumor biopsies.
- Predictive markers in plasma
- Potential genetic variations in gDNA obtained from PBMC, associated with differences in PK (i.e., DMET genes) and profile of pimasertib.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
- OR & Disease control: Baseline; Day 1 of cycles 3, 5, 7, 9, 11, 13 and every 4 cycles thereafter; EoT
- PFS rate: 6 months from time of randomization
- OS: time of death from any cause.
- OS rate: 12 months from time of randomization.
- Change in patient-reported QoL: at last assessment prior to objective disease progression
- TEAEs, SAEs, deaths.: Screening up to Post treatment assessment (30+/- 3 days after last drug intake).
- Vital signs: Baseline; Pre-dose on day 1, 8 of cycle 1, 2; Day 1 of every cycles thereafter; EoT; PTP
- PK: Day 8, 15 of cycle 1; Day 1 of cycle 2
- Gene products and genetic alterations: Baseline
- Predictive markers in plasma: Day 1 of cycle 1
- Potential genetic variations: Cycle 1 day 1 for pimasertib arm only. |
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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 | No |
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) | 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 | 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 | 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 | 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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 73 |
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 | No |
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 |
Australia |
Belgium |
France |
Germany |
Israel |
Italy |
Netherlands |
New Zealand |
South Africa |
Spain |
Sweden |
United Kingdom |
United States |
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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
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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 | 11 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
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 |