Phase 1 will evaluate the safety and tolerability at different dose levels of repotrectinib
in pediatric and young adult subjects with advanced or metastatic malignancies harboring
anaplastic lymphoma kinase (ALK), receptor tyrosine kinase encoded by the gene ROS1 (ROS1),
or neurotrophic receptor kinase genes encoding TRK kinase family (NTRK1-3) alterations to
estimate the Maximum Tolerated Dose (MTD) or Maximum Administered Dose (MAD) and select the
Pediatric Recommended Phase 2 Dose (RP2D).
Enrollment of subjects into Phase 1 will proceed concurrently by age as follows:
• Subjects 4 to <12 years old will initially be enrolled in the Phase 1 part to determine the
pediatric RP2D for this age group.
Approximately 12 pediatric subjects with locally advanced or metastatic solid tumors,
including a primary central nervous system (CNS) tumor, or anaplastic large cell lymphoma
(ALCL), with disease progression or who are non-responsive or intolerant to available
therapies and for which no standard or available curative therapy exists.
Key Inclusion Criteria:
1. Documented genetic ALK, ROS1, or NTRK1-3 alteration (point mutation, fusion,
amplification) as identified by local testing in a Clinical Laboratory Improvement
Amendments (CLIA) laboratory in the US or equivalently accredited diagnostic lab
outside the United States (US) is required.
2. Age 4 to <12 years.
3. Capability to swallow capsules intact (without chewing, crushing, or opening).
4. Prior cytotoxic chemotherapy is allowed.
5. Prior immunotherapy is allowed.
6. 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.
7. All subjects must have measurable disease by RECIST v1.1 or Response Assessment in
Neuro-Oncology Criteria (RANO) criteria at time of enrollment.
8. Subjects with a primary CNS tumor or CNS metastases must be neurologically stable on a
stable or decreasing dose of steroids for at least 14 days prior to enrollment.
9. Subjects must have a Lansky (< 16 years) score of at least 50.
10. Life expectancy greater than or equal to 12 weeks.
11. Adequate hematologic, renal and hepatic function.
Key Exclusion Criteria:
1. Subjects with neuroblastoma with only bone marrow disease evaluable by bone marrow
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
3. Known active infections (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) > 470 msec obtained
from three ECGs, using the screening clinic ECG machine-derived QTc value
- Any clinically important abnormalities in rhythm, conduction, or morphology of
resting ECG (e.g., 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, congenital long QT syndrome, family history of long
QT syndrome, or any concomitant medication known to prolong the QT interval
6. Peripheral neuropathy of CTCAE ≥grade 2.
7. Subjects being treated with or anticipating the need for treatment with strong CYP3A4
inhibitors or inducers.