Trametinib and Akt Inhibitor GSK2141795 in Treating Patients With Relapsed or Refractory Multiple Myeloma
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|ClinicalTrials.gov Identifier: NCT01989598|
Recruitment Status : Completed
First Posted : November 21, 2013
Results First Posted : March 2, 2022
Last Update Posted : March 2, 2022
|Condition or disease||Intervention/treatment||Phase|
|Recurrent Plasma Cell Myeloma Refractory Plasma Cell Myeloma||Other: Laboratory Biomarker Analysis Other: Pharmacological Study Drug: Trametinib Drug: Uprosertib||Phase 2|
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.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||25 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Phase 2 Study of Sequential Trametinib and GSK2141795 in Relapsed or Refractory Multiple Myeloma|
|Actual Study Start Date :||October 30, 2013|
|Actual Primary Completion Date :||August 31, 2019|
|Actual Study Completion Date :||September 28, 2020|
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.
Other: Laboratory Biomarker Analysis
Other: Pharmacological Study
- 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: Every 4 weeks until progression or death, whichever occurs first, an average of 9 months. ]"Per International Myeloma Working Group (IMWG) Criteria: Complete Response (CR), Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and < 5% plasma cells in bone marrow; Partial Response (PR), > 50% reduction of serum M-protein and reduction in 24 hours urinary M-protein by >90% or to < 200 mg/24 h; Overall Response (OR) = CR + PR."
- PFS [ Time Frame: Time from the date of start of treatment to the date of documented progression (based on IMWG criteria) or death, whichever occurs first, due to any cause, assessed every 4 weeks, an average of 9 months. ]Summarized for each cohort using the Kaplan-Meier method, from the date of start of treatment to the date of documented progression (based on IMWG criteria) or death due to any cause, assessed every 4 weeks
- DOR (Duration of Response) [ Time Frame: From time measurement criteria are met for CR or PR (complete or partial response), (whichever recorded first) until first date that recurrent or progressive disease is objectively documented or to death due to multiple myeloma, assessed every 4 weeks ]Summarized for each cohort using the Kaplan-Meier method.
- 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: Every 4 weeks until progression or death, whichever occurs first, an average of 9 months. ]"Per International Myeloma Working Group (IMWG) Criteria: Complete Response (CR), Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and < 5% plasma cells in bone marrow; Partial Response (PR), > 50% reduction of serum M-protein and reduction in 24 hours urinary M-protein by >90% or to < 200 mg/24 h; Overall Response (OR) = CR + PR."
- Incidence of Adverse Event Reactions Reported According to CTCAE v4.0 [ Time Frame: From time of treatment start until treatment completion, an average of 1 year ]Reported by type, frequency, and severity.
- Pharmacodynamic Markers of Trametinib [ Time Frame: Baseline, day 1 of course 2, progression ]Analyses will be descriptively summarized.
- Chromosomal Abnormalities as Determined by FISH [ Time Frame: At baseline ]Analyses will be descriptively summarized.
- Tumor Mutational Profile by Next Generation Sequencing [ Time Frame: At baseline ]Analyses will be descriptively summarized.
- Change in RAS-MEK-ERK Activation Determined by Phospho-flow Cytometry and RPPA (Reversal Phase Protein Arrays) [ Time Frame: At baseline ]Analyses will be descriptively summarized.
- Detection of RAS and RAF Mutations Using cfDNA [ Time Frame: Baseline and every even cycle and at progression, an average of 9 cycles (9 months) ]Ultra-deep sequencing will be performed on cfDNA to assess the feasibility of detecting mutations of NRAS, KRAS and BRAF from peripheral blood samples.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01989598
|Calgary, Alberta, Canada, T2N 2T9|
|Tom Baker Cancer Centre|
|Calgary, Alberta, Canada, T2N 4N2|
|Cross Cancer Institute|
|Edmonton, Alberta, Canada, T6G 1Z2|
|Kingston Health Sciences Centre|
|Kingston, Ontario, Canada, K7L 2V7|
|University Health Network-Princess Margaret Hospital|
|Toronto, Ontario, Canada, M5G 2M9|
|Principal Investigator:||Suzanne Trudel||University Health Network-Princess Margaret Hospital|