Clinical Trials /

Dabrafenib, Trametinib, and IMRT in Treating Patients With BRAF Mutated Anaplastic Thyroid Cancer

NCT03975231

Description:

This trial studies how well dabrafenib, trametinib, and intensity modulated radiation therapy (IMRT) work together in treating patients with BRAF mutated anaplastic thyroid cancer. Dabrafenib and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Radiation therapy uses high energy beams to kill tumor cells and shrink tumors. Giving dabrafenib, trametinib, and IMRT together may kill more tumor cells.

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

Not yet recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Dabrafenib, Trametinib, and IMRT in Treating Patients With BRAF Mutated Anaplastic Thyroid Cancer
  • Official Title: A Phase I Trial of Concurrent Intensity Modulated Radiation Therapy (IMRT) and Dabrafenib/Trametinib in BRAF Mutated Anaplastic Thyroid Cancer

Clinical Trial IDs

  • ORG STUDY ID: OSU-17277
  • SECONDARY ID: NCI-2019-02745
  • SECONDARY ID: P30CA016058
  • NCT ID: NCT03975231

Conditions

  • BRAF NP_004324.2:p.V600E
  • BRAF V600K Mutation Present
  • Thyroid Gland Anaplastic Carcinoma

Interventions

DrugSynonymsArms
DabrafenibBRAF Inhibitor GSK2118436, GSK-2118436A, GSK2118436Treatment (dabrafenib, trametinib, IMRT)
TrametinibGSK1120212, JTP-74057, MEK Inhibitor GSK1120212, MekinistTreatment (dabrafenib, trametinib, IMRT)

Purpose

This trial studies how well dabrafenib, trametinib, and intensity modulated radiation therapy (IMRT) work together in treating patients with BRAF mutated anaplastic thyroid cancer. Dabrafenib and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Radiation therapy uses high energy beams to kill tumor cells and shrink tumors. Giving dabrafenib, trametinib, and IMRT together may kill more tumor cells.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To assess the safety and tolerability (maximum tolerated dose [MTD]) of concurrent
      intensity modulated radiation therapy (IMRT) and BRAF-MEK inhibitors dabrafenib and
      trametinib in patients with BRAF-mutated anaplastic thyroid cancer.

      SECONDARY OBJECTIVES:

      I. To assess overall objective response rate, time to progression of local recurrence,
      progression free survival and overall survival.

      II. To assess pharmacokinetics during concurrent IMRT and dabrafenib plus trametinib therapy.

      III. To assess pharmacodynamics of dabrafenib plus trametinib induction therapy.

      IV. To assess mechanism of resistance to dabrafenib plus trametinib and radiation therapy.

      OUTLINE: This is a dose-escalation study of dabrafenib.

      INDUCTION: Patients receive dabrafenib orally (PO) twice daily (BID) and trametinib PO once
      daily (QD) for 7-28 days in the absence of disease progression and unacceptable toxicity.

      OPTIONAL SURGERY: Patients with resectable disease may undergo surgery 3 days after stop
      treatment of dabrafenib/trametinib, and move to Concurrent Radiation 14 days after surgery
      provided that surgical wound has healed. All other patients continue to receive dabrafenib PO
      BID and trametinib PO QD in the absence of disease progression and unacceptable toxicity.

      CONCURRENT RADIATION: Patients receive dabrafenib PO BID and trametinib PO QD at weeks 6-7.
      Within 2.5 hours of morning doses of dabrafenib/trametinib administration, patients undergo
      intensity modulated radiation therapy (IMRT) on Monday-Friday delivered over 6.5 weeks in the
      absence of disease progression or unacceptable toxicity.

      POST-RADIATION: Patients receive dabrafenib PO BID and trametinib PO QD for 4 weeks in the
      absence of disease progression and unacceptable toxicity.

      MAINTENANCE: Patients with residual disease receive dabrafenib PO BID and trametinib PO QD in
      the absence of disease progression and unacceptable toxicity. Patients stop dabrafenib and
      trametinib 8 weeks after achieving complete response. Patients with no residual disease stop
      dabrafenib and trametinib, with the option of restarting dabrafenib and trametinib at time of
      disease recurrence.

      After completion of study treatment, patients are followed up every 2 months for 1 year.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (dabrafenib, trametinib, IMRT)ExperimentalSee Detailed Description
  • Dabrafenib
  • Trametinib

Eligibility Criteria

        Inclusion Criteria:

          -  Pathologic (histologic or cytologic) diagnosis of anaplastic thyroid cancer (a
             diagnosis that is noted to be ?consistent with anaplastic thyroid cancer? with the
             presence of a thyroid mass is acceptable; pathology showing additional types of
             thyroid cancer is allowed)

               -  Note: Tissue collection for central review is mandatory, but central review is
                  not required for eligibility. Due to the aggressiveness of this disease,
                  treatment will be started prior to central review.

          -  Presence of BRAF mutation (V600E or V600K) in tumor tissue.

          -  Eastern Cooperative Oncology Group (ECOG) performance status < 2.

          -  Absolute neutrophil count > 1,000/mcL.

          -  Hemoglobin >= 9.0 g/dl (Note: The use of transfusion or other intervention to achieve
             hemoglobin [Hgb] >= 9.0 g/dl is acceptable).

          -  Platelets > 75,000/mcL.

          -  Total bilirubin < 1.5 x institutional upper limit of normal (unless due to Gilbert?s
             disease).

          -  Aspartate aminotransferase (AST)(serum glutamic-oxaloacetic transaminase
             [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
             < 2.5 x institutional upper limit of normal.

          -  Serum creatinine < 1.5 x institutional upper limit of normal.

          -  Female patients of childbearing potential are required to have a negative serum
             pregnancy test within 14 days prior to the first dose of study medication.

          -  Females are required to use an effective method of contraception from the time of
             negative serum pregnancy test, throughout the study duration, and for 4 months after
             the last dose of study medication. Should a woman become pregnant or suspect she is
             pregnant while she or her partner is participating in this study, she should inform
             her treating physician immediately. Men treated or enrolled on this protocol must also
             agree to use adequate contraception prior to study enrollment, for the duration of
             study participation, and for 16 weeks after completion of the last dose of study drug.

          -  Specific contraception requirements for females: Female subjects of childbearing
             potential must not become pregnant and are required to be sexually inactive by
             abstinence or use contraceptive methods with a failure rate of < 1%. Sexual inactivity
             by abstinence must be consistent with the preferred and usual lifestyle of the
             subject. Periodic abstinence (e.g. calendar, ovulation, symptothermal, post ovulation
             methods) and withdrawal are not acceptable methods of contraception. Contraceptive
             methods with a failure rate of < 1% include the following:

               -  Intrauterine device (IUD) or intrauterine system (IUS) that meets the < 1%
                  failure rate as stated in the product label,

               -  Male partner sterilization (vasectomy with documentation of Azoospermia) prior to
                  the female subject's entry into the study, and this male is patient?s sole sexual
                  partner. For this definition, ?documented? refers to the outcome of the
                  investigator's/qualified physician designee?s medical examination of the subject
                  or review of the subject's medical history for study eligibility, as obtained via
                  a verbal interview with the subject or from the subject?s medical records.

               -  Double barrier method: condom and occlusive cap (diaphragm or cervical/vault
                  caps) plus spermicidal agent (foam, gel, film, cream, suppository) These allowed
                  methods of contraception are only effective when used consistently, correctly and
                  in accordance with the product label. The investigator is responsible for
                  ensuring subjects understand how to properly use these methods of contraception.

          -  Specific contraception requirements for males: To prevent pregnancy in a female
             partner or to prevent exposure of any partner to the investigational product from a
             male subject?s semen, male subjects must use one of the following contraceptive
             methods during the study and for a total of 16 weeks following the last dose of study
             drug (based upon the lifecycle of sperm):

               -  Abstinence, defined as sexual inactivity consistent with the preferred and usual
                  lifestyle of the subject for 14 days prior to first dose of study drug, through
                  the dosing period, and for at least 16 weeks after the last dose of study drug.
                  Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation
                  methods) and withdrawal are not acceptable methods of contraception.

