Trametinib in Treating Patients With Progressive Metastatic Hormone-Resistant Prostate Cancer

A Single-Arm, Open-Label, Two-Stage Phase II Study of the MEK 1/2 Inhibitor Trametinib in Men With Progressive Metastatic Castrate Resistant Prostate Cancer

This phase II trial studies how well trametinib works in treating patients with hormone-resistant prostate cancer that is growing or getting worse and has spread to other parts of the body. Trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Study Overview

• Status: Active, not recruiting
• Conditions: Metastatic Prostate Carcinoma; Recurrent Prostate Carcinoma; Stage IV Prostate Cancer; Hormone-Resistant Prostate Cancer
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Other: Quality-of-Life Assessment; Drug: Trametinib

Detailed Description

PRIMARY OBJECTIVES I. To assess the activity of trametinib in metastatic castration resistant prostate cancer (mCRPC) that has progressed on either enzalutamide or abiraterone acetate.

SECONDARY OBJECTIVES I. Durability of prostate specific antigen (PSA) response as measured by the time to PSA progression as defined by Prostate Cancer Working Group 2 guidelines for PSA progression.

II. Maximal PSA response. III. Quality of life by Functional Assessment of Cancer Therapy- Prostate (FACT-P).

IV. Time to initiation of alternative antineoplastic therapy. V. Time to radiographic progression. VI. Objective response rate according to Response Evaluation Criteria in Solid Tumors (RECIST) guidelines.

VII. Overall survival measured as time from enrollment until death. VIII. Safety and tolerability. IX. Analysis of trametinib target engagement of mitogen-activated extracellular signal-related kinase (MEK1/2) is assessed by presence of p-ERK, the primary phosphorylation target of activated MEK1/2, in pre-treatment and at progression radiographically directed metastatic tumor biopsies by immunohistochemistry evaluation of p-ERK. Markers of cell proliferation (Ki67) and apoptosis (p27) will also be assessed.

XI. Investigation of molecular correlates to resistance and sensitivity to trametinib using pre-treatment and at progression metastatic biopsies.

XII. Discovery of one or a set of possible discriminative networks that are associated with a response to trametinib.

XII. Enrichment for patients in the second phase who have tumors exhibiting genomic features associated with a response to trametinib.

XIV. Analyses of circulating tumor deoxyribonucleic acid (ctDNA) for genomic aberrations correlated to treatment response.

OUTLINE:

Patients receive trametinib orally (PO) once daily (QD). Treatment continues in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 2 and 4 weeks, and then every 4 weeks thereafter.

• Study Type: Interventional
• Enrollment (Actual): 14
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90095
      • UCLA / Jonsson Comprehensive Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Willing and able to give informed consent
• Histologically confirmed prostate cancer (not exclusive of adenocarcinoma)
• mCRPC that has progressed on at least 1 therapy progression (defined as Prostate Cancer Working Group 2 [PCWG2] or at investigators' discretion) approved for treatment of mCRPC, one of which must include abiraterone acetate and/or enzalutamide
• Metastatic tumor that has been biopsied
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2
• Willing to undergo biopsy of a metastatic lesion at the time of progression
• Patients must have ongoing therapy to maintain serum testosterone < 50 ng/dL
• Absolute neutrophil count > 1,500/uL during screening evaluation
• Platelet count > 100,000/uL during screening evaluation
• Hemoglobin > 9 g/dL during screening evaluation
• Total bilirubin within the reference range during screening evaluation
• Alanine aminotransferase (ALT) within the reference range during screening evaluation
• Aspartate aminotransferase (AST) within the reference range during screening evaluation
• Creatinine < (1.5 mg/dL) during screening evaluation (> 1.5 is allowed if epidermal growth factor receptor [EGFR] > 45 mL/min/1.73 m^2)
• International normalized ratio (INR) < 1.3 (or < 3 if on warfarin or other anticoagulants) during screening evaluation
• Left ventricular ejection fraction (LVEF) >= 45% as measured by echocardiogram during screening evaluation
• Electrocardiogram (EKG) without clinically significant abnormality

Exclusion Criteria:

• A history of retinal vein occlusion (RVO) or risks factors for RVO
• A history of retinal pigment epithelial detachment (RPED) or risk factors for RPED
• Clinically significant abnormality on ophthalmologic examination during screening evaluation

• Clinically significant cardiovascular disease including:

