Clinical Trials /

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

NCT04675710

Description:

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.

Related Conditions:
  • Thyroid Gland Squamous Cell Carcinoma
  • Thyroid Gland Undifferentiated (Anaplastic) Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Pembrolizumab, Dabrafenib, and Trametinib Before Surgery for the Treatment of BRAF-Mutated Anaplastic Thyroid Cancer
  • Official Title: Pembrolizumab in Combination With Dabrafenib and Trametinib as a Neoadjuvant Strategy Prior to Surgery in BRAF-Mutated Anaplastic Thyroid Cancer

Clinical Trial IDs

  • ORG STUDY ID: 2020-0641
  • SECONDARY ID: NCI-2020-09803
  • SECONDARY ID: 2020-0641
  • NCT ID: NCT04675710

Conditions

  • Thyroid Gland Anaplastic Carcinoma
  • Thyroid Gland Squamous Cell Carcinoma

Interventions

DrugSynonymsArms
DabrafenibBRAF Inhibitor GSK2118436, GSK-2118436, GSK-2118436A, GSK2118436Treatment (dabrafenib, trametinib, pembrolizumab)
PembrolizumabKeytruda, Lambrolizumab, MK-3475, SCH 900475Treatment (dabrafenib, trametinib, pembrolizumab)
TrametinibGSK1120212, JTP-74057, MEK Inhibitor GSK1120212, MekinistTreatment (dabrafenib, trametinib, pembrolizumab)

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.

Detailed Description

      PRIMARY OBJECTIVES:

      I. Demonstrate the efficacy of upfront treatment with neoadjuvant pembrolizumab in
      combination dabrafenib and trametinib by comparing the complete gross surgical resection rate
      (R0 or R1 surgical resection) to historical control of 5%.

      II. Demonstrate the efficacy of pembrolizumab in combination with dabrafenib and trametinib
      by comparing the overall survival (OS) to historical OS rate of 9.6 months.

      SECONDARY OBJECTIVES:

      I. Assess the efficacy (Response Evaluation Criteria in Solid Tumors [RECIST]) of neoadjuvant
      dabrafenib, trametinib, and pembrolizumab combination (Part 1) and progression-free survival
      (PFS) for all patients throughout their treatment course.

      II. Demonstrate the extent to which neoadjuvant dabrafenib, trametinib, and pembrolizumab
      changes surgical morbidity/complexity.

      III. Establish surgical safety for neoadjuvant pembrolizumab in combination with BRAF & MEK
      inhibitors, dabrafenib and trametinib; as well as safety for concurrent administration of
      postoperative adjuvant pembrolizumab with intensity modulated radiation therapy (IMRT).

      IV. Assess locoregional control rates in patients who received trial treatment. V. Assess the
      efficacy of dabrafenib, trametinib, and pembrolizumab combination by descriptive landmark
      analysis of OS at 12, 18, and 24 months.

      VI. Evaluate changes in patient reported outcomes: quality of life assessed by validated
      questionnaires at initial diagnosis, through the course of therapy, and during the adjuvant
      targeted therapy phase.

      EXPLORATORY OBJECTIVES:

      I. Determine whether features of the tumor genomic landscape and tumor immune
      microenvironment are associated with response to dabrafenib/trametinib/pembrolizumab (DTP).

      II. Determine if changes of cell free deoxyribonucleic acid (DNA) correlate with response to
      treatment on DTP and overall survival.

      III. Evaluate the safety of dabrafenib/trametinib/pembrolizumab plus IMRT in a subset of 5
      patients.

      OUTLINE:

      PART 1 (NEOADJUVANT PHASE): Patients receive dabrafenib orally (PO) twice daily (BID) and
      trametinib PO once daily (QD) on days 1-21. Starting in week 4, patients also receive
      pembrolizumab intravenously (IV) over 30 minutes on day 1. Treatment repeats every 21 days
      for 3 cycles in the absence of disease progression or unacceptable toxicity. Patients may
      receive 2 additional cycles of DTP at the discretion of the treating physicians. Patients
      whose disease is deemed resectable undergo surgery. Patients who are not surgically
      resectable after 5 cycles of DTP move to Part 3.

      PART 2 (ADJUVANT PHASE): 2-4 weeks after surgery and at the discretion of the treating
      physicians, patients may continue to receive pembrolizumab IV over 30 minutes every 3 weeks
      and concurrently undergo IMRT with or without cisplatin or carboplatin for 6 weeks. 5
      patients also receive dabrafenib PO BID and trametinib PO QD concurrently for 6 weeks.

      PART 3: Patients receive dabrafenib PO BID, trametinib PO QD on days 1-21, and pembrolizumab
      IV over 30 minutes on day 1. Treatment repeats every 21 days for 17 cycles in the absence of
      disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up every 3 months during years
      1-2, every 6 months during years 3-4, and then annually thereafter.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (dabrafenib, trametinib, pembrolizumab)ExperimentalPatients 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.
  • Dabrafenib
  • Pembrolizumab
  • Trametinib

Eligibility 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

          -  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

          -  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)

          -  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 vaccine within 30 days prior to the first dose of study drug.
             Examples of live vaccines include, but are not limited to, the following: measles,
             mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus
             Calmette-Guerin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection
             are generally killed virus vaccines and are allowed; however, intranasal influenza
             vaccines (e.g., FluMist) are live attenuated vaccines and are not allowed

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

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

          -  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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Complete gross surgical resection (R0 or R1 resection)
Time Frame:Up to 5 cycles (1 cycle = 21 days)
Safety Issue:
Description: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%.

Secondary Outcome Measures

Measure:Tumor response
Time Frame:Up to 42 months
Safety Issue:
Description:Objective tumor response will be assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
Measure:Progression free survival (PFS)
Time Frame:Up to 42 months
Safety Issue:
Description: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.
Measure:Surgical morbidity/complexity
Time Frame:Up to 5 cycles (1 cycle = 21 days)
Safety Issue:
Description: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)].
Measure: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)
Safety Issue:
Description: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.
Measure: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
Safety Issue:
Description: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.
Measure:Locoregional control
Time Frame:Up to 42 months
Safety Issue:
Description:Locoregional control will be measured as the time from the start of any trial treatment to the first locoregional recurrence/progression event.
Measure:Health related quality of life
Time Frame:Up to 42 months
Safety Issue:
Description: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)].
Measure:Patient-reported symptoms
Time Frame:Up to 42 months
Safety Issue:
Description:Symptom burden experienced by patients will be measured by the M.D. Anderson Symptom Inventory for Head and Neck Cancer (MDASI-HN) instrument.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:M.D. Anderson Cancer Center

Last Updated

December 19, 2020