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

NCT04675710 | Active Not Recruiting Phase 2 FDA Drug

• 2 other identifiers: 2020-0641NCI-2020-09803
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 6

Brief Summary

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.

Conditions

Thyroid Gland Anaplastic Carcinoma; Thyroid Gland Squamous Cell Carcinoma

Outcome Measures

Primary Outcomes (2)

• Complete gross surgical resection (R0 or R1 resection)

  Overall R0/R1 resection rate will be defined by proportion of patients who undergo successful thyroidectomy with clear (R0) or microscopically positive (R1) surgical margins. We will test the hypothesis that the R0/R1 resection rate is greater than historical rate of 5%.

  Up to 5 cycles (1 cycle = 21 days) Up to 7 cycles

• Overall survival (OS)

  OS will be measured as the time from the start of any trial treatment to death from any causes. Kaplan-Meier method will be used to estimate the median survival time across all patients and its 95% confidence intervals (CI).

  Up to 72 months

Secondary Outcomes (8)

• Tumor response

  Up to 42 months

• Progression free survival (PFS)

  Up to 42 months

• Surgical morbidity/complexity

  Up to 5 cycles (1 cycle = 21 days) Up to 7 cycles

• Number of patients with adverse events as a measure of safety of neoadjuvant dabrafenib, trametinib, and pembrolizumab

  Up to 5 cycles (1 cycle = 21 days)

• Number of patients with adverse events as a measure of safety of postoperative pembrolizumab plus IMRT

  Over the course of adjuvant IMRT plus 2 weeks of safety follow-up, assessed up to 2 months

Study Arms (1)

Treatment (dabrafenib, trametinib, pembrolizumab)

EXPERIMENTAL

Patients receive 21-day cycles of dabrafenib 150 mg orally (PO) twice daily from Days 1-21, trametinib 2mg PO once daily from Days 1-21, and pembrolizumab 200mg intravenously (IV) on Day 1 of each cycle.

Procedure: Conventional Surgery; Drug: Dabrafenib; Radiation: Intensity-Modulated Radiation Therapy; Biological: Pembrolizumab; Other: Quality-of-Life Assessment; Drug: Trametinib

Interventions

Quality-of-Life Assessment OTHER

Ancillary studies

Also known as: Quality of Life Assessment

Treatment (dabrafenib, trametinib, pembrolizumab)

Trametinib DRUG

Given PO

Also known as: GSK1120212, JTP-74057, MEK Inhibitor GSK1120212, Mekinist

Treatment (dabrafenib, trametinib, pembrolizumab)

Conventional Surgery PROCEDURE

Undergo surgery

Treatment (dabrafenib, trametinib, pembrolizumab)

Dabrafenib DRUG

Given PO

Also known as: BRAF Inhibitor GSK2118436, GSK-2118436, GSK-2118436A, GSK2118436

Treatment (dabrafenib, trametinib, pembrolizumab)

Intensity-Modulated Radiation Therapy RADIATION

Undergo IMRT

Also known as: IMRT, Intensity Modulated RT, Intensity-Modulated Radiotherapy, Radiation, Intensity-Modulated Radiotherapy

Treatment (dabrafenib, trametinib, pembrolizumab)

Pembrolizumab BIOLOGICAL

Given IV

Also known as: Keytruda, Lambrolizumab, MK-3475, SCH 900475

Treatment (dabrafenib, trametinib, pembrolizumab)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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:

You may not qualify if:

• 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

Sponsors & Collaborators

• M.D. Anderson Cancer Center: lead

Study Sites (6)

Stanford School of Medicine

Stanford, California, 94304, United States

Location

University of Michigan Rogel Cancer Center

Ann Arbor, Michigan, 48109, United States

Location

Mayo Clinic

Rochester, Minnesota, 55901, United States

Location

Cleveland Clinic Taussig Cancer Institute

Cleveland, Ohio, 44195, United States

Location

M D Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Huntsman Cancer Institute at the University of Utah

Salt Lake City, Utah, 84112, United States

Location

Related Links

• MD Anderson Cancer Center

MeSH Terms

Conditions

Thyroid Carcinoma, Anaplastic

Interventions

dabrafenib; Radiotherapy, Intensity-Modulated; pembrolizumab; trametinib

Condition Hierarchy (Ancestors)

Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms

Intervention Hierarchy (Ancestors)

Radiotherapy, Conformal; Radiotherapy, Computer-Assisted; Radiotherapy; Therapeutics

Study Officials

• Mark Zafereo

  M.D. Anderson Cancer Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 5, 2020
• First Posted: December 19, 2020
• Study Start: June 24, 2021
• Primary Completion (Estimated): October 30, 2026
• Study Completion (Estimated): October 30, 2026
• Last Updated: February 19, 2026

Record last verified: 2026-02

Locations

US (6)