Antineoplastic Agents

All Drugs and Chemicals

Irinotecan

Niraparib

Poly(ADP-ribose) Polymerase Inhibitors

Topoisomerase I Inhibitors

Enzyme Inhibitors

Participants will receive a starting dose of 100 mg of niraparib on days 1-7 each 21-day cycle, and 100 mg/m\^2 of irinotecan on day 1 of each 21 day cycle until unacceptable toxicity, disease progression or participant withdrawal.

Participants will receive a starting dose of 200 mg of niraparib on days 1-7 each 21-day cycle, and 100 mg/m\^2 of irinotecan on day 1 of each 21 day cycle until unacceptable toxicity, disease progression or participant withdrawal.

Participants weighing \< 77 kg will receive a starting dose of 200 mg of niraparib on days 1-7 each 21-day cycle, and 100 mg/m\^2 of irinotecan on day 1 of each 21 day cycle until unacceptable toxicity, disease progression or participant withdrawal.

Participants weighing \>= 77 kg will receive a starting dose of 300 mg of niraparib on days 1-7 each 21-day cycle, and 100 mg/m\^2 of irinotecan on day 1 of each 21 day cycle until unacceptable toxicity, disease progression or participant withdrawal.

Participants weighing \< 77 kg will receive a starting dose of 200 mg of niraparib on days 1-7 each 21-day cycle, and 150 mg/m\^2 of irinotecan on day 1 of each 21 day cycle until unacceptable toxicity, disease progression or participant withdrawal.

Participants weighing \>= 77 kg will receive a starting dose of 300 mg of niraparib on days 1-7 each 21-day cycle, and 150 mg/m\^2 of irinotecan on day 1 of each 21 day cycle until unacceptable toxicity, disease progression or participant withdrawal.

Early Phase Cancer Clinical Trials Recruitment

Early Phase Clinical Trials Recruitment

Pamela Munster, MD

The purpose of this phase 1 clinical trials is to determine whether niraparib (a Poly (ADP-ribose) polymerase inhibitor (PARPi)) can be safely combined with irinotecan with manageable toxicity and reasonable efficacy. Emerging evidence suggest that PARPi is an effective therapeutic strategy in a wider subset of solid tumors that may have defective homologous recombination (HR) or DNA repair gene mutations. BReast CAncer gene (BRCA), partner and localizer of BRCA2 (PALB2), and various other DNA repair germline mutations predispose carriers to cancers of the breast, ovaries, pancreas, prostate and melanoma. A number of preclinical studies have demonstrated that PARP inhibitors can work as chemopotentiators. There is significant interest in this combination, and the recommended phase II dose will be used in the upcoming NCI ComboMatch trial.

This is an open label, non-randomized phase Ib dose finding study of niraparib and irinotecan combination therapy. For this study, individuals with metastatic solid tumor malignancies and BRCA1/2, ataxia telangiectasia mutated gene (ATM), or PALB2 mutations will be enrolled with specific tumors of interest including gastrointestinal cancers (e.g. colon, pancreas, gastric, cholangiocarcinoma), ovarian cancer, and breast cancer.

PRIMARY OBJECTIVES:

I. To assess safety and tolerability of niraparib and irinotecan combination therapy in patients with metastatic solid tumor malignancies and BRCA1/2, ATM, or PALB2 mutations.

II. To determine the MTD and recommended phase II dose of niraparib with irinotecan combination therapy.

SECONDARY OBJECTIVES:

I. To determine the preliminary efficacy of niraparib and irinotecan combination therapy in patients with metastatic solid tumor malignancies and BRCA1/2, ATM, or PALB2 mutations.

OVERVIEW:

Participants will be treated in cohorts of size three to six, and the dosage will be escalated if the clinical toxicity is acceptable. Participants may continue treatment until disease progression, unacceptable toxicity, withdrawal of consent, start of new anti-cancer therapy, or death. Participants will be followed for 30 days after study drug discontinuation for safety and every 12 weeks (+/- 2 weeks) for up to 2 years after start of therapy until disease progression or death from any cause (whichever occurs first).

Combination Therapy in Cancers With Mutations in DNA Repair Genes

Combination Therapy of Niraparib and Irinotecan in Cancers With Mutations in DNA Repair Genes

The percentage of participants with treatment-emergent adverse events as classified and graded by the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5 will be reported

The MTD is defined as the highest dose studied for which the observed incidence of DLT is less than 33% or occurs within at most one out of six patients treated at any given dose level.

The percentage of participants with documented dose-limiting toxicities will be reported by dose level.

The RP2D will be selected based on the evaluation of dose-limiting toxicities and adverse events measured using CTCAE v5.0.

Defined as the proportion of participants who achieve a Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 best overall response of confirmed complete response (CR) or confirmed partial response (PR)

Defined as the duration of time from when measurement criteria are met for CR or PR (whichever is first recorded) until the date that recurrent/ progressive disease (PD) is objectively documented (taking as reference for PD the smallest measurements recorded since the treatment started).

Defined as the duration of time from measurement criteria are met for SD or better until the date that recurrent/ progressive disease (PD) is objectively documented (taking as reference for PD the smallest measurements recorded since the treatment started).

Defined as the duration of time from start of treatment to time of disease recurrence/ progression (PD) or death from any cause, whichever occurs first.

GlaxoSmithKline

University of California, San Francisco

Principal Investigator

Neoplasms

All Conditions

Nervous System Diseases

Musculoskeletal Diseases

Respiratory Tract (Lung and Bronchial) Diseases

Ear, Nose, and Throat Diseases

Skin and Connective Tissue Diseases

Rare Diseases

Carcinoma

Adenocarcinoma

Carcinoma, Neuroendocrine

Neuroblastoma

Chondrosarcoma

Esthesioneuroblastoma, Olfactory

Skull Base Neoplasms

Maxillary Sinus Neoplasms

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Neuroectodermal Tumors, Primitive, Peripheral

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Neuroepithelial

Neoplasms, Germ Cell and Embryonal

Neoplasms, Nerve Tissue

Neuroendocrine Tumors

Neoplasms, Connective Tissue

Neoplasms, Connective and Soft Tissue

Sarcoma

Skull Neoplasms

Bone Neoplasms

Bone Diseases

Olfactory Nerve Diseases

Cranial Nerve Diseases

Paranasal Sinus Neoplasms

Nose Neoplasms

Otorhinolaryngologic Neoplasms

Head and Neck Neoplasms

Nose Diseases

Respiratory Tract Diseases

Paranasal Sinus Diseases

Respiratory Tract Neoplasms

Otorhinolaryngologic Diseases

Olfactory Neuroblastoma

Sinonasal Undifferentiated Carcinoma

Neuroepithelioma

Neuroendocrine Tumor

Soft Tissue Sarcoma

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

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Combination Therapy in Cancers With Mutations in DNA Repair Genes	NCT05694715	Metastatic Soli... BRCA1 Mutation BRCA2 Mutation ATM Gene Mutati... PALB2 Gene Muta...	Niraparib Irinotecan	18 Years -	University of California, San Francisco
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)

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