Trametinib and Akt Inhibitor GSK2141795 in Treating Patients With Relapsed or Refractory Multiple Myeloma

Sponsor
National Cancer Institute (NCI) (NIH)
Overall Status
Completed
CT.gov ID
NCT01989598
Collaborator
(none)
25
Enrollment
5
Locations
1
Arm
83
Actual Duration (Months)
5
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This phase II trial studies how well trametinib and Akt inhibitor GSK2141795 work in treating patients with multiple myeloma that has come back (relapsed) or that does not respond to treatment (refractory). Trametinib and Akt inhibitor GSK2141795 may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Condition or DiseaseIntervention/TreatmentPhase
Phase 2

Detailed Description

PRIMARY OBJECTIVES:
  1. 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).
SECONDARY OBJECTIVES:
  1. To evaluate progression free survival (PFS) and duration of response (DOR) in the two stratified groups.

  2. 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.

  3. 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:
  1. To explore the relationship between clinical response and pharmacodynamic (PD) markers.

  2. 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.

  3. 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.

  4. 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.

  5. To explore the feasibility of extracting circulating free tumor DNA (cfDNA) from peripheral blood and detecting RAS and RAF mutations using cfDNA.

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.

Study Design

Study Type:
Interventional
Actual Enrollment :
25 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase 2 Study of Sequential Trametinib and GSK2141795 in Relapsed or Refractory Multiple Myeloma
Actual Study Start Date :
Oct 30, 2013
Actual Primary Completion Date :
Aug 31, 2019
Actual Study Completion Date :
Sep 28, 2020

Arms and Interventions

ArmIntervention/Treatment
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
Correlative studies

Other: Pharmacological Study
Correlative studies

Drug: Trametinib
Given PO
Other Names:
  • GSK1120212
  • JTP-74057
  • MEK Inhibitor GSK1120212
  • Mekinist
  • Drug: Uprosertib
    Given PO
    Other Names:
  • GSK2141795
  • Oral Akt Inhibitor GSK2141795
  • Outcome Measures

    Primary Outcome Measures

    1. 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) [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."

    Secondary Outcome Measures

    1. PFS [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

    2. DOR (Duration of Response) [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.

    3. ORR After the Addition of AKT Inhibitor GSK2141795 to Trametinib in Patients Who Have Developed Progressive Disease or Have Achieved Less Than a PR [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."

    4. Incidence of Adverse Event Reactions Reported According to CTCAE v4.0 [From time of treatment start until treatment completion, an average of 1 year]

      Reported by type, frequency, and severity.

    Other Outcome Measures

    1. Pharmacodynamic Markers of Trametinib [Baseline, day 1 of course 2, progression]

      Analyses will be descriptively summarized.

    2. Chromosomal Abnormalities as Determined by FISH [At baseline]

      Analyses will be descriptively summarized.

    3. Tumor Mutational Profile by Next Generation Sequencing [At baseline]

      Analyses will be descriptively summarized.

    4. Change in RAS-MEK-ERK Activation Determined by Phospho-flow Cytometry and RPPA (Reversal Phase Protein Arrays) [At baseline]

      Analyses will be descriptively summarized.

    5. Detection of RAS and RAF Mutations Using cfDNA [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.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    • Patients must have histologically or cytologically confirmed multiple myeloma not otherwise specified (NOS) (10028566)

    • Patients must have measurable disease as defined as at least one of the following (these baseline laboratory studies for determining eligibility must be obtained within 28 days prior to enrollment):

    • Serum M-protein >= 0.5 g/dl (>= 5 g/l)

    • Urine M-protein >= 200 mg/24 h

    • Serum free light chains (FLC) assay: involved FLC level >= 10 mg/dl (>= 100 mg/l) and an abnormal serum free light chain ratio (< 0.26 or > 1.65)

    • Biopsy proven plasmacytoma (should be measured within 28 days of first study drug administration); prior biopsy is acceptable

    • If the serum protein electrophoresis is unreliable for routine M-protein measurement, quantitative immunoglobulin levels on nephelometry or turbidimetry will be followed

    • A diagnosis of multiple myeloma (MM) and documentation of relapsed or relapse/refractory status following at least 2 prior lines of therapy

    • Documented laboratory (lab) results confirming tumor mutational status must be obtained at screening; patients in whom mutational status cannot be determined will be deemed ineligible

    • Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)

