Pembrolizumab, Dabrafenib, and Trametinib Before Surgery for the Treatment of BRAF-Mutated Anaplastic Thyroid Cancer

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Trial ID: NCT04675710

Purpose

This phase II trial studies the effect of pembrolizumab, dabrafenib, and trametinib before surgery in treating patients with BRAF V600E-mutated anaplastic thyroid cancer. BRAF V600E is a specific mutation (change) in the BRAF gene, which makes a protein that is involved in sending signals in cells and in cell growth. It may increase the growth and spread of tumor cells. Dabrafenib and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Pembrolizumab, dabrafenib, and trametinib may help to control BRAF V600E-mutated anaplastic thyroid cancer when given before surgery.

Official Title

Pembrolizumab in Combination With Dabrafenib and Trametinib as a Neoadjuvant Strategy Prior to Surgery in BRAF-Mutated Anaplastic Thyroid Cancer

Stanford Investigator(s)

Saad A. Khan, MD
Saad A. Khan, MD

Associate Professor of Medicine (Oncology)

Eligibility


Inclusion Criteria:

   - Pathologic findings supporting the clinical impression of anaplastic thyroid
   carcinoma. Diagnosis may include consistent with or suggestive of terminology
   associated with: anaplastic thyroid carcinoma, undifferentiated carcinoma, squamous
   carcinoma; carcinoma with spindled, giant cell, or epithelial features; poorly
   differentiated carcinoma with pleomorphism, extensive necrosis with tumor cells
   present

   - Must have a BRAFV600E mutation-positive tumor, as determined by BRAF V600E
   immunohistochemistry on tumor tissue, genetic/molecular testing of tumor, or cell free
   (cf)NDA liquid biopsy

   - Have measurable disease based on RECIST 1.1

   - Total bilirubin =< 1.5 x upper limit of normal (ULN). Total bilirubin =< 3 x ULN for
   patients with Gilbert's syndrome

   - Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
   [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
   =< 2.5 x ULN, (5 x ULN for patients with concurrent liver metastases)

   - Serum creatinine =< within 1.5 x ULN

   - Absolute neutrophil count (ANC) >= 1.0 x 10^9/L

   - Platelets >= 100 x 10^9/L

   - Hemoglobin >= 9.0 g/dL or 5.6 mmol/L

   - International normalized ratio (INR) or prothrombin time (PT) =< 1.5 x ULN unless
   participant is receiving anticoagulant therapy as long as PT or activated partial
   thromboplastin time (aPTT) is within therapeutic range of intended use of
   anticoagulant

   - Subjects must be willing to ultimately undergo surgery if their tumor becomes
   surgically resectable. For MD Anderson site only, subjects must be willing to undergo
   tumor biopsy after the run-in with DT, unless in the opinion of the treating
   physician, a biopsy is not feasible or safe. Research subjects retain the right to
   refuse any research interventions.

   - Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1.
   Evaluation of ECOG is to be performed within 7 days prior to the date of
   allocation/randomization

   - The participant (or legally acceptable representative if applicable) provides written
   informed consent for the trial

   - A male participant must agree to use a contraception of this protocol during the
   treatment period and for at least 8 months after the last dose of study treatment and
   refrain from donating sperm during this period

   - A female participant is eligible to participate if she is not pregnant, not
   breastfeeding, and at least one of the following conditions applies:

      - Not a woman of childbearing potential (WOCBP) OR

      - A WOCBP who agrees to follow the contraceptive guidance during the treatment
      period and for at least 6 months after the last dose of study treatment

Exclusion Criteria:

   - Significant cardiovascular impairment: history of congestive heart failure greater
   than New York Heart Association (NYHA) class II

   - Untreated brain metastases

   - Prior chemotherapy within < 1 week prior to study day 1 or patients who have not
   recovered (i.e., =< grade 2) from adverse events due to a previously administered
   agent, except for patients who have been on dabrafenib/trametinib (DT) according to
   the standard run-in outlined in the trial schema

   - 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 (e.g., thyroxine, insulin, or physiologic corticosteroid
   replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
   form of systemic treatment

   - History of human immunodeficiency virus (HIV) or active hepatitis B (chronic or acute)
   or hepatitis C infection. Patients with past or resolved hepatitis B infection
   (defined as having a negative hepatitis B surface antigen [HBsAg] test and a positive
   anti-HBc [antibody to hepatitis B core antigen] antibody test) are eligible. However,
   patients with past or resolved hepatitis B virus (HBV) should be monitored for
   reactivation by a specialist. Patients positive for hepatitis C virus (HCV) antibody
   are eligible only if polymerase chain reaction (PCR) is negative for HCV ribonucleic
   acid (RNA). Note: no testing for HIV, hepatitis B and hepatitis C is required unless
   mandated by local heath authority

   - Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy
   (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of
   immunosuppressive therapy within 7 days prior to the first dose of study drug

   - Has received a live or live-attenuated vaccine within 30 days prior to the first dose
   of study drug. Administration of killed vaccines is allowed

   - Has severe hypersensitivity (>= grade 3) to pembrolizumab and/or any of its excipients

   - Has a history of (non-infectious) pneumonitis/interstitial lung disease that required
   steroids or has current pneumonitis/interstitial lung disease

   - Has known psychiatric or substance abuse disorders that would interfere with
   cooperation with the requirements of the trial

   - Females who are breastfeeding or pregnant at screening or baseline (as documented by a
   positive beta-human chorionic gonadotropin [beta-hCG] (or human chorionic gonadotropin
   [hCG]) test with a minimum sensitivity of 25 IU/L or equivalent units of beta-hCG [or
   hCG]). A women of childbirth potential (WOCBP) who has a positive urine pregnancy test
   within 72 hours prior to the first infusion will be excluded. If the urine test is
   positive or cannot be confirmed as negative, a serum pregnancy test will be required

   - More than 42 days of DT therapy prior to enrollment

   - A known history of retinal vein occlusion (RVO), central serous retinopathy (CSR),
   uncontrolled glaucoma or ocular hypertension

Intervention(s):

procedure: Conventional Surgery

drug: Dabrafenib

radiation: Intensity-Modulated Radiation Therapy

biological: Pembrolizumab

other: Quality-of-Life Assessment

drug: Trametinib

Recruiting

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Contact Information

Stanford University
School of Medicine
300 Pasteur Drive
Stanford, CA 94305
Cristy Miles
+1 650-721-4077

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