| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| NTRK fusion cancers previously treated with a TRK inhibitor |
|
| E.1.1.1 | Medical condition in easily understood language |
| Solid tumors of all type, including primary CNS tumors |
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| 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 | 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 | 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.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Phase 1:
To determine the recommended dose for further study of oral Selitrectinib in 2 patient groups defined as age 12 years and older and age < 12 years with previously treated neurotrophic tyrosine kinase (NTRK) fusion cancers.
Phase 2:
To assess objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1), as determined by an independent radiology review (IRR) in documented NTRK fusion cancer patients previously treated with a TRK inhibitor who have progressed. |
|
| E.2.2 | Secondary objectives of the trial |
Phase 1:
-To characterize the pharmacokinetic (PK) properties of selitrectinib
-To characterize the safety and tolerability of selitrectinib.
-To assess objective response rate (ORR) according to best response by RECIST v1.1 as determined by Investigator, in patients with a documented NTRK fusion cancer previously treated with a tropomyosin receptor kinase (TRK) inhibitor.
-To assess ORR according to best response by Response Assessment in Neuro-Oncology (RANO), as determined by Investigator, in patients with primary central nervous system (CNS) malignancies with NTRK fusion.
Phase 2:
-To characterize the safety and tolerability of selitrectinib at the recommended Phase 2 dose (RP2D) in patients age 12 years and older and patients age < 12 years.
-To assess ORR determined by RECIST v1.1, as determined by an IRR in patients with NTRK fusion cancers who have discontinued prior TRK therapy due to intolerance and/or nonresponse |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Ability to understand and willingness to sign a written informed consent form (ICF). Signed ICF must be obtained prior to any study-specific procedures. Parent/guardian of child or adolescent subjects has the ability to understand, agree to, and sign the study ICF and applicable paediatric Assent form before initiation of any protocol related procedures; subject has the ability to give assent, as applicable, at the time of parental/guardian consent.
2.Advanced solid tumor for which, in the opinion of the Investigator, no other standard therapy offers greater benefit.
3.A solid tumor diagnosis in the setting of:
a.documented NTRK fusion and clinical history of relapse following a response to a prior TRK inhibitor
b.documented NTRK fusion unresponsive to prior TRK inhibitor
c.documented NTRK fusion and clinical history of intolerance to prior TRK inhibitor NTRK (NTRK1, NTRK2, and NTRK3) gene fusions will be identified in a CLIA certified (or equivalently-accredited diagnostic) laboratory. If such a report cannot be provided, other available certifications/accreditations are required and need to be documented.
4.ECOG score ≤ 2 in adults or KPS Score ≥ 50% (age ≥16 years ) or LPS ≥ 50% (age < 16yers)
5.Evaluable and/or measurable disease by RECIST v1.1, RANO or INRC.
6.Life expectancy of at least 3 months.
7.At least 1 mth of age.
8.Tissue submission. Samples from 2 time points required if available
9.Adequate hematologic function, for patients without known or suspected bone marrow involvement, defined as:
a. Hemoglobin (Hb) ≥ 8.0 g/dL
b. Absolute neutrophil count (ANC) ≥ 1.0 × 109/L
c. Platelets (Plt) ≥ 100 × 109 /L without need for regular transfusion support
Patients with known or suspected bone marrow involvement will not be evaluable for hematologic DLT and can enroll with:
a.Hb ≥8.0 g/dL (transfusions allowed)
b.ANC ≥0.75 × 109 /L
c.Plt ≥50 × 109 /L (transfusions allowed)
10.Adequate hepatic function defined as:
a.AST and ALT ≤2.5 × upper limit of normal (ULN) or ≤5 × ULN if in the setting of liver metastases
b.Total bilirubin ≤1.5 × ULN or ≤3 × ULN if in the setting of liver metastases or Gilbert's disease; patients with higher total bilirubin levels due to Gilbert's disease or hepatic metastases may be enrolled with Sponsor approval
11. Patients must have adequate blood clotting, as assessed by the following laboratory requirements to be conducted within 14 days before the first dose of study drug:
- International normalized ration (INR) ≤1.5 X ULN
- Activated partial thromboplastin time (aPTT) or partial thromboplastin time (PTT) ≤1.5 X ULN
-Patients on chronic anticoagulation therapy, including direct-acting oral anticoagulants, will be allowed to participate if there is no sign of active bleeding and PT/INR and aPTT or PTT test results are, at the investigator’s discretion, compatible with acceptable benefit-risk ratio
12.For patients age 18 yrs and older: Adequate renal function defined as serum creatinine ≤2.0 mg/dL or estimated glomerular filtration ≥30 mL/min using CKD-EPI equation. For patients between 1-18 years old: Estimated glomerular filtration rate≥30mL/minute/1.73 m2
based on the modified Schwartz formula.For patients <1 year old, the serum creatinine should be less than 97.5th percentile (approximately 2 standard deviations).