    • Life expectancy of greater than 6 months

    • Able to swallow and retain orally-administered medication and does not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels

    • All prior treatment-related toxicities must be Common Terminology Criteria for Adverse Events (CTCAE) version (v)4 grade =< 1 (except alopecia) at the time of registration; subjects with toxicities attributed to prior anti-cancer therapy which are not expected to resolve and result in long lasting sequelae are permitted to enroll

    • Absolute neutrophil count (ANC) >= 1.0 x 10^9/L

    • Hemoglobin >= 8 g/dL

    • Platelets >= 50 x 10^9/L

    • Albumin >= 2.5 g/dL

    • Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (isolated bilirubin

    1.5 x ULN is acceptable if bilirubin is fractionated and direct bilirubin < 35%)

    • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x institutional ULN

    • Serum creatinine =< 1.5 mg/dL OR calculated creatinine clearance (Cockroft-Gault formula) >= 30 mL/min OR 24-hour urine creatinine clearance >= 30 mL/min

    • Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin time (PTT) =< 1.5 x institutional ULN

    • Fasting serum glucose < 126 mg/dl (7 mmol/l)

    • Left ventricular ejection fraction (LVEF) >= institutional lower limit of normal (LLN) by echocardiogram (ECHO) or multi gated acquisition scan (MUGA)

    • Subjects that have been previously diagnosed with type 2 diabetes or steroid-induced diabetes must also meet the additional following criteria:

    • Diagnosed with diabetes >= 6 months prior to enrollment

    • Hemoglobin A1C (HbA1C) =< 8% at screening visit

    • Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation; women of child-bearing potential must have a negative serum pregnancy test within 7 days prior to the start of protocol therapy; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately; men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of trametinib administration

    • Ability to understand and the willingness to sign a written informed consent document

    Exclusion Criteria:
    • History of another malignancy; exception: patients who have been disease-free for 3 years, or patients with a history of completely resected non-melanoma skin cancer and/or patients with indolent second malignancies, are eligible; consult the Cancer Therapy Evaluation Program (CTEP) medical monitor if unsure whether second malignancies meet the requirements specified above

    • History of interstitial lung disease or pneumonitis

    • Diabetes mellitus currently requiring insulin; subjects with a history of steroid-induced hyperglycemia may be enrolled provided that HbA1C at screening visit is =< 8%

    • Any major surgery, extensive radiotherapy, chemotherapy with delayed toxicity, biologic therapy, or immunotherapy within 28 days prior to randomization and/or daily or weekly chemotherapy or other approved anti-myeloma therapy without the potential for delayed toxicity within 14 days prior to registration

    • Use of other investigational drugs within 28 days preceding the first dose of trametinib and during the study

    • Symptomatic or untreated leptomeningeal or brain metastases or spinal cord compression

    • Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to trametinib or excipients or to dimethyl sulfoxide (DMSO) or GSK214795

    • Current use of a prohibited medication; the following medications or non-drug therapies are prohibited:

    • Other anti-cancer therapy while on study treatment; (note: megestrol [Megace] if used as an appetite stimulant is allowed)

    • Concurrent treatment with bisphosphonates is permitted; however, treatment must be initiated prior to the first dose of study therapy; prophylactic use of bisphosphonates in patients without bone disease is not permitted, except for the treatment of osteoporosis

    • The concurrent use of all herbal supplements is prohibited during the study (including, but not limited to, St. John's wort, kava, ephedra [ma huang], gingko biloba, dehydroepiandrosterone [DHEA], yohimbe, saw palmetto, or ginseng)

    • In vitro data indicate that GSK2141795 is a cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) substrate; drugs that potently inhibit CYP3A4 could lead to increased GSK2141795 exposure in subjects, and should either be prohibited or used with caution; drugs which are strong inducers of cytochrome P450, family 3, subfamily A (CYP3A) and may result in lower exposures of GSK2141795 should also be prohibited; GSK2141795 also appears to be a moderate in vitro inhibitor of cytochrome P450, family 2, subfamily C, polypeptide 8 (CYP2C8) (50% inhibitory concentration [IC50] 3 mcM) and CYP3A4 (IC50 11 mcM); drugs that are substrates of CYP3A4 or CYP2C8 with a narrow therapeutic index may be prohibited; drugs that are sensitive substrates of CYP3A4 or CYP2C8 should be used with caution

    • History or current evidence/risk of retinal vein occlusion (RVO) or retinal pigment epithelial detachment (RPED):

