| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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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 | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10065252 |
| E.1.2 | Term | Solid tumor |
| E.1.2 | System Organ Class | 100000004864 |
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| 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 2 Study
• Determine the antitumor activity of repotrectinib in pediatric and young adult subjects with advanced or metastatic malignancies harboring ALK, ROS1 or NTRK1-3 alterations. |
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| E.2.2 | Secondary objectives of the trial |
• Determine the antitumor activity in terms of DOR, overall survival (OS) and progression-free survival (PFS) following treatment with repotrectinib
• Determine intracranial antitumor activity of repotrectinib
• Evaluate the safety and tolerability of repotrectinib at the pediatric RP2D
• Characterize the PK of repotrectinib at the pediatric RP2D
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Phase 2: EU will not participate in Cohort 1.
Cohort 2: Subjects with NTRK+ advanced solid tumors (including primary CNS tumors), TRK TKI-pretreated. Nonresponse, disease progression or intolerability to at least 1 but no more than 2 prior TRK TKIs. Any prior lines are allowed.
Cohort 3: in the EU: (1) subjects with NTRK fusions without centrally confirmed measurable disease but otherwise eligible for Cohort 2, and (2) subjects with ROS1 fusions.
•Documented genetic ALK, ROS1, or NTRK1-3 alteration as identified by local testing in a CLIA laboratory in the US or equivalent.
•For subjects enrolled per tissue-based test, adequate tumor tissue should be sent prior to enrollment to the central lab. If archived tumor tissue is not available, a fresh biopsy should be obtained.
For subjects enrolled by liquid biopsy test; blood samples should be sent prior to enrollment to the central lab.
2.Subjects must have recovered from the acute toxic effects of all previous therapies prior to study enrollment to CTCAE v4.03 criteria ≤grade 1, with the exception of alopecia. Subjects must not have received the therapies indicated below for the specified time period:
•Chemotherapy: Last dose given at least 14 days or 5 half-lives before the start date for repotrectinib.
•Monoclonal antibodies (not including IO therapeutic antibodies): Last dose given at least 21 days prior to the start date for repotrectinib.
•Immunotherapy (eg, IO therapeutic antibodies or tumor vaccine): Subject is eligible after 28 days of completion prior to first dose of repotrectinib. Steroids are not considered immunotherapy.
•Radiation therapy: Subjects must not have received radiation for a minimum of 2 weeks prior to study enrollment. If extensive bone marrow radiation, at least 42 days must have elapsed.
•HSCT: Subjects are eligible 12 weeks after infusion following myeloablative therapy (timed from first day of repotrectinib). Subjects who have received an infusion to support nonmyeloablative therapy (such as 131I MIBG) are eligible at any time as long as they meet the other criteria.
•131I-MIBG therapy: A minimum of 6 weeks must have elapsed after 131I-MIBG therapy prior to start of repotrectinib.
•Growth factors: Subjects are eligible 14 days after last dose of long-acting growth factor or 7 days after short-acting growth factor.
•Any investigational agent or anticancer therapy other than chemotherapy and not otherwise noted: Not within 2 weeks prior to planned start of repotrectinib or 5 half-lives, whichever is shorter.
•Any prior treatment with a TKI of ALK/ROS1/NTRK does NOT exclude subject from study.
3.All subjects must have measurable disease by RECIST v1.1 or RANO criteria at time of enrollment.
For Phase 2 subjects in Cohort 2 must have prospectively confirmed measurable disease by BICR prior to enrollment.
•Exception: Neuroblastoma subjects are permitted to have evaluable disease only.
4.Subjects with Primary CNS Tumors or metastases must be neurologically stable on a stable or decreasing dose of steroids for at least 14 days prior to enrollment.
5.Subjects must have a Lansky (<16 years) or Karnofsky (≥16 years) score ≥50. Subjects who are unable to walk because of paralysis or tumor pain, but who are up in a wheelchair, will be considered ambulatory for the performance score.
6.Life expectancy ≥12 weeks.
7.Screening Local laboratory values:
ANC≥1.5 × 109/L, ≥0.75 × 109L, if known bone marrow involvement
PLT ≥100 × 109/L independent of platelets transfusion support for at least 7 days prior to dosing, ≥50 × 109/L, if known bone marrow involvement
Hemoglobin≥ 8.0 g/dL independent of red blood cell transfusion support for at least 7 days prior to dosing, unless bone marrow involvement identified at enrollment
Serum creatinine or creatinine clearance* Within normal limits per age or creatinine clearance or nuclear GFR>40 mL/min
Total serum bilirubin < 1.5 × ULN
AST/ALT<2.5 × ULN; <5 × ULN if liver metastases are present
ALP <2.5 × ULN; <5 × ULN if liver and/or bone metastasis are present.
