Principali criteri di inclusione:
1. È richiesta una mutazione puntiforme, fusione o amplificazione di ROS1 o una fusione di NTRK1-3 genetica documentata
, identificata mediante test locali in un laboratorio dotato di certificazione secondo gli Emendamenti per il miglioramento dei laboratori clinici (CLIA)
negli Stati Uniti o in un laboratorio diagnostico dotato di certificazione equivalente al di fuori degli Stati
Uniti (USA).
2. Fase 1: Età <12 years; Phase 2: Age 12- 25 years
3. Prior cytotoxic chemotherapy is allowed.
4. Prior immunotherapy is allowed.
5. Resolution of all acute toxic effects (excluding alopecia) of any prior anti-cancer
therapy to National Cancer Institute Common Terminology Criteria for Adverse Events
(NCI CTCAE) Version 4.03 Grade less than or equal to 1.
6. All subjects must have measurable disease by RECIST v1.1 or Response Assessment in
Neuro-Oncology (RANO) criteria at time of enrollment.
7. Subjects with a primary CNS tumor or CNS metastases must be neurologically stable on a
stable or decreasing dose of steroids for at least 7 days prior to enrollment.
8. Subjects must have a Lansky (< 16 years) or Karnofsky (≥ 16 years) score of at least
50.
9. Life expectancy greater than or equal to 12 weeks, in the investigator's opinion.
10. Adequate hematologic, renal and hepatic function.
Phase 2 Inclusion Criteria:
1. Cohort Specific Inclusion Criteria:
- Cohort 1: Subjects with NTRK fusion gene positive (NTRK+) advanced solid tumors
(including primary CNS tumors), that are tropomyosin receptor kinase (TRK) TKI
naïve;
- Cohort 2: subjects with NTRK+ advanced solid tumors (including primary CNS
tumors), that are TRK TKI pre-treated;
- Cohort 3: subjects with advanced solid tumors with ROS1 gene fusions or other
ROS1 aberrations (including amplifications and point mutations) with measurable
disease.
2. Subjects in Cohorts 1 and 2 must have prospectively confirmed measurable disease by
BICR prior to enrollment.
Key Exclusion Criteria (Phase 1 and Phase 2):
1. Subjects with neuroblastoma with only bone marrow disease evaluable by bone marrow
aspiration only.
2. Major surgery within 14 days (2 weeks) of start of repotrectinib treatment. Central
venous access (Broviac, Mediport, etc.) placement does not meet criteria for major
surgery.
3. Known active infections requiring ongoing treatment (bacterial, fungal, viral
including HIV positivity).
4. Gastrointestinal disease (e.g., Crohn's disease, ulcerative colitis, or short gut
syndrome) or other malabsorption syndromes that would impact drug absorption.
5. Any of the following cardiac criteria:
- Mean resting corrected QT interval (ECG interval measured from the onset of the
QRS complex to the end of the T wave) for heart rate (QTc)> 480 msec ottenuto
da tre ECG, utilizzando il valore
QTc derivato dall’elettrocardiografo della clinica di screening; qualsiasi anomalia clinicamente significativa nel ritmo, nella conduzione o nella morfologia
dell’ECG a riposo (ad es. blocco di branca sinistra completo, blocco cardiaco di terzo grado,
blocco cardiaco di secondo grado, intervallo PR >250 msec)
; qualsiasi fattore che aumenti il rischio di prolungamento del QTc o il rischio di eventi aritmici
come insufficienza cardiaca, sindrome congenita del QT lungo, anamnesi familiare di sindrome del QT lungo
, o qualsiasi farmaco concomitante noto per prolungare l’intervallo QT.
6. Neuropatia periferica di grado ≥2 secondo i criteri CTCAE.
7. Soggetti trattati con o per cui si prevede la necessità di un trattamento con forti inibitori o induttori del CYP3A4
.
8. Qualsiasi potenziale allergia a repotrectinib e/o ai suoi eccipienti.
