Primary objectiveTo compare the progression-free survival (PFS) of subjects treated with either pimasertib or dacarbazine.Secondary objectivesEfficacy- To compare the objective response of subjects treated with either pimasertib or dacarbazine.- To…
ID
Source
Brief title
Condition
- Metastases
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
PFS, 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.
Secondary outcome
Efficacy
All efficacy endpoints involving RECIST v. 1.1 criteria will be based upon
investigator assessment.
- Objective response is defined as complete or partial tumor response according
to RECIST v. 1.1 criteria.
- Disease control is defined as complete response, partial response or stable
disease for >3 months, according to RECIST v. 1.1 criteria.
- PFS rate at 6 months from the time of randomization based upon objective
disease progression (according to RECIST v. 1.1), as defined for PFS above.
- OS defined as the time from randomization to death from any cause.
- OS rate at 12 months from the time of randomization.
- Change in subject-reported QoL (assessed by FACTMelanoma) from baseline
assessment to last assessment prior to objective disease progression (according
to RECIST v. 1.1).
Safety
- Treatment-emergent adverse events (TEAEs), serious adverse events (SAEs),
deaths.
- Clinically significant changes in safety related laboratory parameters
according to NCI-CTC v 4.0 and abnormal vital signs.
Pharmacokinetics
- Plasma PK parameter 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) profile of pimasertib.
Background summary
In human malignancies, activating Ras mutations are common, having been
identified in about 30% of cancers. Ras activation through the Raf/MEK/ERK
pathway modulates the activity of nuclear factors, which regulate the
transcription of genes that are required for proliferation and differentiation.
Activating B-Raf mutations occur in a high percentage of malignant melanomas.
Selectively pharmaceutical inhibition of MEK has resulted in a decreased
proliferation of melanoma cells with Raf muations. Based on this data, MEKs
are the targets of great interest for the development of new therapeutics in
the treatment of N-Ras mutated malignant cutaneous melanoma. Pimasertib is
being developed for the treatment of cancer. The safety and tolerability,
pharmacokinetics, pharmacodynamics and antitumor activity of this compound is
under investigation in patients with advanced malignancies.
Preliminary data from preclinical experiments indicate that pimasertib is an
active against N-Ras mutated cell lines and a potential medication to inhibit
the Raf/MEK/ERH pathway and potentially a positive effect on N-Ras mutated
malignant cutaneous melanoma.
Study objective
Primary objective
To compare the progression-free survival (PFS) of subjects treated with either
pimasertib or dacarbazine.
Secondary objectives
Efficacy
- To compare the objective response of subjects treated with either pimasertib
or dacarbazine.
- To compare the disease control of subjects treated with either pimasertib or
dacarbazine.
- To evaluate the overall survival (OS) of subjects treated with either
pimasertib or dacarbazine.
- To compare the Quality of Life (via FACTMelanoma) of subjects treated with
either pimasertib or dacarbazine.
Safety
- To compare the safety profile of subjects treated with pimasertib or
dacarbazine.
Pharmacokinetics
- To assess the pharmacokinetics (PK) of pimasertib in melanoma subjects and to
evaluate relationships between exposure and response as well as exposure and
adverse events (AEs).
Pharmacogenetics and Biomarkers
- To describe the relationship between basal tumor characteristics (e.g.,
genotype, gene products) and circulating markers and pimasertib anti-tumor
activity.
- To explore genes that are important in the drug metabolizing enzymes and
transporters (DMET) of pimasertib and to identify potential genetic variations
that may account for differences in PK profile.
Study design
This will be a phase II, multicentre, randomized, controlled pimasertib versus
dacarbazine (2 vs. 1), open label trial. The aim of the trial is to confirm the
activity of pimasertib in previously untreated subjects with locally advanced
or metastatic N-Ras mutated malignant cutaneous melanoma and to quantify it
versus dacarbazine. Secondary aims of the trial are to get a better
understanding of the efficacy, safety, pharmacogenomics (PGx) and their
relationship with pimasertib exposure. Subjects progressing in the dacarbazine
arm will be proposed pimasertib treatment (switch).
For each individual subject the trial will include:
- Up to 35-day screening and baseline evaluation period,
- Trial treatment period consisting of consecutive 21-day cycles of treatment,
- Post-treatment period: 30 ±3 days after the last drug intake.
- Survival follow-up data will be collected every 6 months until the end of the
trial.
Intervention
Pimasertib as monotherapy at an oral dose of 60 mg twice daily (BID)
continuously.
Dacarbazine 1000 mg per square meter of body surface area intravenously (IV)
every 3 weeks.
Treatment will consist of repeated 21-day cycles. Treatment will continue until
progression of the disease, unacceptable toxicity, withdrawal of informed
consent, or death.
Study burden and risks
See Flowchart of Protocol version 1.0 (15Jun12) on page 65-75.
Summary of procedures:
ECG
Blood sampling
Urine sampling
Questionnaires
Eye tests
Most frequent side effects of pimasertib are: nausea, vomiting and diarrhoea,
sores in the mouth and esophagus, which may be painful and cause difficulty
swallowing (stomatitis/mucositis), skin changes (including rash, dry skin and
acne). Abnormal vision including but not limited to blurry vision or worsening
of vision has also been observed frequently. Less frequent: temporary loss of
vision.
Rue de Rhone 14
Geneva 1204
CH
Rue de Rhone 14
Geneva 1204
CH
Listed location countries
Age
Inclusion criteria
1. Subjects with measurable, histologically or cytologically confirmed, unresectable locally advanced or metastatic cutaneous melanoma (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 understands 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, 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 females subjects and 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.
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 109/L, platelets < 100 x 109/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.
20. Is suitable for treatment with an approved B-Raf inhibitor or
antihuman
CTLA-4 (CD152) monoclonal antibodies (such as ipilimumab).
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2012-002669-37-NL |
| CCMO | NL41319.042.12 |