Gastrointestinal Stromal Tumors (GIST) and other Relapsed and Refractory Solid Tumors
Conditions
Interventions
Approximately 235 patients will be enrolled in this study, including:
- Approximately 50 patients in Part 1 (Dose Escalation)
- Approximately 185 patients in Part 2 (Expansion)
The total number of pa
Sponsors
Blueprint Medicines
Eligibility
Age
18 Years to 99 Years
Inclusion criteria
Inclusion criteria: 1. Patient is *18 years of age. 2. For Part 1: Histologically- or cytologically-confirmed diagnosis of unresectable GIST or another advanced solid tumor. Patients with unresectable GIST must have disease that has progressed following imatinib and at least 1 of the following: sunitinib, regorafenib, sorafenib, dasatinib, pazopanib or an experimental agent that targets KIT, or disease with a D842 mutation in the PDGFR* gene. Patients with an advanced solid tumor other than GIST must have relapsed or refractory disease without an available effective therapy. - At daily doses <100 mg QD patients may have the diagnosis of either GIST or a relapsed or refractory solid tumor. - At daily doses *100 mg QD, at least 2 patients in a cohort (4 patients if the cohort is expanded) must have the diagnosis of GIST., 3. For Part 2: - Group 1: Patients must have a confirmed diagnosis of unresectable GIST that has progressed following imatinib and at least 1 of the following: sunitinib, regorafenib, sorafenib, dasatinib, pazopanib, or an experimental agent that targets KIT, and the patient does not have a known D842 mutation in PDGFR*. - Group 2: Patients must have a confirmed diagnosis of unresectable GIST with a D842 mutation in the PDGFR* gene. The PDGFR* mutation will be identified by local or central assessment, either in an archival tissue sample or a new tumor biopsy. - Groups 1 and 2: At least 1 measurable lesion defined by the mRECIST 1.1 for patients with GIST. - Groups 1 and 2: A tumor sample (archival tissue or a new tumor biopsy) has been submitted for mutational testing. 4. Patient has Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-2., 5. Patient or legal guardian, if permitted by local regulatory authorities, provides informed consent to participate in the study.
Exclusion criteria
Exclusion criteria: 1. Patient has any of the following within 14 days prior to the first dose of study drug: a. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) > 3 × upper limit of normal (ULN) if no hepatic metastases are present; > 5 × ULN if hepatic metastases are present. b. Total bilirubin > 1.5 × ULN; >3 × ULN with direct bilirubin >1.5 × ULN in the presence of Gilbert*s Disease. c. Estimated (Cockcroft-Gault formula) or measured creatinine clearance <40 mL/min. d. Platelet count < 90 × 10e9/L. e. Absolute neutrophil count (ANC) < 1.0 ×10e9/L. f. Hemoglobin (Hgb) < 9 g/dL. Transfusion and erythropoietin may be used to reach at least 9 g/dL, but must have been administered at least 2 weeks prior to the first dose of study drug., 2. Patient received a prior anti-cancer drug less than 5 half-lives or 14 days (whichever is shorter) prior to the first dose of study drug., 3. Patient has received neutrophil growth factor support within 14 days of the first dose of study drug., 4. Patient requires therapy with a concomitant medication that is a strong inhibitor or strong inducer of cytochrome P450 34A. (see Appendix 2 of the protocol), 5. Patient has had a major surgical procedure (minor surgical procedures such as central venous catheter placement, tumor needle biopsy, and feeding tube placement are not considered major surgical procedures) within 14 days of the first dose of study drug., 6. Patient has a history of another primary malignancy that has been diagnosed or required therapy within 1 year prior to the first dose of study drug. (The following are exempt from the 1-year limit: completely resected basal cell and squamous cell skin cancer, curatively treated localized prostate cancer, and completely resected carcinoma in situ of any site.), 7. Patient has QT interval corrected using Fridericia*s formula (QTcF) > 450 milliseconds., 8. Patient has a history of a seizure disorder (e.g., epilepsy) or requirement for anti-seizure medication., 9. Patient has a history of a cerebrovascular accident or transient ischemic attacks within 1 year prior to the first dose of study drug. , 10. Patient has a known risk of intracranial bleeding, such as a brain aneurysm or history of subdural or subarachnoid bleeding., 11. Patient has a primary brain malignancy or metastases to the brain., 12. Patient has clinically significant, uncontrolled, cardiovascular disease, including congestive heart failure Grades II, III or IV according to the New York Heart Association (NYHA) classification, myocardial infarction or unstable angina within the previous 6 months, or poorly controlled hypertension., 13. Patient has a known diagnosis of human immunodeficiency virus infection or active viral hepatitis; viral testing is not required., 14. Patient is unwilling or unable to comply with scheduled visits, drug administration plan, laboratory tests, or other study procedures and study restrictions., 15. Women who are unwilling, if not postmenopausal or surgically sterile, to abstain from sexual intercourse or employ highly effective contraception during the study drug administration period and for at least 30 days after the last dose of study drug. , 16. Pregnant women, as documented by a serum beta human chorionic gonadotropin (* hCG) pregnancy te
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Part 1: - MTD and RP2D of avapritinib. - Overall safety profile of avapritinib, as assessed by the type, frequency, severity, timing, and relationship to study drug of any adverse events (AEs), serious adverse events (SAEs), and changes in vital signs, ECGs, and safety laboratory tests. Part 2: * ORR, defined as the rate of confirmed complete response (CR) or partial response (PR) by mRECIST version 1.1. * Overall safety profile of avapritinib, as assessed by the type, frequency, severity, timing, and relationship to study drug of any adverse events (AEs), serious adverse events (SAEs), and changes in vital signs, ECGs, and safety laboratory tests. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary Endpoints: - PK parameters of avapritinib: Maximum systemic concentration (Cmax), time to maximum systemic concentration (tmax), area under the systemic concentration versus time curve (AUC) from 0 to 24 hours (AUC0-24), area under the systemic concentration versus time curve from 0 to infinity (AUC0-*), apparent volume of distribution (Vd/F), terminal half-life (t*), apparent oral clearance (CL/F), accumulation factor (R), and correlation between PK parameters and safety findings of interest, including ECG intervals. * DOR; PFS; and CBR as per mRECIST version 1.1 . * Response rate as defined by Choi Criteria. * PFS on last prior anti-cancer therapy. * KIT, PDGFR*, and other cancer-relevant mutations present in tumor tissue at baseline and at EOT. * Change from baseline in the levels of KIT, PDGFR*, and other cancerrelevant mutant allele fractions in peripheral blood. Exploratory Endpoints: - Overall Survival (OS). - Correlation of baseline KIT and PDGFR* mutation status with antineoplastic activity. - Correlation of KIT and PDGFR* mutant allele fractions in ctDNA with antineoplastic activity. - Levels of exploratory blood and tumor markers. | — |
Countries
Netherlands
Outcome results
None listed