Enasidenib for Sinonasal and Skull Base Cancer

Overseen By Charalampos Floudas, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: IDH1/2 inhibitors, QT prolongers

Disqualifiers: Active brain metastases, Cardiovascular disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

Duration: Indefinite, as long as the drug is helping

40 Participants Needed

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. ^{1 2 3 4 5}

Research Team

Charalampos Floudas, M.D.

Principal Investigator

National Cancer Institute (NCI)

Eligibility 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

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.

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

Treatment Details

Interventions

• Enasidenib

Trial Overview 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.

Participant Groups

Group I: 1 Experimental Treatment 1 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

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Findings from Research

In a study of 11 cases of sinonasal undifferentiated carcinoma, 55% exhibited IDH2 R172X mutations, indicating a potential oncogenic driver specific to this aggressive cancer type.

The presence of IDH2 mutations not only helps in diagnosing sinonasal undifferentiated carcinoma but also suggests that patients may benefit from targeted therapies using IDH inhibitors, marking a significant advancement in treatment options for this rare malignancy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recurrent IDH2 R172X mutations in sinonasal undifferentiated carcinoma. Jo, VY., Chau, NG., Hornick, JL., et al.[2023]

Whole-exome and transcriptome sequencing identified a KIT exon 11 mutation in a patient with metastatic sinonasal carcinoma, leading to a successful treatment with imatinib, which resulted in a dramatic and durable response.

The study demonstrates that genomic profiling can reveal actionable mutations in rare tumors, suggesting that KIT mutations can be targeted therapeutically across different cancer types.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mutant KIT as imatinib-sensitive target in metastatic sinonasal carcinoma. Dieter, SM., Heining, C., Agaimy, A., et al.[2022]

This case study highlights a 42-year-old female with SMARCB1-deficient sinonasal carcinoma (SDSC) that progressed aggressively, leading to brain metastasis and leptomeningeal spread, resulting in a survival of only 13 months after diagnosis.

Next generation sequencing revealed that the brain metastasis had a higher tumor mutational burden compared to the primary tumor, suggesting that genetic profiling could provide valuable insights into the progression of rare cancers like SDSC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

SMARC-B1 deficient sinonasal carcinoma metastasis to the brain with next generation sequencing data: a case report of perineural invasion progressing to leptomeningeal invasion. Gomez-Acevedo, H., Patterson, JD., Sardar, S., et al.[2023]

In a study of 139 sinonasal intestinal-type adenocarcinoma (ITAC) cases, significant upregulation of the mTOR and ERK signaling pathways was found, with 68% and 57% activation respectively, indicating potential targets for new treatments.

In vitro tests on the ITAC-3 cell line showed that the mTOR inhibitor everolimus and the ERK inhibitor selumetinib effectively inhibited tumor growth, especially when used together, suggesting a promising avenue for personalized therapy in ITAC patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Signaling Pathways mTOR and ERK as Therapeutic Targets in Sinonasal Intestinal-Type Adenocarcinoma. Codina-Martínez, H., Lorenzo-Guerra, SL., Cabal, VN., et al.[2023]

In a study of 80 patients with sinonasal undifferentiated carcinoma (SNUC), the 5-year disease-free survival rate was 58% and overall survival rate was 63%, indicating a significant challenge in managing this aggressive disease.

While surgery did not show a clear benefit in overall or disease-free survival, there was a trend suggesting that chemotherapy (either neoadjuvant or concomitant) may improve disease-free survival, highlighting its potential role in treatment strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Management of 80 sinonasal undifferentiated carcinomas. Retrospective multicentre study of the French Network of Rare Head and Neck Cancers (REFCOR). Pouvreau, P., Coelho, J., Rumeau, C., et al.[2023]

References

1. United States pubmed.ncbi.nlm.nih.gov

Recurrent IDH2 R172X mutations in sinonasal undifferentiated carcinoma. [2023]

2. England pubmed.ncbi.nlm.nih.gov

Mutant KIT as imatinib-sensitive target in metastatic sinonasal carcinoma. [2022]

3. England pubmed.ncbi.nlm.nih.gov

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]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Signaling Pathways mTOR and ERK as Therapeutic Targets in Sinonasal Intestinal-Type Adenocarcinoma. [2023]

5. England pubmed.ncbi.nlm.nih.gov

Management of 80 sinonasal undifferentiated carcinomas. Retrospective multicentre study of the French Network of Rare Head and Neck Cancers (REFCOR). [2023]