    • History of RVO or RPED, or predisposing factors to RVO or RPED (e.g., uncontrolled glaucoma or ocular hypertension, uncontrolled systemic disease such as hypertension, diabetes mellitus, or history of hyperviscosity or hypercoagulability syndromes)

    • Visible retinal pathology as assessed by ophthalmic exam that is considered a risk factor for RVO or RPED such as evidence of new optic disc cupping, evidence of new visual field defects, and intraocular pressure > 21 mmHg

    • History or evidence of cardiovascular risk including any of the following:

    • Left ventricular ejection fraction (LVEF) < LLN

    • A QT interval corrected for heart rate using the Bazett's formula Fridericia corrected QT interval (QTcB) >= 480 msec (>= 500 msec for subjects with bundle branch block)

    • History or evidence of current clinically significant uncontrolled arrhythmias (exception: patients with controlled atrial fibrillation for > 30 days prior to randomization are eligible)

    • Other clinically significant electrocardiogram (ECG) abnormalities including second (2nd) degree (type II) or third (3rd) degree atrioventricular (AV) block

    • Subject with intra-cardiac defibrillators or pacemakers

    • History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months prior to randomization

    • History or evidence of current >= class II congestive heart failure as defined by the New York Heart Association (NYHA) functional classification system

    • Treatment-refractory hypertension defined as a blood pressure of systolic > 140 mmHg and/or diastolic > 90 mmHg which cannot be controlled by anti-hypertensive therapy

    • Known cardiac metastases

    • Known human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV) infection (with the exception of chronic or cleared HBV and HCV infection, which will be allowed)

    • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements

    • The study drug must not be administered to pregnant women or nursing mothers; women of childbearing potential should be advised to avoid pregnancy and use effective methods of contraception; men with a female partner of childbearing potential must have either had a prior vasectomy or agree to use effective contraception; if a female patient or a female partner of a patient becomes pregnant while the patient receives trametinib, the potential hazard to the fetus should be explained to the patient and partner (as applicable); these potential risks may also apply to GSK2141795

    Contacts and Locations

    Locations

    SiteCityStateCountryPostal Code
    1Foothills HospitalCalgaryAlbertaCanadaT2N 2T9
    2Tom Baker Cancer CentreCalgaryAlbertaCanadaT2N 4N2
    3Cross Cancer InstituteEdmontonAlbertaCanadaT6G 1Z2
    4Kingston Health Sciences CentreKingstonOntarioCanadaK7L 2V7
    5University Health Network-Princess Margaret HospitalTorontoOntarioCanadaM5G 2M9

    Sponsors and Collaborators

    • National Cancer Institute (NCI)

    Investigators

    • Principal Investigator: Suzanne Trudel, University Health Network-Princess Margaret Hospital

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    National Cancer Institute (NCI)
    ClinicalTrials.gov Identifier:
    NCT01989598
    Other Study ID Numbers:
    • NCI-2013-02148
    • NCI-2013-02148
    • PHL-091
    • 9460
    • 9460
    • N01CM00032
    • UM1CA186644
    • NCT01951495
    First Posted:
    Nov 21, 2013
    Last Update Posted:
    Mar 2, 2022
    Last Verified:
    Feb 1, 2022
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group TitleTreatment (Trametinib, Akt Inhibitor GSK2141795)
    Arm/Group DescriptionPatients receive trametinib orally PO QD (once daily) 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. Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies Trametinib: Given PO Uprosertib: Given PO
    Period Title: Overall Study
    STARTED25
    Dual Therapy With Trametinib and GSK214179512
    COMPLETED25
    NOT COMPLETED0

    Baseline Characteristics

    Arm/Group TitleTreatment (Trametinib, Akt Inhibitor GSK2141795)
    Arm/Group DescriptionPatients 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. Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies Trametinib: Given PO Uprosertib: Given PO
    Overall Participants25
    Age (Count of Participants)
    <=18 years
    0
    0%
    Between 18 and 65 years
    13
    52%
    >=65 years
    12
    48%
    Age (years) [Median (Full Range) ]
    Median (Full Range) [years]
    64
    Sex: Female, Male (Count of Participants)
    Female
    14
    56%
    Male
    11
    44%
    Race and Ethnicity Not Collected (Count of Participants)
    Region of Enrollment (participants) [Number]
    Canada
    25
    100%

    Outcome Measures

    1. Primary Outcome
    TitleORR 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)
    Description"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."
    Time FrameEvery 4 weeks until progression or death, whichever occurs first, an average of 9 months.

