A Phase II Trial of Abbreviated MAPK Targeted Therapy Plus Pembrolizumab in Patients With Unresectable or Metastatic Melanoma
A Phase II Trial of Abbreviated MAPK Targeted Therapy Plus Pembrolizumab in Patients With Unresectable or Metastatic Melanoma
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:
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.
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.
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:
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.
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.
Individuals with a history of a different malignancy are ineligible except for the following circumstances.
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