GSK1120212+GSK2141795 for Cervical Cancer
Condition: Cervical Cancer
MeSH terms: Uterine Cervical Neoplasms
Intervention: GSK1120212 (trametinib); GSK2141795
Intervention description: Trametinib dose is 1.5 mg orally once per day; The dose of GSK2141795 is 50 mg orally once per day
Intervention MeSH terms: Trametinib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 14.0
Sex: Female
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Cervical Cancer; Cervical; Cervix

Summary:

      This research study is evaluating the combination of two drugs called GSK1120212 (trametinib)
      and GSK2141795 as a possible treatment for recurrent or persistent cervical cancer.
      Trametinib and GSK2141795 are drugs that may stop cancer cells from growing. Trametinib is a
      MEK inhibitor - it blocks a protein called MEK that is commonly overactive in tumor cells.
      GSK2141795 is an AKT inhibitor which blocks a pathway in cancer cells that is commonly
      overactive in tumor cells called the PI3kinase pathway. In this research study, the
      investigator is looking to see whether the combination of Trametinib and GSK2141795 is useful
      in treating recurrent and persistent cervical cancer.

      Additionally, the investigator is looking to see if participants whose tumors contain a
      particular genetic make-up will have better response to combination trametinib and
      GSK2141795. Participants' tumors will be tested for mutations in genes which could make some
      cancers more susceptible to trametinib and GSK2141795.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Recurrent or metastatic cervical cancer of any histology

          -  Measurable disease by RECIST 1.1.

          -  Prior Therapy:

          -  At least one prior chemotherapy regimen for management of cervical cancer.
             Radiation-sensitizing chemotherapy will not be counted as a systemic chemotherapy
             regimen

          -  Patients can have received one additional regimen for treatment

          -  No prior receipt of PI3K or RAS-ERK pathway inhibitors

          -  Age ≥ 18 years

          -  Life expectancy > 3 mos

          -  ECOG performance status ≤ 2

          -  Participants must have normal organ function as defined below:

          -  Absolute Neutrophil Count (ANC)≥ 1,500/mcL

          -  Platelets ≥ 100,000/mcL

          -  Hemoglobin > 9.0/dL

          -  AST (SGOT) and ALT (SGPT) ≤ 2.5 × institutional ULN

          -  Total Bilirubin within normal institutional limits

          -  Albumin ≥ 2.5 g/dL

          -  Creatinine ≤ upper limit of institutional normal or creatinine clearance ≥ 50
             mL/min/1.73 m2 for subjects with creatinine levels above institutional normal or ≥ 50
             mL/min 24-hour creatinine clearance

          -  Normal LVEF

          -  Normal fasting Blood Glucose

          -  Availability of a formalin fixed paraffin embedded (FFPE) block of cancer tissue

          -  Normal blood pressure (systolic < 140 mmHg and diastolic < 90 mmHg)

          -  Women of childbearing potential must agree to use two forms of contraception (hormonal
             or barrier method of birth control; abstinence) prior to study entry and for the
             duration of study participation

          -  Toxicities of prior therapy (excepting alopecia) should be resolved to ≤ grade 1

          -  Ability to tolerate oral medications and no malabsorption

          -  Ability to sign an informed consent

        Exclusion Criteria:

          -  No previous chemotherapy within 3 weeks (6 weeks for nitrosoureas or mitomycin C,) or
             radiation therapy within 2 weeks prior to entering the study

          -  No use of investigational agents nor have participated in an investigational trial
             within the past 4 weeks (or five half-lives whichever is shorter; with a minimum of 14
             days from the last dose).

          -  Presence of active GI disease that could affect GI absorption or predispose a subject
             to GI ulceration.

          -  Evidence of mucosal of internal bleeding

          -  Major surgery within the last 4 weeks

          -  No Type 1 diabetes; however, patients with Type 2 diabetes are eligible if diagnosed ≥
             6 months prior to enrollment and if hemoglobin A1C (HbA1C) ≤ 8% at screening.

          -  Symptomatic or unstable brain metastases or asymptomatic and untreated but > 1 cm in
             the longest dimension

          -  Symptomatic or untreated leptomeningeal or spinal cord compression.

          -  Individuals with a history of a different malignancy are ineligible except for the
             following circumstances: the following cancers are eligible if diagnosed and treated
             within the past 3 years: breast cancer in situ and basal cell or squamous cell
             carcinoma of the skin, stage I colon carcinoma confined to a polyp.

          -  Any serious and/or unstable pre-existing medical disorders

          -  Known infection with HIV, Hepatitis B Virus, or Hepatitis C Virus

          -  Chronic use of drugs that are strong inhibitors or inducers of p450 CYP3A4

          -  known immediate or delayed hypersensitivity reaction or idiosyncrasy to study drugs

          -  History of interstitial lung disease or pneumonitis.

          -  Presence of cardiac metastases

          -  Subject with intra-cardiac defibrillators or pacemaker.

          -  History or current evidence / risk of retinal vein occlusion (RVO) or central serous
             retinopathy (CSR)

          -  History of RVO or CSR, or predisposing factors to RVO or CSR

          -  Visible retinal pathology as assessed by ophthalmic exam

          -  History or evidence of cardiovascular risk including any of the following

          -  QTcF≥ 480 msec ( ≥ 500 msec for subject with bundle branch block)

          -  History or evidence of current clinically significant uncontrolled arrhythmias.
             (Exception: controlled atrial fibrillation for >30 days prior to randomization)

          -  History of acute coronary syndromes (including myocardial infarction and unstable
             angina), coronary angioplasty, or stenting within 6 months of study entry.

          -  Class II or higher congestive heart failure.