Clinical Trials /

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

NCT02881242

Description:

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.

Related Conditions:
  • Prostate Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • 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

Clinical Trial IDs

  • ORG STUDY ID: 16-001044
  • SECONDARY ID: NCI-2016-01201
  • SECONDARY ID: 16-001044
  • SECONDARY ID: P30CA016042
  • NCT ID: NCT02881242

Conditions

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

Interventions

DrugSynonymsArms
TrametinibGSK1120212, JTP-74057, MEK Inhibitor GSK1120212, MekinistTreatment (trametinib)

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (trametinib)ExperimentalPatients receive trametinib PO QD. Treatment continues in the absence of disease progression or unacceptable toxicity.
  • Trametinib

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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Male
Healthy Volunteers:No

Primary Outcome Measures

Measure:PSA response rate
Time Frame:At 12 weeks
Safety Issue:
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.

Secondary Outcome Measures

Measure:Change in markers of cell proliferation (Ki67) and apoptosis (p27), assessed by immunohistochemistry
Time Frame:Baseline up to 24 weeks
Safety Issue:
Description: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.
Measure:Change in trametinib target engagement of MEK1/2 defined by the presence of p-ERK, assessed by immunohistochemistry
Time Frame:Baseline up to 24 weeks
Safety Issue:
Description: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.
Measure:Durability of PSA response as measured by time to PSA progression as defined by PCWG2 guidelines
Time Frame:Up to 30 months
Safety Issue:
Description:
Measure:Incidence of adverse events, graded according to the Common Terminology Criteria for Adverse Events version 4.0
Time Frame:Up to 30 months
Safety Issue:
Description:
Measure:Maximal PSA response
Time Frame:Up to 30 months
Safety Issue:
Description:
Measure:Molecular correlates defined by gene expression, assessed using ribonucleic acid-sequencing, and mutational events, assessed using DNA exome-seq
Time Frame:Up to 24 weeks
Safety Issue:
Description: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.
Measure:Objective radiographic response rate according to RECIST guidelines
Time Frame:Up to 24 weeks
Safety Issue:
Description:
Measure:Overall survival
Time Frame:Time from enrollment until death, assessed for up to 30 months
Safety Issue:
Description:
Measure:Quality of life, assessed by FACT-P
Time Frame:Up to 30 months
Safety Issue:
Description:
Measure:Time to initiation of alternative anti-neoplastic therapy
Time Frame:Up to 30 months
Safety Issue:
Description:
Measure:Time to radiographic progression
Time Frame:Up to 24 weeks
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Jonsson Comprehensive Cancer Center

Last Updated

August 25, 2016