This is a multicenter, open-label, Phase 1 study. The study will enroll subjects with advanced solid tumors. It consists of six parts. Objectives for Dose-Escalation Parts (Part 1 and Part 4) To evaluate the safety and tolerability of YL211 as monotherapy in patients with selected advanced solid tumors (Part 1) and in combination with pembrolizumab in patients with second or third line locally advanced unresectable or metastatic non-squamous non-small cell lung cancer (NSCLC) (Part 4) To determine the maximum tolerated dose (MTD) and select the recommended expansion dose(s) (RED(s)) of YL211 as monotherapy in patients with advanced solid tumors (Part 1) and in combination with pembrolizumab in patients with second line locally advanced unresectable or metastatic non-squamous NSCLC (Part 4) Objectives for Backfill Enrollment Parts (Part 2 and Part 5) To better estimate and characterize the safety and efficacy of YL211 as monotherapy in patients with metastatic colorectal cancer (mCRC) or locally advanced unresectable or metastatic NSCLC (Part 2) and in combination with pembrolizumab in patients with previously untreated locally advanced unresectable or metastatic non-squamous NSCLC (Part 5) To select the RED(s) of YL211 as monotherapy in patients with metastatic colorectal cancer (mCRC) or locally advanced unresectable or metastatic NSCLC (Part 2) and in combination with pembrolizumab in patients with previously untreated locally advanced unresectable or metastatic non-squamous NSCLC (Part 5) Objectives for the Dose-Expansion Parts (Part 3 and Part 6) To further characterize the safety and efficacy of YL211 as monotherapy (Part 3) in patients with locally advanced unresectable or metastatic non-squamous or squamous NSCLC and in combination with pembrolizumab in patients with previously untreated locally advanced unresectable or metastatic non- squamous NSCLC (Part 6) To compare the clinical activity of YL211 in combination with pembrolizumab against pembrolizumab, pemetrexed, and platinum-based chemotherapy (cisplatin or carboplatin) in participants with previously untreated advanced unresectable or metastatic non-squamous NSCLC (Part 6)
Informed of the trial before the start of the trial and voluntarily sign their name and date on the ICF.
Aged ≥18 years.
Be able and willing to comply with protocol visits and procedures.
Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or
Prior treatment with an agent targeting c-MET (including antibody, ADC, chimeric antigen receptor T cell [CAR-T], and other drugs) with the exception of prior treatment with MET-targeted TKIs which are allowed.
Previously received an ADC consisting of a TopoI
Received continuous systemic steroids therapy for more than 28 days or require long-term (≥ 28 days) use of systemic steroids therapy within 28 days before the first administration, or have other acquired or congenital immune deficiency diseases. (Note: The protocol lists specific situational exceptions immediately following this clause).
A history of leptomeningeal carcinomatosis or carcinomatous meningitis
Parallel
YL211
DrugPatients will be treated with YL211 intravenous (IV) infusion only.
YL211+Pembrolizumab
DrugPatients will be treated with YL211 and Pembro by infusion.
YL211 + Pembro or Pembro+ Pemetrexed + (Carboplatin or Cisplatin)
Drugparticipants will receive therapy YL211 + Pembro or Pembro+ Pemetrexed + (Carboplatin or Cisplatin) by infusion.(Part 6)
6
Treatment groupsSee each treatment group below.
Nature and frequency of adverse events (AEs) with severity determined according to NCI CTCAE v5.0 (Part 1 and Part 4)
AE's
Nature and frequency of dose-limiting toxicities (DLTs) (Part 1 and Part 4)
DLTs
Nature and frequency of AEs with severity, physical examination findings (including ECOG PS), vital sign measurements, standard clinical laboratory parameters, SpO2 measurements, ECG parameters, and ECHO findings (Part 2 and Part 5)
Safety
ORR assessed using RECIST version 1.1 (Part 2 and Part 5)
Efficacy
physical examination findings (including Eastern Cooperative Oncology Group performance status; ECOG PS), vital sign measurements, standard clinical laboratory parameters, SpO2 measurements, ECG parameters, and ECHO findings (Part 1 and Part 4)
other safety endpoints
PK enpoints (Part 1 and Part 4)
Pharmacokinetic endpoints: for each participant will be estimated using standard non-compartmental methods. Descriptive statistics will be provided for all serum concentration data and PK parameter values, with a break down by dose level/cohort as appropriate. PK parameters of YL211-ADC, YL211-TAb, unconjugated payload YL0010014, metabolite YL0010034 and if applicable, other potential metabolite(s), include but not limited to area under the curve (AUC), maximum concentration (Cmax), trough concentration (Ctrough), time of maximum observed concentration (Tmax), clearance (CL), volume of distribution (Vd), and half-life time (t1/2)
Incidence of anti-YL211 antibody (ADA) (Part 1 and Part 4)
ADA
Efficacy endpoints (Part 1 and Part 4)
Tumor response will be evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Efficacy variables include objective response rate (ORR, the sum of complete response \[CR\] rate and partial response \[PR\] rate), disease control rate (DCR, the sum of CR rate, PR rate, and stable disease \[SD\] rate), duration of response (DoR), duration of SD, time to response (TTR), and progression free survival (PFS), overall survival (OS), percent change in target lesion, time on therapy of the most recent prior regimen the participant received and that of YL211. The efficacy variable(s) will be also evaluated at 18 weeks after Day 1 of Cycle 1.
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MediLink Therapeutics (Suzhou) Co., Ltd.
Lead sponsor
Hoffmann-La Roche
Collaborator
