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| General |
| Study Status |
Completed |
Application Number /
Requirement Number |
P170019 S017/ PAS001 |
| Date Original Protocol Accepted |
05/06/2022
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| Date Current Protocol Accepted |
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| Study Name |
NTRK Clinical Efficacy PAS for Larotrectinib
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| Device Name |
FoundationOne CDx (F1CDx)
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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 |
Historical Control
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| Analysis Type |
Descriptive
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| Study Population |
Infant: 29 days-2 yrs,
Child: 2-12 yrs,
Adolescent: 13-18 yrs,
Transit. Adolescent B (as adults) : 18-21 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 efficacy of F1CDx assay in detecting the NTRK 1/2/3 fusions positive patients for treatment with larotrectinib using solid tumors. This study is intended to fulfill the clinical PAS issued in the approval order for P170019/S017.
The objective of this PAS validation protocol is to determine the clinical efficacy of the variant detection component of the F1CDx assay for rearrangements in the NTRK1, NTRK2, and NTRK3 (NTRK1/2/3) genes as compared to the results obtained for the clinical registrational study samples. Samples from the Bayer-sponsored SCOUT and NAVIGATE clinical trials protocols will be used for this confirmation study. Per FDA approved sample criteria, the standard criteria samples for F1CDx are required to meet the range of greater than or equal to 55 ng to less than or equal to 1000 ng and for the conditional criteria samples for F1CDx are required to meet the range of greater than or equal to 27 ng to <55 ng for DNA yield. Formalin-fixed, paraffin-embedded (FFPE) tissue slide samples meeting either approved or conditional sample criteria will be included in this PAS analysis.
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| Study Population |
A total of seventeen (17) samples in the form of FFPE slides will be prospectively obtained from NTRK fusion positive patients enrolled in NAVIGATE and SCOUT (cutoff date July 20th, 2021) that were not included in the F1CDx sPMA. All samples with patient informed consent and sufficient tissue meeting either standard or conditional criteria will be retested using the F1CDx assay. Of the 17 total samples, eight (8) samples are expected to meet the standard criteria (greater than or equal to 55 ng to less than or equal to 1000 ng), and nine (9) samples are expected to meet the conditional criteria (greater than or equal to 27 ng to <55 ng).
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| Sample Size |
A total of 17 samples (8 Standard and 9 Conditional Criteria)
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| Key Study Endpoints |
Primary: The Overall Response Rate (ORR) determined by Independent Review Committee (IRC) using RECIST v1.1 will be the primary efficacy end point
Secondary: Duration of Response (DoR), determined with the methods in the drug clinical trials.
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| Follow-up Visits and Length of Follow-up |
2 years for the ORR
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| Interim or Final Data Summary |
| Actual Number of Patients Enrolled |
Seventeen (17) from NAVIGATE and SCOUT for PAS (QSR-VAL-414) Analysis
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| Actual Number of Sites Enrolled |
Approximately 40 institutions were recruited to enroll patients in SCOUT and NAVIGATE clinical studies.
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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 |
An additional post approval study was conducted to evaluate the clinical effectiveness of F1CDx by testing 17 available remaining formalin fixed paraffin embedded (FFPE) tissues samples from patients with solid tumors enrolled in LOXO-TRK-15002 (NAVIGATE) and LOXO-TRK-15003 (SCOUT) studies (cutoff date July 20, 2021) that had NTRK1/2/3 fusion positive status as determined by multiple local tests (LT). Of the 17 patients, 11 (64.7%) had an NTRK1/2/3 gene fusion detected by F1CDx, while 6 patients (35.3%) were NTRK1/2/3 gene fusion negative by F1CDx. The ORR in the F1CDx NTRK1/2/3 fusion positive population was 63.6% (95% CI: [30.8%, 89.1%]), which is similar to the ORR of the local testing fusion positive population, n=11, from the NAVIGATE and SCOUT clinical studies of 64.7% (95% CI: [38.3%, 85.8%]). 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 VITRAKVI therapy.
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| Study Strengths & Weaknesses |
Eight (8) of 17 cases evaluated in the post approval clinical study were pediatric cases from patients that are less than 18 years of age. Of the 6 out of 17 patients that were missed by F1CDx in the PAS study, i.e., had NTRK1/2/3 gene fusions by LT but had [F1CDx negative (-) status, 4 (66.7%) were pediatric cases (ages were less than 18 years of age), 2 were patients with infantile fibrosarcoma (IFS) and 2 were patients with soft tissue sarcoma. Given that these are rare cancers that have high prevalence of NTRK1/2/3 fusions, additional clinical investigation for NTRK1/2/3 fusions determined to be negative by F1CDx is recommended for cancers with high NTRK1/2/3 fusion rates (e.g., soft tissue infantile fibrosarcoma, kidney mesoblastic nephroma, salivary gland secretory carcinoma (MASC), breast secretory carcinoma) such that patients may not forgo 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 |
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/R049/A004
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