larotinib (Z650) / Sunshine Lake Pharma - LARVOL DELTA

Design, synthesis, and biological evaluation of novel 4-aminoquinoline benzoyl hydrazine derivatives as noncovalent BTK inhibitors for hematologic malignancies. (PubMed, Eur J Med Chem) - "Systematic optimization yielded compound 10m, which exhibited moderate but promising BTK inhibitory activity (IC50 = 126.70 ± 16.69 nM), acceptable kinase selectivity with reduced activity against key off-targets of ibrutinib (EGFR, ITK, BMX, TEC), and potent antiproliferative activity in U-937 cells (IC50 = 0.89 ± 0.01 μM). Molecular docking studies showed that 10m retains the binding mode of larotinib while forming additional hydrogen bonds, consistent with a reversible binding mode supported by docking and positioned away from Cys481. These results validate the design strategy and position 10m as a promising lead for next-generation non-covalent BTK inhibitors for the treatment of hematologic malignancies."

Journal • Hematological Disorders • Hematological Malignancies • Oncology • EGFR

An Effective and Systematic Strategy for Metabolic Profiling of Golvatinib In Vitro by Combining UHPLC-MS/MS and UHPLC-Q-Orbitrap-HRMS. (PubMed, J Sep Sci) - "Detection was carried out by multiple reaction monitoring mode using the transitions m/z 634.3→184.2 for golvatinib and m/z 650.3→200.2 for golvatinib N-oxide. Further study demonstrated that CYP3A4 was the principal enzyme involved in metabolizing golvatinib. To the best of our knowledge, this is the first report combining ultra-high-performance liquid chromatography-tandem MS (UHPLC-MS/MS) with UHPLC-Quadrupole-Orbitrap-HRMS for profiling golvatinib metabolism in vitro, thereby laying a foundation for subsequent pharmacokinetic study."

Journal • Preclinical • Hepatocellular Cancer • Oncology • Solid Tumor • CYP3A4

Quantification of PEG2000-DMG and TS-202, an ionic lipid, in rabbit plasma by LC-MS/MS: Application to complement C5 siRNA lipid nanoparticles. (PubMed, J Pharm Biomed Anal) - "A simple and robust assay was developed for the quantification of PEG2000-DMG and TS-202, key components of the lipid nanoparticle (LNP) formulation of E8001-LNP, which encapsulates small-interfering RNA targeting complement C5, in rabbit plasma...Detection was performed using selected reaction monitoring in positive ion mode, with mass transitions of m/z 780.8 → 698.9 for PEG2000-DMG and m/z 650.5 → 126.3 for TS-202...Application to a toxicokinetic study in rabbits revealed that PEG2000-DMG was eliminated much faster than TS-202. The incurred sample reanalysis further confirmed the assay reproducibility."

Journal • Preclinical

Study of Larotinib in Unresectable Advanced or Recurrent Esophageal Cancer (clinicaltrials.gov) - P3 | N=416 | Recruiting | Sponsor: Sunshine Lake Pharma Co., Ltd. | Trial completion date: Nov 2023 ➔ Dec 2026 | Trial primary completion date: Aug 2023 ➔ Aug 2026

Trial completion date • Trial primary completion date • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Oncology • Squamous Cell Carcinoma • EGFR

A Study to Evaluate Drug-Drug Interaction of Larotinib With Itraconazole and Rifampin in Healthy Adult Participants (clinicaltrials.gov) - P1 | N=32 | Completed | Sponsor: Sunshine Lake Pharma Co., Ltd. | Active, not recruiting ➔ Completed

Trial completion

Pharmacokinetics Study of Larotinib in Subjects With Impaired Hepatic Function (clinicaltrials.gov) - P1 | N=32 | Not yet recruiting | Sponsor: Sunshine Lake Pharma Co., Ltd. | Trial completion date: Dec 2024 ➔ Dec 2026 | Trial primary completion date: Dec 2024 ➔ Dec 2026

Trial completion date • Trial primary completion date • Esophageal Cancer • Hepatology • Oncology • Solid Tumor

Molecular Subtyping and Genomic Profiling Expand Precision Medicine in KRAS Wild-Type Pancreatic Cancer. (PubMed, Cancer Sci) - "Kinase fusions (NTRK and RET) were linked to response to larotinib and RET-specific inhibitors, respectively. KRAS-WT PDAC contains actionable mutations and fusions, offering significant potential for targeted and immune-based therapies. Further clinical studies are needed to validate these therapeutic approaches."

