Trametinib and Akt Inhibitor GSK2141795 in Treating Patients With Relapsed or Refractory Multiple Myeloma
|Recurrent Plasma Cell Myeloma Refractory Plasma Cell Myeloma||Drug: Akt Inhibitor GSK2141795 Other: Laboratory Biomarker Analysis Other: Pharmacological Study Drug: Trametinib||Phase 2|
|Study Design:||Intervention Model: Single Group Assignment
Masking: No masking
Primary Purpose: Treatment
|Official Title:||A Phase 2 Study of Sequential Trametinib and GSK2141795 in Relapsed or Refractory Multiple Myeloma|
- ORR evidenced by confirmed response rate, defined as number of patients with partial response or better by International Myeloma Working Group (IMWG) criteria divided by the number of patients in the applicable group (biomarker positive or negative) [ Time Frame: Up to 4 weeks ]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 minor response and PD will also be observed.
- DOR [ Time Frame: From the time measurement criteria are met for CR or PR (whichever is first recorded) until first date that recurrent or progressive disease is objectively documented or to death due to multiple myeloma, assessed up to 4 weeks ]Summarized for each cohort using the Kaplan-Meier method.
- Incidence of adverse event reactions reported according to CTCAE v4.0 [ Time Frame: Up to 4 weeks ]Reported by type, frequency, and severity.
- ORR after the addition of AKT inhibitor GSK2141795 to trametinib in patients who have developed progressive disease or have achieved less than a PR [ Time Frame: Up to 4 weeks ]
- PFS [ Time Frame: Time from the date of start of treatment to the date of documented progression (based on IMWG criteria) or death due to any cause, assessed up to 4 weeks ]Summarized for each cohort using the Kaplan-Meier method.
- Cell surface expression of integrin beta 7 determined by flow cytometry on cluster of differentiation 138 positive myeloma cells derived from screening bone marrow samples [ Time Frame: Up to 4 weeks ]Analyses will be descriptively summarized.
- Change in PI3K/AKT activation determined by phospho-flow cytometry and reversal phase protein arrays (RPPA) [ Time Frame: Baseline to up to 4 weeks ]Analyses will be descriptively summarized.
- Change in RAS-MEK-ERK activation determined by phospho-flow cytometry and RPPA [ Time Frame: Baseline to up to 4 weeks ]Analyses will be descriptively summarized.
- Chromosomal abnormalities as determined by FISH [ Time Frame: Up to 4 weeks ]Analyses will be descriptively summarized.
- Detection of RAS and RAF mutations using cfDNA [ Time Frame: Up to 4 weeks ]Ultra-deep sequencing will be performed on cfDNA to assess the feasibility of detecting mutations of NRAS, KRAS and BRAF from peripheral blood samples.
- Pharmacodynamic markers of trametinib [ Time Frame: Baseline, day 1 of course 2, progression ]Analyses will be descriptively summarized.
- Quantification of MAF expression by qPCR and FISH [ Time Frame: Baseline up to 4 weeks ]Analyses will be descriptively summarized.
- Tumor mutational profile by next generation sequencing [ Time Frame: Up to 4 weeks ]Analyses will be descriptively summarized.
|Actual Study Start Date:||October 30, 2013|
|Estimated Primary Completion Date:||December 31, 2017 (Final data collection date for primary outcome measure)|
Experimental: Treatment (trametinib, Akt inhibitor GSK2141795)
Patients receive trametinib orally PO 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.
Drug: Akt Inhibitor GSK2141795
Other Names:Other: Laboratory Biomarker Analysis
Correlative studiesOther: Pharmacological Study
Correlative studiesDrug: Trametinib
I. To evaluate the antitumor activity of trametinib determined by overall response rate (ORR) in patients that are stratified into groups 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).
I. To evaluate progression free survival (PFS) and duration of response (DOR) in the two stratified groups.
II. 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.
III. To evaluate PFS and DOR in patients receiving trametinib plus GSK2141795. IV. To evaluate the safety profile of trametinib with and without GSK2141795.
I. To explore the relationship between clinical response and pharmacodynamic (PD) markers.
II. 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.
III. To explore the role of integrin beta7 as a biomarker of MAF expression. IV. To explore the relationship between objective clinical response as well as progressive disease and the tumor mutational profile.
V. 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.
IV. To explore the feasibility of extracting circulating free tumor DNA (cfDNA) from peripheral blood and detecting RAS and RAF mutations using cfDNA.
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01989598
|Calgary, Alberta, Canada, T2N 2T9|
|Tom Baker Cancer Centre|
|Calgary, Alberta, Canada, T2N 4N2|
|Cross Cancer Institute|
|Edmonton, Alberta, Canada, T6G 1Z2|
|Cancer Centre of Southeastern Ontario at Kingston General Hospital|
|Kingston, Ontario, Canada, K7L 5P9|
|University Health Network-Princess Margaret Hospital|
|Toronto, Ontario, Canada, M5G 2M9|
|Principal Investigator:||Suzanne Trudel||University Health Network-Princess Margaret Hospital|