Enhancing Radioiodine Incorporation Into Radio Iodine Refractory Thyroid Cancers With MAPK Inhibition

Studien-Informationen Einschlusskriterien Studien-Rationale Studien-Arme Geprüfte Regime

Rekrutierend

NCT-Nummer:
NCT04619316

Studienbeginn:
Februar 2018

Letztes Update:
22.06.2023

Wirkstoff:
Trametinib 2 MG [Mekinist], Trametinib 2 MG [Mekinist] and Dabrafenib 75 MG (2-0-2) [Tafinlar]

Indikation (Clinical Trials):
Thyroid Neoplasms, Thyroid Diseases

Geschlecht:
Alle

Altersgruppe:
Erwachsene (18+)

Phase:
Phase 2

Sponsor:
University Hospital, Essen

Collaborator:
-

Studienleiter

Wolfgang P Fendler, MD
Principal Investigator
Department of Nuclear Medicine, Essen University Hospital

Kontakt

Wolfgang P Fendler, MD
Kontakt:
Phone: +49 201 723 2032
E-Mail: wolfgang.fendler@uk-essen.de» Kontaktdaten anzeigen

Manuel M Weber, MD
Kontakt:
Phone: +49 201 723 2032
E-Mail: manuel.weber@uk-essen.de» Kontaktdaten anzeigen

Studienlocations
(1 von 1)

Manuel M. Weber
45147 Essen
(Nordrhein-Westfalen)
GermanyRekrutierend» Google-Maps
Ansprechpartner:
Wolfgang P Fendler, MD
Phone: +49 201 723 2032
E-Mail: wolfgang.fendler@uk-essen.de

Manuel M Weber, MD
Phone: +49 201 723 2032
E-Mail: manuel.weber@uk-essen.de» Ansprechpartner anzeigen

Studien-Informationen

Detailed Description:

This is a prospective interventional study testing the hypothesis that the inhibition of MEK

can restore iodine incorporation in BRAF wild type (WT) and a combined inhibition of BRAF and

MEK can restore iodine incorporation in BRAFV600E mutant (MUT), radioiodine-refractory (RAIR)

thyroid cancer. Patients with proven iodine negative tumor lesion(s) will be included in this

study. Patients will then receive Trametinib (WT-group) or Dabrafenib and Trametinib

combination-therapy (MUT-group) for approximately 3 weeks, after which a Thyrogen-stimulated

123I SPECT imaging will be performed. For patients whose tumor(s) demonstrate sufficient

iodine incorporation in the post drug treatment 123I SPECT imaging, a treatment according to

guidelines for iodine positive lesions will be performed. The follow up of the patients will

be conducted as standard of care.

Ein-/Ausschlusskriterien

Inclusion Criteria:

- Patients must have histologically or cytologically confirmed radioiodine refractory

metastatic thyroid carcinoma of follicular origin (including papillary and its

respective variants).

- Confirmation of the mutation status of BRAF gene (primary tumor, recurrent tumor, or

metastasis) .

- Patients who do not undergo a systemic treatment with sorafenib or lenvatinib or

chemotherapy or with other TKIs or other investigational drugs.

- Patients must have measurable disease, defined as at least one lesion that can be

accurately measured in at least one dimension (longest diameter to be recorded for

non-nodal lesions and short axis for nodal lesions) as ≥ 15 mm with CT scan, MRI, or

calipers by clinical exam. Tumors in previously irradiated fields may be considered

measureable if there is evidence of tumor progression after radiation treatment.

- RAI-refractory disease on structural imaging, defined as following:

A metastatic lesion that is not radioiodine-avid on a diagnostic or therapeutic radioiodine

scan performed less than 1 year prior to enrollment in the current study, There are no size

limitations for the index lesion used to satisfy this entry criterion.

- No recent treatment for thyroid cancer as defined as:

1. No prior 131I therapy is allowed < 6 months prior to initiation of therapy on

this protocol. A diagnostic study using < 400 MBq (±100) of 131I is not

considered 131I therapy.

2. No external beam radiation therapy < 4 weeks prior to initiation of therapy on

this protocol. (Previous treatment with radiation for any indication is allowed

if the investigator judges that the previous radiation does not significantly

compromise patient safety on this protocol.)

3. No chemotherapy or targeted therapy (e.g., tyrosine kinase inhibitor) is allowed

< 4 weeks prior to the initiation of therapy on this protocol.

- Age ≥ 18 years

- ECOG performance status ≤ 2.

- Life expectancy of greater than 3 months. Able to swallow and retain

orally-administered medication and does not have any clinically significant

gastrointestinal abnormalities that may alter absorption such as malabsorption

syndrome or major resection of the stomach or bowels.

- Patients must have normal organ and bone marrow function as defined below:

- Absolute neutrophil count (ANC) > 1.5x10^9/L

- Hemoglobin ≥ 9 g/dL

- Platelets ≥ 100 x 10^9/L

- Albumin ≥ 2.5 g/dL

- Total bilirubin ≤ 1.5x institutional ULN

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2x institutional

ULN unless it is related to the primary disease

- creatinine ≤ 1.5 mg/dL OR calculated creatinine clearance (Cockcroft-Gault formula) ≥

50 mL/min OR 24-hour urine creatinine clearance ≥ 50 mL/min

- Negative pregnancy test within 7 days prior to starting the study premenopausal women.