13.At least 5 half-lives since most recent larotrectinib or entrectinib dose. At least 5 halflives OR at least 7 days (whichever is longer) since last dose of other tyrosine kinase inhibitor. In case the most recent anticancer therapy was chemotherapy, immunotherapy, monoclonal antibody, other non kinase inhibitors or other anticancer treatment types, then the wash-out period should be 5 half-lives OR at least 21 days since last systemic anticancer therapy (whichever is shorter).
14. Patients with stable CNS primary tumor, brain metastases, or treated spinal cord compression are eligible if neurological symptoms have been stable for 7 days prior to the first dose of selitrectinib and there has been no change in steroid dose, if taking steroids to manage CNS symptoms, for 7 days prior to the first dose of selitrectinib. The patient can be receiving any dose of steroids as long as dosing meets specifications noted above.
15. Negative serum pregnancy test prior to C1D1 study drug if a woman of child-bearing potential. Pregnancy tests are not required for pre-pubertal (Tanner 1) girls, surgically sterilized women or post-menopausal women.
16. Agreement to adequate contraception in male and female patients with reproductive potential for the duration of treatment and for 3 mths following study completion.
17. Ability to swallow capsules or liquid suspension orally or receive liquid enterally via a naso- or gastro-feeding tube, and comply with outpatient treatment, laboratory monitoring, and required clinic visits for the duration of study participation. |
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| E.4 | Principal exclusion criteria |
1.Prior exposure to second generation TRK inhibitor (e.g. selitrectinib, repotrectinib (TPX0005), taletrectinib (DS-6501b/AB-106)). Exception is in case patient presented intolerance to the second generation TRK inhibitor agent and the duration of exposure was less than 28 days. No previous treatment with selitrectinib is allowed.
2. If received recent therapy, evidence of moderate-severe/uncontrolled toxicities that in the opinion of the investigator are limiting of subsequent therapy or unstable organ dysfunction due to previous treatment.
3. Concurrent treatment with a strong CYP3A4 inhibitor or inducer, consumption of grapefruit juice or Seville orange, or drugs associated with QT prolongation. The Investigator should review concomitant medications with their site pharmacist as the list can change frequently.
4. Clinically significant active cardiovascular disease or history of myocardial infarction within 3 months prior to planned start of Selitrectinib, cardiomyopathy; current or known history within the past 6 months of prolonged QTc interval >480 milliseconds. If there is a known explanation for a limited period of a prolonged QT interval (i.e., a medication known to cause prolonged QT interval was administered and has since been discontinued with clearly documented normal QT interval thereafter), that subject may be enrolled. If subject suffers from congestive heart failure, with onset more than 3 months prior to planned start of selitrectinib, then NYHA should be functional capacity I at maximum.
5. Major surgery within 7 days of enrollment. Catheter placement, endoscopic procedures, and dental surgery are not considred major surgery.
6. Uncontrolled systemic bacterial, fungal or viral infection. Infections treated with a stable dose of antimicrobial therapy for at least 7 days are allowed. Prophylactic antibiotics are allowed.
