Clinical trial NCT02978261: Study of a c-Met Inhibitor PLB1001 in Patients With PTPRZ1-MET Fusion Gene Positive Recurrent High-grade Gliomas
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Glioma
Lead sponsor: Beijing Pearl Biotechnology Limited Liability Company
Sponsor class: INDUSTRY
First posted: 2016-11-30
Enrollment: 18
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Percentage of participants with dose-limiting toxicities
timeFrame: 2 years
Secondary outcomes:
measure: Area under the plasma concentration versus time curve (AUC) of PLB1001 and its metabolite
timeFrame: Day 1-3 Single Dose and Day 1-28 Steady State
measure: Maximum plasma concentration observed (Cmax) of PLB1001 and its metabolite
timeFrame: Day 1-3 Single Dose and Day 1-28 Steady State
measure: Time to Cmax (Tmax) of PLB1001 and its metabolite
timeFrame: Day 1-3 Single Dose and Day 1-28 Steady State
measure: Preliminary antitumor activity of PLB1001
timeFrame: 2 years
Other outcomes:
Locations:
city: Beijing
country: China
facility: Beijing Shijitan Hospital,CMU
state: Beijing
Study officials:
affiliation: Beijing Shijitan Hospital, CMU
name: Wenbin Li, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Hu H, Mu Q, Bao Z, Chen Y, Liu Y, Chen J, Wang K, Wang Z, Nam Y, Jiang B, Sa JK, Cho HJ, Her NG, Zhang C, Zhao Z, Zhang Y, Zeng F, Wu F, Kang X, Liu Y, Qian Z, Wang Z, Huang R, Wang Q, Zhang W, Qiu X, Li W, Nam DH, Fan X, Wang J, Jiang T. Mutational Landscape of Secondary Glioblastoma Guides MET-Targeted Trial in Brain Tumor. Cell. 2018 Nov 29;175(6):1665-1678.e18. doi: 10.1016/j.cell.2018.09.038. Epub 2018 Oct 18.