A Phase 1/2, Open-Label, Safety, Tolerability, Pharmacokinetics, and Anti-Tumor Activity of Repotrectinib in Pediatric and Young Adult Subjects with Advanced or Metastatic Malignancies Harboring ALK, ROS1, or NTRK-3 Alterations (CARE)

Protocol # :
Locally Advanced Solid Tumors
Metastatic Solid Tumors
Primary CNS Tumors
Disease Sites
Gastroesophageal Junction
Lip, Oral Cavity and Pharynx
Small Intestine
Other Digestive Organ
Other Respiratory and Intrathoracic Organs
Bones and Joints
Soft Tissue
Mycosis Fungoides
Other Skin
Corpus Uteri
Other Female Genital
Other Male Genital
Urinary Bladder
Other Urinary
Eye and Orbit
Brain and Nervous System
Unknown Sites
Ill-Defined Sites
Other Endocrine System
Kaposi's Sarcoma
Melanoma, Skin
Principal Investigator
Dubois, Steven
Site Research Nurses
Cavanaugh, Kerri, Lynn
Ezrre, Suzanne
McManus, Jeanine
Strachan, Marylynne

Trial Description

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).

Phase 2 will determine the anti-tumor activity of repotrectinib in pediatric and young adult
subjects with advanced or metastatic malignancies harboring ROS1 or NTRK1-3 alterations.

Eligibility Requirements

Key Inclusion Criteria:

1. Documented genetic ROS1 point mutation, fusion, or amplification or NTRK1-3 fusion 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. Phase 1: Age <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

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

- 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

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

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 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.

8. Any potential allergies to repotrectinib and/or its excipients.