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group TitleTreatment (Trametinib)Treatment (Trametinib, Akt Inhibitor GSK2141795)
    Arm/Group DescriptionPatients receive trametinib orally PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.Patients who develop progressive disease on trametinib monotherapy or achieve less then a PR after 4 cycles of treatment will have the option to continue on trametinib with the addition of GSK2141795
    Measure Participants2411
    Number [participants]
    1
    4%
    2
    NaN
    2. Secondary Outcome
    TitlePFS
    DescriptionSummarized 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
    Time FrameTime 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.

    Outcome Measure Data

    Analysis Population Description
    Note: 25 patients enrolled, however, one patient unevaluable was not included in analysis
    Arm/Group TitleTreatment (Trametinib, Akt Inhibitor GSK2141795)
    Arm/Group DescriptionPatients 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. Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies Trametinib: Given PO Uprosertib: Given PO
    Measure Participants24
    Median (95% Confidence Interval) [months]
    1.8
    3. Secondary Outcome
    TitleDOR (Duration of Response)
    DescriptionSummarized for each cohort using the Kaplan-Meier method.
    Time FrameFrom 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

    Outcome Measure Data

    Analysis Population Description
    Not reported. Data were not collected and not analyzed for this outcome measure.
    Arm/Group TitleTreatment (Trametinib)Treatment (Trametinib, Akt Inhibitor GSK2141795)
    Arm/Group DescriptionPatients receive trametinib orally PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.Patients who develop progressive disease on trametinib monotherapy or achieve less then a PR after 4 cycles of treatment will have the option to continue on trametinib with the addition of GSK2141795
    Measure Participants00
    4. Secondary Outcome
    TitleORR After the Addition of AKT Inhibitor GSK2141795 to Trametinib in Patients Who Have Developed Progressive Disease or Have Achieved Less Than a PR
    Description"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."
    Time FrameEvery 4 weeks until progression or death, whichever occurs first, an average of 9 months.

    Outcome Measure Data

    Analysis Population Description
    Trametinib monotherapy arm not applicable for this outcome measure
    Arm/Group TitleTreatment (Trametinib)Treatment (Trametinib, Akt Inhibitor GSK2141795)
    Arm/Group DescriptionPatients receive trametinib orally PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.Patients who develop progressive disease on trametinib monotherapy or achieve less then a PR after 4 cycles of treatment will have the option to continue on trametinib with the addition of GSK2141795
    Measure Participants011
    Count of Participants [Participants]
    0
    0%
    2
    NaN
    5. Secondary Outcome
    TitleIncidence of Adverse Event Reactions Reported According to CTCAE v4.0
    DescriptionReported by type, frequency, and severity.
    Time FrameFrom time of treatment start until treatment completion, an average of 1 year

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group TitleTreatment (Trametinib)Treatment (Trametinib, Akt Inhibitor GSK2141795)
    Arm/Group DescriptionPatients receive trametinib orally PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.Patients who develop progressive disease on trametinib monotherapy or achieve less then a PR after 4 cycles of treatment will have the option to continue on trametinib with the addition of GSK2141795
    Measure Participants2512
    Number [Adverse Events]
    2
    4
    6. Other Pre-specified Outcome
    TitlePharmacodynamic Markers of Trametinib
    DescriptionAnalyses will be descriptively summarized.
    Time FrameBaseline, day 1 of course 2, progression

    Outcome Measure Data

    Analysis Population Description
    Data for this measure was not analyzed
    Arm/Group TitleTreatment (Trametinib, Akt Inhibitor GSK2141795)
    Arm/Group DescriptionPatients 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. Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies Trametinib: Given PO Uprosertib: Given PO
    Measure Participants0
    7. Other Pre-specified Outcome
    TitleChromosomal Abnormalities as Determined by FISH
    DescriptionAnalyses will be descriptively summarized.
    Time FrameAt baseline

    Outcome Measure Data

    Analysis Population Description
    Data for this measure was not analyzed
    Arm/Group TitleTreatment (Trametinib, Akt Inhibitor GSK2141795)
    Arm/Group DescriptionPatients 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. Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies Trametinib: Given PO Uprosertib: Given PO
    Measure Participants0
    8. Other Pre-specified Outcome
    TitleTumor Mutational Profile by Next Generation Sequencing
    DescriptionAnalyses will be descriptively summarized.
    Time FrameAt baseline

