A Study of Trametinib and GSK2141795 Multiple Myeloma

Titre officiel

A Phase 2 Study of Sequential Trametinib and GSK2141795 in Relapsed or Refractory Multiple Myeloma

Sommaire:

Cette étude de phase 2 a pour but d'examiner l'efficacité du médicament expérimental, le trametinib, en association avec ou sans le GSK2141795, dans le traitement des patients atteints de myélome multiple dont le cancer récidive ou pour lesquels il n'existe pas encore de traitements standard pour leur maladie.

Description de l'essai

Primary Outcome Measures:

• ORR evidenced by confirmed response rate, defined as partial response or better by International Myeloma Working Group (IMWG) criteria
  The patient will be classified as having had a response if he/she has a confirmed response (i.e., a stringent complete response, or complete response or near complete response or very good partial response or partial response noted as the objective status of two consecutive assessments). The rate of minimal response (MR) and PD will also be observed.

• PFS
• DOR
• ORR after the addition of AKT inhibitor GSK2141795 to trametinib in patients who have developed progressive disease or have achieved less than a PR
• Incidence of adverse event reactions reported according to CTCAE v4.0
• Reported by type, frequency, and severity.

• Pharmacodynamic markers of trametinib
• Quantification of MAF expression by qPCR and FISH
• Chromosomal abnormalities as determined by FISH
• Cell surface expression of integrin beta 7 determined by flow cytometry on cluster of differentiation (CD)138 positive myeloma cells derived from screening bone marrow samples
• Tumour mutational profile by sequenom analysis
• Change in PI3K/AKT activation determined by phospho-flow cytometry and reversal phase protein arrays (RPPA)
• Change in RAS-MEK-ERK activation determined by phospho-flow cytometry and RPPA

PRIMARY OBJECTIVES:

• To evaluate the antitumor activity of trametinib determined by overall response rate (ORR) in patients that are stratified into grouped based on: biomarker positive (neuroblastoma RAS viral [v-ras] oncogene homolog [NRAS], v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog [KRAS], v-raf murine sarcoma viral oncogene homolog B1 [BRAF] mutated) and biomarker negative (without NRAS, KRAS, BRAF mutation).

SECONDARY OBJECTIVES:

• To evaluate progression free survival (PFS) and duration of response (DOR) in the two stratified groups.
• To document ORR after the addition of GSK2141795 (Akt inhibitor GSK2141795) to trametinib in patients who have developed progressive disease or have achieved less than a partial response (PR) after 4 cycles of treatment.
• To evaluate PFS and DOR in patients receiving trametinib plus GSK2141795. IV. To evaluate the safety profile of trametinib with and without GSK2141795.

TERTIARY OBJECTIVES:

• To explore the relationship between clinical response and pharmacodynamic (PD) markers.
• To explore the relationship between v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog (MAF) expression as determined by quantitative polymerase chain reaction (qPCR), chromosomal abnormalities detected by florescence in situ hybridization (FISH), and clinical response.
• To explore the role of integrin beta7 as a biomarker of MAF expression.
  
• To explore the relationship between objective clinical response as well as progressive disease and the tumor mutational profile.
• To explore mechanism of phosphatidylinositol 3 kinase (PI3K)/v-akt Murine Thymoma Viral Oncogene Homolog 1 (AKT) and retrovirus-associated deoxyribonucleic acid (DNA) sequence (RAS)-mitogen-activated protein kinase kinase (MEK)-mitogen-activated protein kinase 1 (ERK) activation and correlate these with clinical response and PD markers.

OUTLINE:

Patients receive trametinib orally (PO) once daily (QD) on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients with progressive disease or who achieve less than PR after 4 courses may also receive Akt inhibitor GSK2141795 PO daily on days 1-28.

After completion of study treatment, patients are followed up for 4 weeks.

Voir cet essai sur ClinicalTrials.gov