| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Pediatric Patients with Advanced RET-Altered Solid or Primary Central Nervous System Tumors |
|
| E.1.1.1 | Medical condition in easily understood language |
| Pediatric patients with an activating RET alteration and an advanced solid or primary Central Nervous System (CNS) Tumors |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10007958 |
| E.1.2 | Term | Central nervous system neoplasm |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10007959 |
| E.1.2 | Term | Central nervous system neoplasm NOS |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10049516 |
| E.1.2 | Term | Malignant tumor |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | HLT |
| E.1.2 | Classification code | 10007960 |
| E.1.2 | Term | Central nervous system neoplasms malignant NEC |
| E.1.2 | System Organ Class | 100000004852 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10027105 |
| E.1.2 | Term | Medullary thyroid cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
PHASE 1
The primary objective is to determine the safety profile, including dose-limiting toxicities (DLTs), of the oral RET inhibitor Selpercatinib.
PHASE 2
To determine the objective response rate (ORR) as determined by an Independent Review Committee (IRC) and measured by the proportion of patients with best overall confirmed response of complete response (CR) or partial response (PR) by Response Evaluation Criteria in Solid Tumors, version 1.1(RECIST v 1.1), or Response Assessment in Neuro-Oncology (RANO) criteria, as appropriate, following treatment with Selpercatinib. |
|
| E.2.2 | Secondary objectives of the trial |
PHASE1 •characterize Selpercatinib PK properties •identify MTD and/or the RP2D Selpercatinib dose •ORR and CBR based on RECIST 1.1 or RANO as appropriate to tumor type as determined by an IRC and treating investigator
PHASE 2 •determine: -ORR using RECIST1.1 or RANO criteria -DOR in patients with best overall response of CR or PR -PFS duration following Selpercatinib initiation -OS following Selpercatinib initiation -CBR based on proportion of patients with best overall response of CR, PR or stable disease lasting ≥16 weeks •assess Selpercatinib safety profile, tolerability •characterize Selpercatinib PK properties in pediatric patients •evaluate concordance of prior molecular profiling that detected an activating RET alteration within the tumor •characterize post-operative staging and surgical margin status in patients who have definitive surgery following Selpercatinib treatment •evaluate change from baseline in patient-reported pain at BOR visit (Wong-Baker Faces Scale). |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Pediatric patients ≥ 12 years of age and ≤ 21 years of age at Cycle 1 Day 1 (C1D1) with a locally advanced or metastatic solid or primary CNS tumor that has relapsed, progressed or was nonresponsive to available therapies and/or for which no standard or available systemic curative therapy exists.
a) Patients with locally advanced disease who would require, in the opinion of the Investigator, disfiguring surgery or limb amputation to achieve a complete surgical resection are also eligible.
b) In geographies where a selective RET-inhibitor is approved, patients may enroll without prior systemic treatment.
2. Evidence of an activating RET gene alteration in tumor and/or blood as identified through molecular assays, as performed for clinical evaluation.
3. Patients with primary CNS tumors or cerebral metastasis:
a) Must be neurologically stable based on stable neurologic exam for 7 days prior to enrollment
b) Must have not required increasing doses of steroids within the 7 days prior to enrolmentto manage CNS symptoms
4. Imaging study must be performed within 28 days of C1D1 while on stable dose steroid medication (if needed) for at least 7 days immediately before the imaging study.
5. Histologic verification of malignancy at original diagnosis or relapse, except in patients with intrinsic brain stem tumors, optic pathway gliomas, or patients with pineal tumors and elevations of cerebral spinal fluid (CSF) or serum tumor markers including alpha-fetoprotein or beta-human chorionic gonadotropin (HCG).
6. Must have measurable or non-measurable but evaluable disease.
7. Karnofsky (patients 16 years and older) or Lansky (patients younger than 16 years) performance score of at least 50.
8. Must have fully recovered from the acute toxic effects of all prior anti-cancer chemotherapy to CTCAE (v5.0) Grade ≤ 2.
9. An archival (FFPE or fresh frozen) or fresh tumor tissue sample must be available (refer to Section 7.5 of the protocol).
10. Adequate hematologic status, defined as:
a) Absolute neutrophil count (ANC) ≥1.0× 10^9/L not requiring growth factor support for at least 7 days prior to treatment.
b) Platelet count ≥ 75 × 10^9/L not requiring transfusion support for at least 7 days prior to treatment.
c) Hemoglobin (Hb) ≥ 8 mg/dL not requiring transfusion support or erythropoietin for at least 7 days prior to treatment.
11. Adequate hepatic/pancreatic function, defined as:
a) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × the upper limit of normal (ULN) or ≤ 5 × ULN with documented liver involvement (such as liver metastasis or a primary biliary tumor), and
b) Total bilirubin ≤ 1.5 × ULN or ≤ 3 × ULN with documented liver involvement (patients with Gilbert's Disease may be enrolled with prior Sponsor approval)
12. Adequate renal function, defined as:
a) Estimated glomerular filtration rate ≥ 30 mL/min/1.73 m2 based on local institutional practice for determination, or a maximum serum creatinine by age and gender as presented in Synopsis Table 2.
13. Ability to comply with outpatient treatment, laboratory monitoring, and required clinic visits for the duration of study participation.
