A Study of Avapritinib in Pediatric Patients With Solid Tumors Dependent on KIT or PDGFRA Signaling

Sponsor

Blueprint Medicines Corporation (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04773782

Collaborator

(none)

Enrollment

Locations

Arm

38.1

Anticipated Duration (Months)

2.3

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is a Phase 1/2, multicenter, open-label trial of avapritinib in patients aged 2 to less than 18 years of age with with relapsed/refractory (R/R) solid tumors with mutations (including non-synonymous point mutations, insertions, and deletions) in KIT or PDGFRA, or gliomas with the H3K27M mutation, and no available alternative treatment options. This is a single-arm trial in which all patients will receive avapritinib. The study consists of 2 parts: dose confirmation, safety, and PK (Part 1) and initial efficacy, safety, and PK at the Part 2 recommended dose (Part 2).

Condition or Disease	Intervention/Treatment	Phase
Solid Tumor, Unspecified, Child Relapsed Solid Neoplasm CNS Tumor	Drug: avapritinib	Phase 1/Phase 2

Study Design

Study Type:

Interventional

Anticipated Enrollment :

37 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase 1/2, Single-arm Study to Evaluate the Safety, Pharmacokinetics, and Antitumor Activity of Avapritinib in Pediatric Patients With Solid Tumors Dependent on KIT or PDGFRA Signaling

Actual Study Start Date :

Feb 24, 2022

Anticipated Primary Completion Date :

Dec 31, 2024

Anticipated Study Completion Date :

Apr 30, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: avapritinib Avapritinib tablets for oral administration. Avapritinib will be dosed daily for 28 day cycles.	Drug: avapritinib oral administration Other Names: BLU-285

Arm

Intervention/Treatment

Experimental: avapritinib

Avapritinib tablets for oral administration. Avapritinib will be dosed daily for 28 day cycles.

Drug: avapritinib

oral administration

Other Names:

BLU-285

Outcome Measures

Primary Outcome Measures

Determination of recommended Part 2 dose (Part 1) [up to 8 months]
Overall Response Rate (Part 2) [up to 36 months]

Secondary Outcome Measures

Rate and severity of adverse events (Part 1 and Part 2) [up to 42 months]
Overall Response Rate (Part 2) [Up to 36 months]
Duration of Response (Part 2) [up to 42 months]
Progression-free survival (Part 2) [up to 42 months]
Disease control rate (Part 2) [up to 42 months]
Cmax (Part 1 and Part 2) [up to 36 months]
AUC(0-24) (Part 1 and Part 2) [up to 36 months]
Tmax (Part 1) [up to 36 months]
T 1/2 (Part 1) [up to 36 months]
Ctrough (Part 2) [up to 36 months]

Eligibility Criteria

Criteria

Ages Eligible for Study:

2 Years to 17 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Patient has confirmed diagnosis of a R/R solid or CNS tumor with a mutation in KIT or PDGFRA (confirmed by local mutational testing of tumor sample) that has progressed despite standard therapy and no alternative treatment option is available OR Confirmed diagnosis of H3K27M mutant glioma that has failed standard therapy or for which no standard therapy that may convey clinical benefit exists, as judged by the Investigator.
Patients with CNS disease should be on a stable dose (≤10% change) of corticosteroids for at least 7 days prior to first dose of avapritinib, with no plans for dose escalation.
Disease extent

Part 1: All patients must have at least 1 measurable lesion as defined by RECIST v1.1 or RANO (for CNS tumors). If radiation therapy has been administered, at least

1 measurable lesion must not have been irradiated, or must have clearly progressed since being irradiated.

Part 2: At least one measurable lesion as defined by RECIST v1.1 (RANO for CNS tumors). If radiation therapy has been administered, at least 1 measurable lesion must not have been irradiated within the previous 12 weeks, or must have clearly progressed since being radiated (per RANO). For up to 5 patients with H3K27M mutant gliomas where there is no standard therapy that may convey clinical benefit as judged by the investigator, progression of disease of a measurable lesion after irradiation is not required.

A Lansky (≤16 years of age) or Karnofsky (>16 years of age) score of at least 50. If the patient is unable to walk due to paralysis, but is mobile in a wheelchair, the patient is considered ambulatory for the purpose of assessing their performance status.
Patient agrees to utilize contraception consistent with local regulations

Exclusion Criteria:

Patient has any of the following within 14 days before the first dose of study treatment:

Platelet count <75 × 109/L (<100 × 109/L if a CNS tumor).
Absolute neutrophil count (ANC) <1.0 × 109/L.
Hemoglobin <8.0 g/dL (RBC transfusion ≥14 days before test is permitted to meet criterion).
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >3 × the upper limit of normal (ULN) for age; except in patients with tumor involvement of the liver who must not have AST and ALT >5 × ULN for age.
Total bilirubin >1.5 mg/dL for age; and in presence of Gilbert's syndrome, total bilirubin.

3 × ULN or direct bilirubin > 1.5 × ULN.

Serum creatinine >1.5 × ULN for age.
International normalized ratio (INR) or prothrombin time (PT) >ULN (>1.5 × ULN if on prophylactic reversible anticoagulants).