IO biomarker • Journal • Hepatology • Oncology • Pancreatic Adenocarcinoma • Pancreatic Cancer • Pancreatic Ductal Adenocarcinoma • Solid Tumor • ARID1A • CCDC6 • ETV6 • HRD • KMT2C • KRAS • NTRK • NTRK3 • PIK3CA • ROS1

Precision Treatment of Recurrent/Metastatic Salivary Gland Carcinoma Guided by Molecular Typing (clinicaltrials.gov) - P2 | N=10 | Recruiting | Sponsor: Peking Union Medical College | N=30 ➔ 10

Enrollment change • Metastases • Oncology • Salivary Gland Cancer

Precision Treatment of Recurrent/Metastatic Salivary Gland Carcinoma Guided by Molecular Typing (clinicaltrials.gov) - P2 | N=30 | Recruiting | Sponsor: Peking Union Medical College | Initiation date: Dec 2023 ➔ May 2024

Metastases • Trial initiation date • Oncology • Salivary Gland Cancer

Precision Treatment of Recurrent/Metastatic Salivary Gland Carcinoma Guided by Molecular-based Stagingcarcinoma (clinicaltrials.gov) - P2 | N=30 | Recruiting | Sponsor: Peking Union Medical College

New P2 trial • Oncology • Salivary Gland Cancer

Z650 in Advanced Esophageal Squamous Cell Carcinoma With EGFR Over Expression or Gene Amplification (clinicaltrials.gov) - P1/2 | N=81 | Completed | Sponsor: Sunshine Lake Pharma Co., Ltd. | Recruiting ➔ Completed | N=45 ➔ 81 | Trial completion date: Apr 2023 ➔ Dec 2022

Enrollment change • Metastases • Trial completion • Trial completion date • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Oncology • Solid Tumor • Squamous Cell Carcinoma • EGFR

ADME Study of [14C]- Larotinib in Healthy Male Subjects (clinicaltrials.gov) - P1 | N=6 | Completed | Sponsor: Sunshine Lake Pharma Co., Ltd. | Active, not recruiting ➔ Completed

Trial completion

Pharmacokinetics Study of Larotinib in Subjects With Impaired Hepatic Function (clinicaltrials.gov) - P1 | N=32 | Not yet recruiting | Sponsor: Sunshine Lake Pharma Co., Ltd. | Trial completion date: Nov 2023 ➔ Dec 2024 | Trial primary completion date: Nov 2023 ➔ Dec 2024

Trial completion date • Trial primary completion date • Esophageal Cancer • Gastrointestinal Cancer • Hepatology • Oncology • Solid Tumor

A Study to Evaluate Drug-Drug Interaction of Larotinib With Itraconazole and Rifampin in Healthy Adult Participants (clinicaltrials.gov) - P1 | N=32 | Active, not recruiting | Sponsor: Sunshine Lake Pharma Co., Ltd. | Trial completion date: Oct 2022 ➔ Mar 2023 | Trial primary completion date: Aug 2022 ➔ Jan 2023

Trial completion date • Trial primary completion date

Study of Larotinib in Unresectable Advanced or Recurrent Esophageal Cancer (clinicaltrials.gov) - P3 | N=416 | Recruiting | Sponsor: Sunshine Lake Pharma Co., Ltd. | Trial completion date: Nov 2022 ➔ Nov 2023 | Trial primary completion date: Aug 2022 ➔ Aug 2023

Trial completion date • Trial primary completion date • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Gastrointestinal Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • EGFR

Z650 in Advanced Esophageal Squamous Cell Carcinoma With EGFR Over Expression or Gene Amplification (clinicaltrials.gov) - P1/2 | N=45 | Recruiting | Sponsor: Sunshine Lake Pharma Co., Ltd. | Active, not recruiting ➔ Recruiting | Trial completion date: Jun 2021 ➔ Apr 2023 | Trial primary completion date: Apr 2021 ➔ Dec 2022

