JOURNAL ONKOLOGIE – STUDIE

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

Studien-Informationen Einschlusskriterien Studien-Rationale Geprüfte Regime

Rekrutierend

NCT-Nummer:
NCT04773782

Studienbeginn:
Februar 2022

Letztes Update:
15.06.2023

Wirkstoff:
Avapritinib

Indikation (Clinical Trials):
Neoplasms

Geschlecht:
Alle

Altersgruppe:
Kinder (0-17)

Phase:
-

Sponsor:
Blueprint Medicines Corporation

Collaborator:
-

Kontakt

Blueprint Medicines
Kontakt:
Phone: 617-714-6707
E-Mail: medinfo@blueprintmedicines.com» Kontaktdaten anzeigen

Studienlocations
(3 von 26)

Universitaetsmedizin Göttingen
37075 Göttingen
(Niedersachsen)
GermanyRekrutierend» Google-Maps

Hopp Children's Cancer Center
Heidelberg
(Baden-Württemberg)
GermanyRekrutierend» Google-Maps

Phoenix Children's Hospital
85016 Phoenix
United StatesRekrutierend» Google-Maps

University of California San Francisco, Benioff Children's Hospital
94518 San Francisco
United StatesRekrutierend» Google-Maps

Children's Hospital Colorado
80045 Aurora
United StatesRekrutierend» Google-Maps

Ann and Robert H. Lurie Children's Hospital of Chicago
60611 Chicago
United StatesRekrutierend» Google-Maps

The Johns Hopkins Hospital
21287 Baltimore
United StatesRekrutierend» Google-Maps

Dana Farber Cancer Institute
02215 Boston
United StatesRekrutierend» Google-Maps

University of Michigan
48109 Ann Arbor
United StatesRekrutierend» Google-Maps

Washington University School of Medicine
63110 Saint Louis
United StatesRekrutierend» Google-Maps

Columbia University Medical Center
10032 New York
United StatesRekrutierend» Google-Maps

Duke University Medical Center
27710 Durham
United StatesRekrutierend» Google-Maps

Nationwide Children's Hospital
43205 Columbus
United StatesRekrutierend» Google-Maps

Oregon Health and Science University
97239 Portland
United StatesRekrutierend» Google-Maps

UPMC Children's Hospital of Pittsburgh
15224 Pittsburgh
United StatesRekrutierend» Google-Maps

Children's Medical Center
75235 Dallas
United StatesRekrutierend» Google-Maps

University of Texas MD Anderson Cancer Center
77030 Houston
United StatesRekrutierend» Google-Maps

Sydney Children's Hospital, Kids Cancer Center
2031 Sydney
AustraliaRekrutierend» Google-Maps

Royal Children's Hospital
3052 Parkville
AustraliaRekrutierend» Google-Maps

Medizinische Universitat Wein
1090 Wien
AustriaRekrutierend» Google-Maps

The Hospital for Sick Children
M5G1X8 Toronto
CanadaRekrutierend» Google-Maps

Gustave Roussy
94805 Villejuif
FranceRekrutierend» Google-Maps

Dipartimento di Oncologia Medica ed Ematologia - S.C. Pediatria Oncologica
20133 Milan
ItalyRekrutierend» Google-Maps

Asan Medical Center
05505 Seoul
Korea, Republic ofRekrutierend» Google-Maps

Samsung Medial Center
06351 Seoul
Korea, Republic ofRekrutierend» Google-Maps

Great Ormond Street Hospital For Children
WC1N 3JH London
United KingdomRekrutierend» Google-Maps

Alle anzeigen

Studien-Informationen

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).

Ein-/Ausschlusskriterien

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.

Studien-Rationale

Primary outcome:

1. Determination of recommended Part 2 dose (Part 1) (Time Frame - up to 8 months)

2. Objective Response Rate (Part 2) (Time Frame - up to 36 months)

3. Rate and severity of adverse events (Part 1) (Time Frame - up to 8 months)

Secondary outcome:

1. Objective Response Rate (Part 1 and Part 2) (Time Frame - up to 42 months)

2. Rate and severity of adverse events (Part 1 and Part 2) (Time Frame - up to 42 months)

3. Palatability assessments as measured by the 5-point Hedonic scale (Part 1 and Part 2) (Time Frame - up to 42 months)

4. Duration of Response (Part 1 and Part 2) (Time Frame - up to 42 months)

5. Progression-free survival (Part 1 and Part 2) (Time Frame - up to 42 months)

6. Disease control rate (Part 1 and Part 2) (Time Frame - up to 42 months)

7. Time to response (Part 1 and Part 2) (Time Frame - up to 42 months)

8. Cmax (Part 1 and Part 2) (Time Frame - up to 36 months)

9. AUC(0-24) (Part 1 and Part 2) (Time Frame - up to 36 months)

10. Tmax (Part 1) (Time Frame - up to 36 months)

11. T 1/2 (Part 1) (Time Frame - up to 36 months)

12. Ctrough (Part 2) (Time Frame - up to 36 months)

13. Change from baseline in levels of KIT and PDGFRA mutant allele fractions in peripheral blood (Part 1 and Part 2) (Time Frame - up to 42 months)

Geprüfte Regime

avapritinib (BLU-285):
oral administration

Quelle: ClinicalTrials.gov

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