Patient has a QT interval corrected using Fridericia's formula (QTcF) >470 msec. Patient has a familial or personal history of prolonged QT syndrome or Torsades de pointes.
Patient has clinically significant, uncontrolled, cardiovascular disease including congestive heart failure Grade III or IV according to the New York Heart Association (NYHA) classification; myocardial infarction or unstable angina within the previous 6 months, uncontrolled hypertension (>99th percentile for age), or clinically significant, uncontrolled arrhythmias, including bradyarrhythmias that may cause QT prolongation (eg, Type II second degree heart block or third-degree heart block).
Patient received the following systemic antineoplastic therapies:

Systemic antineoplastic therapy (including experimental therapy within 5 half-lives or 28 days [6 weeks if prior nitrosurea], whichever is shorter).
Focal external beam radiotherapy, including stereotactic radiosurgery, within 6 weeks prior to the first dose of avapritinib to either target or non-target lesions. Systemic radiopharmaceuticals, including nonstereotactic radiosurgery, within 2 weeks of the first dose of avapritinib (within 6 weeks for patients with CNS tumors). Craniospinal irradiation within 12 weeks prior to the first dose of avapritinib.
All AEs related to other antineoplastic therapies (eg, systemic antineoplastics, radiotherapy) must have resolved to Grade ≤1 (Grade ≤2 for peripheral neuopathy and/or ototoxicity) prior to the first dose of avapritinib.

Patient has previously received treatment with avapritinib.
Patient received autologous stem cell transplant (SCT) following myeloablative therapy or chimeric antigen receptor T cell (CAR-T) therapy within 3 months prior to the first dose of avapritinib or prior allogeneic SCT within 1 year and no evidence of Grade 1 or greater graft-versus-host disease and no immunosuppressants for graft-versus-host disease (steroids for primary malignancy being permitted). Patients who received stem cell reinfusion following nonmyeloablative therapy are eligible once they meet the peripheral blood count criteria in Exclusion Criterion #1.
Patient requires on going treatment or has received treatment within 28 days before the start of avapritinib administration with drugs or foods that are strong CYP3A inhibitors or inducers or EIAEDs (eg, carbamazepine, phenytoin, phenobarbital, and primidone). Please refer to Appendix 1 for a list of these drugs and/or foods.
Patient has had a major surgical procedure within 14 days of the first dose of study treatment (procedures such as central venous catheter placement, tumor needle biopsy, and feeding tube placement are not considered major surgical procedures).
Patient has a history of another primary malignancy that has been diagnosed or required therapy within 3 years before the first dose of avapritinib. The following prior malignancies are not exclusionary: completely resected basal cell and squamous cell skin cancer, curatively treated localized prostate cancer, and completely resected carcinoma in situ of any site.
Female subjects of childbearing potential who are unwilling, if not post-menopausal or surgically sterile, to abstain from sexual intercourse or employ highly effective contraception from the time of informed consent and for at least 6 weeks after the last dose of study treatment. Male subjects who are unwilling, if not surgically sterile, to abstain from sexual intercourse or employ highly effective contraception from the time of informed consent and for at least 6 weeks after the last dose of study treatment. Refer to Section 5.4.2 for acceptable methods of contraception.
Patient is pregnant
Patient is breastfeeding.
Patient has prior or ongoing clinically significant illness, medical condition, surgical history, physical finding, or laboratory abnormality that, in the Investigator's opinion, could affect the safety of the patient; alter the absorption, distribution, metabolism, or excretion of the study drug; or impair the assessment of study results.
History of thrombosis requiring treatment within the past 6 months.
Patients who require anticoagulants, with the exception of stable doses of prophylactic reversible anticoagulants.
Patients who are unable to swallow tablets (in Part 1) or mini-tablets (in Part 2) within the sprinkle capsules.
Patients with a known risk of intracranial bleeding, such as a brain aneurysm that has not been removed or repaired, or a history of intracranial bleeding within the past year, or radiographic evidence of hemorrhage on Screening MRI. Exceptions are patients with primary CNS tumors who are eligible unless CNS bleeding has occurred within 2 weeks of the first dose of avapritinib and patients with punctate hemorrhages <3 mm.
History of a seizure disorder that is not well controlled on current antiepileptic medications. EIAEDs carbamazepine, phenytoin, phenobarbital, and primidone are prohibited.
Patient is unwilling or unable to comply with scheduled visits, treatment administration plan, laboratory tests, or other study procedures and study restrictions

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Phoenix Children's Hospital	Phoenix	Arizona	United States	85016
2	University of California San Francisco, Benioff Children's Hospital	San Francisco	California	United States	94518
3	Children's Hospital Colorado	Aurora	Colorado	United States	80045
4	Ann and Robert H. Lurie Children's Hospital of Chicago	Chicago	Illinois	United States	60611
5	The Johns Hopkins Hospital	Baltimore	Maryland	United States	21287
6	Dana Farber Cancer Institute	Boston	Massachusetts	United States	02215
7	University of Michigan	Ann Arbor	Michigan	United States	48109
8	Washington University School of Medicine	Saint Louis	Missouri	United States	63110
9	Oregon Health and Science University	Portland	Oregon	United States	97239
10	Children's Medical Center	Dallas	Texas	United States	75235
11	Medizinische Universitat Wein	Wien	Vienna	Austria	1090
12	The Hospital for Sick Children	Toronto	Ontario	Canada	M5G1X8
13	Universitaetsmedizin Göttingen	Göttingen	Lower Saxony	Germany	37075
14	Dipartimento di Oncologia Medica ed Ematologia - S.C. Pediatria Oncologica	Milan		Italy	20133
15	Asan Medical Center	Seoul		Korea, Republic of	05505
16	Samsung Medial Center	Seoul		Korea, Republic of	06351