Advanced or metastatic malignancies

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 subjects with advanced or metastatic malignancies harboring ALK, ROS1, or NTRK1-3 alterations.

Repotrectinib

(7S,13R)-11-fluoro-7,13-dimethyl-6,7,13,14-tetrahydro-1,15-ethenopyrazolo[4,3-f][1,4,8,10] benzoxatr

capsule
capsule
suspension

40mg (capsule), 100mg (capsule), 32 mg/mL (suspension)

Primary Endpoints：
Phase 1:
• Incidence of first cycle DLTs to determine the MTD
• Pediatric RP2D
Phase 2:
• Overall Response Rate (ORR) as
determined by Blinded Independent Central
Review (BICR)

Secondary Endpoints：
Phase 1:
• Overall Response Rate (ORR) as determined by BICR
• Clinical Benefit Rate (CBR)
• Time to response (TTR)
• Duration of response (DOR)
• Intracranial objective response rate (IC-ORR)
• PK parameters
• Type, incidence, severity, timing, seriousness, and relatedness of adverse events (AEs) and laboratory abnormalities
Phase 2:
• DOR, TTR, and CBR
• Intracranial tumor response
• CNS 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

Exploratory Endpoints：
• Association of genomic alterations at baseline and after dosing with ORR and PFS.

1. Disease:
• For Phase 1: Subjects with locally advanced or metastatic solid tumors, including a primary central nervous system (CNS) tumor, or ALCL, with disease progression or who is non-responsive or intolerant to available therapies and for which no standard or available curative therapy exists.
• For Phase 2: 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. No prior TRK TKI is allowed (including, but not limited to, larotrectinib, entrectinib, or loxo 195). Any number of prior lines of chemotherapy or immunotherapy are allowed. Subjects must have at least one measurable lesion at baseline according to RECIST v1.1.
 Cohort 2: Subjects with NTRK+ advanced solid tumors (including primary CNS tumors), that are TRK TKI pre-treated. Nonresponse, disease progression on or intolerability to at least 1 but no more than 2 prior TRK TKIs (e.g., larotrectinib, entrectinib, or loxo-195) is required. Any number of prior lines of chemotherapy or immunotherapy are allowed. Subjects must have measurable disease at baseline according to RECIST v1.1.
• Cohort 3: Exploratory
 Subjects with advanced solid tumors or ALCL having ALK or ROS1 fusion gene (ALK+ or ROS1+)
 Subjects with NTRK+ advanced solid tumors with measurable disease determined locally but without being prospectively confirmed or not otherwise eligible for Cohort 1 and Cohort 2 (eligibility for this cohort to be determined in consultation with the Medical Monitor). Subjects with other ALK/ROS1/NTRK aberrations (including amplification, point mutation) may be enrolled in this cohort including ALK+ ALCL.
• 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. Only the following test modalities are permitted:
 Tissue-based or liquid biopsy NGS or quantitative polymerase chain reaction (qPCR)
 Fluorescence in situ hybridization (FISH)
 FISH is permitted to detect gene fusions with the targeted fusion genes ALK, ROS1, or NTRK1-3
 ETS variant gene 6 (ETV6) break apart FISH is permitted to detect ETV6-NTRK3 gene fusions in infantile fibrosarcoma (IFS)
• Tissue and Liquid Biopsy Requirements
 For subjects enrolled per a tissue-based diagnostic test, adequate tumor tissue should be sent prior to enrollment to the Sponsor’s designated central laboratory for retrospective confirmation. In cases where archived tumor tissue is not available, a fresh biopsy should be obtained for this purpose. See the Study Laboratory Manual for details.
 For subjects enrolled by a liquid biopsy test; blood samples will be required and should be sent prior to enrollment and used for retrospective confirmation in the Sponsor’s designated central laboratory. Additionally, it is recommended that adequate tumor tissue samples be sent to the designated central laboratory. See the Study Laboratory Manual for details.
2. Prior Therapy: Subjects must have recovered from the acute toxic effects of all previous chemotherapy, immunotherapy, or radiotherapy prior to study enrollment to Common Terminology Criteria for Adverse Events (CTCAE) v 4.03 Grade 1 or lower with the exception of alopecia. Subjects must not have received the therapies indicated below for the specified time period prior to the first day of administration of repotrectinib on this study:
• Chemotherapy: Last dose was given at least 14 days or 5 half-lives before the start date for repotrectinib.
• Monoclonal antibodies (not including immuno-oncology [I/O] therapeutic antibodies): Last dose of any monoclonal antibodies at least 21 days prior to the start date for repotrectinib.
• Immunotherapy (e.g., I/O 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 two weeks prior to study enrollment for small port. If extensive bone marrow radiation, at least 42 days must have elapsed.
• Hematopoietic Stem Cell Transplant (HSCT): Subjects are eligible 12 weeks after date of autologous hematopoietic stem cell infusion following myeloablative therapy (timed from first day of repotrectinib). Subjects who have received an autologous hematopoietic stem cell infusion to support non-myeloablative therapy (such as 131I metaiodobenzylguanidine [131I MIBG]) are eligible at any time as long as they meet the other criteria for eligibility.
• 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 (e.g., pegylated granulocyte colony stimulating factor [peg-GCSF]) 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 with the exception of Phase 2, Cohort 1 (Subjects are eligible for study at least 7 days or 5 half-lives, whichever is shorter, after last dose).
3. Disease Status
• All subjects must have measurable disease by RECIST v1.1 or Response Assessment in Neuro-Oncology Criteria (RANO) criteria at time of enrollment.
For Phase 2 only: subjects in Cohorts 1 and 2 must have prospectively confirmed measurable disease by BICR prior to enrollment.
• Exception: Neuroblastoma subjects are permitted to have evaluable disease only (e.g., bone disease only, evaluable by MIBG or positron emission tomography [PET]).
4. Subjects with Primary CNS Tumors:
• 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.
5. Performance Score: Subjects must have a Lansky (< 16 years) or Karnofsky (≥ 16 years) score of at least 50 (Appendix 3 and Appendix 2, respectively). 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 purpose of assessing the performance score.
6. Life expectancy greater than or equal to 12 weeks.
7. Screening laboratory values (analyzed by a local lab) fulfilling the following requirements detailed in protocol.
8. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test during screening and be neither breastfeeding nor intending to become pregnant during study participation. Female patients will be considered to be of childbearing potential unless they have undergone permanent contraception or have premature menopause. Premature menopause is defined as at least 12 months without menses with no other medical reasons (e.g., chemical menopause due to anticancer treatment). For WOCBP and for men, agreement to use an effective contraceptive method from the time of screening throughout the study until 1 month (WOCBP) or 6 months (men) after administration of the last dose of any study medication. Highly effective contraceptive methods are described in Appendix 1.
9. Ability to comply with outpatient visits, laboratory testing, and study procedures during study participation
10. The subject, parent or guardian must voluntarily sign and date an informed consent approved (in addition to pediatric assent, if required) by an Independent Ethics Committee (IEC)/Institutional Review Board (IRB), prior to the initiation of any screening or study specific procedures.
11. Age:
• Phase 1: Age <12 years (age at C1 Day 1)
• Phase 2: Up to age 25 years (age at C1 Day 1). While the Phase 1 dose escalation is ongoing, subjects 12 years old and above may be enrolled directly in the Phase 2 part of the study. Subjects age < 12 years old will be enrolled in the Phase 2 part after determination of the pediatric RP2D in Phase 1.
(Above details are quoted from protocol. In case of any conflicts, the study protocol takes control.)

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 C1 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 human immunodeficiency virus [HIV]).
6. Subjects with gastrointestinal disease (e.g., 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 (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 (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, hypokalemia, congenital long QT syndrome, family history of long QT syndrome, or any concomitant medication known to prolong the QT interval
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.
(Above details are quoted from protocol. In case of any conflicts, the study protocol takes control.)