Phase II Study of Enasidenib in IDH2-mutated Malignant Sinonasal and Skull Base Tumors
Overview
- Phase
- Phase 2
- Status
- Recruiting
- Enrollment
- 40
- Locations
- 2
- Primary Endpoint
- Progression Free Survival (PFS) in all study participants
Overview
Brief Summary
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....
Detailed Description
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.
Study Design
- Study Type
- Interventional
- Allocation
- Na
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to 120 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •INCLUSION CRITERIA:
- •Histologically or cytologically confirmed locally advanced or metastatic SNUC, ONB, LCNEC, SNAC, and CS with documented somatic (tumor) IDH2 mutations R140 or R
- •Primary tumors must be located in the sinonasal cavity and/or 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.
- •Lesions in a previously irradiated field are considered measurable if they have been demonstrated as progressing during or following radiotherapy.
- •Age \>=18 years.
- •ECOG performance status 0-2
- •Adequate organ and marrow function as defined below:
Exclusion Criteria
- •Prior treatment with IDH1/2 inhibitor.
- •Use of other investigational agents within 3 weeks or 5 half-lives prior to first treatment administration.
- •Systemic anticancer treatment within 3 weeks prior to first treatment administration. All residual treatment-related toxicities must have resolved or be minimal and not constitute a safety risk. Note: Bisphosphonates and denosumab are permitted medications.
- •Large-field radiotherapy within 4 weeks prior to first treatment administration. All residual treatment-related toxicities must have resolved (except xerostomia) or be minimal and not constitute a safety risk.
- •Major surgery within 2 weeks prior to first treatment administration. If participant underwent major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting study treatment. Minimally invasive procedures are permitted.
- •Participants with new or progressive (active) brain metastases or leptomeningeal disease.
- •History of allergic reactions attributed to compounds of similar chemical or biologic composition to enasidenib.
- •Treatment with botanical preparations (e.g., herbal supplements or traditional Chinese medicines) intended for general health support or to treat the disease under study within 2 weeks prior to first treatment administration.
- •Participants taking the following sensitive cytochrome P450 (CYP) substrate medications that have a narrow therapeutic range are excluded from the study unless they can be transferred to other medications prior to enrolling: warfarin, phenytoin (CYP2C9), S-mephenytoin (CYP2C19), thioridazine (CYP2D6), theophylline and tizanidine (CYP1A2). Excluded medications should not be given within 3 weeks or 5 half-lives (whichever is shorter) prior to the first dose of study medication. Other CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP1A2 substrates may be given concurrently if medically necessary.
- •Participants taking sensitive substrates of P-glycoprotein (P-gp), breast cancer resistant protein (BCRP), OAT1, OATP1B1, OATP1B3, and OCT2 should be excluded from the study unless the substrate medication can be dose modified according to the package insert of the substrate (if applicable) and adverse events can be closely monitored during concurrent administration. Alternately, participants can be transferred to other medications prior to enrolling. Excluded medications should not be given within 3 weeks or 5 half-lives (whichever is shorter) prior to the first of study medication.
Arms & Interventions
1
Participants with IDH2 mutated (R140/R172) malignant sinonasal and skull base tumors.
Intervention: Enasidenib (Drug)
Outcomes
Primary Outcomes
Progression Free Survival (PFS) in all study participants
Time Frame: up to 5 years post study treatment
The date of first treatment until the date of disease progression or death without progression
Secondary Outcomes
- safety(from study treatment initiation up to 28 days post study treatment)
- clinical benefit rate (CBR: CR+PR+SD>4 months) in participants with IDH2m SNUC(up to 5 years post study treatment)
- PFS in non-SNUC IDH2m tumors(up to 5 years post study treatment)
- Overall survival (OS) in non-SNUC IDH2m tumors(up to 5 years post study treatment)
- clinical benefit rate (CBR: CR+PR+SD>4 months) in participants with non-SNUC IDH2m tumors(up to 5 years post study treatment)
- Overall survival (OS) in participants with IDH2m SNUC(up to 5 years post study treatment)
- PFS in participants with IDH2m SNUC(up to 5 years post study treatment)
- Correlate UGTIA1 genotypes with toxicity(from study treatment initiation up to 28 days post study treatment)