  • LVEF < 45% measured by echocardiogram
  • History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months
  • Uncontrolled angina within 3 months
  • New York Heart Association (NYHA) class III or IV congestive heart failure
  • Clinically significant abnormality on EKG
  • History of clinically significant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, torsades de pointes)
  • Patients with intra-cardiac defibrillators or permanent pacemakers
• Presence of a comorbid disease or medical condition that would impair the ability of the patient to receive or comply with the study protocol
• History of interstitial lung disease or pneumonitis
• Use of any medication or herbal products that may have hormonal anti-prostate cancer activity and/or are known to modulate PSA levels (e.g., saw palmetto) or systemic corticosteroids greater than the equivalent of 10 mg of prednisone per day within 4 weeks of enrollment
• Prior use of trametinib or other mitogen activated protein kinase (MAPK) inhibitor in any context
• Known or suspected brain metastasis or active leptomeningeal disease or spinal cord compression
• Gastrointestinal disorder affecting absorption (e.g., gastrectomy, active peptic ulcer disease within last 3 months, inflammatory bowel disease)
• Any major surgery, extensive radiotherapy, chemotherapy with delayed toxicity, biologic therapy, or immunotherapy within 30 days of enrollment and/or daily or weekly chemotherapy without the potential for delayed toxicity within 14 days of enrollment
• Hospitalization within 30 days of enrollment for cancer related events
• History of another malignancy within the previous 5 years other than curatively treated non-melanoma skin cancer
• Use of an investigational agent within 4 weeks of enrollment
• Use of any medications known to affect the serum androgen level
• Any condition or reason that, in the opinion of the investigator, interferes with the ability of the patient to participate in the trial, which places the patient at undue risk, or complicates the interpretation of safety data

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment (trametinib); Patients receive trametinib PO QD. Treatment continues in the absence of disease progression or unacceptable toxicity.	Other: Laboratory Biomarker Analysis; Correlative studies; Other: Quality-of-Life Assessment; Ancillary studies; Other Names: Quality of Life Assessment; Drug: Trametinib; Given PO; Other Names: Mekinist; GSK1120212; JTP-74057; MEK Inhibitor GSK1120212

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
PSA response rate		At 12 weeks
Response rate assessed by RECIST criteria	Will be defined as decline in PSA of 30% or more, any decline of PSA of 50% or more, partial or complete response at 12 weeks, and freedom from radiographic progression at 24 weeks.	Up to 24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in markers of cell proliferation (Ki67) and apoptosis (p27), assessed by immunohistochemistry	Mixed effects logistic regression models to assess changes in markers over time, correlations between markers over time and associations between markers and treatment response (conditional logistic regression) will be used.	Baseline up to 24 weeks
Change in trametinib target engagement of MEK1/2 defined by the presence of p-ERK, assessed by immunohistochemistry	Mixed effects logistic regression models to assess changes in markers over time, correlations between markers over time and associations between markers and treatment response (conditional logistic regression) will be used.	Baseline up to 24 weeks
Durability of PSA response as measured by time to PSA progression as defined by PCWG2 guidelines		Up to 30 months
Incidence of adverse events, graded according to the Common Terminology Criteria for Adverse Events version 4.0		Up to 30 months
Maximal PSA response		Up to 30 months
Molecular correlates defined by gene expression, assessed using ribonucleic acid-sequencing, and mutational events, assessed using DNA exome-seq	Statistical bootstrap and Pearsons Correlation will be used to determine the relationship of phenotype to mutations and clinical variables. Fisher exact tests and logistic regression models will be used to evaluate the relationships between specific variations and treatment response.	Up to 24 weeks
Objective radiographic response rate according to RECIST guidelines		Up to 24 weeks
Overall survival		Time from enrollment until death, assessed for up to 30 months
Quality of life, assessed by FACT-P		Up to 30 months
Time to initiation of alternative anti-neoplastic therapy		Up to 30 months
Time to radiographic progression		Up to 24 weeks

Other Outcome Measures

Outcome Measure	Time Frame
ctDNA genomic aberrations, assessed by exome sequencing	Up to 24 weeks

Collaborators and Investigators

• Sponsor: Jonsson Comprehensive Cancer Center
• Collaborators: Novartis; Stand Up To Cancer; Prostate Cancer Foundation

Study record dates

Study Major Dates

• Study Start (Actual): January 30, 2018
• Primary Completion (Anticipated): January 31, 2024
• Study Completion (Anticipated): January 31, 2025

Study Registration Dates

• First Submitted: August 23, 2016
• First Submitted That Met QC Criteria: August 25, 2016
• First Posted (Estimate): August 26, 2016

Study Record Updates

• Last Update Posted (Actual): May 1, 2023
• Last Update Submitted That Met QC Criteria: April 27, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Genital Neoplasms, Male; Prostatic Diseases; Prostatic Neoplasms; Carcinoma; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Trametinib
• Other Study ID Numbers: 16-001044 (UCLA / Jonsson Comprehensive Cancer Center); NCI-2016-01201 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes