Clinical trial NCT04773782: A Study of Avapritinib in Pediatric Patients With Solid Tumors Dependent on KIT or PDGFRA Signaling
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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
PHASE2
Conditions: Solid Tumor, Unspecified, Child
Relapsed Solid Neoplasm
CNS Tumor
Keywords: KIT
PDGFRA
Relapsed/Refractory Solid Tumor
Glioma
H3K27M
DMG-H3K27a
Lead sponsor: Blueprint Medicines Corporation
Sponsor class: INDUSTRY
First posted: 2021-02-26
Enrollment: 37
Sex: ALL
Minimum age (years): 2
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This is a Phase 1/2, multicenter, open-label trial of avapritinib in participants 2 to \< 18 years of age with advanced relapsed/refractory (R/R) solid tumors, including central nervous system (CNS) tumors, that harbor a PDGFRA and/or KIT mutation (including non-synonymous point mutations, insertions, and deletions) or amplification, or DMG-H3K27a who have no available curative treatment options. This is a single-arm trial in which all participants 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).


Eligibility criteria: Inclusion Criteria

1. Participant must be 2 to \< 18 years of age at the time of signing the informed consent.
2. Diagnosis

   1. Participant has confirmed diagnosis of R/R solid tumor, including CNS tumors, with a mutation (including non-synonymous point mutations, insertions, and deletions) in PDGFRA and/or KIT (confirmed by local mutational testing of tumor sample) that has progressed despite standard therapy and no alternative treatment option is available. Participant with R/R solid tumors with only PDGFRA and/or KIT amplifications may be included with approval from the Sponsor.

      OR
   2. Participant has confirmed diagnosis of DMG-H3K27a (confirmed by local testing of tumor sample) that has failed standard therapy or for which no standard therapy that may convey clinical benefit exists, as judged by the investigator.
3. Participants with CNS disease should be on a stable (≤ 10% change) or decreasing dose of corticosteroids for at least 7 days prior to first dose of avapritinib, with no plans for dose escalation.
4. Disease extent: a. Part 1: All participants must have at least 1 measurable lesion as defined by RECIST v1.1 or Response Assessment in Neuro-Oncology (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 as per RANO and must be ≥ 12 weeks from radiation to any target lesion.

   b. Part 2: All participants must have at least 1 measurable lesion as defined by RECIST v1.1 or RANO (for CNS tumors). For Participants with DMG-H3K27a or PDGFRA and/or KIT mutant/amplified solid tumors, including CNS tumors that have progressed despite prior therapy, who have received radiation therapy, at least 1 measurable lesion must not have been irradiated, or must have clearly progressed since being irradiated as per RANO and must be ≥ 12 weeks from radiation to any target lesion. For up to 5 Participants with newly diagnosed DMG-H3K27a where there is no standard therapy that may convey clinical benefit exists as judged by the investigator, progression of disease of a measurable lesion after irradiation is not required.
5. A Lansky (\< 16 years of age) or Karnofsky (≥ 16 years of age) score of at least 50. If the Participant is unable to walk due to paralysis, but is mobile in a wheelchair, the participant is considered ambulatory for the purpose of assessing their performance status.
6. Participant agrees to utilize contraception consistent with local regulations.

   * Male participants: Are vasectomized, or agree to use condoms, as defined in Section 5.4.2, from the start of Screening until 6 weeks after the last dose of study treatment, or practice true abstinence (when this is in line with the preferred and usual lifestyle of the Participant, see Section 5.4.2), or have a female partner who is NOT of childbearing potential.
   * Female participants: Agree to use effective contraception, as defined in Section 5.4.2, from the start of Screening until 6 weeks after the last dose of study treatment and have a male partner who uses a condom, or practice true abstinence (when this is in line with the preferred and usual lifestyle of the Participant), or have a male partner who is vasectomized with confirmed azoospermia.
7. Participant can give written informed consent/assent before any study-specific Screening procedures (if feasible). Parental/legal guardian consent will be determined by local, regional, and/or national guidelines.

Exclusion Criteria

1. Participant has any of the following within 14 days before the first dose of study treatment:

   1. Platelet count \< 75 × 10\^9/L (\< 100 × 10\^9/L if a CNS tumor) with no platelet transfusion within 14 days prior to the measurement.
   2. Absolute neutrophil count (ANC) \< 1.0 × 10\^9/L.
   3. Hemoglobin \< 8.0 g/dL with no RBC transfusion ≤ 7 days prior to the measurement.
   4. AST or ALT \> 3 × the ULN for age; except in Participants with tumor involvement of the liver who must not have AST and ALT \> 5 × ULN for age.
   5. Total bilirubin \> 1.5 × ULN 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 or prothrombin time (PT) \> ULN (\> 1.5 × ULN if on prophylactic reversible anticoagulants).
2. Participant has a QTcF \> 470 msec. Participant has a familial or personal history of prolonged QT syndrome or Torsades de pointes.
3. Participant has clinically significant, uncontrolled cardiovascular disease including congestive heart failure Grade III or IV according to the New York Heart Association classification; myocardial infarction or unstable angina within the previous 6 months, uncontrolled hypertension (\> 95th 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).
4. Participant received the following systemic antineoplastic therapies:

