Clinical Trials /

Abbreviated MAPK Targeted Therapy Plus Pembrolizumab in Melanoma

NCT03149029

Description:

This research study is studying a combination of drugs as a possible treatment for unresectable or metastatic melanoma. The drugs involved in this study are: - Pembrolizumab (Keytruda) - Trametinib (Mekinist) - Dabrafenib (Tafinlar)

Related Conditions:
  • Melanoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Abbreviated MAPK Targeted Therapy Plus Pembrolizumab in Melanoma
  • Official Title: A Phase II Trial of Abbreviated MAPK Targeted Therapy Plus Pembrolizumab in Patients With Unresectable or Metastatic Melanoma

Clinical Trial IDs

  • ORG STUDY ID: 16-642
  • NCT ID: NCT03149029

Conditions

  • Metastatic Melanoma

Interventions

DrugSynonymsArms
PembrolizumabKeytrudaBRAFV600 mutant
DabrafenibTafinlarBRAFV600 mutant
TrametinibMekinistBRAFV600 mutant

Purpose

This research study is studying a combination of drugs as a possible treatment for unresectable or metastatic melanoma. The drugs involved in this study are: - Pembrolizumab (Keytruda) - Trametinib (Mekinist) - Dabrafenib (Tafinlar)

Detailed Description

      -  This research study is a Phase II clinical trial. Phase II clinical trials test the
           safety and effectiveness of an investigational drug to learn whether the drug works in
           treating a specific disease. "Investigational" means that the drug is being studied.

        -  The FDA (the U.S. Food and Drug Administration) has approved pembrolizumab, dabrafenib,
           and trametinib for this specific disease but the combination of all three has not been
           approved.

        -  This study is being conducted to document whether trametinib with or without dabrafenib
           taken for brief period of time prior to and with pembrolizumab works better than the
           investigators expect pembrolizumab to work in participants with unresectable and/or
           metastatic melanoma. All three of these drugs are FDA-approved for unresectable and/or
           metastatic melanoma; however, they are not FDA-approved for use all together.

             -  Pembrolizumab is a type of antibody that inhibits the cancer cell growth. An
                antibody is a cell that attaches to other cells to fight off infection.

             -  Trametinib is a cell inhibitor that binds to the cancer cells to inhibit the cancer
                cells' signals to decrease cell growth.

             -  Dabrafenib is also a cell inhibitor and works by stopping the cancer cell from
                duplicating.
    

Trial Arms

NameTypeDescriptionInterventions
BRAFV600 mutantExperimentalPembrolizumab administered intravenously every three weeks Dabrafenib taken every twelve hours orally Trametinib taken every twelve hours orally
  • Pembrolizumab
  • Dabrafenib
  • Trametinib
BRAFV600 wild typeExperimentalPembrolizumab administered intravenously every three weeks Trametinib taken every twelve hours orally
  • Pembrolizumab
  • Trametinib

Eligibility Criteria

        Inclusion Criteria:

          -  Participants must have histologically confirmed metastatic or unresectable melanoma.

          -  Participants must have measurable disease, defined as at least one lesion that can be
             accurately measured in at least one dimension (longest diameter to be recorded) as ≥
             20 mm with conventional techniques or as ≥10 mm with spiral CT scan. See section 11
             for the evaluation of measureable disease.

          -  Participants may have previously received ipilimumab, adjuvant anti-PD1 therapy, or
             high-dose IL-2. They may not have previously been treated with BRAF inhibitors
             (vemurafenib, dabrafenib, encorafenib), MEK inhibitors (selumetinib, trametinib,
             binimetinib, cobimetinib), and/or anti-PD1/PDL1 monoclonal antibodies for metastatic
             or unresectable disease. Participants must allow 2 weeks between prior chemotherapy
             targeted small molecule therapy, or radiation therapy prior to study Day 1 or recovery
             (i.e., ≤ Grade 1 or at baseline) from adverse events due to a previously administered
             agent.

