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

Primary Purpose

Hormone-Resistant Prostate Cancer, Metastatic Prostate Carcinoma, Recurrent Prostate Carcinoma

Status

Active

Phase

Phase 2

Locations

United States

Study Type

Interventional

Intervention

Laboratory Biomarker Analysis

Quality-of-Life Assessment

Trametinib

About this trial

This is an interventional treatment trial for Hormone-Resistant Prostate Cancer

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)MaleDoes not accept healthy volunteers

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

Sites / Locations

UCLA / Jonsson Comprehensive Cancer Center

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (trametinib)

Arm Description

Patients receive trametinib PO QD. Treatment continues in the absence of disease progression or unacceptable toxicity.

Outcomes

Primary Outcome Measures

PSA response rate

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.

Secondary Outcome Measures

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.

Change in trametinib target engagement of MEK1/2 defined by the presence of p-ERK, assessed by immunohistochemistry

Durability of PSA response as measured by time to PSA progression as defined by PCWG2 guidelines

Incidence of adverse events, graded according to the Common Terminology Criteria for Adverse Events version 4.0

Maximal PSA response

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.

Objective radiographic response rate according to RECIST guidelines

Overall survival

Quality of life, assessed by FACT-P

Time to initiation of alternative anti-neoplastic therapy

Time to radiographic progression

Full Information

NCT ID

NCT02881242

First Posted

August 23, 2016

Last Updated

April 27, 2023

Sponsor

Jonsson Comprehensive Cancer Center

Collaborators

Stand Up To Cancer, Novartis, Prostate Cancer Foundation

1. Study Identification

Unique Protocol Identification Number

NCT02881242

Brief Title

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

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

April 2023

Overall Recruitment Status

Active, not recruiting

Study Start Date

January 30, 2018 (Actual)

Primary Completion Date

January 31, 2024 (Anticipated)

Study Completion Date

January 31, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Jonsson Comprehensive Cancer Center

Collaborators

Stand Up To Cancer, Novartis, Prostate Cancer Foundation

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Yes

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Hormone-Resistant Prostate Cancer, Metastatic Prostate Carcinoma, Recurrent Prostate Carcinoma, Stage IV Prostate Cancer

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

14 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Treatment (trametinib)

Arm Type

Experimental

Arm Description

Patients receive trametinib PO QD. Treatment continues in the absence of disease progression or unacceptable toxicity.

Intervention Type

Other

Intervention Name(s)

Laboratory Biomarker Analysis

Intervention Description

Correlative studies

Intervention Type

Other

Intervention Name(s)

Quality-of-Life Assessment

Other Intervention Name(s)

Quality of Life Assessment

Intervention Description

Ancillary studies

Intervention Type

Drug

Intervention Name(s)

Trametinib

Other Intervention Name(s)

GSK1120212, JTP-74057, MEK Inhibitor GSK1120212, Mekinist

Intervention Description

Given PO

Primary Outcome Measure Information:

Title

PSA response rate

Time Frame

At 12 weeks

Title

Response rate assessed by RECIST criteria

Description

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.

Time Frame

Up to 24 weeks

Secondary Outcome Measure Information:

Title

Change in markers of cell proliferation (Ki67) and apoptosis (p27), assessed by immunohistochemistry

Description

Time Frame

Baseline up to 24 weeks

Title

Change in trametinib target engagement of MEK1/2 defined by the presence of p-ERK, assessed by immunohistochemistry

Description

Time Frame

Baseline up to 24 weeks

Title

Durability of PSA response as measured by time to PSA progression as defined by PCWG2 guidelines

Time Frame

Up to 30 months

Title

Incidence of adverse events, graded according to the Common Terminology Criteria for Adverse Events version 4.0

Time Frame

Up to 30 months

Title

Maximal PSA response

Time Frame

Up to 30 months

Title

Molecular correlates defined by gene expression, assessed using ribonucleic acid-sequencing, and mutational events, assessed using DNA exome-seq

Description

Time Frame

Up to 24 weeks

Title

Objective radiographic response rate according to RECIST guidelines

Time Frame

Up to 24 weeks

Title

Overall survival

Time Frame

Time from enrollment until death, assessed for up to 30 months

Title

Quality of life, assessed by FACT-P

Time Frame

Up to 30 months

Title

Time to initiation of alternative anti-neoplastic therapy

Time Frame

Up to 30 months

Title

Time to radiographic progression

Time Frame

Up to 24 weeks

Other Pre-specified Outcome Measures:

Title

ctDNA genomic aberrations, assessed by exome sequencing

Time Frame

Up to 24 weeks

10. Eligibility

Sex

Male

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Matthew Rettig

Organizational Affiliation

UCLA / Jonsson Comprehensive Cancer Center

Official's Role

Principal Investigator

Facility Information:

Facility Name

UCLA / Jonsson Comprehensive Cancer Center

City

Los Angeles

State/Province

California

ZIP/Postal Code

90095

Country

United States

12. IPD Sharing Statement

Learn more about this trial

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

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