Women of non-childbearing potential may be included without pregnancy test if they are

either surgically sterile or have been postmenopausal for ≥ 1 year.

- Fertile men and women must use an effective method of contraception during treatment

and for at least 6 months after completion of treatment as directed by their

physician. Effective methods of contraception are defined as those, which result in a

low failure rate (i.e., less than 1% per year) when used consistently and correctly

(for example implants, injectables, combined oral contraception or intra-uterine

devices). At the discretion of the investigator, acceptable methods of contraception

may include total abstinence in cases where the lifestyle of the patient ensures

compliance. (Periodic abstinence [e.g., calendar, ovulation, symptothermal,

postovulation methods] and withdrawal are not acceptable methods of contraception.)

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

- Patients must agree to undergo to research biopsy of a malignant lesion if the

mutation status cannot be proven through archival tissue specimen.

- Availability of archival tumor tissue from the thyroid cancer primary or metastasis (a

tissue block or a minimum of 30 unstained slides would be required. Patients with less

archival tissue available may still be eligible for the study after discussion with

the Principal Investigator). This does not apply to patients who undergo a biopsy.

Exclusion Criteria:

- Concomitant malignancies or previous malignancies of life-limiting potential within

the last 3 years.

- Use of other investigational drugs within 28 days preceding the first dose of drug

treatment during this study.

- Known leptomeningeal or brain metastases or spinal metastases.

- Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs

chemically related to trametinib and/or to dabrafenib or other known contents of the

two investigational drugs.

- History or evidence of cardiovascular risk including any of the following:

- History or evidence of current, clinically significant uncontrolled arrhythmias

(exception: patients with controlled atrial fibrillation for > 30 days prior to the

initiation of therapy on this protocol are eligible).

- History of acute coronary syndromes (specifically, myocardial infarction and unstable

angina), severe/unstable angina, coronary angioplasty, or stenting within 6 months

prior to the initiation of therapy on this protocol.

- History of symptomatic congestive heart failure within 6 months prior to the

initiation of therapy on this protocol.

- History of cerebrovascular attack or transient ischemic attack within 6 months prior

to the initiation of therapy on this protocol.

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active

infection or psychiatric illness/social situations that would limit compliance with

study requirements.

- Pregnant, lactating, or breast feeding women.

- Patients unable to follow a low iodine diet or requiring medication with high content

in iodide (amiodarone).

- Patients who received iodinated intravenous contrast as part of a radiographic

procedure within 3 months of study registration. Those that have had iodinated

intravenous contrast within this time frame may still be eligible if a urinary iodine

analysis reveals that the excess iodine has been adequately cleared after the last

intravenous contrast administration.

- Unwillingness or inability to comply with study and follow-up procedures.

- Disorders of eye background as listed in the respective study drug prescribing

information.

- Patients with pancreatitis, prolonged QTc-time on EKG, uncontrolled hypertension,

thrombosis or high risk of bleedings.

- Condition of patient which is critical to participate in this study in the discretion

of the PI.

Studien-Rationale

Primary outcome:

1. Proportion of patients with sufficiently increased tumoral iodine incorporation (Time Frame - At the time point of 123I whole-body scintigraphy, 3 weeks after the start of redifferentiation therapy):
To determine the proportion of patients with BRAF WT RAIR thyroid cancer in which trametinib and the proportion of patients with BRAF MUT RAIR thyroid cancer in which the combination-therapy of dabrafenib and trametinib can increase tumoral iodine incorporation sufficiently.

Secondary outcome:

1. Changes in thyroglobulin levels (Time Frame - Within 12 months after redifferentiation therapy):
Declines or increases in thyroglobulin levels after redifferentiation therapy

2. The incidence and severity of adverse effects under trametinib (+dabrafenib) treatment (Time Frame - Within 3 months):
The incidence and severity of adverse effects and necessary therapeutic measures are monitored pursuant to CTCAE 4.0 criteria

Studien-Arme

Other: BRAF wild type
In BRAF wild type patients trametinib 2mg (1-0-0) is applied daily over a time span of 3 weeks, then the effect is evaluated via 123I whole-body scintigraphy
Other: BRAF V600E Mutation
In BRAF wild type patients trametinib 2mg (1-0-0) and dabrafenib 75mg (2-0-2) are applied daily over a time span of 3 weeks, then the effect is evaluated via 123I whole-body scintigraphy

Geprüfte Regime

Trametinib 2 MG [Mekinist]:
Monotherapy with Trametinib is given in patients with BRAF wildtype.
Trametinib 2 MG [Mekinist] and Dabrafenib 75 MG (2-0-2) [Tafinlar]:
Combination therapy is given in patients with BRAF V600E mutation.

Quelle: ClinicalTrials.gov

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