    Outcome Measure Data

    Analysis Population Description
    Data for this measure was not analyzed
    Arm/Group TitleTreatment (Trametinib, Akt Inhibitor GSK2141795)
    Arm/Group DescriptionPatients 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. Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies Trametinib: Given PO Uprosertib: Given PO
    Measure Participants0
    9. Other Pre-specified Outcome
    TitleChange in RAS-MEK-ERK Activation Determined by Phospho-flow Cytometry and RPPA (Reversal Phase Protein Arrays)
    DescriptionAnalyses will be descriptively summarized.
    Time FrameAt baseline

    Outcome Measure Data

    Analysis Population Description
    Data for this measure was not analyzed
    Arm/Group TitleTreatment (Trametinib, Akt Inhibitor GSK2141795)
    Arm/Group DescriptionPatients 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. Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies Trametinib: Given PO Uprosertib: Given PO
    Measure Participants0
    10. Other Pre-specified Outcome
    TitleDetection of RAS and RAF Mutations Using cfDNA
    DescriptionUltra-deep sequencing will be performed on cfDNA to assess the feasibility of detecting mutations of NRAS, KRAS and BRAF from peripheral blood samples.
    Time FrameBaseline and every even cycle and at progression, an average of 9 cycles (9 months)

    Outcome Measure Data

    Analysis Population Description
    64 cfDNA specimens from 53 Myeloma patients including 13 patients from this trial that were included in this analysis
    Arm/Group TitleDetection of KRAS Mutations Using cfDNADetection of NRAS Mutations Using cfDNADetection of BRAF Mutations Using cfDNA
    Arm/Group DescriptionUltra-deep sequencing will be performed on cfDNA to assess the feasibility of detecting mutations of KRAS from peripheral blood samples.Ultra-deep sequencing will be performed on cfDNA to assess the feasibility of detecting mutations of NRAS from peripheral blood samples.Ultra-deep sequencing will be performed on cfDNA to assess the feasibility of detecting mutations of BRAF from peripheral blood samples.
    Measure Participants22137
    Number [MUTATIONS]
    10
    2
    2

    Adverse Events

    Time FrameFrom treatment start until 4 weeks after treatment end or death (whichever occurs first), for each patient, an average of 1 year.
    Adverse Event Reporting Description Adverse events collected as per protocol using CTCAE version 4.0
    Arm/Group TitleTreatment (Trametinib, Akt Inhibitor GSK2141795)
    Arm/Group DescriptionPatients 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. Laboratory Biomarker Analysis: Correlative studies Pharmacological Study: Correlative studies Trametinib: Given PO Uprosertib: Given PO
    All Cause Mortality
    Treatment (Trametinib, Akt Inhibitor GSK2141795)
    Affected / at Risk (%)# Events
    Total7/25 (28%)
    Serious Adverse Events
    Treatment (Trametinib, Akt Inhibitor GSK2141795)
    Affected / at Risk (%)# Events
    Total15/25 (60%)
    Infections and infestations
    Sepsis6/25 (24%)
    Lung infection2/25 (8%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED2/25 (8%)
    Nervous system disorders
    Intracranial hemorrhage2/25 (8%)
    Psychiatric disorders
    Confusion3/25 (12%)
    Other (Not Including Serious) Adverse Events
    Treatment (Trametinib, Akt Inhibitor GSK2141795)
    Affected / at Risk (%)# Events
    Total25/25 (100%)
    Gastrointestinal disorders
    Nausea14/25 (56%)
    Investigations
    thrombocytopenia13/25 (52%)
    Skin and subcutaneous tissue disorders
    Rash17/25 (68%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.

    Results Point of Contact

    Name/TitleDr. Suzanna Trudel
    OrganizationPrincess Margaret Cancer Centre
    Phone4169464501 ext 4566
    EmailSuzanne.Trudel@uhn.ca
    Responsible Party:
    National Cancer Institute (NCI)
    ClinicalTrials.gov Identifier:
    NCT01989598
    Other Study ID Numbers:
    • NCI-2013-02148
    • NCI-2013-02148
    • PHL-091
    • 9460
    • 9460
    • N01CM00032
    • UM1CA186644
    • NCT01951495
    First Posted:
    Nov 21, 2013
    Last Update Posted:
    Mar 2, 2022
    Last Verified:
    Feb 1, 2022