Details

Details

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

IRB OSU1113

CC 021413C

Hospital Main Campus

Phase Phase 2

Disease Breast

Drug GSK2141795, Trametinib

Description

Description

Primary Objectives
  • To assess the anti-tumor activity associated with trametinib monotherapy in patients with triple negative breast cancer (TNBC)
Secondary Objectives
  • To assess the anti-tumor activity associated with trametinib in combination with AKT inhibitor GSK2141795 after progression on trametinib in patients with metastatic TNBC.
  • To determine the progression-free survival following the initiation of treatment with trametinib monotherapy in patients with metastatic TNBC.
  • To determine the progression-free survival following the initiation of treatment with trametinib in combination with GSK2141795 in patients with metastatic TNBC.
  • To determine the overall survival following the initiation of treatment with trametinib with GSK214179 in patients with metastatic TNBC.
  • To determine the nature and degree of toxicities associated with trametinib monotherapy and trametinib in combination with GSK2141795 in patients with metastatic TNBC.
  • To determine the biomarker potential of PTEN to predict response to single agent trametinib
  • To determine molecular markers of sensitivity and resistance to trametinib monotherapy and trametinib in combination with GSK2141795 in patients with metastatic TNBC.
Inclusion Criteria

Inclusion Criteria

  1. 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.
  2. Patients must have measurable disease (RECIST 1.1).
  3. Patients must have had exposure to at least 1 and no more than 3 prior chemotherapy regimens for the treatment of metastatic breast cancer.
  4. 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.27
  5. Age ≥18 years. Because no dosing or adverse event data are currently available on the use of trametinib monotherapy or in combination with GSK2141795 in patients <18 years of age, children are excluded from this study, but will be eligible for future pediatric trials.
  6. ECOG performance status 0-1 (Appendix A).
  7. Life expectancy of greater than 3 months.
  8. 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.
  9. All prior treatment-related toxicities must be CTCAE v4 grade ≤1 (except alopecia) at the time of enrollment.
  10. Patients must have normal organ and marrow function as defined below:
    • Absolute neutrophil count ≥1,500/mcL
    • Platelets ≥75,000/mcL
    • Total bilirubin ≤1.5 x institutional upper limit of normal
    • AST(SGOT)/ALT(SGPT) ≤2.5x institutional upper limit of normal
    • LVEF ≥ institutional lower limit of normal by ECHO or MUGA
    • Serum creatinine ≤1.5 mg/dL OR calculated creatinine clearance (Cockroft-Gault formula) ≥50 mL/min OR 24-hour urine creatinine clearance ≥50 mL/min
  11. Patients must have controlled blood pressure with a systolic blood pressure < 140 mmHg and diastolic < 90 mmHg. Anti-hypertensive medications are permitted.
  12. 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. Patients must be at least 4 weeks from last surgical procedure and recovered from all post-operative complications.
  13. The effects of trametinib monotherapy or trametinib in combination with GSK2141795 on the developing human fetus are unknown. For this reason, 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.
  14. Ability to understand and the willingness to sign a written informed consent document.
  15. Both men and women and members of all races and ethnic groups are eligible for this trial. Because of the relative rarity of male breast cancer, we expect the majority of participants to be women. It is expected that the mix of patients entering this study will reflect the demographics of our clinical population and geographic area. We expect that participants will be racial/ethnic minorities which reflects the catchment area.
Exclusion Criteria

Exclusion Criteria

  1. 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. Consult the CTEP Medical Monitor if unsure whether second malignancies meet the requirements specified above.
  2. History of interstitial lung disease or pneumonitis.
  3. History of Type I diabetes mellitus. If a patient has Type II diabetes, they must have a Hemoglobin A1C ≤ 8%. Patients with a screening fasting glucose > 120 mg/dL will be excluded.
  4. Uncontrolled hypothyroidism. Patients must have a normal TSH per institutional standards at baseline.
  5. Patients who are receiving any other investigational agents.
  6. 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.
  7. History of allergic reactions attributed to compounds of similar chemical or biologic composition to trametinib monotherapy or trametinib in combination with GSK2141795.
  8. 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).
    • Because the composition, PK, and metabolism of many herbal supplements are unknown, 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 CYP3A4 (See section 5.2) are ineligible.

    Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated list such as http://medicine.iupui.edu/clinpharm/ddis/table.aspx; medical reference texts such as the Physicians' Desk Reference may also provide this information. As part of the enrollment/informed consent procedures, the patient should be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product.

  9. 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.
  10. 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.
  11. Pregnant women are excluded from this study because trametinib monotherapy or trametinib in combination with GSK2141795 has potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with trametinib monotherapy or trametinib in combination with GSK2141795, breastfeeding should be discontinued if the mother is treated with trametinib monotherapy or trametinib in combination with GSK2141795.
  12. HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with trametinib monotherapy or trametinib in combination with GSK2141795. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated.