Avapritinib for the Treatment of CKIT or PDGFRA Mutation-Positive Locally Advanced or Metastatic Malignant Solid Tumors
Avapritinib for the Treatment of CKIT or PDGFRA Mutation-Positive Locally Advanced or Metastatic Malignant Solid Tumors
This phase II trial studies the effect of avapritinib in treating malignant solid tumors that
 have a genetic change (mutation) in CKIT or PDGFRA and have spread to nearby tissue or lymph
 nodes (locally advanced) or other places in the body (metastatic). Avapritinib may stop the
 growth of tumor cells by blocking some of the enzymes needed for cell growth. Avapritinib may
 help to control the growth of malignant solid tumors.
PRIMARY OBJECTIVE:

 I. To determine the objective response rate (ORR) of avapritinib in patients with pathogenic
 CKIT or PDGFRA activating mutation-positive malignant solid tumors, as assessed by the
 Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.

 SECONDARY OBJECTIVES:

 I. To evaluate the duration of response (DoR) to avapritinib in patients with pathogenic CKIT
 or PDGFRA activating mutation-positive malignant solid tumors.

 II. To evaluate the disease control rate (DCR) of avapritinib in patients with pathogenic
 CKIT or PDGFRA activating mutation-positive malignant solid tumors.

 III. To determine the safety and tolerability of avapritinib in patients with pathogenic CKIT
 or PDGFRA activating mutation-positive malignant solid tumors, as assessed by the National
 Cancer institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5.0.

 EXPLORATORY OBJECTIVES:

 I. To evaluate the overall survival (OS) of patients with pathogenic CKIT or PDGFRA
 activating mutation-positive malignant solid tumors receiving avapritinib.

 II. To evaluate the ORR and DoR of avapritinib in patients with measurable brain or central
 nervous system (CNS) metastases at baseline.

 III. To evaluate the progression-free survival (PFS) of patients with pathogenic CKIT or
 PDGFRA activating mutation-positive malignant solid tumors receiving avapritinib.

 IV. To evaluate the correlation between genomic mutations and clinical outcome. V. To
 evaluate time on treatment (including patients treated beyond progression).

 VI. To evaluate baseline genomics and circulating cell-free deoxyribonucleic acid (cfDNA) and
 functional analyses of variants.

 OUTLINE:

 Patients receive avapritinib orally (PO) once daily (QD) on days 1-28. Cycles repeat every 28
 days in the absence of disease progression or unacceptable toxicity.

 After completion of study treatment, patients are followed up at 30 days and then every 8
 weeks.
Inclusion Criteria:

 -  The patient (or legally acceptable representative if applicable) provides written
 informed consent for the study

 -  >= 18 years of age on the day of informed consent signing

 -  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 not otherwise specified (NOS), and primary central nervous system (CNS)
 tumors. Patients with any other solid tumor type with the exception of
 gastrointestinal stromal tumor (GIST) will be eligible for enrollment in the
 study

 -  Measurable disease per the RECIST v1.1 or Response Assessment in Neuro-Oncology
 Criteria (RANO) criteria, as appropriate (for Cohorts 1 and 2 only). NOTE: Patients in
 Cohort 3 can have measurable or non-measurable disease

 -  Documented pathogenic CKIT activating mutation (Cohort 1) OR pathogenic PDGFRA
 activating mutation (Cohort 2) based on tissue-based next-generation sequencing (NGS)
 diagnostic test (Oncomine Comprehensive Assay [OCA] or FoundationOne CDx) OR plasma
 cfDNA-detected (Guardant360) pathogenic CKIT or PDGFRA activating mutation (for
 patients with measurable disease) or tissue or cfDNA-detected pathogenic CKIT or
 PDGFRA activating mutation (for patients with non-measurable disease; Cohort 3).
 Mutation pathogenicity will be verified by the MD Anderson Cancer Center (MDACC)
 Precision Oncology Decision Support (PODS) team

 -  Has available archival tissue for CKIT or PDGFRA mutation testing

 -  Lymphocyte count >= 500/uL (within 28 days of study treatment initiation)

 -  White blood cell count > 2,500/uL and < 15,000/uL (within 28 days of study treatment
 initiation)

 -  Absolute neutrophil count >= 1.5 x 10^9/L (without granulocyte colony-stimulating
 factor support within 2 weeks of laboratory test used to determine eligibility)
 (within 28 days of study treatment initiation)

 -  Platelet count >= 75 x 10^9/L (without transfusion within 2 weeks of laboratory test
 used to determine eligibility) (within 28 days of study treatment initiation)

 -  Hemoglobin >= 9.0 g/dL (without blood transfusion within 7 days of laboratory test
 used to determine eligibility) (within 28 days of study treatment initiation)

 -  Total bilirubin =< 1.5 x upper limit of normal (ULN); if hepatic metastases are
 present, =< 2.0 x ULN (within 28 days of study treatment initiation)

 -  Aspartate transaminase (AST) and alanine transaminase (ALT) =< 2.5 x ULN; if hepatic
 metastases are present, =< 5.0 x ULN (within 28 days of study treatment initiation)

 -  Creatinine clearance >= 50 mL/min (within 28 days of study treatment initiation)

 -  Cardiac ejection fraction < 45% per screening echocardiogram or multigated acquisition
 scan

 -  Eastern Cooperative Oncology Group (ECOG) performance status of 0-2

 -  Life expectancy >= 3 months

 -  Willing and able to comply with the protocol for the duration of the study including
 treatment and scheduled visits and examinations

 -  Willing to undergo biopsy as required by the study

 -  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

 -  Females of childbearing potential must either abstain from heterosexual intercourse or
 use a highly effective method of contraception for the course of the study through 30
 days after the last dose of study treatment

 -  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 who have GIST

 -  Patients with tyrosine kinase inhibitor (TKI)-resistant CKIT mutation V654A or T670I

 -  Patient 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 (MRI) scan should show no increase in brain lesion
 size/volume

 -  History of documented congestive heart failure (New York Heart Association functional
 classification III-IV) or serious cardiac arrhythmias requiring treatment

 -  QT interval corrected using Fridericia's formula of > 470 msec

 -  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

 -  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 adverse events (AEs) due to previous
 therapies to =< grade 1 or baseline

 -  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

 -  Arterial thrombotic or embolic events within 6 months prior to study treatment
 initiation, or venous thrombotic events within 2 weeks prior to study treatment
 initiation

 -  CTCAE >= grade 3 hemorrhage or bleeding event within 4 weeks prior to study treatment
 initiation

 -  Known risk of intracranial bleeding, or a history of intracranial bleeding

 -  History of cerebrovascular accident or transient ischemic attacks

 -  Symptomatic non-healing wound, ulcer, gastrointestinal perforation, or bone fracture

 -  History of a seizure disorder or requirement for anti-seizure medication

 -  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

 -  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

 -  Females who are pregnant or breastfeeding

 -  Unable to swallow and retain oral medications

 -  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)

 -  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

 -  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