               -  Condom (during non-vaginal intercourse with any partner - male or female) OR

               -  Condom and occlusive cap (diaphragm or cervical/vault caps) plus spermicidal
                  agent (foam/gel/film/cream/suppository) (during sexual intercourse with a
                  female).

          -  Ability to understand and the willingness to sign a written informed consent document.

        Exclusion Criteria:

          -  Patients with resectable stage IVA anaplastic thyroid cancer who are candidates for
             surgery and wish to proceed with surgery.

          -  Patients who have had external beam radiotherapy to neck or chest for cancer that
             would result in overlap of radiation therapy fields.

          -  Patients who have had cytotoxic chemotherapy, stereotactic brain radiation or external
             beam radiation within 2 weeks prior to study treatment initiation.

          -  Patients who have had oral multikinase inhibitors within 1 week prior to study
             treatment initiation.

          -  Patients that have not recovered from adverse events related to prior therapy for
             cancer to Common Terminology Criteria for Adverse Events (CTCAE) 4.03 grade 2 or less
             except for alopecia.

          -  Patients previously treated with potent BRAF inhibitor or MEK inhibitor. Previous
             treatment with sorafenib is permitted.

          -  Patients that are receiving any other investigational agent.

          -  Patients that are currently taking any prohibitive medication.

          -  Patients with a history of other active malignancy requiring cancer treatment.

          -  Patients with uncontrolled brain metastases. Patients who are on a stable dose of
             corticosteroids for more than 1 week or off corticosteroids for 2 weeks prior to study
             enrollment can be enrolled. Enzyme-inducing anti-epileptic drugs are not permitted.

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

          -  Patients with class II, III, or IV heart failure as defined by the New York Heart
             Association (NYHA) functional classification system.

          -  Corrected QT (QTc) interval greater than or equal to 480 msecs (>= 500 msec for
             subjects with Bundle Branch Block).

          -  Patients with uncontrolled intercurrent illness including, but not limited to, ongoing
             or active infection requiring intravenous (IV) antibiotics, symptomatic congestive
             heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric
             illness/social situations that would limit compliance with study requirements.

          -  Pregnant women and nursing women are excluded from this study because dabrafenib has
             the potential for teratogenic or abortifacient effects. In embroyfetal developmental
             studies in rats, developmental toxicities including reduced fetal body weight,
             embryo-lethality, cardiac ventricular septal defect malformations, delayed skeletal
             development and variation in thymic shape have been observed.

          -  Known human immunodeficiency virus (HIV)-positive patients or those on combination
             antiretroviral therapy are ineligible because of the potential for pharmacokinetic
             interactions with study drugs.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose of combination therapy of dabrafenib and trametinib administered concurrently with intensity-modulated radiation therapy (IMRT)
Time Frame:1 year
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Objective response rate
Time Frame:1 year
Safety Issue:
Description:Will be defined as the proportion of patients who have a partial response (PR), or complete response (CR) within the first 4 weeks of IMRT. Complete response (CR) and partial response (PR) will be defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Will be calculated with the exact binomial 95% confidence intervals.
Measure:Time to progression for local disease recurrence
Time Frame:1 year
Safety Issue:
Description:Will be evaluated by RECIST criteria for disease limited to the radiation field (neck) following the first set of scans after completion of IMRT. Estimated by Kaplan-Meier method.
Measure:Overall survival
Time Frame:From the start date of the treatment to the date of death, assessed up to 1 year
Safety Issue:
Description:Estimated by Kaplan-Meier method.
Measure:Progression free survival
Time Frame:Time from start of treatment to time of progression or death, whichever occurs first, assessed up to 1 year
Safety Issue:
Description:Estimated by Kaplan-Meier method.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Manisha Shah

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