Enasidenib for Sinonasal and Skull Base Cancer
Recruiting in Palo Alto (17 mi)
Overseen byCharalampos Floudas, M.D.
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: National Cancer Institute (NCI)
Must not be taking: IDH1/2 inhibitors, QT prolongers
Disqualifiers: Active brain metastases, Cardiovascular disease, others
No Placebo Group
Prior Safety Data
Approved in 2 Jurisdictions
Trial Summary
What is the purpose of this trial?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....
Will I have to stop taking my current medications?
The trial requires that you stop taking certain medications before starting the study. Specifically, you must stop taking sensitive cytochrome P450 (CYP) substrate medications with a narrow therapeutic range, sensitive substrates of P-glycoprotein (P-gp), and medications known to prolong the QT interval, unless you can switch to other medications. You should discuss your current medications with the study team to see if any changes are needed.
How is the drug Enasidenib unique for treating sinonasal and skull base cancer?
Enasidenib is unique for treating sinonasal and skull base cancer because it targets specific IDH2 mutations, which are common in sinonasal undifferentiated carcinoma, a rare and aggressive cancer. This makes it a targeted therapy option, unlike traditional treatments that do not specifically address these genetic mutations.
12345Eligibility Criteria
Adults over 18 with rare cancers in the nasal cavity or skull base, specifically those with an IDH2 gene mutation. The cancer must have returned after treatment or spread elsewhere. Eligible types include sinonasal undifferentiated carcinoma, olfactory neuroblastoma, large-cell neuroendocrine carcinoma of the sinus, poorly differentiated adenocarcinoma of the sinus, and chondrosarcoma.Inclusion Criteria
I can take care of myself and am up and about more than half of the day.
- Absolute neutrophil count (ANC) >=1,000/mcL
- Platelets >=75,000/mcL
+22 more
Exclusion Criteria
- Rate-corrected QT (QTc using Fridericia formula [QTcF]) >450 msec
Uncontrolled intercurrent illness (including psychiatric) or social situations, that may limit interpretation of results or increase risk to the participant:
I haven't had major radiation therapy in the last 4 weeks and any side effects are minimal.
+20 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
1 visit (in-person)
Treatment
Participants receive enasidenib 100mg orally once daily in 28-day cycles
Indefinite, as long as the drug is helping
Monthly visits (in-person) for drug dispensation and monitoring
Follow-up
Participants are monitored for safety and effectiveness after treatment
up to 5 years post study treatment
Regular follow-up visits as per study protocol
Participant Groups
The trial is testing Enasidenib—a drug targeting IDH2 mutations—in patients with advanced-stage nasal cavity or skull base cancers. Participants will take Enasidenib orally every day in continuous 28-day cycles and attend clinic visits at the start of each cycle to receive their medication supply.
1Treatment groups
Experimental Treatment
Group I: 1Experimental Treatment1 Intervention
Participants with IDH2 mutated (R140/R172) malignant sinonasal and skull base tumors.
Enasidenib is already approved in United States, European Union for the following indications:
🇺🇸 Approved in United States as Idhifa for:
- Relapsed or refractory acute myeloid leukemia (AML) with an isocitrate dehydrogenase-2 (IDH2) mutation
🇪🇺 Approved in European Union as Idhifa for:
- Acute myeloid leukaemia (AML) with an isocitrate dehydrogenase 2 (IDH2) mutation
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
National Institutes of Health Clinical CenterBethesda, MD
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Who Is Running the Clinical Trial?
