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

• ClinicalTrials.gov Identifier: NCT01964924
• Recruitment Status: Completed
• First Posted: October 17, 2013
• Results First Posted: September 20, 2019
• Last Update Posted: September 20, 2019
• Sponsor: National Cancer Institute (NCI)
• Collaborator: GlaxoSmithKline
• Information provided by (Responsible Party): National Cancer Institute (NCI)

Tracking Information

• First Submitted Date: October 15, 2013
• First Posted Date: October 17, 2013
• Results First Submitted Date: December 17, 2018
• Results First Posted Date: September 20, 2019
• Last Update Posted Date: September 20, 2019
• Actual Study Start Date: October 2, 2013
• Actual Primary Completion Date: January 20, 2017 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 27, 2019)

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 ]

Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.

Original Primary Outcome Measures (submitted: October 15, 2013)

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 ]

Exact binomial 95% confidence intervals for the true PR+CR response rate will be calculated.

Current Secondary Outcome Measures (submitted: August 27, 2019)

• Clinical Benefit Rate (CBR = CR+PR+Stable Disease [SD]) [ Time Frame: Up to 52 weeks ]
  The clinical benefit rate (CR+PR+SD) will be reported for patients after Part 1 and after Part 2.
• Duration of Objective Response [ Time Frame: up to 52 weeks ]
  Summary statistics of duration of response for patients with objective response
• Incidence of Adverse Events That Are Classified as Either Possibly, Probably, or Definitely Related to Study Treatment [ Time Frame: Up to 52 weeks ]
  Incidence of adverse events for patients that are classified as either possibly, probably, or definitely related to study treatment graded by National Cancer Institute (NCI) CTCAE v4.0
• Incidence of Severe (Grade 3+) Adverse Events or Toxicities Graded Per NCI CTCAE Version 4.0 [ Time Frame: Up to 52 weeks ]
  NCI CommonTerminology Criteria for Adverse Events (CTCAE) version 4.0 was utilized for grading incidence of toxicities (grade 3+).
• Overall Survival [ 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 ]
  The Kaplan-Meier method will be used to estimate overall survival distribution.
• 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 ]
  The Kaplan-Meier method will be used to estimate progression-free survival distribution.
• Proportion of Patients Who go Off Treatment Due to Adverse Reactions [ Time Frame: Up to 52 weeks ]
  The proportion of patients who go off treatment due to adverse reactions or even those who refuse further treatment for lesser toxicities that inhibit their willingness to continue participation on the trial was captured. These tolerability measures were assessed within each of the treatment parts independently. All patients who have received at least one dose of any of the therapeutic agents was evaluable for toxicity and tolerability.
• 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 ]
• Tolerability of the Regimen Defined as the Number of Patients Who Required Dose Modifications and/or Dose Delays [ Time Frame: Up to 52 weeks ]

Original Secondary Outcome Measures (submitted: October 15, 2013)

• 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 ]
  The Kaplan-Meier method will be used to estimate overall survival distribution.
• 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 ]
  The Kaplan-Meier method will be used to estimate progression-free survival distribution.
• Duration of objective response [ Time Frame: Date of documentation of response to the date of progression and/or death, assessed up to 52 weeks ]
  The methods of Kaplan and Meier will be used to evaluate this.
• Clinical Benefit Rate (CBR = CR+PR+Stable Disease [SD]) [ Time Frame: Up to 52 weeks ]
• Toxicity defined as adverse events that are classified as either possibly, probably, or definitely related to study treatment graded by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.0 [ Time Frame: Up to 52 weeks ]
  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.
• Incidence of severe (grade 3+) adverse events or toxicities [ Time Frame: Up to 52 weeks ]
• Tolerability of the Regimen Defined as the Number of Patients Who Required Dose Modifications and/or Dose Delays [ Time Frame: Up to 52 weeks ]
• Proportion of patients who go off treatment due to adverse reactions [ Time Frame: up to 52 weeks ]
• 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 ]

Current Other Pre-specified Outcome Measures (submitted: July 22, 2015)

• Predictive Value of PTEN and Other Biomarkers on Patient Outcome (Survival, ORR, and CBR) [ Time Frame: At time of disease progression, assessed up to 52 weeks ]
• Protein Intensity Fold-change Ratios Assessed by Reverse Phase Protein Assay Intensity Values [ Time Frame: Up to 52 weeks ]
  Ratios between tumors sampled prior to initiating trametinib single agent treatment and at time of progression (TOP) on either single agent trametinib or the combination (TOP/pre-treat ratio), will be calculated. These ratios will be median-centered and clustered using Cluster 2.0 software. Student's t-test for differences between average protein intensity ratios at these intervals will be calculated using Microsoft Excel by grouping all the ratios for individual clusters.

Original Other Pre-specified Outcome Measures (submitted: October 15, 2013)

• Protein intensity fold-change ratios assessed by reverse phase protein assay (RPPA) intensity values [ Time Frame: Up to 52 weeks ]
  Ratios between tumors sampled prior to initiating trametinib single agent treatment and at time of progression (TOP) on either single agent trametinib or the combination (TOP/pre-treat ratio), will be calculated. These ratios will be median-centered and clustered using Cluster 2.0 software. Student's t-test for differences between average protein intensity ratios at these intervals will be calculated using Microsoft Excel by grouping all the ratios for individual clusters.
• Predictive Value of PTEN and Other Biomarkers on Patient Outcome (Survival, ORR, and CBR) [ Time Frame: At time of disease progression, assessed up to 52 weeks ]

Descriptive Information

• 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
• Brief Summary: 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.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

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

Intervention

• Drug: Akt Inhibitor GSK2141795
  Given PO
  Other Names:

  • GSK2141795
  • Oral Akt Inhibitor GSK2141795
• Other: Laboratory Biomarker Analysis
  Correlative studies
• Drug: Trametinib
  Given PO
  Other Names:

  • GSK1120212
  • JTP-74057
  • MEK Inhibitor GSK1120212
  • Mekinist

Study Arms

Experimental: Treatment (trametinib, Akt inhibitor GSK2141795)

PART 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.

Interventions:

• Drug: Akt Inhibitor GSK2141795
• Other: Laboratory Biomarker Analysis
• Drug: Trametinib

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: August 27, 2019): 37
• Original Estimated Enrollment (submitted: October 15, 2013): 41
• Actual Study Completion Date: April 23, 2018
• Actual Primary Completion Date: January 20, 2017 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT01964924
• Other Study ID Numbers: NCI-2013-01895; NCI-2013-01895 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); 2013C0069; OSU 13117; 9455 ( Other Identifier: Ohio State University Comprehensive Cancer Center ); 9455 ( Other Identifier: CTEP ); N01CM00070 ( U.S. NIH Grant/Contract ); N01CM00100 ( U.S. NIH Grant/Contract ); P30CA016058 ( U.S. NIH Grant/Contract ); UM1CA186712 ( U.S. NIH Grant/Contract ); UM1CA186716 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: National Cancer Institute (NCI)
• Study Sponsor: National Cancer Institute (NCI)
• Collaborators: GlaxoSmithKline

Investigators

• Principal Investigator: Bhuvaneswari Ramaswamy, MD; Ohio State University Comprehensive Cancer Center

• PRS Account: National Cancer Institute (NCI)
• Verification Date: August 2019