Safety,Tolerability, Pharmacokinetics, and Efficacy of YL211 in Patients With Advanced Solid Tumors

Official title

A Phase 1, Multicenter, Open-Label, First-in-Human Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Efficacy of YL211 in Patients With Advanced Solid Tumors

Overview

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)

Interventions

• Drug YL211
  Patients will be treated with YL211 intravenous (IV) infusion only.
• Drug YL211+Pembrolizumab
  Patients will be treated with YL211 and Pembro by infusion.
• Drug YL211 + Pembro or Pembro+ Pemetrexed + (Carboplatin or Cisplatin)
  participants will receive therapy YL211 + Pembro or Pembro+ Pemetrexed + (Carboplatin or Cisplatin) by infusion.(Part 6)

Primary outcome measures

• Nature and frequency of adverse events (AEs) with severity determined according to NCI CTCAE v5.0 (Part 1 and Part 4) [Time frame: Approximately within 36 months]
• Nature and frequency of dose-limiting toxicities (DLTs) (Part 1 and Part 4) [Time frame: Approximately within 36 months]
• 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) [Time frame: Approximately within 36 months]
• ORR assessed using RECIST version 1.1 (Part 2 and Part 5) [Time frame: Approximately within 36 months]
• PFS using RECIST version 1.1 defined as the time interval of randomization to the date of first documentation of PD or death due to any cause, whichever occurs first (Part 3 and Part 6) [Time frame: approximately 36 months]
• 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 3 and Part 6) [Time frame: approximately within 36 months]

Secondary outcome measures (12)

• 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) [Time frame: Approximately within 36 months]
• PK enpoints (Part 1 and Part 4) [Time frame: Approximately within 36 months]
• Incidence of anti-YL211 antibody (ADA) (Part 1 and Part 4) [Time frame: Approximately within 36 months]
• Efficacy endpoints (Part 1 and Part 4) [Time frame: approximately 36 months]
• PK parameters of YL211-ADC, YL211-TAb, unconjugated payload YL0010014, and if applicable, potential metabolite(s), including but not limited to AUC, Cmax, Ctrough, Tmax, CL, Vd, and t1/2 (Part 2 and Part 5) [Time frame: approximately 36 months]
• DCR, DoR, TTR, PFS, OS, and best tumor response assessed using RECIST version 1.1 (Part 2 and Part 5) [Time frame: approximately 36mo]
• Incidence of ADA (Part 2 and Part 5) [Time frame: approximately 36mo]
• c-MET protein expression level in tumor tissues and its relationship with efficacy endpoints (Part 5) [Time frame: approximately 36mo]
• Plasma or serum concentration of YL211-ADC, YL211-TAb, unconjugated payload YL0010014, and if applicable, potential metabolite(s), at specified time points (Part 3 and Part 6) [Time frame: approximately 36mo]
• Incidence of ADA (Part 3 and Part 6) [Time frame: approximately 36mo]
• ORR, DCR, DoR, TTR, OS, and best tumor response assessed using RECIST version 1.1 (Part 3 and Part 6) [Time frame: approximately 36mo]
• c-MET protein expression level in tumor tissues and its relationship with efficacy endpoints (Part 3 and Part 6) [Time frame: Approximately 36mo]

Eligibility criteria

Inclusion criteria

• 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
• Adequate organ and bone marrow function.

For Part 1: History of an advanced solid tumors (including locally advanced unresectable or metastatic NSCLC, metastatic colorectal carcinoma (mCRC), advanced gastric adenocarcinoma (GAC)/ gastroesophageal junction adenocarcinoma (GEJA), pancreatic ductal adenocarcinoma (PDAC), hepatocellular carcinoma (HCC), intrahepatic biliary tract cancer (ih-BTC), and head and neck squamous cell carcinoma (HNSCC) who failed currently available standard therapies and are not amenable to surgical resection, or for whom no available standard therapy or no other approved therapeutic options that have demonstrated clinical benefit.

For Part 2: For patients with CRC: History of histologically or cytologically confirmed diagnosis of metastatic CRC and at least 2 prior regimens of standard treatment For patients with NSCLC: History of histologically or cytologically confirmed diagnosis of locally advanced unresectable or metastatic NSCLC and no more than 2 lines of prior cytotoxic systemic therapy in the locally advanced or metastatic setting.

For Part 3: History of histologically or cytologically confirmed diagnosis of locally advanced unresectable or metastatic non-squamous (Part 3A) or squamous (Part 3B) NSCLC and no more than 2 lines of prior systemic therapy

For Part 4: History of histologically or cytologically confirmed diagnosis of locally advanced unresectable or metastatic non-squamous NSCLC who have progressed on or after 1 or 2 prior lines of systemic therapy

For Part 5 and Part 6 Histologically or cytologically documented locally advanced unresectable or metastatic non-squamous NSCLC that is not eligible for curative surgery and/or definitive chemoradiotherapy and no prior systemic treatment for advanced unresectable or metastatic NSCLC

Exclusion criteria

• 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
• Brain metastasis, except for the following situations:

Participants with asymptomatic brain metastasis who do not require immediate local or systemic treatment (such as mannitol or steroids, surgery, or radiotherapy) are allowed to be enrolled If the participant's brain metastasis is treated and the condition of the metastasis is stable (brain imaging examination at least 2 weeks before the first administration shows that the lesion is stable, there is no evidence of new or original brain metastasis enlargement, there are no new neurological symptoms, and immediate local or systemic treatment is not required), admission is allowed

• Clinically significant concomitant pulmonary disease, including but not limited to:

A history of drug-induced pneumonitis A history of (non-infectious) interstitial lung disease (ILD)/pneumonitis that requires steroids, current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Single group

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 11 centers

• University of Colorado Hospital - Anschutz Cancer Pavilion — Aurora
• Sarah Cannon Research Institute (SCRI) at HealthONE — Denver
• Yale School of Medicine - Yale Cancer Center - Smilow Cancer Hospital Care Centers - North — North Haven
• Sarah Cannon Research Institute at Florida Cancer Specialists — Orlando
• Florida Cancer Specialists & Research Institute (FCS) - Sarasota Cattlemen Office — Sarasota
• Comprehensive Cancer Centers of Nevada (CCCN) - Central Valley — Las Vegas
• University of Cincinnati Vontz Center for Molecular Studies — Cincinnati
• The University of Texas - MD Anderson Cancer Center — Houston
• … and 3 more centers

China · 5 centers

• China-Japan Friendship Hospital — Beijing
• The First Affiliated Hospital - Zhejiang University School of Medicine — Hangzhou
• Wenzhou Medical University - The First Affiliated Hospital — Wenzhou
• West China Hospital, Sichuan University — Chengdu
• Sun Yat-sen University Cancer Center — Guangzhou

Australia · 3 centers

• Gosford Hospital — Gosford
• One Clinical Research - Nedlands — Nedlands
• Monash Health — Melbourne

Canada · 2 centers

• Princess Margaret Hospital — Toronto
• The Ottawa Hospital - General Campus — Ottawa

Identifiers

NCT: NCT06384352 · YL211-INT-101-01

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