Trametinib and Akt Inhibitor GSK2141795 in Treating Patients With Relapsed or Refractory Multiple Myeloma
Condition: Recurrent Plasma Cell Myeloma; Refractory Plasma Cell Myeloma
MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell
Intervention: Laboratory Biomarker Analysis; Pharmacological Study; Trametinib; Uprosertib
Intervention description: Correlative studies; Correlative studies; Given PO; Given PO
Intervention MeSH terms: Trametinib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 25.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

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.
    

Eligibility criteria:

        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