Serum calcium, magnesium, and potassium: Normal or ≤CTCAE grade 1 with or without supplementation.
8.WOCBP must have a negative serum pregnancy test during screening and be neither breastfeeding nor intending to become pregnant during study participation. Female subjects will be considered to be of childbearing potential unless they have undergone permanent contraception or have premature menopause. For WOCBP and for men, agreement to use an effective contraceptive method from the time of screening until 5 weeks (WOCBP) or 6 months (men) after administration of the last dose of any study medication.
9.Ability to comply with study procedures.
10.The subject, parent or guardian must voluntarily sign and date an informed consent approved (in addition to pediatric assent, if required) by an IEC, prior to the initiation of any study specific procedures.
11.≤25 years at C1D1. |
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| E.4 | Principal exclusion criteria |
1. Concurrent participation in another therapeutic clinical trial.
2. Subjects with neuroblastoma with only bone marrow disease evaluable by bone marrow aspiration only.
3. Major surgery within 14 days (2 weeks) prior to Cycle 1 Day 1. Central venous access (Broviac, Mediport, etc.) placement does not meet criteria for major surgery.
4. Subjects who are pregnant or breast feeding.
5. Subjects with known active infections requiring ongoing treatment (bacterial, fungal, or viral, including HIV).
6. Subjects with gastrointestinal disease (eg, Crohn’s disease, ulcerative colitis, short gut syndrome) or other malabsorption syndromes that would impact on drug absorption.
7. Any of the following cardiac criteria:
• Mean resting corrected QT interval (electrocardiogram [ECG] interval measured from the onset of the QRS complex to the end of the T wave) for heart rate (QTc) > 480 msec obtained from 3 ECGs, using the screening clinic ECG machine-derived QTc value
• Any clinically important abnormalities in rhythm, conduction, or morphology of resting ECG (eg, complete left bundle branch block, third degree heart block, second degree heart block, PR interval >250 msec)
• Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome, or any concomitant medication known to prolong the QT interval (Appendix 5)
8. Subjects with peripheral neuropathy with CTCAE grade ≥ 2.
9. Subjects with other severe acute or chronic medical or psychiatric conditions or laboratory abnormalities that, per the judgement of the Investigator or Sponsor, may increase the risk associated with study participation or study drug administration, or that may interfere with the interpretation of study results, or make the subject inappropriate for entry into the study, or could compromise protocol objectives.
10. Subjects being treated with or anticipating the need for treatment with strong CYP3A4 inhibitors or inducers as listed in Appendix 4.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Endpoint for Phase 2:
• ORR as determined by BICR |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The ORR will be defined as the proportion of subjects with a confirmed complete response (CR) or partial response (PR). A confirmed response is a response that persists on a repeat-imaging performed at least 4 weeks after initial documentation of response. Subjects with a confirmed objective response (CR or PR) will be referred to as responders. Non-responders will include subjects without a confirmed objective response, SD, or PD.
The ORR will be reported as the proportion of responders along with the corresponding 2-sided 95% Clopper-Pearson exact CI.
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| E.5.2 | Secondary end point(s) |
Secondary Endpoints for Phase 2:
• DOR, TTR, and CBR
• Intracranial tumor response
• Central nervous system progression-free survival (CNS-PFS) in subjects with measurable brain metastases
• PFS and OS
• Type, incidence, severity, timing, seriousness, and relatedness of AEs and laboratory abnormalities
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
The DOR will be defined from the first date of objective response (either CR or PR) to first documentation of radiographic disease progression, as assessed by RECIST v1.1. The DOR will be censored at the last tumor assessment date for subjects without disease progression who have not died within 28 days of the last dose of study treatment.
The DOR will only be calculated for the subgroup of subjects with a confirmed objective tumor response. The DOR will be summarized in the populations of subjects with a confirmed CR or PR using the Kaplan-Meier method and will be displayed graphically where appropriate. The median event time (if appropriate) and 2-sided 95% CI for the median will be provided.
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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 | No |
| 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) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 16 |
| 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 |
| Korea, Republic of |
| Singapore |
| Taiwan |
| United States |
| France |
| Spain |
| Italy |
| Denmark |
| United Kingdom |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| 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 | 5 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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