Avapritinib for the Treatment of CKIT or PDGFRA Mutation-Positive Locally Advanced or Metastatic Malignant Solid Tumors

Inclusion Criteria: 1. The patient (or legally acceptable representative if applicable) provides written informed consent for the study. 2. Male or female ≥18 years of age on the day of informed consent signing. Adolescent patients aged 12 years and older are allowed with signed assent and parental consent according to institutional guidelines and requirements. 3. Cohorts 1 and 2: Patient has a locally advanced or metastatic solid tumor and has progressed on appropriate standard therapy, has not shown clinically meaningful benefit to appropriate standard therapy, has no available standard therapy, or has declined appropriate standard therapy. • NOTE: Specific solid tumor types include but are not limited to melanoma, breast cancer, lung cancer, gastroesophageal cancer, colorectal cancer, sarcoma, solid tumors NOS, and primary CNS tumors. Patients with any other recurrent solid tumor type with the exception of gastrointestinal stromal tumor (GIST) will be eligible. 4. Cohort 3: Patient has newly diagnosed IDH wild-type, MGMT-unmethylated glioblastoma. Patients must have received prior treatment with radiation and concurrent temozolomide per standard of care.27 Patients must have completed radiation and concurrent temozolomide 3-8 weeks prior to study treatment initiation. 5. Measurable disease per the RECIST v1.1 or RANO criteria, as appropriate, for Cohorts 1 and 2. Patients in Cohort 3 can have measurable or non-measurable disease per the RANO criteria. 6 Documented pathogenic CKIT activating mutation (Cohort 1) OR pathogenic PDGFRA activating mutation (Cohort 2) based on Clinical Laboratory Improvement Amendments-certified next-generation sequencing diagnostic test. Cohort 3 should have pathogenic CKIT or PDGFRA activating mutation/amplification based on CLIA-certified NGS diagnostic test. CKIT and PDGFRA mutation pathogenicity will be verified by the MD Anderson Cancer Center's Precision Oncology Decision Support team. Acceptable CKIT/PDGFRA mutations for study eligibility are listed in Appendix E. 7\. Has available archival tissue for CKIT/PDGFRA mutation (amplification \[Cohort 3 only\]) retrospective testing. 8\. Adequate organ and marrow function as defined below within 7 days of study treatment initiation: * White blood cell count \>2,500/µL and \<15,000/µL * Absolute neutrophil count ≥1.5 × 109/L (without granulocyte colony-stimulating factor support within 2 weeks of laboratory test used to determine eligibility) * Platelet count ≥75 × 109/L (without transfusion within 2 weeks of laboratory test used to determine eligibility) * Hemoglobin ≥9.0 g/dL (without blood transfusion within 7 days of laboratory test used to determine eligibility) * Total bilirubin ≤1.5 × upper limit of normal (ULN); if hepatic metastases are present, ≤3.0 × ULN * Aspartate transaminase and alanine transaminase ≤2.5 × ULN; if hepatic metastases are present, ≤5.0 × ULN * Serum creatinine ≤2.0 × ULN or creatinine clearance ≥45 mL/min. 9. Cardiac ejection fraction \>45% per screening echocardiogram or multigated acquisition scan. 10\. Eastern Cooperative Oncology Group performance status of 0-2. 11\. Life expectancy ≥3 months. 12\. Willing and able to comply with the protocol for the duration of the study including treatment and scheduled visits and examinations. 13\. Willing to undergo biopsy as required by the study. 14\. Females must be postmenopausal (defined as ≥45 years of age with at least 12 months of spontaneous amenorrhea) or premenopausal with documented surgical sterilization (tubal ligation, hysterectomy, bilateral salpingectomy, or bilateral oophorectomy), or evidence of non-childbearing status for women of childbearing potential (negative serum beta-human chorionic gonadotropin pregnancy test) within 3 days of study treatment initiation. 15\. Females of childbearing potential must either abstain from heterosexual intercourse or use a highly effective method of contraception for the course of the study and for 6 weeks after the last dose of study treatment. 16\. Males with female partners of reproductive potential must either abstain from sexual intercourse or they and their partners must use a highly effective method of contraception when engaging in sexual intercourse for the course of the study through 30 days after the last dose of study treatment. Exclusion Criteria: Patients eligible for this study must not meet any of the following criteria: 1. Patients who have GIST. 2. Patients with tyrosine kinase inhibitor-resistant CKIT mutation V654A or T670I. 3. Patients with meningeal carcinomatosis, leptomeningeal carcinomatosis, spinal cord compression, or symptomatic or unstable brain metastases. Note: Patients with stable brain metastases (defined as asymptomatic or no requirement for high-dose or increasing dose of systemic corticosteroids) and without imminent need of radiation therapy) are eligible (including those with untreated brain metastases). If applicable, patients must have completed brain radiation therapy and recovered adequately from any associated toxicity and/or complications prior to eligibility assessment. For patients who have received prior radiation therapy, post-treatment magnetic resonance imaging scan should show no increase in brain lesion size/volume. 4. History of documented congestive heart failure (New York Heart Association functional classification III-IV) or serious cardiac arrhythmias requiring treatment. 5. QT interval corrected using Fridericia's formula of \>470 msec. 6. Is currently participating or has participated in a study of an investigational agent or has used an investigational device within 2 weeks prior to study treatment initiation. 7. Prior anticancer chemotherapy, hormone therapy, immunotherapy, targeted therapy, radiation therapy, or surgery within 2 weeks prior to study treatment initiation. * NOTE: Patients must have recovered from all AEs due to previous therapies to ≤ Grade 1 or baseline (except alopecia). Patients with ≤ Grade 2 neuropathy are eligible. * NOTE: If patient received major surgery, she/he must have recovered adequately from the toxicity and/or complications from the intervention prior to study treatment initiation. * NOTE: Patients in Cohort 3 must have completed radiation and concurrent temozolomide 3-8 weeks prior to study treatment initiation. 8. Symptomatic non-healing wound, ulcer, gastrointestinal perforation, or bone fracture. 9. History of psychotic or depressive disorder. Patients whose disorder is well controlled on a stable antipsychotic or antidepressant medication for at least 12 months prior to study entry will be eligible. 10. Concomitant use of a known strong cytochrome P450 (CYP)3A4 inhibitor or strong CYP3A4 inducer. The required washout period prior to study treatment initiation is 2 weeks or 5 half-lives, whichever is shortest. 11. Females who are pregnant or breastfeeding. 12. Unable to swallow and retain oral medications. 13. Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of the study treatment (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection). 14. Known additional malignancy that is progressing or requires active treatment. NOTE: Patients with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or cervical cancer in situ that have undergone potentially curative therapy are not excluded. 15. History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the patient's participation for the full duration of the study, or is not in the best interest of the patient to participate, in the opinion of the investigator. 16. Prior treatment with an intracerebral agent or bevacizumab (Cohort 3 only). 17. Prior treatment including radiation, chemotherapy, or immunotherapy for low-grade glioma (Cohort 3 only).