| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Solid Tumors Dependent on KIT or PDGFRA Signaling |
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| E.1.1.1 | Medical condition in easily understood language |
| Certain genetically defined pediatric solid tumors |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Part 1
- To determine the Part 2 recommended dose of avapritinib as a single agent in pediatric patients 2 to <18 years of age with advanced solid tumors, including CNS tumors, harboring PDGFRA and/or KIT mutations (including nonsynonymous point mutations, insertions, and deletions) or amplifications, or DMG-H3K27a.
- 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 v1.1 or Response Assessment in Neuro-Oncology (RANO). |
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| E.2.2 | Secondary objectives of the trial |
Part 1
- To assess anti-tumor activity of avapritinib in pediatric patients by RECIST v1.1 or RANO.
Part 1 and Part 2
- To assess the safety and tolerability of avapritinib in pediatric patients (Part 2).
- To assess the anti-tumor activity of avapritinib in pediatric patients by Response Assessment in Pediatric Neuro-Oncology (RAPNO) in patients with DMG and HGG, at institutions where assessment by RAPNO is performed.
- To assess duration of response (DOR), progression-free survival, and disease control rate (DCR) of avapritinib in pediatric patients.
- To characterize the pharmacokinetic (PK) profile of avapritinib and any clinically-relevant metabolites in pediatric patients.
- To characterize pharmacodynamic markers. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Patient is 2 to <18 years of age at the time the parent/guardian signs the Informed Consent Form.
- Confirmed diagnosis of R/R solid tumor, including CNS tumor, 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
Confirmed diagnosis of DMG-H3K27a that has failed standard therapy or for which no standard therapy that may convey clinical benefit exists, as judged by the Investigator.
- 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 as per RANO and must be ≥ 12 weeks from radiation to any target lesion.
-Part 2: All patients must have at least 1 measurable lesion as defined by RECIST v1.1 or RANO (for CNS tumors). For patients 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 patients 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.
- Patients with CNS disease should be on a stable dose of corticosteroids for at least 7 days prior to first dose of avapritinib, with no plans for dose escalation.
- Patients must have a Lansky (<16 years of age) or Karnofsky (≥16 years of age) score of at least 50. |
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| E.4 | Principal exclusion criteria |
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 (NYHA) 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 os 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 (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 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). 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.
Please Refer to protocol for further information.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Determination of recommended Part 2 dose (Part 1)
Objective Response Rate (Part 2) |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Determination of recommended Part 2 dose (Part 1): up to 8 months
2. Objective Response Rate (Part 2): up to 36 months |
|
| E.5.2 | Secondary end point(s) |
1. ORR (Part 1 and 2)
2. Incidence and severity of AEs and SAEs (Part 1 and Part 2)
3. DOR (Part 2)
4. PFS (Part 2)
5. DCR (Part 2)
6. Cmax (Part 1 and Part 2)
7. AUC(0-24) (Part 1 and Part 2)
8. Tmax (Part 1)
9. T 1/2 (Part 1)
9. Ctrough (Part 2)
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Objective Response Rate (ORR) (Part 1 and 2) up to 42 months
2. Incidence and severity of AEs and SAEs (Part 1 and Part 2) up to 42 months
3. Duration of Response (Part 2): up to 42 months
4. Progression-free survival (Part 2) up to 42 months
5. Disease Control Rate (Part 2) : up to 42 months
6. Cmax (Part 1 and Part 2) : up to 36 months
7. AUC(0-24) (Part 1 and Part 2) : up to 36 months
8. Tmax (Part 1): up to 36 months
9. T 1/2 (Part 1): up to 36 months
10. Ctrough (Part 2) : up to 36 months |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
|
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 6 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Austria |
| Canada |
| Denmark |
| France |
| Germany |
| Italy |
| Korea, Republic of |
| United Kingdom |
| United States |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
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