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Participants with IDH2 mutated (R140/R172) malignant sinonasal and skull base tumors.

100mg PO (orally) once daily, on days 1-28 of a 28-day cycle

Enasidenib

NCI Medical Oncology Referral Office

Charalampos Floudas, M.D.

National Cancer Institute Referral Office

Background:

Cancers of the nasal cavity or skull base are rare. They often are not diagnosed until they are at an advanced stage, and they often spread to other parts of the body. These cancers may have mutations in a gene called IDH2. Researchers want to find out if a drug (enasidenib) that targets the IDH2 mutation can help people with these cancers.

Objective:

To test enasidenib in people with cancers of the nasal cavity or skull base.

Eligibility:

People aged 18 years and older with rare cancers of the nasal cavity or the base of the skull. Their cancer must have an IDH2 gene mutation, and it must have recurred locally or spread to other parts of the body. These cancers can include sinonasal undifferentiated carcinoma; olfactory neuroblastoma; sinonasal large-cell neuroendocrine carcinoma; poorly differentiated sinonasal adenocarcinoma; or chondrosarcoma.

Design:

Participants will be screened. They will have a physical exam with blood and urine tests and tests of their heart function. They will have imaging scans of their brain, skull base, neck, chest, abdomen, and pelvis. A sample of tumor tissue will be collected.

Enasidenib is a tablet taken by mouth with a glass of water. Participants will take the drug once a day, every day, in 28-day cycles. They will not have resting periods between cycles.

Participants will visit the clinic on the first day of each cycle to receive the tablets they will need to take at home until the beginning of the next cycle. They will keep a diary to record the time of each dose they take.

Participants may remain in the study as long as the drug is helping them....

Background:

* Sinonasal undifferentiated carcinoma (SNUC) and olfactory neuroblastoma (ONB) are rare malignant sinonasal and skull base tumors, a group that also includes sinonasal adenocarcinoma, squamous cell carcinoma, large cell neuroendocrine carcinoma, sinonasal papilloma, chondrosarcoma (CS), chordoma and others.
* These malignancies are often diagnosed at a locally advanced stage. They tend to invade locally and have high rates of regional spread to the neck, and distally to the lungs and bones. For early locoregional disease multimodality treatment is used: surgery with postoperative radiotherapy, with or without induction chemotherapy. Treatment approaches for metastatic disease are largely based on institutional case series and consist largely of systemic chemotherapy.
* Recent genomic studies have reported isocitrate dehydrogenase-2 (IDH2) hotspot mutations in up to 87% of SNUC, 17% of ONB, and in 12% of chondrosarcomas; it has also been reported in sinonasal large-cell neuroendocrine carcinoma (LCNEC) and poorly differentiated sinonasal adenocarcinoma (SNAC).
* IDH2 hotspot mutations have been identified in acute myeloid leukemia, glioblastoma, myelodysplastic syndromes, and cholangiocarcinoma.
* Enasidenib is an orally bioavailable, selective and potent inhibitor of mutated IDH2, which is approved in relapsed IDH2 mutated (IDH2m) AML.
* Inhibition of mutated IDH2 may be clinically useful in IDH2m malignant sinonasal and skull base tumors.

Objectives:

- To estimate the overall progression free survival (PFS) based on treatment with enasidenib in all study participants with IDH2m malignant sinonasal and skull base tumors.

Eligibility:

* Histologically or cytologically confirmed locally advanced or metastatic SNUC, ONB, LCNEC, SNAC, and CS with documented somatic (tumor) IDH2 mutations R140 or R172.

  * Eligible primary tumor locations are sinonasal cavity and skull base.
  * Locally advanced disease must not be amenable to potentially curative surgery/radiotherapy.
  * Must have recurred or progressed following prior systemic therapy administered in the recurrent or metastatic setting. Any number of prior systemic therapies is allowed
* Measurable disease, per RECIST 1.1
* Age \>= 18 years
* ECOG Performance Status 0-2
* Adequate organ function

Design:

* Single-arm Phase II trial to determine PFS in participants with recurrent or metastatic IDH2m malignant sinonasal and skull base tumors.
* Enasidenib will be given at a dose of 100mg orally once daily until progressive disease or unacceptable toxicity.

Enasidenib in IDH2-Mutated Malignant Sinonasal and Skull Base Tumors

Phase II Study of Enasidenib in IDH2-mutated Malignant Sinonasal and Skull Base Tumors

.All collected IPD will be shared. All IPD recorded in the medical record will be shared with intramural investigators upon request. In addition, all large scale genomic sequencing data will be shared with subscribers to dbGaP.@@@@@@

The date of first treatment until the date of disease progression or death without progression

Adverse events assessed per CTCAE version 5

Fraction of participants experiencing CBR = CR+PR+ SD \> 16 weeks

The date of first treatment until date of death or last follow-up

Descriptive statistics of AE occurence per UGTIA1 genotype

National Cancer Institute (NCI)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Enasidenib in IDH2-Mutated Malignant Sinonasal and Skull Base Tumors	NCT06176989	Metastatic Chon... Locally Advance... Metastatic Sino... Locally Advance... Metastatic Larg... Locally Advance... Metastatic Olfa... Locally Advance... Metastatic Sino... Locally Advance...	Enasidenib	18 Years - 120 Years	National Institutes of Health Clinical Center (CC)
Enasidenib in IDH2-Mutated Malignant Sinonasal and Skull Base Tumors	NCT06176989	Metastatic Chon... Locally Advance... Metastatic Sino... Locally Advance... Metastatic Larg... Locally Advance... Metastatic Olfa... Locally Advance... Metastatic Sino... Locally Advance...	Enasidenib	18 Years - 120 Years	National Institutes of Health Clinical Center (CC)

Spots Global Cancer Trial Database for metastatic sinonasal undifferentiated carcinoma