Clinical Trials /

Trametinib and Akt Inhibitor GSK2141795 in Treating Patients With Metastatic Triple-Negative Breast Cancer

NCT01964924

Description:

This phase II trial studies how well trametinib and v-akt murine thymoma viral oncogene homolog 1 (Akt) inhibitor GSK2141795 work in treating patients with triple-negative breast cancer (breast cancer cells that do not have estrogen receptors, progesterone receptors, or large amounts of human epidermal growth factor receptor 2 [HER2/neu] protein) that has spread to other places in the body. Trametinib and Akt inhibitor GSK2141795 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Trametinib and Akt Inhibitor GSK2141795 in Treating Patients With Metastatic Triple-Negative Breast Cancer
  • Official Title: A Single Arm, Phase II Study of Single Agent Trametinib Followed by Trametinib in Combination With GSK2141795 in Patients With Advanced Triple Negative Breast Cancer

Clinical Trial IDs

  • ORG STUDY ID: NCI-2013-01895
  • SECONDARY ID: NCI-2013-01895
  • SECONDARY ID: 2013C0069
  • SECONDARY ID: OSU 13117
  • SECONDARY ID: 9455
  • SECONDARY ID: 9455
  • SECONDARY ID: N01CM00070
  • SECONDARY ID: N01CM00100
  • SECONDARY ID: P30CA016058
  • SECONDARY ID: UM1CA186712
  • SECONDARY ID: UM1CA186716
  • NCT ID: NCT01964924

Conditions

  • Estrogen Receptor Negative
  • HER2/Neu Negative
  • Invasive Breast Carcinoma
  • Progesterone Receptor Negative
  • Recurrent Breast Carcinoma
  • Stage IV Breast Cancer
  • Triple-Negative Breast Carcinoma

Interventions

DrugSynonymsArms
Akt Inhibitor GSK2141795GSK2141795, Oral Akt Inhibitor GSK2141795Treatment (trametinib, Akt inhibitor GSK2141795)
TrametinibGSK1120212, JTP-74057, MEK Inhibitor GSK1120212, MekinistTreatment (trametinib, Akt inhibitor GSK2141795)

Purpose

This phase II trial studies how well trametinib and v-akt murine thymoma viral oncogene homolog 1 (Akt) inhibitor GSK2141795 work in treating patients with triple-negative breast cancer (breast cancer cells that do not have estrogen receptors, progesterone receptors, or large amounts of human epidermal growth factor receptor 2 [HER2/neu] protein) that has spread to other places in the body. Trametinib and Akt inhibitor GSK2141795 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To assess the anti-tumor activity associated with trametinib monotherapy in patients with
      triple negative breast cancer (TNBC).

      SECONDARY OBJECTIVES:

      I. To assess the anti-tumor activity associated with trametinib in combination with AKT
      inhibitor GSK2141795 after progression on trametinib in patients with metastatic TNBC.

      II. To determine the progression-free survival following the initiation of treatment with
      trametinib monotherapy in patients with metastatic TNBC.

      III. To determine the progression-free survival following the initiation of treatment with
      trametinib in combination with GSK2141795 in patients with metastatic TNBC.

      IV. To determine the overall survival following the initiation of treatment with trametinib
      with GSK214179 in patients with metastatic TNBC.

      V. To determine the nature and degree of toxicities associated with trametinib monotherapy
      and trametinib in combination with GSK2141795 in patients with metastatic TNBC.

      VI. To determine the biomarker potential of phosphatase and tensin homolog (PTEN) to predict
      response to single agent trametinib.

      VII. To determine molecular markers of sensitivity and resistance to trametinib monotherapy
      and trametinib in combination with GSK2141795 in patients with metastatic TNBC.

      OUTLINE:

      PART 1: 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 who
      experience disease progression continue to Part 2.

      PART 2: Patients receive trametinib as in Part 1 and also receive Akt inhibitor GSK2141795 PO
      QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or
      unacceptable toxicity.

      After completion of study treatment, patients are followed up every 3 months for 52 weeks.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (trametinib, Akt inhibitor GSK2141795)ExperimentalPART 1: Patients receive trametinib PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients who experience disease progression continue to Part 2. PART 2: Patients receive trametinib as in Part 1 and also receive Akt inhibitor GSK2141795 PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Akt Inhibitor GSK2141795
  • Trametinib

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have histologically or cytologically confirmed metastatic invasive
             breast cancer that is negative for the estrogen receptor (ER), progesterone receptor
             (PR) and HER2 by institutional guidelines

          -  Patients must have measurable disease (Response Evaluation Criteria in Solid Tumors
             version 1.1 [RECIST 1.1])

          -  Patients must have had exposure to at least 1 and no more than 3 prior chemotherapy
             regimens for the treatment of metastatic breast cancer

          -  Patients must consent to both a pretreatment and a post-treatment mandatory research
             biopsy prior to enrolling on trial, and therefore, must have tissue (excluding bone or
             brain) that is amenable to biopsy

          -  Eastern Cooperative Oncology Group (ECOG) performance status 0-1

          -  Life expectancy of greater than 3 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 version 4 (CTCAE v4) grade =< 1 (except alopecia) at the time of enrollment

          -  Absolute neutrophil count >= 1,500/mcL

          -  Platelets >= 75,000/mcL

          -  Total bilirubin =< 1.5 × institutional upper limit of normal

          -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
             [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
             =< 2.5 × institutional upper limit of normal

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

          -  Serum creatinine =< 1.5 mg/dL OR calculated creatinine clearance (Cockcroft-Gault
             formula) >= 50 mL/min OR 24-hour urine creatinine clearance >= 50 mL/min

          -  Patients must have controlled blood pressure with a systolic blood pressure < 140 mmHg
             and diastolic < 90 mmHg; anti-hypertensive medications are permitted

          -  Patients must be at least 4 weeks from last radiation dose; patients must be at least
             4 weeks from last chemotherapy, targeted therapy, or biologic therapy (exception
             allowed for a 2 week washout for patients who were on chemotherapy at less than a
             standard of care dose, as long as all other eligibility criteria are met); patients
             must be at least 4 weeks from last surgical procedure and recovered from all
             post-operative complications

          -  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; 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 monotherapy or in
             combination with GSK2141795 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 secondary malignancies, are eligible

          -  History of interstitial lung disease or pneumonitis

          -  History of type I diabetes mellitus; if a patient has type II diabetes, they must have
             a hemoglobin (hemoglobin A1C) =< 8%; patients with a screening fasting glucose > 120
             mg/dL will be excluded

          -  Uncontrolled hypothyroidism; patients must have a normal thyroid-stimulating hormone
             (TSH) per institutional standards at baseline

          -  Patients who are receiving any other investigational agents

          -  Individuals with symptomatic or progressive brain metastases are ineligible; subjects
             with treated brain metastases are eligible if they have no radiographic or other signs
             of progression in the brain for >= 3 weeks after completion of local therapy; any
             corticosteroid use for brain metastases must have been discontinued without the
             subsequent appearance of symptoms for >= 3 weeks prior to study enrollment

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to trametinib monotherapy or trametinib in combination with GSK2141795

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

               -  Other anti-cancer therapy while on study treatment (megestrol if used as an
                  appetite stimulant is allowed)

               -  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, yohimbe, saw palmetto, or ginseng)

               -  Patients receiving strong inhibitors or inducers of cytochrome P450, family 3,
                  subfamily A, polypeptide 4 (CYP3A4) are ineligible

          -  History or current evidence/risk of retinal vein occlusion (RVO) or central serous
             retinopathy (CSR) or predisposing factors to RVO or CSR (e.g., uncontrolled glaucoma
             or ocular hypertension, uncontrolled hypertension, history of hyperviscosity or
             hypercoagulability syndromes; visible retinal pathology as assessed by ophthalmic exam
             that is considered a risk factor for RVO or CSR such as evidence of new optic disc
             cupping, evidence of new visual field defects, and intraocular pressure > 21 mm Hg

          -  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

          -  Pregnant women are excluded from this study, breastfeeding should be discontinued if
             the mother is treated with trametinib monotherapy or trametinib in combination with
             GSK2141795

          -  Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
             therapy are ineligible
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective response rate (ORR), defined as the proportion of patients who have had a partial response (PR) or complete response (CR) (RECIST 1.1 based) within the first 6 months after initiation of therapy with trametinib
Time Frame:6 months
Safety Issue:
Description:Exact binomial 95% confidence intervals for the true PR+CR response rate will be calculated.

Secondary Outcome Measures

Measure:Clinical benefit rate (CBR = CR+PR+stable disease [SD])
Time Frame:Up to 52 weeks
Safety Issue:
Description:The clinical benefit rate (CR+PR+SD) will be reported for patients after Part 1 and after Part 2.
Measure:Duration of objective response
Time Frame:Date of documentation of response to the date of progression and/or death, assessed up to 52 weeks
Safety Issue:
Description:The methods of Kaplan and Meier will be used to evaluate this.
Measure:Incidence of adverse events that are classified as either possibly, probably, or definitely related to study treatment graded by National Cancer Institute (NCI) CTCAE v4.0
Time Frame:Up to 52 weeks
Safety Issue:
Description:The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables will be reviewed to determine toxicity patterns. All adverse event data that are graded as 3, 4, or 5 and classified as either "unrelated" or "unlikely to be related" to study treatment will be reviewed in the event of an actual relationship developing.
Measure:Incidence of severe (grade 3+) adverse events or toxicities graded per NCI CTCAE version 4.0
Time Frame:Up to 52 weeks
Safety Issue:
Description:
Measure:Overall survival (Part 2)
Time Frame:Start date of the treatment to the date of the event (i.e., death) or the date of last follow-up to evaluate that event, assessed up to 52 weeks
Safety Issue:
Description:The Kaplan-Meier method will be used to estimate overall survival distribution.
Measure:Progression-free survival
Time Frame:The duration of time from start of treatment to time of progression or death, whichever comes first, assessed up to 52 weeks
Safety Issue:
Description:The Kaplan-Meier method will be used to estimate progression-free survival distribution.
Measure:Proportion of patients who go off treatment due to adverse reactions
Time Frame:Up to 52 weeks
Safety Issue:
Description:
Measure:Proportion of patients who refuse further treatment for lesser toxicities that inhibit their willingness to continue participation on the trial
Time Frame:Up to 52 weeks
Safety Issue:
Description:
Measure:Tolerability of the regimen defined as the number of patients who required dose modifications and/or dose delays
Time Frame:Up to 52 weeks
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

September 15, 2017