14. Willingness of male and female patients with reproductive potential to utilize double effective birth control methods
15. Ability to swallow capsules, liquid suspension, or gastric access via a naso- or gastric tube.
16. The Patient and, when applicable the parent/guardian of child or adolescent patient has the ability to understand, agree to, and sign the study Informed Consent Form (ICF) and applicable Pediatric Assent Form before initiation of any protocol-related procedures; patient has the ability to give assent, as applicable, at the time of parental/guardian consent. |
|
| E.4 | Principal exclusion criteria |
1. Major surgery within 2 weeks prior to C1D1.
2. Clinically significant active cardiovascular disease or history of myocardial infarction within 6 months prior to C1D1; ongoing cardiomyopathy; or current prolonged QT interval corrected for heart rate (QTc) interval > 440 milliseconds for patients ≤ 15 years old and > 470 milliseconds for patients > 15 years old. For patients ≤ 15 years old, Bazett's Formula will be utilized to determine QTc. For patients > 15 years old, either method, Fridericia or Bazett's Formula may be applied.
3. Active uncontrolled systemic bacterial, viral, or fungal infection, which in the opinion of the Investigator makes the risk: benefit ratio for the patient to participate in the trial unfavorable.
4. Clinically significant active malabsorption syndrome or other condition likely to affect gastrointestinal absorption of the study drug.
5. Pregnancy or lactation.
6. Uncontrolled hypotension or hypertension ≥ Grade 3 CTCAE (v 5.0).
7. Uncontrolled symptomatic hyperthyroidism or hypothyroidism (i.e. the patient required a modification to current thyroid medication in the 7
days before start of selpercatinib).
8. Uncontrolled symptomatic hypercalcemia or hypocalcemia.
9. (removed)
10. Known hypersensitivity to any of the components of the investigational agent, selpercatinib or Ora-Sweet® SF and OraPlus®, for patients who will receive selpercatinib suspension.
11. (removed)
12. (removed) |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
PHASE 1
1. Frequency, severity and relatedness of TEAEs and SAEs, including DLTs in pediatric patients receiving selpercatinib
PHASE 2
1. ORR based on RECIST v 1.1 or RANO as appropriate to tumor type as determined by an IRC |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
PHASE 1:
1. From the time of informed consent, for approx.24 months (or earlier if the patient discontinues from the study), and through Safety FU (28 days after the last dose). DLTs during the first 28-day cycle of selpercatinib treatment
PHASE 2:
1. approximately every 8 weeks for one year, then every 12 weeks, 7 days after the last dose (for up to 2 years) in patients who have not progressed.
|
|
| E.5.2 | Secondary end point(s) |
PHASE 1:
1. Plasma concentrations of selpercatinib and PK parameters, including, but not limited to area under the concentration versus time curve from time 0 to 24 hours (AUC0-24), maximum drug concentration (Cmax), time to maximum plasma concentration (Tmax), degree of accumulation, and other characterizations
2. The MTD and/or the RP2D of selpercatinib in pediatric patients
3. ORR and CBR based on RECIST 1.1 or RANO as appropriate to tumor type as determined by an IRC and treating investigator
PHASE 2
1. ORR based on RECIST v 1.1 or RANO as appropriate to tumor type per the treating Investigator’s response assessment
2. DOR (IRC and treating Investigator)
3. PFS (IRC and treating Investigator)
4. OS
5. CBR (IRC and treating Investigator)
6. Frequency, severity, and relatedness of TEAEs and SAEs, changes in hematology and blood chemistry values, and assessments of physical examinations, vital signs, and ECGs
7. Plasma concentrations of selpercatinib and PK parameters, including, but not limited to AUC 0-24, Cmax, Tmax, degree of accumulation, and other characterizations
8. The percent positive agreement between prior molecular profiling that detected a RET alteration within the patient's tumor and diagnostic test(s) being evaluated by the Sponsor
9. Number of patients with putative pretreatment surgical plan and the actual post treatment approach with an emphasis on the functional and cosmetic outcome
10. Change from baseline in patient-reported pain at BOR visit as assessed by the Wong-Baker Faces Scale. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
PHASE 1:
1.Day 1 & 8 of Cycle 1, Day 1 of Cycle 3 and Day 8 after Intra-patient Dose Escalation
2.MTD: Day 1 & 8 of Cycle 1, Day 1 of Cycle 3 and Day 8 after Intra-patient Dose Escalation
2.RP2D: first 28 days of treatment (Cycle 1) and every cycle for approx.12 months
3.Approx.every 8 weeks for one year, then every 12 weeks, 7 days after the last dose (for up to 2 years) in patients who have not progressed
4.Up to 24 months
PHASE 2:
1-5.Approx. every 8 weeks for one year, then every 12 weeks, and 7 days after the last dose (for up to 2 years) in patients who have not progressed.
6.From the time of informed consent, for approx.24 months (or earlier if the patient discontinues from the study), and through Safety FU (28 days after the last dose)
7.6months
8.6months
9.6months |
|
| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| 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 |
| Canada |
| Denmark |
| France |
| Germany |
| Italy |
| Japan |
| Spain |
| United Kingdom |
| United States |
|
| 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
|
| Individual patients will continue dosing until PD, unacceptable toxicity, or other reason for treatment discontinuation. It is anticipated that a patient on this study will receive treatment with open-label selpercatinib until the patient does not meet criteria requiring discontinuation of treatment, and the patient’s participation in the study has not ended. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 26 |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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