| 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 |
|
| 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: Assessment of:
- PK properties of selitrectinib
- Safety and tolerability of selitrectinib .
- ORR according to best response by RECIST v1.1, as determined by an investigator, in patients with a documented NTRK fusion cancer previously treated with a TRK inhibitor.
- ORR determined by the Investigator using RANO in patients with primary CNS malignancies with NTRK fusion.
Phase 2: Assessment of:
- Safety and tolerability of selitrectinib at the RP2D in patients age 12 and older and patients age < 12.
- ORR determined by an IRR in patients with NTRK fusion cancers who have discontinued prior TRK therapy due to intolerance and/or nonresponse
- ORR determined by RECIST v1.1 or RANO as appropriate by Investigator in patients with NTRK fusion cancers who have discontinued prior TRK therapy due to disease progression or intolerance and/or non response.
- additional parameters including: DOR, PFS, OS, Clinical benefit rate (CBR). |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Ability to understand and the willingness to sign a written informed consent. A signed informed consent must be obtained prior to any study specific procedures.
2. Advanced solid tumour for which, in the opinion of the Investigator, no other standard therapy offers greater benefit.
3. A solid tumour diagnosis in the setting of:
a. a documented NTRK fusion and a clinical history of relapse following a
response to a prior TRK inhibitor
b. a documented NTRK fusion unresponsive to a prior TRK inhibitor
c. a documented NTRK fusion and a clinical history of intolerance to a prior TRK inhibitor
A list of agents with known TRK inhibitor activity is provided in Appendix A. Other agents not listed may also be considered upon Sponsor review. 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. Acceptable methods of detection of NTRK fusion include NGS, fluorescence in situ hybridization (FISH), real-time polymerase chain reaction (RT-PCR) with the following documented in a written report:
• For NGS, the report indicates that a fusion was detected between an NTRK gene (NTRK1, NTRK2, or NTRK3) and a specific partner gene.
• For FISH, the report indicates that a probe mapping to an NTRK gene (NTRK1, NTRK2, or NTRK3) and/ or a probe mapping to a specific partner gene were found to be colocalized by microscopy.
• For RT-PCR, the report indicates that a pair of primers targeting an NTRK gene (NTRK1, NTRK2, or NTRK3) on one end and a specific partner gene on the other end amplified a detectable target.
If enrolling a patient based on the pan-TRK IHC result, documentation of NTRK fusion must be provided using NGS. If enrolling a patient based on FISH result, additional documentation of NTRK fusion using NGS is preferred.
Exception: Patients with infantile fibrosarcoma (IFS) or congenital mesoblastic nephroma (CMN) may be enrolled based on confirmation of an ETV6 aberration without an identified partner gene (for example, patients may have been diagnosed with IFS or CMN based on an ETV6+ FISH test without identifying [or testing] for NTRK3).
4. Performance Status: Eastern Cooperative Oncology Group (ECOG)
score ≤ 2 (in adults), Karnofsky Performance Status (KPS) ≥ 50% (age
≥ 16 years) or Lansky Performance Score (LPS) ≥ 50% (age < 16
years).
5. Evaluable and/or measurable disease by RECIST v1.1 or RANO or INRC.
6. Life expectancy of at least 3 months.
7. At least 1 month of age.
8. Tissue submission. Samples from 2 time points are required if available.
a. Tumour sample obtained after patient progression on therapy with last kinase inhibitor with anti TRK activity prior to consenting for this trial. A fresh biopsy in this setting is preferred if it can be safely obtained or this may be an archived sample. See Section 7.6.3 for specifics.
b. Archived tumour tissue sample obtained prior to when patient started on the first anti-TRK therapy.
If the site has tissue from both time points, but will only provide tissue from 1 time point, the sample obtained post-progression on the last anti- TRK therapy is preferred. If no tumour tissue samples from either time point are available, the patient may still be eligible with Sponsor approval.
9. Adequate hematologic function, for patients without known or suspected bone marrow involvement, defined as in Section 4.1
10. Adequate hepatic function defined as in Section 4.1
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 ratio (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 years and older: Adequate renal function defined as serum creatinine ≤ 2.0 mg/dL or estimated glomerular filtration ≥ 30 mL/min using Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation.
13. At least 5 half-lives since most recent kinase inhibitor dose OR at least 7 days since last systemic anticancer therapy (whichever is shorter) and recovered to baseline from all toxicity of last cytotoxic
chemotherapy dose and/or anticancer treatment, including TRK inhibitor. Alopecia and other non-acute toxicities are acceptable.
|
|
| E.4 | Principal exclusion criteria |
1. Prior exposure to second generation TRK inhibitor ((e.g. selitrectinib, repotrectinib (TPX-0005), 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 (Appendix K).
5.Major surgery within 7 days of enrollment. Catheter placement, endoscopic procedures, and dental surgery are not considered 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 take the selitrectinib suspension. Please refer to Appendix H for the complete list of ingredients for Ora-Sweet® SF and Ora-Plus®.
9. Known history of human immunodeficiency virus (HIV). Refer to
Section 4.2 Exclusion Criteria of the protocol for additional details.
10. Hepatitis B (HBV) or C (HCV) infection. Refer to Section 4.2 Exclusion Criteria of the protocol for additional details.
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.
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 an IRR in 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 IRR and 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 an IRR and Investigator.
Overall survival (OS) Clinical benefit rate (CBR) as determined by an IRR and Investigator.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Phase 1:
PK properties of LOXO-195 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 |
|
| 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 |
| Canada |
| Hong Kong |
| Korea, Republic of |
| Singapore |
| United States |
| Belgium |
| Denmark |
| France |
| Germany |
| Ireland |
| Italy |
| Spain |
| United Kingdom |
|
| 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
|
|
| 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 | 1 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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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