Gastrointestinal Stromal Tumor Clinical Trials

• Participant must have histologically confirmed SDH-deficient GIST. Participants must have locally advanced or metastatic disease that is not amenable to surgery.

• Participants must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as ≥20 mm (≥2 cm) by chest x-ray or as ≥10 mm (≥1 cm) with CT scan, MRI, or calipers by clinical exam. See Section 12 (Measurement of Effect) for the evaluation of measurable disease.

• Participants must have radiographically documented progressive disease prior to study enrollment as per investigator assessment.

• Age ≥18 years

• ECOG performance status ≤2

• Participants must have adequate organ and marrow function as defined below:

‣ Hemoglobin \> 8 g/dL. Patients with a hemoglobin of 7.5-8.0 g/dL may be eligible if the value is chronic, there is no clinical evidence of active bleeding, and eligibility is confirmed upon review and approval of the Sponsor-Investigator

⁃ Absolute neutrophil count ≥1,000/mcL

⁃ platelets ≥100,000/mcL

⁃ total bilirubin ≤1.5 × institutional upper limit of normal (ULN)

⁃ AST(SGOT)/ALT(SGPT) ≤3.0 × institutional ULN (unless liver metastases are present in which case it must be ≤ 5 × ULN)

⁃ glomerular filtration rate (GFR) ≥60 mL/min/1.73 m2 (using the CDK-EPI formula see Appendix B)

• Human immunodeficiency virus (HIV)-infected participants on effective non-CYP3A4 interacting (see Section 3.2.3) anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.

• For participants with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated.

• Participants with a history of hepatitis C virus (HCV) infection must have been treated and cured. For participants with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.

• Participants with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression.

• Participants must be disease-free of prior invasive malignancies for \> 5 years with the exception of curatively-treated basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix. NOTE: If there is a history of prior malignancy, participants must not be receiving other specific treatment for that cancer.

• Participants should have completed prior treatment for their cancer: chemotherapy or radiotherapy must have been completed for greater than 2 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study.

• Participants should have recovered from adverse events due to prior anti-cancer therapy (i.e.,have residual toxicities \> Grade 1) with the exception of alopecia.

• Participants with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, participants should be class 2B or better.

• Participants must have a QTc interval length of below 450 msec. QTc will be calculated via the Fridericia's formula.

• Participant is willing to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up.

• Participant must be able to swallow and maintain pills.

• Women of childbearing potential must have a negative urine or serum pregnancy test within 28 days of initial dose of pemigatinib (INCB054828), and again within 7 days prior to treatment on day 1. If screening occurs within 7 days of day 1, only one regnancy test is required.

• Ability to understand and the willingness to sign a written informed consent document. Participants with impaired decision-making capacity (IDMC) who have a legally authorized representative (LAR) and/or family member available will also be eligible.