Avapritinib With Decitabine in Patients With SM-AHN

Inclusion Criteria:

• Diagnosis of SM-AHN defined by World Health Organization 2022 criteria.

• ECOG 0-3

• Ability to understand and the willingness to sign a written informed consent.

• Ability to adhere to study visit schedule and other protocol requirements.

• Willing to receive blood products as deemed clinically necessary.

• Adequate organ and marrow function as defined by the protocol.

• Human immunodeficiency virus (HIV)-infected participants on effectiveanti-retroviral therapy with undetectable viral load within 6 months are eligiblefor this trial.

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

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

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

• Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, forthe duration of study participation, and for at least 6 months after the last doseof decitabine and 6 weeks after the last dose of avapritinib. Should a woman becomepregnant or suspect she is pregnant while she or her partner is participating inthis study or in the 6 months after last dose of decitabine or 6 weeks after lastdose of avapritinib she should inform her treating physician immediately. Mentreated or enrolled on this protocol must also agree to use adequate contraceptionprior to the study, for the duration of study participation, and 3 months aftercompletion of study drug administration.

Exclusion Criteria:

• History of decitabine use with documented disease progression of AHN by 2006 IWG MDSresponse criteria while on decitabine.

• History of avapritinib use with documented progression of mastocytosis while onavapritinib per m-IWG-MRT-ECNM criteria.

• History of treatment with decitabine in combination with avapritinib.

• Use of azacitidine within 4 weeks of first dose of study drug.

• Diagnosis of AML defined as presence of ≥ 20% myeloblasts in the peripheral blood orbone marrow or presence of a myeloid sarcoma.

• Patients who are receiving any other investigational agents or are participating inanother interventional study.

• History of allergic reactions attributed to compounds of similar chemical orbiologic composition to azacytidine, decitabine, cedazuridine, avapritinib,propylene glycol, mannitol (only for patients receiving azacytidine).

• History of intracranial hemorrhage or need for full anticoagulation with warfarin,direct oral anticoagulant, or treatment dose low molecular weight heparin (LMWH), orany condition that, in the investigator's opinion, would put the patient at anincreased risk for spontaneous, unprovoked hemorrhage such as: I) Cerebrovascularaccident (CVA) or transient ischemic attack (TIA) within one year of the first doseof study drug II) Presence of a vascular aneurysm in the brain III) Knownintracranial arteriovenous malformation (AVM).

• Patient has a history of a seizure disorder (eg, epilepsy) or requirement forantiseizure medication.

• Patient has a QT interval corrected using Fridericia's formula (QTcF) > 480 msec.

• Previous allogeneic hematopoietic stem cell transplant within 6 months prior toenrollment, active graft versus host disease (GVHD), or requiring transplant relatedimmunosuppression.

• Patients receiving any medications or substances that are strong or moderate CYP3Ainhibitors or strong or moderate CYP3A inducers. Because the lists of these agentsare constantly changing, it is important to regularly consult a frequently updatedmedical reference. As part of the enrollment/informed consent procedures, theparticipant will be counseled on the risk of interactions with other agents and whatto do if new medications need to be prescribed or if the participant is consideringa new over-the-counter medicine or herbal product.

• Participants with uncontrolled intercurrent illness.

• Participants with psychiatric illness/social situations that would limit compliancewith study requirements.

• Pregnant women are excluded from this study because, based on the mechanism ofaction and data from animal reproduction studies, in utero exposure to avapritinibmay cause fetal harm.

• Women who are breast feeding.

• Patient is unwilling or unable to comply with scheduled visits, drug administrationplan, laboratory tests, or other study procedures and study restrictions.

• Patient has a primary brain malignancy or metastases to the brain.

• Patient has had a major surgical procedure within 14 days of the first dose of studydrug. Surgical procedures such as central venous catheter placement, bone marrow (BM) biopsy, and feeding tube placement are considered minor surgical procedures.

• Patient has eosinophilia and known positivity for the FIP1L1-PGDFRA fusion, unlessthe patient has demonstrated relapse or progressive disease (PD) on prior imatinibtherapy. Patients with eosinophilia (> 1.5 × 109/L), who do not have a detectableKIT D816 mutation, must be tested for a PDGFRA fusion mutation by fluorescence insitu hybridization (FISH) or polymerase chain reaction (PCR).

• Patient is participating in another interventional clinical study.