Enrollment open • Trial completion date • Trial primary completion date • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Oncology • Solid Tumor • Squamous Cell Carcinoma • EGFR

A Study to Evaluate Drug-Drug Interaction of Larotinib With Itraconazole and Rifampin in Healthy Adult Participants (clinicaltrials.gov) - P1 | N=32 | Active, not recruiting | Sponsor: Sunshine Lake Pharma Co., Ltd. | Not yet recruiting ➔ Active, not recruiting | Trial completion date: Jun 2022 ➔ Oct 2022 | Trial primary completion date: Mar 2022 ➔ Aug 2022

Enrollment closed • Trial completion date • Trial primary completion date

Pharmacokinetics Study of Larotinib in Subjects With Impaired Hepatic Function (clinicaltrials.gov) - P1 | N=32 | Not yet recruiting | Sponsor: Sunshine Lake Pharma Co., Ltd. | Initiation date: Nov 2021 ➔ Nov 2022

Trial initiation date • Esophageal Cancer • Gastrointestinal Cancer • Hepatology • Oncology • Solid Tumor

Gemcitabine and Z650 in Treating Patients With Metastatic or Recurrent Pancreatic Cancer (clinicaltrials.gov) - P1 | N=13 | Terminated | Sponsor: Sunshine Lake Pharma Co., Ltd. | N=45 ➔ 13 | Trial completion date: Mar 2022 ➔ Sep 2021 | Recruiting ➔ Terminated | Trial primary completion date: Dec 2021 ➔ Sep 2021; Combined with the analysis of the existing data of the trial, there was no obvious advantage compared with the clinical standard treatments, and the clinical trial was decided to be terminated based on the benefit of the subjects.

Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor

ADME Study of [14C]- Larotinib in Healthy Male Subjects (clinicaltrials.gov) - P1 | N=6 | Active, not recruiting | Sponsor: Sunshine Lake Pharma Co., Ltd. | Not yet recruiting ➔ Active, not recruiting | Trial primary completion date: Dec 2022 ➔ Jan 2022

Enrollment closed • Trial primary completion date

Larotinib in patients with advanced and previously treated esophageal squamous cell carcinoma with epidermal growth factor receptor overexpression or amplification: an open-label, multicenter phase 1b study. (PubMed, BMC Gastroenterol) - P1/2 | "Larotinib demonstrated promising antitumor activity and manageable safety profiles in patients with pre-treated advanced ESCC with EGFR overexpression or amplification, especially at the dose of 350 mg, which showed better efficacy and acceptable safety. A phase 3 study is underway on 350 mg larotinib in ESCC patients with EGFR overexpression."

Clinical • Journal • P1 data • P1 data • Dermatology • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Oncology • Squamous Cell Carcinoma • EGFR

ADME Study of [14C]- Larotinib in Healthy Male Subjects (clinicaltrials.gov) - P1; N=8; Not yet recruiting; Sponsor: Sunshine Lake Pharma Co., Ltd.

Clinical • New P1 trial

Z650: A Study to Evaluate Drug-Drug Interaction of Larotinib With Itraconazole and Rifampin in Healthy Adult Participants (clinicaltrials.gov) - P1; N=32; Not yet recruiting; Sponsor: Sunshine Lake Pharma Co., Ltd.

Clinical • New P1 trial

Pharmacokinetics Study of Larotinib in Subjects With Impaired Hepatic Function (clinicaltrials.gov) - P1; N=32; Not yet recruiting; Sponsor: Sunshine Lake Pharma Co., Ltd.

Clinical • New P1 trial • Esophageal Cancer • Gastrointestinal Cancer • Hepatology • Oncology • Solid Tumor

Z650 in Advanced Esophageal Squamous Cell Carcinoma With EGFR Over Expression or Gene Amplification (clinicaltrials.gov) - P1/2; N=45; Active, not recruiting; Sponsor: Sunshine Lake Pharma Co., Ltd.; Trial completion date: Dec 2020 ➔ Jun 2021; Trial primary completion date: Dec 2020 ➔ Apr 2021

Clinical • Trial completion date • Trial primary completion date • Esophageal Cancer • Esophageal Squamous Cell Carcinoma • Oncology • Solid Tumor • Squamous Cell Carcinoma