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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if enasidenib (Idhifa) can benefit individuals with rare nasal cavity or skull base cancers that have an IDH2 gene mutation. These cancers are often diagnosed late and can spread to other body parts. The trial targets those whose cancer has returned or spread despite prior treatments and who have the IDH2 mutation. Participants will take enasidenib daily in tablet form to evaluate its effectiveness. Individuals with specific types of sinonasal or skull base cancers and the IDH2 mutation may be suitable for this study. As a Phase 2 trial, the research measures how well enasidenib works in an initial, smaller group, offering a chance to benefit from a potentially effective treatment.

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.

Is there any evidence suggesting that enasidenib is likely to be safe for humans?

Research has shown that enasidenib has been tested for safety in people with certain types of cancer, particularly those with IDH2 mutations. In earlier studies, most participants tolerated enasidenib well. Common side effects included nausea, fatigue, and reduced appetite. Serious side effects, such as changes in blood cell counts and liver function, were less common but did occur. These side effects were manageable and closely monitored during the studies.

The current trial is in its second phase, indicating that earlier research has already checked enasidenib for basic safety. Participants should discuss any concerns with their healthcare providers to understand how these findings might relate to them. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Enasidenib is unique because it targets a specific genetic mutation, IDH2, found in some sinonasal and skull base cancers. Unlike standard treatments such as surgery, radiation, and chemotherapy that attack cancer more broadly, Enasidenib specifically inhibits the mutant IDH2 enzyme. This targeted approach can potentially reduce side effects and improve effectiveness by directly addressing the cancer's underlying cause. Researchers are excited because targeting this specific mutation could lead to more personalized and effective treatment options for patients with this rare cancer type.

What evidence suggests that enasidenib might be an effective treatment for sinonasal and skull base cancer?

Research has shown that enasidenib targets a specific change in the IDH2 gene, often found in some rare nasal and skull base cancers. This change causes a build-up of a substance called 2-HG, which promotes cancer cell growth. Enasidenib blocks this build-up, allowing cancer cells to mature properly and slow their growth. Previous patients with other types of cancers that have the IDH2 change responded well to enasidenib. This trial will evaluate the effectiveness of enasidenib for participants with nasal and skull base cancers that have the same IDH2 mutation, suggesting it might also be effective for these cancers. ^{1 2 5 6 7}

Who Is on the Research Team?

Charalampos Floudas, M.D.

Principal Investigator

National Cancer Institute (NCI)

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06176989

NCT06176989 | Enasidenib in IDH2-Mutated Malignant ... Study Overview · Single-arm Phase II trial to determine PFS in participants with recurrent or metastatic IDH2m malignant sinonasal and skull base tumors.

2. ascopubs.org ascopubs.org/doi/10.1200/JCO.2024.42.16_suppl.TPS3183

Phase II study of enasidenib in IDH2-mutated malignant ... Enasidenib is an oral small molecule inhibitor of the mutant IDH2 protein which prevents 2-HG accumulation and releases cancer cells from the differentiation ...

3. withpower.com withpower.com/trial/phase-2-metastatic-olfactory-neuroblastoma-11-2023-72a3a

Enasidenib for Sinonasal and Skull Base Cancer This Phase 2 medical study run by National Cancer Institute (NCI) is evaluating whether Enasidenib will have tolerable side effects & efficacy for patients ...

4. ascopubs.org ascopubs.org/doi/pdf/10.1200/JCO.2024.42.16_suppl.TPS3183

Phase II study of enasidenib in IDH2-mutated malignant ... Enasidenib is an oral small molecule inhibitor of the mutant IDH2 protein which prevents 2-HG accumulation and releases cancer cells from the differentiation ...

5. ccr.cancer.gov ccr.cancer.gov/news/article/clinical-trial-researching-medication-therapy-for-idh2-mutated-nasal-cavity-or-skull-base-tumors

Clinical trial researching medication therapy for IDH2-mutated ... 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 ...

6. researchgate.net researchgate.net/publication/381509784_Phase_II_study_of_enasidenib_in_IDH2-mutated_malignant_sinonasal_and_skull_base_tumors

Phase II study of enasidenib in IDH2-mutated malignant ... A phase II clinical trial evaluating the use of enasidenib in IDH2-mutated malignant sinonasal and skull base tumors, including olfactory neuroblastoma, was ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9512446/

Emerging Concepts in Sinonasal Tumor Research - PMC Although survival outcomes vary with tumor type, sinonasal malignancies may behave aggressively and are often diagnosed at late stages. Treatment consists of ...