National Cancer Institute (NCI)Lead Sponsor
References
Recurrent IDH2 R172X mutations in sinonasal undifferentiated carcinoma. [2023]Sinonasal undifferentiated carcinoma is a rare and aggressive malignancy. Sinonasal undifferentiated carcinoma has long been considered a diagnosis of exclusion; to date, the molecular pathogenetic basis for sinonasal undifferentiated carcinoma is unknown. To identify potential oncogenic drivers in sinonasal undifferentiated carcinoma, targeted next-generation sequencing of 300 cancer-related genes was performed on 11 cases of sinonasal undifferentiated carcinoma. We identified IDH2 R172X mutations in 55% of sinonasal undifferentiated carcinomas including R172S, R172T, and R172M. Multispecific mutant IDH1/2 immunohistochemistry was performed and identified mutant-specific protein expression in all cases with available tissue: 3/3 sinonasal undifferentiated carcinomas with R172 mutations were positive and 4/4 wild-type cases were negative. Review of sequencing data for our institutional head and neck cohorts (n=412) confirmed the absence of IDH-activating mutations in other tumor types. Alterations in the IDH2-wild-type sinonasal undifferentiated carcinomas included SMARCA4 loss-of-function with confirmed loss of immunohistochemical expression, NOTCH1 gain-of-function, and TET2 loss-of-function. We demonstrate that the majority of histologically defined sinonasal undifferentiated carcinomas are characterized by IDH2 R172X mutations and overexpression of mutant protein. IDH2 R172X mutations are specific to sinonasal undifferentiated carcinoma among carcinomas of the head and neck, confirming this tumor type as a distinct clinicopathologic entity. These findings have significant implications for diagnosis and therapy with IDH inhibitors for patients with this rare and poorly understood tumor.
Mutant KIT as imatinib-sensitive target in metastatic sinonasal carcinoma. [2022]Sinonasal carcinomas (SNCs) comprise various rare tumor types that are characterized by marked histologic diversity and largely unknown molecular profiles, yet share an overall poor prognosis owing to an aggressive clinical course and frequent late-stage diagnosis. The lack of effective systemic therapies for locally advanced or metastatic SNC poses a major challenge to therapeutic decision making for individual patients. We here aimed to identify actionable genetic alterations in a patient with metastatic SNC whose tumor, despite all diagnostic efforts, could not be assigned to any known SNC category and was refractory to multimodal therapy.
SMARC-B1 deficient sinonasal carcinoma metastasis to the brain with next generation sequencing data: a case report of perineural invasion progressing to leptomeningeal invasion. [2023]SMARCB1-deficient sinonasal carcinoma (SDSC) is an aggressive subtype of head and neck cancers that has a poor prognosis despite multimodal therapy. We present a unique case with next generation sequencing data of a patient who had SDSC with perineural invasion to the trigeminal nerve that progressed to a brain metastasis and eventually leptomeningeal spread.
Signaling Pathways mTOR and ERK as Therapeutic Targets in Sinonasal Intestinal-Type Adenocarcinoma. [2023]Despite advances in surgery and radiotherapy, the overall prognosis of sinonasal intestinal-type adenocarcinoma (ITAC) is poor, and new treatment options are needed. Recent studies have indicated alterations in cellular signaling pathways that may serve as targets for modern inhibitors. Our aim was to evaluate the frequency of mTOR and ERK pathway upregulation in a retrospective series of 139 ITAC and to test the efficacy and mechanism of action of candidate targeted inhibitors in cell line ITAC-3. An immunohistochemical analysis on p-AKT, p-mTOR, p-S6, p-4E-BP1, and p-ERK indicated, respectively, a 68% and 57% mTOR and ERK pathway activation. In vitro studies using low doses of mTOR inhibitor everolimus and ERK inhibitor selumetinib showed significant growth inhibition as monotherapy and especially as combined therapy. This effect was accompanied by the downregulation of mTOR and ERK protein expression. Our data open a new and promising possibility for personalized treatment of ITAC patients.
Management of 80 sinonasal undifferentiated carcinomas. Retrospective multicentre study of the French Network of Rare Head and Neck Cancers (REFCOR). [2023]Sinonasal undifferentiated carcinoma (SNUC) is a rare and aggressive disease requiring multimodal treatment, and multiple new entities once included in the spectrum of SNUC, such as SWI/SNF-deficient carcinomas, are emerging. We aimed to provide new data regarding the role of chemotherapy and surgery and the prognostic factors of disease-free survival.