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Study of Cemiplimab Combined with Dabrafenib and Trametinib in People with Anaplastic Thyroid Cancer

Trial Status: Active

This phase II studies how well dabrafenib, trametinib, and cemiplimab work for the treatment of patients with anaplastic thyroid cancer that is BRAF-mutated, and is no longer responding to dabrafenib and trametinib. This study will also look at the safety of this combination treatment. 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 cemiplimab, may help the body’s immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving cemiplimab in combination with dabrafenib and trametinib may work better than dabrafenib and trametinib alone in treating patients with BRAF-mutated anaplastic thyroid cancer.

Inclusion Criteria

  • Pathologically (histologically or cytologically) proven diagnosis of BRAF-V600E mutant anaplastic thyroid cancer (ATC) (a diagnosis that is noted to be consistent with ATC is acceptable)
  • Either metastatic disease or locoregional disease that is considered not resectable for cure. * Ideally a surgeon should determine that the disease is not resectable for cure, but this can also be done by any investigator
  • Patients must have measurable disease according to RECIST 1.1 criteria, defined as at least 1 lesion that can be accurately measured in at least 1 dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >= 20 mm with conventional techniques or as >= 10 mm with spiral computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (or Karnofsky performance score >= 60)
  • Able to swallow and retain orally administered medication
  • Absolute neutrophil count >= 1.5 X 10^9/L
  • Hemoglobin >= 8 g/dL
  • Platelets >= 100 X 10^9/L
  • Serum bilirubin =< 1.5 X institutional upper limit of normal (ULN) (unless the patient has Gilbert’s Disease, in which case total bilirubin =< 3 X institutional ULN)
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 X institutional ULN (=< 5 X institutional ULN if there is liver metastasis)
  • Serum creatinine =< 1.5 mg/dL or calculated creatinine clearance (Cockcroft-Gault formula) >= 50 mL/min or 24-hour (h) urine creatinine clearance >= 50 mL/min
  • Left ventricular ejection fraction greater than or equal to institutional lower limit of normal (LLN) by echocardiogram or multigated acquisition (MUGA)
  • Negative pregnancy test (serum or urine) within 14 days of registration for women of childbearing potential. Women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) before study entry and for the duration of study participation. Men treated or enrolled on this protocol must also agree to use adequate contraception before the study, for the duration of study participation, and for 4 months after completion of trametinib administration
  • Must agree to allow 2-4 separate biopsies of any malignant lesion. For patients whose biopsies are deemed as unsafe or contraindicated, they will not be eligible
  • Ability to understand and willingness to sign a written informed consent document. * Note: Use of legally authorized representative (LAR) is permitted

Exclusion Criteria

  • Previous documentation or current evidence of treatment with dabrafenib and trametinib. * Exception: Patients who started dabrafenib and trametinib for ATC at an institution outside of Memorial Sloan Kettering (MSK) are eligible. However, this exception is limited to 6 subjects
  • Active brain metastases, unless an exception is granted by the principal investigator
  • Current interstitial lung disease or pneumonitis
  • Prior history of idelalisib therapy. Exceptions allowed with the consent of the principal investigator (Dr. Sherman)
  • History or current evidence or risk of retinal vein occlusion (RVO) or central serous retinopathy (CSR): * History of RVO or CSR or predisposing factors to RVO or CSR (e.g., uncontrolled glaucoma or ocular hypertension). * Visible retinal pathologic abnormality as assessed by ophthalmic exam that is considered a high risk factor for RVO or CSR, such as evidence of new optic disc cupping, evidence of new visual field defects, and intraocular pressure > 21 mm Hg
  • History or current evidence of cardiovascular risk, including any of the following: * Left ventricular ejection fraction (LVEF) < LLN * A QT interval corrected for heart rate using the Bazett’s formula of QTcB >= 480 msec * Current evidence of clinically significant uncontrolled arrhythmias (exception: patients with controlled atrial fibrillation for > 30 days before enrollment are eligible) * History of acute coronary syndromes (including myocardial infarction and unstable angina), coronary angioplasty, or stenting within 6 months before treatment
  • Known hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (with the exception of chronic or cleared HBV and HCV infection, which will be allowed)
  • Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with trametinib. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy
  • Uncontrolled intercurrent illness that would limit compliance with study requirements
  • Inability to receive immunotherapy for the following reasons: * Any prior grade >= 3 immune-related adverse event (irAE) while receiving any previous immunotherapy agent or any unresolved irAE grade > 1 * Active or prior documented autoimmune disease within the past 2 years ** Note: Subjects with vitiligo, Grave’s disease, or psoriasis not requiring systemic treatment (within the past 2 years) are not excluded. Exceptions allowed with the consent of the principal investigator (Dr. Sherman) * Active inflammatory bowel disease (e.g., Crohn’s disease, ulcerative colitis) * History of primary immunodeficiency * History of allogeneic organ transplant * Known history of previous clinical diagnosis of active tuberculosis (this does not include a history of being purified protein derivative [PPD] positive)

New York

New York
Memorial Sloan Kettering Cancer Center
Status: ACTIVE
Contact: Eric Jeffrey Sherman
Phone: 616-888-4234

PRIMARY OBJECTIVE:

I. Estimate the overall response rate to the combination of dabrafenib, trametinib, and cemiplimab using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.

SECONDARY/EXPLORATORY OBJECTIVES:

I. Estimate the safety of cemiplimab, dabrafenib, and trametinib in patients with anaplastic thyroid cancer (ATC).

II. Estimate overall survival in patients with ATC receiving cemiplimab, dabrafenib, and trametinib.

III. Estimate progression-free survival in patients with ATC receiving cemiplimab, dabrafenib, and trametinib.

IV. Evaluate tumoral gene expression changes and changes in immune cell populations that may correlate with response to cemiplimab plus dabrafenib/trametinib, by use of serial research biopsy specimens.

V. Estimate the level of M1 and M2 macrophages through ribonucleic acid sequencing (RNAseq) and immunohistochemistry (IHC) in serial research biopsy specimens.

OUTLINE:

Patients receive standard of care dabrafenib orally (PO) twice daily (BID) and trametinib PO once daily (QD). When tumor is no longer responding to dabrafenib and trametinib, patients also receive cemiplimab intravenously (IV) over 30 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After the completion of study treatment, patients are followed up every 3 months for 1 year.

Trial Phase Phase II

Trial Type Treatment

Lead Organization
Memorial Sloan Kettering Cancer Center

Principal Investigator
Eric Jeffrey Sherman

  • Primary ID 19-464
  • Secondary IDs NCI-2020-00631
  • Clinicaltrials.gov ID NCT04238624