               -  Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and
                  may qualify for the study.

               -  Note: If subject received major surgery, they must have recovered adequately from
                  the toxicity and/or complications from the intervention prior to starting therapy

          -  Age greater than or equal to 18 years. Because no dosing or adverse event data are
             currently available on the use of the combination of trametinib with or without
             dabrafenib, and pembrolizumab in participants less than 18 years of age, children are
             excluded from this study.

          -  ECOG performance status ≤1.

          -  Life expectancy of greater than three months.

          -  Participants must have normal organ and marrow function as defined below:

               -  Leukocytes ≥ 3,000/mcL

               -  Absolute neutrophil count ≥ 1,500/mcL

               -  Platelets ≥ 100,000/mcL

               -  total bilirubin ≤ 1.5 X institutional upper limits of normal; total bilirubin >
                  1.5X above institutional upper limits of normal will be allowed if direct
                  bilirubin is within normal limits or if patients has a documented history of
                  Gilbert's disease

               -  AST (SGOT)/ALT (SGPT) ≤ 2.5 X institutional upper limit of normal

               -  Creatinine within normal institutional limits or creatinine clearance ≥ 60
                  mL/min/1.73 m2 for subjects with creatinine levels about institutional normal.

          -  Participants must have BRAFV600-mutation status known.

          -  Participants must have disease amenable to and be willing to undergo serial core or
             excisional biopsies of a tumor lesion(s).

          -  Because both dabrafenib and trametinib are class D agents with the potential for
             teratogenic or abortifacient effects. Because there is an unknown but potential risk
             of adverse events in nursing infants secondary to treatment of the mother with either
             dabrafenib and trametinib, breastfeeding should be discontinued if the mother is
             treated with either dabrafenib, trametinib, or the combination of dabrafenib and
             trametinib. Female subjects of childbearing potential should be willing to use 2
             methods of birth control or be surgically sterile, or abstain from heterosexual
             activity for the course of the study through 120 days after the last dose of study
             medication. Subjects of childbearing potential are those who have not been surgically
             sterilized or have not been free from menses for > 1 year. 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. Male subjects should
             agree to use an adequate method of contraception starting with the first dose of study
             therapy through 120 days after the last dose of study therapy.

          -  Ability to understand and the willingness to sign a written informed consent document

        Exclusion Criteria:

          -  Participants treated with prior chemotherapy, or radiation therapy within 2 weeks
             prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from
             adverse events due to a previously administered agent.

               -  Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and
                  may qualify for the study.

               -  Note: If subject received major surgery, they must have recovered adequately from
                  the toxicity and/or complications from the intervention prior to starting therapy

          -  Participants previously treated with BRAF inhibitors (vemurafenib, dabrafenib,
             encorafenib), MEK inhibitors (selumetinib, trametinib, binimetinib, cobimetinib),
             and/or anti-PD1/PDL1 monoclonal antibodies for metastatic or unresectable disease. Any
             other prior therapy will be allowed (including ipilimumab, adjuvant anti-PD1 therapy,
             high-dose IL-2).

          -  Participants with symptomatic brain metastases will be excluded from this clinical
             trial because of their poor prognosis and because they often develop progressive
             neurologic dysfunction that would confound the evaluation of neurologic and other
             adverse events. Subjects with asymptomatic, stable brain metastases and/or who have
             been previously treated for these conditions that are asymptomatic in the absence of
             corticosteroid therapy are allowed to enroll. Brain metastasis must be stable with
             verification by imaging (brain MRI completed at screening demonstrating no current
             evidence of progressive brain metastases.

          -  Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study
             Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events
             due to agents administered more than 4 weeks earlier.

          -  Patients may not be receiving any other anti-neoplastic agents.

          -  Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
             other form of immunosuppressive therapy within 7 days prior to the first dose of trial
             treatment.