   1. Temozolomide within 4 weeks prior to the first dose of study drug
   2. Nitrosurea within 6 weeks prior to the first dose of study drug
   3. Any other systemic antineoplastic therapy (including experimental therapy) within 5 half-lives or 28 days prior to the first dose of study drug, whichever is shorter.
   4. Focal external beam radiotherapy, including stereotactic radiosurgery, within 6 weeks prior to the first dose of avapritinib to either target or nontarget lesions. Systemic radiopharmaceuticals, including nonstereotactic radiosurgery, within 2 weeks of the first dose of avapritinib (within 6 weeks for Participants with CNS tumors). Craniospinal irradiation within 6 weeks prior to the first dose of avapritinib.
   5. All AEs related to other antineoplastic therapies (eg, systemic antineoplastics, radiotherapy) must have resolved to Grade ≤ 1 (Grade ≤ 2 for peripheral neuropathy and/or ototoxicity) prior to the first dose of avapritinib.
5. Participant has previously received treatment with avapritinib.
6. Participant received autologous stem cell transplant following myeloablative therapy or chimeric antigen receptor T cell therapy within 3 months prior to the first dose of avapritinib or prior allogeneic stem cell transplant 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). Participants who received stem cell reinfusion following nonmyeloablative therapy are eligible once they meet the peripheral blood count criteria in Exclusion Criterion #1.
7. Participant requires ongoing 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.
8. Participant 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).
9. Participant 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.
10. Female subjects of childbearing potential who are unwilling, if not postmenopausal 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.
11. Participant is pregnant, as documented by a serum β-hCG pregnancy test consistent with pregnancy obtained at Screening and within 72 hours before the first dose of study treatment. Participants with β-hCG values that are within the range for pregnancy but are not pregnant (false-positives) may be enrolled with written consent of the Sponsor after pregnancy has been ruled out. Female subjects of nonchildbearing potential (premenarchal, bilateral tubal ligation, bilateral oophorectomy, or hysterectomy) do not require a serum β-hCG test.
12. Participant is breastfeeding.
13. Participant 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 Participant; alter the absorption, distribution, metabolism, or excretion of the study drug; or impair the assessment of study results.
14. History of thrombosis requiring treatment within the past 6 months. This exclusion does not apply to catheter-related thrombosis if the catheter has been removed and did not require any other treatment in the previous 3 months.
15. Participants who require anticoagulants, with the exception of stable doses of prophylactic reversible anticoagulants.
16. Participants who are unable to swallow tablets (in Part 1) or minitablets (in Part 2) within the sprinkle capsules.
17. Participants 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: Participants with primary CNS tumors (provided they have not had CNS bleeding within 2 weeks of the first dose of avapritinib) or Participants with punctate hemorrhages \< 3 mm.
18. History of a seizure disorder that is not well controlled on current antiepileptic medications.
19. Participant is unwilling or unable to comply with scheduled visits, treatment administration plan, laboratory tests, or other study procedures and study restrictions.

Primary outcomes:
measure: Determination of recommended Part 2 dose (Part 1)
timeFrame: up to 8 months
measure: Objective Response Rate (Part 2)
timeFrame: up to 36 months
measure: Rate and severity of adverse events (Part 1)
timeFrame: up to 8 months
Secondary outcomes:
measure: Objective Response Rate (Part 1 and Part 2)
timeFrame: up to 42 months
measure: Rate and severity of adverse events (Part 1 and Part 2)
timeFrame: up to 42 months
measure: Palatability assessments as measured by the 5-point Hedonic scale (Part 1 and Part 2)
timeFrame: up to 42 months
measure: Duration of Response (Part 1 and Part 2)
timeFrame: up to 42 months
measure: Progression-free survival (Part 1 and Part 2)
timeFrame: up to 42 months
measure: Disease control rate (Part 1 and Part 2)
timeFrame: up to 42 months
measure: Time to response (Part 1 and Part 2)
timeFrame: up to 42 months
measure: Cmax (Part 1 and Part 2)
timeFrame: up to 36 months
measure: AUC(0-24) (Part 1 and Part 2)
timeFrame: up to 36 months
measure: Tmax (Part 1)
timeFrame: up to 36 months
measure: T 1/2 (Part 1)
timeFrame: up to 36 months
measure: Ctrough (Part 2)
timeFrame: up to 36 months
measure: Change from baseline in levels of KIT and PDGFRA mutant allele fractions in peripheral blood (Part 1 and Part 2)
timeFrame: up to 42 months
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Phoenix Children's Hospital
state: Arizona
city: San Francisco
country: United States
facility: University of California San Francisco, Benioff Children's Hospital
state: California
city: Aurora
country: United States
facility: Children's Hospital Colorado
state: Colorado
city: Chicago
country: United States
facility: Ann and Robert H. Lurie Children's Hospital of Chicago
state: Illinois
city: Baltimore
country: United States
facility: The Johns Hopkins Hospital
state: Maryland
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Columbus
country: United States
facility: Nationwide Children's Hospital
state: Ohio
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Pittsburgh
country: United States
facility: UPMC Children's Hospital of Pittsburgh
state: Pennsylvania
city: Dallas
country: United States
facility: Children's Medical Center
state: Texas
city: Houston
country: United States
facility: University of Texas MD Anderson Cancer Center
state: Texas
city: Sydney
country: Australia
facility: Sydney Children's Hospital, Kids Cancer Center
state: New South Wales
city: Parkville
country: Australia
facility: Royal Children's Hospital
state: Victoria
city: Wien
country: Austria
facility: Medizinische Universitat Wein
state: Vienna
city: Toronto
country: Canada
facility: The Hospital for Sick Children
state: Ontario
city: Villejuif
country: France
facility: Gustave Roussy
city: Göttingen
country: Germany
facility: Universitaetsmedizin Göttingen
state: Lower Saxony
city: Heidelberg
country: Germany
facility: Hopp Children's Cancer Center
city: Milan
country: Italy
facility: Dipartimento di Oncologia Medica ed Ematologia - S.C. Pediatria Oncologica
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Seoul
country: Korea, Republic of
facility: Samsung Medial Center
city: London
country: United Kingdom
facility: Great Ormond Street Hospital For Children
Study officials:
References: