Study of PBI-200 in Subjects With NTRK-Fusion-Positive Solid Tumors

Study Overview
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Brief Summary
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This is a first-in-human, Phase 1/2 open-label, multicenter, dose-escalation, safety, PK, and biomarker study of PBI-200 in subjects with NTRK-fusion-positive advanced or metastatic solid tumors.

Detailed Description
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This is a first-in-human, Phase 1/2 open-label, multicenter, dose-escalation, safety, PK, and biomarker study of PBI-200 in subjects with NTRK-fusion-positive advanced or metastatic solid tumors. Phase 1 will also include subjects with NTRK-amplified advanced or metastatic solid tumors or refractory EWSR1-WT1-fusion-positive desmoplastic small round cell tumors (DSRCTs). Phase 1 is the dose-escalation portion of the study in which the evaluation of safety and tolerability and establishing the RP2D are primary objectives. Once the RP2D has been established, two expansion cohorts will open to accrual, a Non-Brain Primary Tumor cohort and a Primary Brian Tumor cohort.

Official Title
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A Phase 1/2 Study of PBI-200 in Subjects With NTRK-Fusion-Positive Advanced or Metastatic Solid Tumors

Conditions
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Solid Tumor, Adult, Brain Tumor, Primary, Desmoplastic Small Round Cell Tumor

Intervention / Treatment
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* Drug: PBI-200


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Subject has one of the following solid tumors which has progressed on or following at least one systemic therapy regimen administered for advanced or metastatic disease or for which no approved therapy exists: NTRK-fusion-positive, locally advanced (i.e., not amenable to surgical resection) or metastatic solid tumor Note: Subjects with any grade of malignant glioma previously treated with systemic therapy are eligible. Phase 1 NTRK-gene amplified, locally advanced or metastatic solid tumor EWSR1-WT1-positive DSRCTs. Subjects with NTRK-fusion-positive solid tumors other than primary brain tumors must have previously received treatment with a TRK inhibitor, unless the subject does not have access to TRK-inhibitor therapy (e.g., no TRK inhibitor is marketed and available to the subject in the subject's country) or the subject has declined treatment with available marketed TRK inhibitors. Subjects with NTRK-gene amplified solid tumors, primary brain tumors or EWSR1-WT1-positive DSRCTs may have received prior treatment with a TRK inhibitor but this is not required. Phase 2 Has measurable disease by RECIST v1.1 for subjects with non-brain primary tumors or RANO criteria for subjects with primary brain tumors. Subjects with non-brain primary tumors must have previously received treatment with a TRK inhibitor and a documented resistance mutation(s) (e.g., solvent front, gatekeeper or xDFG mutation). Archival tissue from a prior biopsy taken after the subject completed TRK inhibitor treatment but prior to additional systemic therapy may be used to meet this eligibility criterion with Medical Monitor approval. Subjects with primary brain tumors may have received prior treatment with a TRK inhibitor but this is not required. Biopsies of brain tumors are not required for eligibility. Key Exclusion Criteria: Cytotoxic chemotherapy, biologic agent, investigational agent, or radiation therapy ≤ 3 weeks prior to the first dose of PBI-200 (6 weeks for nitrosoureas). Subjects with either primary brain tumors or brain metastasis must have completed brain radiation therapy 12 weeks prior to the brain MRI obtained within 4 weeks of the first dose of PBI-200. Small-molecule kinase inhibitors or hormonal agents ≤ 14 days and within 5 half-lives prior to the first dose of PBI-200.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Dose Escalation: Single-subject cohorts will be enrolled initially, until a subject has a Grade 2 or greater adverse event (AE), at which time a 3+3 design will be utilized. Dose escalation will continue until the maximum-tolerated dose (MTD) is reached, or the Recommended Phase 2 Dose (RP2D) is established. Cohort Expansion: Two cohorts will be opened to accrual. Cohort A will enroll subjects with a non-brain primary tumor and Cohort B will enroll subjects with a primary brain tumor.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1 Dose Escalation<br> | Drug: PBI-200<br>* PBI-200 will be administered orally over continuous 28-day cycles<br>|
| Experimental: Phase 2 Cohort Expansion<br> | Drug: PBI-200<br>* PBI-200 will be administered orally over continuous 28-day cycles<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1: Number of patients with AEs | Severity of AEs will be assessed according to the NCI CTCAE v5.0 | Through study completion, estimated as an average of 36 months | 
| Phase 1: Recommended Phase 2 Dose |  | Approximately 12 months | 
| Phase 2: Cohort A - Overall Response Rate (ORR) | Assessed using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 | Through study completion, estimated as an average of 36 months | 
| Phase 2: Cohort B - ORR | Assessed using Response Assessment in Neuro-Oncology (RANO) criteria | Through study completion, estimated as an average of 36 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1: Area under the plasma drug concentration-time curve from 0 to 24 hours after one dose and after 28 doses |  | 29 days | 
| Phase 1: ORR | Assessed by RECIST for subjects with non-brain primary tumors and by RANO for subjects with primary brain tumors | Through study completion, estimated as an average of 36 months | 
| Duration of Response (DoR) | Assessed by RECIST for subjects with non-brain primary tumors and by RANO for subjects with primary brain tumors | Through study completion, estimated as an average of 36 months | 
| Progression-free Survival | Assessed by RECIST for subjects with non-brain primary tumors and by RANO for subjects with primary brain tumors | Through study completion, estimated as an average of 36 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NTRK, NTRK Fusion, Resistance Mutation