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

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ClinicalTrials.gov Identifier: NCT04675710
Recruitment Status : Recruiting
First Posted : December 19, 2020
Last Update Posted : August 13, 2021
Sponsor:
Information provided by (Responsible Party):
M.D. Anderson Cancer Center

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.

Condition or disease Intervention/treatment Phase
Thyroid Gland Anaplastic Carcinoma Thyroid Gland Squamous Cell Carcinoma Procedure: Conventional Surgery Drug: Dabrafenib Radiation: Intensity-Modulated Radiation Therapy Biological: Pembrolizumab Other: Quality-of-Life Assessment Drug: Trametinib Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 30 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Pembrolizumab in Combination With Dabrafenib and Trametinib as a Neoadjuvant Strategy Prior to Surgery in BRAF-Mutated Anaplastic Thyroid Cancer
Actual Study Start Date : June 24, 2021
Estimated Primary Completion Date : June 30, 2024
Estimated Study Completion Date : June 30, 2024


Arm Intervention/treatment
Experimental: Treatment (dabrafenib, trametinib, pembrolizumab)
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
Undergo surgery

Drug: Dabrafenib
Given PO
Other Names:
  • BRAF Inhibitor GSK2118436
  • GSK-2118436
  • GSK-2118436A
  • GSK2118436

Radiation: Intensity-Modulated Radiation Therapy
Undergo IMRT
Other Names:
  • IMRT
  • Intensity Modulated RT
  • Intensity-Modulated Radiotherapy
  • Radiation, Intensity-Modulated Radiotherapy

Biological: Pembrolizumab
Given IV
Other Names:
  • Keytruda
  • Lambrolizumab
  • MK-3475
  • SCH 900475

Other: Quality-of-Life Assessment
Ancillary studies
Other Name: Quality of Life Assessment

Drug: Trametinib
Given PO
Other Names:
  • GSK1120212
  • JTP-74057
  • MEK Inhibitor GSK1120212
  • Mekinist




Primary Outcome Measures :
  1. Complete gross surgical resection (R0 or R1 resection) [ Time Frame: Up to 5 cycles (1 cycle = 21 days) ]
    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%.

  2. Overall survival (OS) [ Time Frame: Up to 72 months ]
    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).


Secondary Outcome Measures :
  1. Tumor response [ Time Frame: Up to 42 months ]
    Objective tumor response will be assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.

  2. Progression free survival (PFS) [ Time Frame: Up to 42 months ]
    PFS will be measured as the time from the start of the treatment to the first occurrence of disease progression or death from any cause, whichever occurs first, as determined by RECIST version 1.1.

  3. Surgical morbidity/complexity [ Time Frame: Up to 5 cycles (1 cycle = 21 days) ]
    Surgical morbidity/complexity will be measured at enrollment, prior to surgery and at surgery. The Thyroid Neck Group Morbidity Complexity Scoring and MGH/MEE-MSK-MD Anderson (MMM) Surgical Morbidity Complexity Score are incorporated, specifying on a scale with 5 levels of complexity and morbidity of the surgery [mild (level 0), moderate (level 1), severe (level 2), very severe (level 3), and unresectable (level 4)].

  4. Number of patients with adverse events as a measure of safety of neoadjuvant dabrafenib, trametinib, and pembrolizumab [ Time Frame: Up to 5 cycles (1 cycle = 21 days) ]
    Frequency and severity of adverse events as a measure of safety profile for neoadjuvant concurrent administration of dabrafenib, trametinib, and pembrolizumab (DTP) will be assessed using Common Terminology Criteria for Adverse Events version 5.0.

  5. Number of patients with adverse events as a measure of safety of postoperative pembrolizumab plus IMRT [ Time Frame: Over the course of adjuvant IMRT plus 2 weeks of safety follow-up, assessed up to 2 months ]
    Frequency and severity of adverse events as a measure of safety profile for concurrent administration of postoperative pembrolizumab with IMRT will be assessed using Common Terminology Criteria for Adverse Events version 5.0.

  6. Locoregional control [ Time Frame: Up to 42 months ]
    Locoregional control will be measured as the time from the start of any trial treatment to the first locoregional recurrence/progression event.

  7. Health related quality of life [ Time Frame: Up to 42 months ]
    Changes of health-related quality of life will be measured by the European Quality of Life 5 Dimension Questionnaire (EQ-5D). The EQ-5D consists of health state description and evaluation. The health state description consists of five dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression), with each dimension specifying five levels of severity [best (1)-worst (5)]. The health state evaluation is assessed using the visual analogue scale ([worse (0)-best (100)].

  8. Patient-reported symptoms [ Time Frame: Up to 42 months ]
    Symptom burden experienced by patients will be measured by the M.D. Anderson Symptom Inventory for Head and Neck Cancer (MDASI-HN) instrument.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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 undergo tumor biopsy prior to and after the run-in with dabrafenib/trametinib (DT), unless in the opinion of the treating physician, a biopsy is not feasible or safe. Subjects must be willing to ultimately undergo surgery if their tumor becomes surgically resectable. 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 30 days of DT therapy prior to enrollment
  • A known history of retinal vein occlusion (RVO), central serous retinopathy (CSR), uncontrolled glaucoma or ocular hypertension

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04675710


Contacts
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Contact: Mark Zafereo 713-563-9683 MZafereo@mdanderson.org

Locations
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United States, Texas
M D Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Mark Zafereo    713-563-9683    MZafereo@mdanderson.org   
Principal Investigator: Mark Zafereo         
Sponsors and Collaborators
M.D. Anderson Cancer Center
Investigators
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Principal Investigator: Mark Zafereo M.D. Anderson Cancer Center
Additional Information:
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Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT04675710    
Other Study ID Numbers: 2020-0641
NCI-2020-09803 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
2020-0641 ( Other Identifier: M D Anderson Cancer Center )
First Posted: December 19, 2020    Key Record Dates
Last Update Posted: August 13, 2021
Last Verified: August 2021

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Carcinoma
Thyroid Neoplasms
Thyroid Carcinoma, Anaplastic
Thyroid Diseases
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Endocrine System Diseases
Endocrine Gland Neoplasms
Neoplasms by Site
Head and Neck Neoplasms
Pembrolizumab
Trametinib
Dabrafenib
Antineoplastic Agents, Immunological
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action