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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Blueprint Medicines Corp.

Participant type

Pediatric, Patients

Age range

0-17 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

22 May 2022 → 21 Nov 2025

Decision date (initial)

2024-05-12

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Blueprint Medicines Corporation

External identifiers

EU CT number

2023-508617-16-00

EudraCT number

2020-005234-15

WHO UTN

U1111-1299-6672

ClinicalTrials.gov

NCT04773782

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Therapy, Pharmacokinetic, Safety, Pharmacodynamic

Part 1
- To determine the Part 2 recommended dose.
- To assess the safety and tolerability of avapritinib in pediatric patients.
Part 2
- To assess anti-tumor activity of avapritinib in pediatric patients by Response Evaluation Criteria in Solid Tumors (RECIST version [v]1.1 or Response Assessment in Neuro-Oncology (RANO)

Secondary objectives 6

1. Part 1 . To assess anti-tumor activity of avapritinib in pediatric patients by RECIST v1.1 or RANO
2. Part 2. To assess the safety and tolerability of avapritinib in pediatric patients.
3. Part 1 and Part 2. To assess anti-tumor activity of avapritinib in pediatric patients by RAPNO in patients with DMG and HGG, at institutions where assessment by RAPNO is performed.
4. Part 1 and Part 2. To assess DOR, PFS, and DCR of avapritinib in pediatric patients.
5. Part 1 and Part 2. To characterize the PKprofile of avapritinib and any clinically-relevant metabolites in pediatric patients.
6. Part 1 and Part 2. To characterize pharmacodynamic markers.

Conditions and MedDRA coding

Solid Tumors Dependent on KIT or PDGFRA Signaling

Regulatory references

EMA paediatric investigation plan (PIP)

EMEA-002358-PIP02-18

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 7

1. Patient must be 2 to < 18 years of age at the time of signing the informed consent.
2. Confirmed diagnosis of R/R solid tumor, including CNS tumors, with a mutation (including nonsynonymous point mutations, insertions, and deletions) in PDGFRA and/or KIT that has progressed despite standard therapy and no alternative treatment options are available. Patient with R/R solid tumors with only PDGFRA and/or KIT amplifications may be included with approval from the Sponsor OR 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 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 as per RANO and must be ≥ 12 weeks from radiation to any target lesion. This is missing the criterion for Part 2 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. Patients must have a Lansky (<16 years of age) or Karnofsky (≥16 years of age) score of at least 50.
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 19

1. Patient has any of the following within 14 days before the first dose of study treatment: a. 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. b. Absolute neutrophil count (ANC) <1.0 × 10*9/L. c. Hemoglobin <8.0 g/dL with no RBC transfusion ≤7 days prior to the measurement. d.AST or ALT >3 × the ULN for age; except in patients with tumor involvement of the liver who must not have AST and ALT >5 × ULN for age. e. Total bilirubin xULN for age; and in presence of Gilbert's syndrome, total bilirubin >3 × ULN or direct bilirubin > 1.5 × ULN. f. Serum creatinine >1.5 × ULN for age. g. International normalized ratio or prothrombin time (PT) >ULN (>1.5 × ULN if on prophylactic reversible anticoagulants).
2. Patient has a QTcF >470 msec. Patient has a familial or personal history of prolonged QT syndrome or Torsades de pointes.
3. Patient 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. Patient received the following systemic antineoplastic therapies: a. Temozolomide within 4 weeks prior to the first dose of study drug b. Nitrosurea within 6 weeks prior to the first dose of study drug c. 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. d. 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 patients with CNS tumors). Craniospinal irradiation within 6 weeks prior to the first dose of avapritinib. e. 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. Patient has previously received treatment with avapritinib.
6. Patient 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 graftversus-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.
7. Patient 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. 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).
9. 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.
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. Refer to Section 5.4.2 for acceptable methods of contraception.
11. Patient 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. Patients with β-hCG values that are within the range for pregnancy but are notpregnant (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. Patient is breastfeeding.
13. 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.
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. Patients who require anticoagulants, with the exception of stable doses of prophylactic reversible anticoagulants.
16. Patients who are unable to swallow tablets (in Part 1) or minitablets (in Part 2) within the sprinkle capsules.
17. 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 (provided they have not had CNS bleeding within 2 weeks of the first dose of avapritinib) or patients with punctate hemorrhages < 3 mm.
18. History of a seizure disorder that is not well controlled on current antiepileptic medications.
19. Patient is unwilling or unable to comply with scheduled visits, treatment administration plan, laboratory tests, or other study procedures and study restrictions.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. Part 1. Determination of the Part 2 recommended dose based on dose-limiting toxicity (DLT).
2. Part 1. Incidence and severity of adverse events
3. Part 2.Objective response rate (ORR)

Secondary endpoints 9

1. Part 1 ORR
2. Part 2. Incidence and severity of adverse events
3. Part 2. Palatability assessments as measured by the 5-point Hedonic scale
4. Part 1 and Part 2. DOR: median and estimated rate at 6 and 12 months
5. Part 1 and Part 2. PFS: median and estimated rate at 6 and 12 months
6. Part 1 and Part 2. DCR at 24 weeks
7. Part 1 and Part 2. Time to response
8. Part 1 and Part 2. Avapritinib PK parameters including maximum plasma concentration, time to maximum plasma drug concentration (Tmax), area under the plasma concentration-time curve from 0 to 24 hours (AUC0-24), terminal elimination half-life (T1/2), and plasma concentration-time profiles (AUCs)
9. Part 1 and Part 2. Change from baseline in levels of KIT and PDGFRA mutant allele fractions in peripheral blood at selected time points.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Blueprint Medicines Corp.

Sponsor organisation

Blueprint Medicines Corp.

Address

45 Sidney Street

City

Cambridge

Postcode

02139-4133

Country

United States

Scientific contact point

Organisation

Blueprint Medicines Corp.

Contact name

Medical Monitor

Public contact point

Organisation

Blueprint Medicines Corp.

Contact name

Medical Monitor

Third parties 7

Locations

4 EU/EEA countries · 5 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 62 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

3 submissions — initial application plus substantial / non-substantial modifications