7. Pregnancy or lactation.
8. Known hypersensitivity to any of the components of the investigational agent, Selitrectinib or Ora-Sweet® SF and OraPlus®, for patients who will receive Selitrectinib suspension.
9. Known history of human immunodeficiency virus (HIV) infection. If previous test was collected more than 3 months prior to the first dose of study drug, then a new test must be performed up to 28 days prior to the study drug start using a blood test for HIV according to local regulations.
10. Hepatitis B (HBV) or C (HCV) infection. If previous test was collected more than 3 months prior to the first dose of study drug, then a new test must be performed screened for HBV and HCV up to 28 days prior to study drug start using the routine hepatitis virus laboratorial panel.
a. Patients positive for hepatitis B surface antigen (HBsAg) or Hepatitis B core antibody (HBcAb) will be eligible if they are negative for HBV-DNA, these patients should receive prophylactic antiviral therapy.
b. Patients positive for anti-HCV antibody will be eligible if they are negative for HCVRNA.
11. Any malabsorption condition.
12. Substance abuse, medical, psychological, or social conditions that may interfere with the patient's participation in the study or evaluation of the study results. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase 1:
Identification of MTD and/or recommended dose for further study of Selitrectinib in patients age 12 years and older and age < 12 years.
Phase 2:
ORR as determined by IRR using RECIST v1.1 in patients age 12 years and older and age < 12 years with documented NTRK fusion cancers and demonstration of progression following (or during receipt of) previous treatment with a TRK inhibitor. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Phase 1:
Every cohort from baseline until disease progression,unacceptable toxicity, patient's withdrawal of consent, or death.
Phase 2:
Approximately every 8 weeks for the first 12 cycles, then every 12 weeks while on treatment, and every 12 weeks after the last dose (for up to 2 years) in patients who have not progressed. |
|
| E.5.2 | Secondary end point(s) |
Phase 1:
Incidence, severity, and duration of AEs, including all, serious, and those considered treatment related.
Changes from baseline in clinical safety laboratory values and vital signs.
ORR as determined by the investigator in patients with a documented NTRK fusion cancer previously treated with a TRK inhibitor, using RECIST 1.1 for solid tumors.
ORR as determined by the treating Investigator using RANO in patients with primary CNS malignancies.
Overall survival (OS) defined as the number of months from the initiation of Selitrectinib to the date of death due to any cause.
To characterize the PK properties of Selitrectinib (Cmax, AUC(0-10), AUC(0-12) and AUC(0-24), if applicable..
Phase 2:
Incidence, severity, and duration of AEs, including all, serious, and those considered treatment related in patients age 12 years and older and age < 12 years
Changes from baseline in clinical safety laboratory values and vital signs.
ORR using RECIST v1.1 as determined by IRRin Cohort 2
ORR using RECIST v1.1 or RANO criteria as appropriate by Investigator in Cohort 1 and Cohort 2
Duration or response (DOR) will be determined for patients with best overall response of confirmed CR or PR by 1) an IRRand 2) the treating Investigator; DOR is defined as the number of months from the start of CR or PR (whichever response is recorded first) and subsequently confirmed to the first date that recurrent or progressive disease is documented, or death.
Progression-free survival (PFS) as determined by IRRand Investigator.
Overall survival (OS) Clinical benefit rate (CBR) as determined by IRR and Investigator.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Phase 1:
PK properties of Selitrectinib will be determined between C1D6 and C1D8
Phase 1 and Phase 2: EORTC QLQ-C30 and EQ-5D or PedsQL should be conducted at the same cycle visits as the disease assessment. |
|
| 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 | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| 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 |
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| 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.8.3 |
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 | 10 |
| 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 |
| Belgium |
| Canada |
| Denmark |
| France |
| Germany |
| Hong Kong |
| Ireland |
| Italy |
| Korea, Republic of |
| Singapore |
| Spain |
| 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 | 2 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | 21 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 21 |
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