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| General |
| Study Status |
Ongoing |
Application Number /
Requirement Number |
P170019 S014/ PAS001 |
| Date Original Protocol Accepted |
05/26/2023
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| Date Current Protocol Accepted |
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| Study Name |
ROZYLTREK PAS
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| Device Name |
FoundationOne CDx
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| Clinical Trial Number(s) |
NCT02097810
NCT02568267
NCT02650401
NCT03330990
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| General Study Protocol Parameters |
| Study Design |
Retrospective Cohort Study
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| Data Source |
Sponsor Registry
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| Comparison Group |
No Control
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| Analysis Type |
Descriptive
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| Study Population |
Child: 2-12 yrs,
Adolescent: 13-18 yrs,
Adult: >21
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| Detailed Study Protocol Parameters |
| Study Objectives |
This clinical post-approval study (PAS) is being conducted to confirm the clinical effectiveness of the F1CDx assay in detecting NTRK1/2/3 fusion positive patients with solid tumors for treatment with entrectinib. This study is intended to fulfil the clinical PAS issued in the approval order for P170019/S014. This PAS will supplement the premarket clinical bridging study with additional patients from the STARTRK-2 trial (non-NDA population) who have a later enrollment date as well as patients enrolled in the TAPISTRY trial (NCT04589845).
The first objective of this clinical bridging study is to evaluate the concordance of F1CDx and LDT results in the identification of NTRK1/2/3 fusions. Samples from various tumor types will be included.
The second objective of this study is to evaluate the overall response rate (ORR) and duration of response (DOR) for entrectinib treatment among clinical study subjects who solid tumor specimens are NTRK1/2/3 fusion positive, per the CDx biomarker definition, by retrospective testing with F1CDx, per the CDx biomarker definition.
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| Study Population |
The study consists of approximately 101 NTRK1/2/3 fusion positive patients from the STARTRK-2 trial enrolled after April 2018 and by Q2 2022, and approximately 15 patients from Cohort B of the TAPISTRY trial enrolled by Q2 2022. Of these, an estimated 67 samples will have sufficient residual DNA (or total nuclei acid (TNA)) and patient consent for F1CDx testing.
Approximately 250 NTRK1/2/3 fusion negative specimens of various disease ontologies from the FMI archive will be included in the agreement analysis.
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| Sample Size |
Approximately 116 NTRK1/2/3 fusion positive patients and approximately 250 NTRK1/2/3 fusion negative specimens (for concordance analysis only)
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| Key Study Endpoints |
Primary Effectiveness Endpoint: Concordance of F1CDx and LDT results in the identification of NTRK1/2/3 fusions
Secondary Effectiveness Endpoints: ORR and DOR of entrectinib
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| Follow-up Visits and Length of Follow-up |
1 year for the ORR
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| Interim or Final Data Summary |
| Actual Number of Patients Enrolled |
NTRK
A total 72 valid results with F1CDx testing, including 45 subjects enrolled by laboratory developed test (LDT) and F1CDx retesting, and 27 subjects enrolled by F1CDx utilizing remaining clinical trial formalin fixed paraffin-embedded (FFPE) tumor tissue specimens from the FMI archives from ALKA, STARTRK-1, STARTRK-2, and TAPISTRY clinical trials.
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| Actual Number of Sites Enrolled |
N/A
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| Patient Follow-up Rate |
N/A
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| Final Safety Findings |
N/A
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| Final Effect Findings |
NTRK
An additional post approval study was conducted to evaluate the clinical effectiveness of F1CDx by testing a total 72 valid results with F1CDx testing, including 45 subjects enrolled by LDT and F1CDx retesting, and 27 subjects enrolled by F1CDx utilizing remaining clinical trial formalin fixed paraffin-embedded (FFPE) tumor tissue specimens from the FMI archives from ALKA, STARTRK-1, STARTRK-2, and TAPISTRY clinical trials. The ORR in the F1CDx NTRK1/2/3 fusion positive and clinical trial assay (CTA) positive population was 65.22% (95% CI: [44.89%, 81.19%]), which is similar to the ORR of the clinical trial assay (CTA) positive population (n=141) was 62.41% (95% CI: [54.19%, 69.98%]). The results of the post approval study further confirmed the clinical effectiveness for F1CDx to identify patients with solid tumors with NTRK fusions that may benefit from ROZLYTREK therapy.
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| Study Strengths & Weaknesses |
NTRK
The concordance analysis in PAS results shows that the low positive percent agreement (PPA) for NTRK1/2/3 fusion is 51.11% (23/45), is driven by primarily by the low PPA observed for NTRK3 fusions, PPA of 39.29% (11/28). The low PPA was also observed in the clinical bridging study in the sPMA data submitted under P170019/S014 for NTRK3 fusions as the PPA was 61.90% (13/21). Hence, there is unacceptably high negative rate for NTRK3 gene fusion calls made by F1CDx and appears that the low concordance (PPA) is primarily driven by NTRK3. Therefore, given that F1CDx device as designed does not fully cover the NTRK3 gene and common fusion partners and therefore misses a significant number of patients who may have NTRK3 gene fusions that may benefit from a potentially effective therapy. A limitation to address this issue will be added to the device labeling, see above.
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| Recommendations for Labeling Changes |
NTRK
A summary of the PAS study results should be added to the technical information document. The final text will be finalized during the review of the labeling PMA supplement that FMI should submit 30 days after the completion of the review of P170019/R058.
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