Phase I Study of a Selective ALK Inhibitor PLB1003 in Patients With ALK+ NSCLC.

Study Overview
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Brief Summary
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This phase I, first-in-human 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 PLB1003.

Detailed Description
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This is a Phase I, open-label study of PB1003 administered orally to patients with ALK-positive (ALK+) advanced NSCLC. The study includes a Dose-escalation Part (part A) and a Dose Expansion Part (part B). The aim of the part A is to estimate the MTD and to identify the dose limited toxicity(DLT) and the recommended phase II dose (RP2D) for PLB1003 single agent as well as to determine the PK/PD profile. Once response has been observed in certain dose level, then followed by the expansion part to further assess the clinical efficacy and safety of PLB1003 single agent. Aprox 40 patients will be enrolled in PART A, while 12-24 patients for expansion cohort . PLB1003 is a potent selective ALK inhibitor. PLB1003 acts on cancer by blocking abnormal ALK-mediated signaling, leading to profound tumour growth inhibition in xenografts of non-small cell lung cancer (NSCLC) tumours.

Official Title
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A Phase I Open-label, Multicenter Dose Escalation Study to Assess the Safety, Tolerability and Pharmacokinetics (PK) of PLB1003 in Patients With ALK-positive (ALK+) Advanced Non-small Cell Lung Cancer (NSCLC)

Conditions
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Non-Small Cell Lung Cancer

Intervention / Treatment
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* Drug: PLB1003


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed Informed Consent Form Age≥18 years Diagnosed with a locally advanced or metastatic non-small cell lung cancer that has progressed despite standard therapy. Must have evidence of ALK positivity from the results of molecular pre-screening evaluations At least one measurable lesion as per RECIST v1.1 Patients must have recovered from all toxicities related to prior anticancer therapies to grade ≤ 1 ECOG Performance Status of 0-2 Exclusion Criteria: Symptomatic central nervous system (CNS) metastases that are neurologically unstable or requiring increasing doses of steroids to control, and patients with any CNS deficits. Clinically significant, uncontrolled heart diseases. Unstable angina. History of documented congestive heart failure (New York Heart Association functional classification III-IV) . Active peptic ulcer disease or gastritis Major surgery within 4 weeks prior to starting PLB1003 Previous anti-cancer and investigational agents within 4 weeks before first dose of PLB1003.. Pregnant or nursing women Involved in other clinical trials < 30 days prior to Day 1

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: PLB1003<br>ALK-positive (ALK+) advanced NSCLC | Drug: PLB1003<br>* PLB1003 is a capsule and is administered orally.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Dose Limiting Toxicities (DLTs) . | The maximum tolerated dose (MTD) was defined as the highest dose for a given schedule that was expected to cause DLTs in no more than 33% of patients during the first cycle of treatment. | 18 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the plasma concentration versus time curve (AUC) of PLB1003 and its metabolite. | In the study of PK Run-in period, full Pharmacokinetics (PK) profiles of PLB1003 will be obtained following administration of a single oral dose of PLB1003 on Day 1 to Day 2. At multiple-dose, Pharmacokinetics (PK) sampling will include a pre-dose and at the 0.5, 2, 3,4, 6, 9, 10, 12 and 24 hour time points on days 1, 22 of dosing in the first 21-Day cycle of Treatment period, and pre-dose on days 16, 17 and 18 of the first 21-Day cycle of Treatment period. | Day 1-3 PK Run-in period and Day 1-21 Treatment period | 
| Maximum plasma concentration observed (Cmax) of PLB1003 and its metabolite. | In the study of PK Run-in period, full Pharmacokinetics (PK) profiles of PLB1003 will be obtained following administration of a single oral dose of PLB-1003 on Day 1 to Day 2. At multiple-dose, Pharmacokinetics (PK) sampling will include a pre-dose and at the 0.5, 2, 3,4, 6, 9, 10, 12 and 24 hour time points on days 1, 22 of dosing in the first 21-Day cycle of Treatment period, and pre-dose on days 16, 17 and 18 of the first 21-Day cycle of Treatment period. | Day 1-3 PK Run-in period and Day 1-21 Treatment period | 
| Time to Cmax (Tmax) of PLB1003 and its metabolite. | In the study of PK Run-in period, full Pharmacokinetics (PK) profiles of PLB1003 will be obtained following administration of a single oral dose of PLB-1003 on Day 1 to Day 2. At multiple-dose, Pharmacokinetics (PK) sampling will include a pre-dose and at the 0.5, 2, 3,4, 6, 9, 10, 12 and 24 hour time points on days 1, 22 of dosing in the first 21-Day cycle of Treatment period, and pre-dose on days 16, 17 and 18 of the first 21-Day cycle of Treatment period. | Day 1-3 PK Run-in period and Day 1-21 Treatment period | 
| Preliminary antitumor activity of PLB1003. | Preliminary antitumor activity of PLB1003 assessed using RECIST1.1. | 30 months. |