          -  Pregnant women are excluded from this study because both dabrafenib and trametinib are
             class D agents with the potential for teratogenic or abortifacient effects. Because
             there is an unknown but potential risk of adverse events in nursing infants secondary
             to treatment of the mother with either dabrafenib and trametinib, breastfeeding should
             be discontinued if the mother is treated with either dabrafenib, trametinib, or the
             combination of dabrafenib and trametinib.

          -  Participants known to be HIV-positive and on combination antiretroviral therapy are
             ineligible because of the potential for pharmacokinetic interactions with either
             dabrafenib or trametinib. Appropriate studies will be undertaken in participants
             receiving combination antiretroviral therapy when indicated.

          -  Participants who have had major surgery < 2 weeks prior to entering the study.

          -  Has a known history of active TB (Bacillus Tuberculosis)

          -  Hypersensitivity to pembrolizumab or any of its excipients.

          -  No symptomatic or untreated leptomeningeal disease.

          -  Participants are not permitted to receive enzyme inducing anti-epileptic drugs.

          -  Has active autoimmune disease that has required systemic treatment in the past 2 years
             (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive
             drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid
             replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
             form of systemic treatment.

          -  Has a history of (non-infectious) pneumonitis that required steroids or current/active
             pneumonitis.

          -  History of current evidence of retinal vein occlusion (RVO) or retinal pigment
             epithelial detachment (RPED):

          -  History of RVO or RPED

          -  Visible retinal pathology as assessed by ophthalmic exam that is considered a risk
             factor for RVO or RPED such as evidence of new optic disc cupping, evidence of visual
             field defects, and intraocular pressure >21 mm Hg.

               -  Uncontrolled intercurrent illness including, but not limited to:

               -  Ongoing or active infection

               -  LVEF <50% as determined by either MUGA scan or Echo

               -  Edema > Grade 1

               -  Documented myocardial infarction or unstable/uncontrolled cardiac disease (eg,
                  unstable angina, severe arrhythmias, congestive heart failure [New York Heart
                  Association (NYHA) > Class II]) within 6 months of study entry

               -  Arterial thrombosis or vascular ischemic events, such as transient ischemic
                  attack, cerebral infarction, within 6 months prior to study entry

               -  Serious or non-healing wound

               -  History of any medical condition including cardiovascular disease or chronic
                  obstructive pulmonary disease (COPD), that in the opinion of the investigator,
                  may increase the risks associated with study participation or study treatments or
                  may interfere with the conduct of the study or interpretation of study results

               -  Psychiatric illness/social situations that would limit compliance with study
                  requirements

          -  Individuals with a history of a different malignancy are ineligible except for the
             following circumstances.

               -  Individuals with a history of other malignancies are eligible if they have been
                  disease-free for at least 3 years and are deemed by the investigator to be at low
                  risk for recurrence of that malignancy.

               -  Individuals with the following cancers are eligible if diagnosed and treated
                  within the past 3 years: cervical cancer in situ and basal cell or squamous cell
                  carcinoma of the skin.

          -  Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA
             [qualitative] is detected).

          -  Has received a live vaccine within 30 days of planned start of study therapy
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:The rate of clinical benefit
Time Frame:6 months
Safety Issue:
Description:Rate of complete response, partial response, stable disease

Secondary Outcome Measures

Measure:Overall Survival
Time Frame:2 years
Safety Issue:
Description:
Measure:Safety and Tolerability: AE and SAE rate by CTCAE4
Time Frame:2 years
Safety Issue:
Description:AE and SAE rate by CTCAE4
Measure:Complete Response (CR) Rate
Time Frame:2 years
Safety Issue:
Description:CR by RECIST1.1
Measure:Partial Response (PR) Rate
Time Frame:2 years
Safety Issue:
Description:PR by RECIST1.1
Measure:Stable Disease (SD) Rate
Time Frame:2 years
Safety Issue:
Description:SD by RECIST1.1

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Massachusetts General Hospital

Trial Keywords

  • Metastatic Melanoma

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