Study of a c-Met Inhibitor PLB1001 in Patients With PTPRZ1-MET Fusion Gene Positive Recurrent High-grade Gliomas

Study Overview
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Brief Summary
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This phase I, open-label, dose-escalation study was conducted to determine the maximum tolerated dose (MTD), recommended phase II dose (RP2D), dose-limiting toxicities (DLTs), pharmacokinetics (PK) profile, and preliminary antitumor activity of single and multiple doses of PLB1001 in Patients with PTPRZ1-MET fusion gene positive recurrent high-grade Gliomas.

Detailed Description
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This is a Phase I, open-label study of PLB1001 administered orally to patients with PTPRZ1-MET fusion gene positive recurrent high-grade Gliomas. The aim of dose-escalation study is to estimate the MTD and to identify the dose-limiting toxicity(DLT) and the recommended phase II dose (RP2D) for PLB1001 single agent as well as to determine the PK/PD profile. Aprox. 20 patients will be enrolled in this study. PLB1001 is a potent selective c-Met inhibitor. PLB1001 acts on cancer by blocking abnormal cMET-mediated signaling (including PTPRZ1-MET fusion gene), leading to profound tumor growth inhibition in xenografts of PTPRZ1-MET fusion gene positive glioblastoma tumor.

Official Title
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A Phase I, Open-label, Dose Escalation Study to Assess the Safety, Tolerability and Pharmacokinetics (PK) of PLB1001 in Patients With PTPRZ1-MET Fusion Gene Positive Recurrent High-grade Gliomas

Conditions
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Glioma

Intervention / Treatment
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* Drug: PLB1001


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed Informed Consent Form Age≥18 years Histologically or cytologically confirmed recurrent high-grade glioma after concurrent or adjuvant chemoradiotherapy Prior treatment with temozolomide Must have evidence of PTPRZ1-MET fusion gene positivity from the results of molecular pre-screening evaluations At least one measurable lesion as per RANO No evidence of recent haemorrhage on baseline MRI of the brain Stable or decreasing dose of corticosteroids within 5 days prior to the first dose Major surgery within 4 weeks prior to first dose of PLB1001 Previous anti-cancer and investigational agents within 4 weeks before first dose of PLB1001. If previous treatment is a monoclonal antibody, then the treatment must be discontinued at least 6 weeks before first dose of PLB1001 Pregnant or nursing women Involved in other clinical trials <30 days prior to first dose Prior therapy with gamma knife or other focal high-dose radiotherapy is allowed, but the patient must have subsequent histologic documentation of recurrence, unless the recurrence is a new lesion outside the irradiated field Karnofsky performance status ≥ 50% Exclusion Criteria: Previous or current treatment with a c-Met inhibitor or HGF-targeting therapy The subject is unable to undergo MRI scan (e.g. has pacemaker) Clinically significant, uncontrolled heart diseases： Unstable angina; History of documented congestive heart failure (New York Heart Association functional classification> II); Uncontrolled hypertension defined by a Systolic Blood Pressure (SBP) ≥ 145 mm Hg and/or Diastolic Blood Pressure (DBP) ≥85 mm Hg; Arrhythmias. Active peptic ulcer disease or gastritis Adverse events from prior anti-cancer therapy that have not resolved to Grade ≤ 1, except for alopecia Major surgery within 4 weeks prior to first dose of PLB1001 Previous anti-cancer and investigational agents within 4 weeks before first dose of PLB1001. If previous treatment is a monoclonal antibody, then the treatment must be discontinued at least 6 weeks before first dose of PLB1001 Pregnant or nursing women Involved in other clinical trials <30 days prior to first dose

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PLB1001<br>There are 4 dose cohorts, including 50mg BID,100mg BID, 200mg BID and 300mg BID in the dose escalation stage and PLB1001 will be administered orally to patients twice daily for each dose cohort. | Drug: PLB1001<br>* PLB1001 is a capsule in the form of 25 mg and 100mg, twice daily.<br>* Other names: Bozitinib;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of participants with dose-limiting toxicities | The primary endpoint is evaluation of safety and tolerability during all the study of therapy following the initiation of single and multiple doses of PLB1001. The safety and tolerability variables to be evaluated in this study are adverse events, vital signs, and electrocardiograms (ECGs), Incidence and nature of DLTs (Dose-Limiting Toxicities), to determine the MTD (Maximum Tolerated Dose). | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the plasma concentration versus time curve (AUC) of PLB1001 and its metabolite | In the study of single-dose, full Pharmacokinetics(PK) profiles of PLB1001 will be obtained following administration of a single oral dose of PLB1001 on Day 1 to Day 2. At multiple-dose, Pharmacokinetics(PK) sampling will include a pre-dose and at the 0.5, 1, 2, 4, 6, 8, 10, 12, 14 and 16 hour time points on days 1and 15 of dosing in the first 28-Day cycle of therapy, and pre-dose on days 2, 16 and 17 of the first 28-Day cycle of therapy | Day 1-3 Single Dose and Day 1-28 Steady State | 
| Maximum plasma concentration observed (Cmax) of PLB1001 and its metabolite | In the study of single-dose, full Pharmacokinetics(PK) profiles of PLB1001 will be obtained following administration of a single oral dose of PLB1001 on Day 1 to Day 2. At multiple-dose, Pharmacokinetics(PK) sampling will include a pre-dose and at the 0.5, 1, 2, 4, 6, 8, 10, 12, 14 and 16 hour time points on days 1and 15 of dosing in the first 28-Day cycle of therapy, and pre-dose on days 2, 16 and 17 of the first 28-Day cycle of therapy | Day 1-3 Single Dose and Day 1-28 Steady State | 
| Time to Cmax (Tmax) of PLB1001 and its metabolite | In the study of single-dose, full Pharmacokinetics(PK) profiles of PLB1001 will be obtained following administration of a single oral dose of PLB1001 on Day 1 to Day 2. At multiple-dose, Pharmacokinetics(PK) sampling will include a pre-dose and at the 0.5, 1, 2, 4, 6, 8, 10, 12, 14 and 16 hour time points on days 1and 15 of dosing in the first 28-Day cycle of therapy, and pre-dose on days 2, 16 and 17 of the first 28-Day cycle of therapy | Day 1-3 Single Dose and Day 1-28 Steady State | 
| Preliminary antitumor activity of PLB1001 | Preliminary antitumor activity of PLB1001 assessed using RANO | 2 years |