| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| ALK fusion-positive extracranial solid or primary CNS tumors who have progressed following prior treatment or who have no satisfactory treatment available |
|
| E.1.1.1 | Medical condition in easily understood language |
| Solid tumors are masses of abnormal tissue growth that originate in organs or soft tissues and do not include fluid areas and cysts |
|
| 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 | 10028992 |
| E.1.2 | Term | Neoplasm CNS |
| 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 | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10065252 |
| E.1.2 | Term | Solid tumor |
| 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 |
• To confirm the recommended Phase II dose (RP2D) in pediatric participants as the dose equivalent to adult exposure without dose-limiting toxicities (DLTs)
• To evaluate the safety and tolerability of alectinib as a single agent
• To characterize the pharmacokinetics of alectinib and its major metabolite M4 and to confirm the pediatric RP2D
• To evaluate the anti-cancer activity of alectinib at the pediatric RP2D dose |
|
| E.2.2 | Secondary objectives of the trial |
| • To evaluate the efficacy of alectinib in all enrolled participants receiving alectinib at the pediatric RP2D, in CNS participants and in solid participants. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Age at study entry <18 years old
• Histologically confirmed diagnosis of CNS or solid tumors with documented evidence of ALK gene fusions as assessed centrally through the use of the investigational F1CDx assay or based on pre-existing NGS test results
• Participants with prior treatment proven to be ineffective (relapsed or refractory), or for whom there is no satisfactory treatment available
• Participants with tumor tissue availability for submission to the Sponsor from active disease, obtained subsequent to last anti-cancer therapy regimen administered and obtained prior to study enrollment (preferred option), or willing to undergo a core or excisional biopsy sample collection prior to enrollment
• Life expectancy >=8 weeks, in the investigator's judgment
• Adequate performance status (For participants < 16 years old: Lansky Performance Status should be >= 50% and for participants >= 16 years old: Karnofsky Performance Status should be >= 50%)
• Participants with adequate end-organ function
• Females of childbearing potential must agree to remain abstinent (refrain from heterosexual intercourse) or use contraception, and agreement to refrain from donating eggs during the treatment period and for at least 3 months after the final dose of study drug
• Females of childbearing potential must have a negative serum pregnancy test during screening and be neither breastfeeding nor intending to become pregnant during study participation
• Males who are not surgically sterile must agree to remain abstinent (refrain from heterosexual intercourse) or use contraception, and agreement to refrain from donating sperm, during the treatment period and for at least 3 months after the final dose of study drug |
|
| E.4 | Principal exclusion criteria |
• Medical history of prior use of ALK inhibitors, any gastrointestinal (GI) disorder that may affect absorption of oral medications, organ transplant, recent stem cell infusions (with or without traumatic brain injury)
• Diagnosis of Anaplastic Large Cell Lymphoma (ALCL)
• History of hypersensitivity to any of the additives in the alectinib drug formulation to be used in the study
• Substance abuse within 12 months prior to screening, in the investigator's judgment
• Familial or personal history of congenital bone disorders, bone metabolism alterations or osteopenia
• Treatment with investigational therapy 28 days prior to initiation of study drug
• Liver disease
• Abnormal levels of creatinine or glomerular filtration rate (GFR)
• National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 (NCI-CTCAE v5.0) Grade >=3 toxicities attributed to any prior therapy such as radiotherapy (excluding alopecia), which have not shown improvement and are strictly considered to interfere with alectinib
• Co-administration of anti-cancer therapies other than those administered in this study
• Active hepatitis B or C virus (HBV, HBC) or known human immunodeficiency virus (HIV) positivity or Acquired immunodeficiency syndrome (AIDS)-related illness
• Any clinically significant concomitant disease or condition that could interfere with, or for which the treatment might interfere with, the conduct of the study or the absorption of oral medications or that would, in the opinion of the Principal Investigator, pose an unacceptable risk to the participants in this study
• Any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol requirements and/or follow-up procedures
• Planned procedure or surgery during the study except as permitted treatment
• Infection considered by the investigator to be clinically uncontrolled or of unacceptable risk to the participant upon induction of neutropenia such as fungal infection or bacterial infection or neutropenic fever or participants who have received <5 days of appropriate therapeutic antibiotic therapy for an identified infection
• Pregnant or breastfeeding women, or intending to become pregnant during the study or within 3 months after the final dose of alectinib |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Incidence of dose-limiting toxicities (DLTs) assessed during the first cycle of study treatment
2. Incidence and severity of adverse events, with severity determined according to the NCI-CTCAE v5.0, as well as changes from baseline in physical findings, targeted vital signs, clinical lab test results and ECG parameters
3. Plasma concentrations of alectinib and its metabolites (M4) at specified timepoints
4. Confirmed objective response rate (ORR) as determined by blinded independent central review |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Assessment during the first cycle
2-3. Baseline to 5 years
4. When a minimum of 10 pediatric participants treated at the pediatric RP2D have been enrolled in the initial expansion portion of the study and a minimum of 30 pediatric participants treated at the pediatric RP2D have been enrolled across the dose confirmation/safety run-in and expansion phases of the study, and followed for at least 6 months, respectively. |
|
| E.5.2 | Secondary end point(s) |
1. Confirmed ORR as determined by the investigator, Duration of response (DOR), Time to response (TTR), Clinical benefit rate (CBR), Progression-free survival (PFS) as determined by blinded independent central review and by the investigator
2. Overall survival (OS) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. When a minimum of 10 pediatric participants treated at the pediatric RP2D have been enrolled in the initial expansion portion of the study and a minimum of 30 pediatric participants treated at the pediatric RP2D have been enrolled across the dose confirmation/safety run-in and expansion phases of the study, and followed for at least 6 months, respectively.
2. When participants have been followed up to 5 years. |
|
| 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 | 15 |
| 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 |
| China |
| Korea, Republic of |
| United Kingdom |
| United States |
| Denmark |
| France |
| Germany |
| Italy |
| Spain |
|
| 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
|
| The end of this study is defined as the date when the last patient, last visit occurs (LPLV) or 5 years after the last patient is enrolled and treated with study drug, whichever occurs first. For an individual patient, the completion of the study (i.e., the last visit) will occur when the patient withdraws consent, has completed follow-up, has been lost to followup, dies, or when the study is stopped. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 7 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 8 |
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