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

• ClinicalTrials.gov Identifier: NCT04773782
• Recruitment Status: Recruiting
• First Posted: February 26, 2021
• Last Update Posted: February 21, 2023
• Sponsor: Blueprint Medicines Corporation
• Information provided by (Responsible Party): Blueprint Medicines Corporation

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 (Clinical Trial)
• Estimated 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: February 24, 2022
• Estimated Primary Completion Date: December 31, 2024
• Estimated Study Completion Date: April 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 Name: BLU-285

Outcome Measures

Primary Outcome Measures :

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

Secondary Outcome Measures :

1. Rate and severity of adverse events (Part 1 and Part 2) [ Time Frame: up to 42 months ]
2. Overall Response Rate (Part 2) [ Time Frame: Up to 36 months ]
3. Duration of Response (Part 2) [ Time Frame: up to 42 months ]
4. Progression-free survival (Part 2) [ Time Frame: up to 42 months ]
5. Disease control rate (Part 2) [ Time Frame: up to 42 months ]
6. Cmax (Part 1 and Part 2) [ Time Frame: up to 36 months ]
7. AUC(0-24) (Part 1 and Part 2) [ Time Frame: up to 36 months ]
8. Tmax (Part 1) [ Time Frame: up to 36 months ]
9. T 1/2 (Part 1) [ Time Frame: up to 36 months ]
10. Ctrough (Part 2) [ Time Frame: up to 36 months ]

Eligibility Criteria

• Ages Eligible for Study: 2 Years to 17 Years (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

  1. 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.

  2. 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:

  1. Platelet count <75 × 109/L (<100 × 109/L if a CNS tumor).
  2. Absolute neutrophil count (ANC) <1.0 × 109/L.
  3. Hemoglobin <8.0 g/dL (RBC transfusion ≥14 days before test is permitted to meet criterion).
  4. 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.

  5. 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.

  6. Serum creatinine >1.5 × ULN for age.
  7. 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:

  1. Systemic antineoplastic therapy (including experimental therapy within 5 half-lives or 28 days [6 weeks if prior nitrosurea], whichever is shorter).
  2. 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.
  3. 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

Contacts

Contact: Blueprint Medicines; 617-714-6707; medinfo@blueprintmedicines.com

Locations

United States, Arizona

Phoenix Children's Hospital; Recruiting

Phoenix, Arizona, United States, 85016

Principal Investigator: Lindsey Hoffman, DO

United States, California

University of California San Francisco, Benioff Children's Hospital; Recruiting

San Francisco, California, United States, 94518

Principal Investigator: Sabine Mueller, MD, PhD, MAS

United States, Colorado

Children's Hospital Colorado; Recruiting

Aurora, Colorado, United States, 80045

Principal Investigator: Kathleen Dorris, MD, MS

United States, Illinois

Ann and Robert H. Lurie Children's Hospital of Chicago; Recruiting

Chicago, Illinois, United States, 60611

Principal Investigator: Ashley Plant, MD

United States, Maryland

The Johns Hopkins Hospital; Recruiting

Baltimore, Maryland, United States, 21287

Principal Investigator: Kenneth J Cohen, MD

United States, Massachusetts

Dana Farber Cancer Institute; Recruiting

Boston, Massachusetts, United States, 02215

Principal Investigator: Susan Chi, MD

United States, Michigan

University of Michigan; Recruiting

Ann Arbor, Michigan, United States, 48109

Principal Investigator: Carl Koschmann, MD

United States, Missouri

Washington University School of Medicine; Recruiting

Saint Louis, Missouri, United States, 63110

Principal Investigator: Mohamed Abdelbaki, MD

United States, New York

Columbia University Medical Center; Recruiting

New York, New York, United States, 10032

Principal Investigator: Luca Szalontay, MD

United States, North Carolina

Duke University Medical Center; Recruiting

Durham, North Carolina, United States, 27710

Principal Investigator: Daniel Landi, MD

United States, Ohio

Nationwide Children's Hospital; Recruiting

Columbus, Ohio, United States, 43205

Principal Investigator: Margot Lazow, MD

United States, Oregon

Oregon Health and Science University; Recruiting

Portland, Oregon, United States, 97239

Principal Investigator: Yoon-Jae Cho, MD

United States, Pennsylvania

UPMC Children's Hospital of Pittsburgh; Recruiting

Pittsburgh, Pennsylvania, United States, 15224

Principal Investigator: James Felker, MD

United States, Texas

Children's Medical Center; Recruiting

Dallas, Texas, United States, 75235

Principal Investigator: Ashley Bui, MD

University of Texas MD Anderson Cancer Center; Recruiting

Houston, Texas, United States, 77030

Principal Investigator: Wafik Zaky, MD

Australia, New South Wales

Sydney Children's Hospital, Kids Cancer Center; Recruiting

Sydney, New South Wales, Australia, 2031

Principal Investigator: David Ziegler, MD

Australia, Victoria

Royal Children's Hospital; Recruiting

Parkville, Victoria, Australia, 3052

Principal Investigator: Dong Anh Khuong Quang, MD, PhD

Austria

Medizinische Universitat Wein; Recruiting

Wien, Vienna, Austria, 1090

Principal Investigator: Johannes Gojo, MD, PhD

Canada, Ontario

The Hospital for Sick Children; Recruiting

Toronto, Ontario, Canada, M5G1X8

Principal Investigator: Daniel Morgenstern, MB BChir, PhD

France

Gustave Roussy; Recruiting

Villejuif, France, 94805

Principal Investigator: Samuel Abbou, Ph.D

Germany

Universitaetsmedizin Göttingen; Recruiting

Göttingen, Lower Saxony, Germany, 37075

Principal Investigator: Christof Kramm, MD

Hopp Children's Cancer Center; Recruiting

Heidelberg, Germany

Principal Investigator: Cornelis Van Tilburg, MD

Italy

Dipartimento di Oncologia Medica ed Ematologia - S.C. Pediatria Oncologica; Recruiting

Milan, Italy, 20133

Principal Investigator: Michela Casanova, MD

Korea, Republic of

Asan Medical Center; Recruiting

Seoul, Korea, Republic of, 05505

Principal Investigator: Kyung-Nam Koh, MD, PhD

Samsung Medial Center; Recruiting

Seoul, Korea, Republic of, 06351

Principal Investigator: Ki Woong Sung, MD, PhD

Sponsors and Collaborators

Blueprint Medicines Corporation

More Information

• Responsible Party: Blueprint Medicines Corporation
• ClinicalTrials.gov Identifier: NCT04773782
• Other Study ID Numbers: BLU-285-3101
• First Posted: February 26, 2021
• Last Update Posted: February 21, 2023
• Last Verified: February 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Blueprint Medicines Corporation:

KIT; PDGFRA; Relapsed/Refractory Solid Tumor; Glioma; H3K27M

Additional relevant MeSH terms:

Neoplasms