JS212 Combination Therapies in Metastatic Colorectal Cancer

Официальное название

An Open-label, Multicenter Phase 2 Clinical Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of JS212 Combination Therapies in Patients With Metastatic Colorectal Cancer

Обзор

This is an open-label, multicenter Phase 2 clinical study designed to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of JS212-based combination therapies in patients with metastatic colorectal cancer (mCRC). JS212 is a bispecific antibody-drug conjugate (ADC) targeting epidermal growth factor receptor (EGFR) and HER3 with a topoisomerase I inhibitor payload. Preclinical and early clinical data suggest that dual targeting of EGFR and HER3 may enhance antitumor activity and overcome resistance mechanisms associated with EGFR- or HER2-directed therapies. This study will investigate JS212 in combination with capecitabine, with or without Bevacizumab, and JS212 in combination with chemotherapy (XELOX: capecitabine and oxaliplatin), with or without the PD-1/VEGF bispecific antibody JS207, in patients with mCRC. The study will assess safety, determine the recommended Phase 3 dose (RP3D), and evaluate preliminary antitumor activity of the combination regimens.

Подробное описание

JS212 is a bispecific antibody-drug conjugate (ADC) targeting epidermal growth factor receptor (EGFR) and HER3, conjugated with a topoisomerase I inhibitor payload. Activation of EGFR and HER3 signaling pathways plays an important role in tumor development and resistance to anticancer therapies. Dual targeting of these pathways may enhance antitumor activity and broaden the population that may benefit from treatment. Early clinical data from study JS212-001-I/II have demonstrated promising safety and antitumor activity of JS212.

In addition, ADCs may induce immunogenic cell death and enhance antitumor immune responses. Combination therapy with immune checkpoint inhibitors may further enhance therapeutic efficacy. JS207 is a bispecific antibody targeting programmed death-1 (PD-1) and vascular endothelial growth factor (VEGF), which may provide synergistic antitumor effects by simultaneously modulating immune checkpoint signaling and tumor angiogenesis.

This study will evaluate JS212 in combination with capecitabine, with or without Bevacizumab, and JS212 in combination with chemotherapy (capecitabine and oxaliplatin, XELOX), with or without JS207, in patients with mCRC.

The study includes 4 cohorts:

Cohort 1: JS212 in combination with capecitabine. A dose-escalation phase using a Bayesian optimal interval (BOIN) design will be conducted to determine the maximum tolerated dose (MTD) and recommended Phase 3 dose (RP3D), followed by a dose-expansion phase to further evaluate safety and efficacy.

Cohort 2: JS212 in combination with capecitabine and Bevacizumab. A safety run-in phase will be conducted to evaluate tolerability of the triple combination, followed by a dose-expansion phase to further assess safety and preliminary antitumor activity.

Cohort 3: JS212 in combination with XELOX chemotherapy. safety run-in phase will be conducted to evaluate tolerability of the triple combination, followed by a dose-expansion phase to further assess safety and preliminary antitumor activity.

Cohort 4: JS212 in combination with XELOX chemotherapy and JS207. A safety run-in phase will be conducted to evaluate tolerability of the triple combination, followed by a dose-expansion phase to further assess safety and preliminary antitumor activity.

Eligible participants include adults with histologically confirmed metastatic colorectal adenocarcinoma that is microsatellite stable or mismatch repair proficient and who have not received prior systemic therapy for advanced disease.

The study will evaluate safety, pharmacokinetics, immunogenicity, and preliminary efficacy outcomes including objective response rate (ORR), duration of response (DoR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) based on RECIST version 1.1.

Вмешательства

• Препарат JS212
  Bispecific antibody-drug conjugate targeting EGFR and HER3
• Препарат Capecitabine
  Oral fluoropyrimidine chemotherapy
• Препарат Bevacizumab
  Humanized anti-VEGF monoclonal antibody
• Препарат Oxaliplatin
  Platinum-based chemotherapy administered intravenously
• Препарат JS207
  Bispecific antibody targeting PD-1 and VEGF

Первичные конечные точки

• Investigator-assessed objective response rate (ORR) [Срок оценки: Up to approximately 12 months]
• Safety and Tolerability(AEs) [Срок оценки: From first dose up to approximately 90 days after last dose]
• Safety and Tolerability(SAEs) [Срок оценки: From first dose up to approximately 90 days after last dose]
• Safety and Tolerability(DLTs) [Срок оценки: From first dose up to approximately 90 days after last dose]
• Maximum Tolerated Dose (MTD) [Срок оценки: Up to approximately 6 months]
• Recommended Phase 3 Dose (RP3D) [Срок оценки: Up to approximately 6 months]

Вторичные конечные точки (8)

• Investigator-assessed objective response rate (DCR) [Срок оценки: Up to approximately 12 months]
• Investigator-assessed Duration of Response (DoR) [Срок оценки: Up to approximately 12 months]
• Investigator-assessed Progression-Free Survival (PFS) [Срок оценки: Up to approximately 12 months]
• Investigator-assessed overall survival (OS) [Срок оценки: Up to approximately 20 months]
• PK of Cmax [Срок оценки: Up to approximately 12 months]
• PK of AUC [Срок оценки: Up to approximately 12 months]
• PK of half-time [Срок оценки: Up to approximately 12 months]
• Immunogenicity [Срок оценки: Up to approximately 12 months]

Критерии участия

Критерии включения

• 1Participants must meet the following key criteria
• Adults aged 18-75 years with histologically confirmed metastatic colorectal adenocarcinoma
• Microsatellite stable (MSS) or mismatch repair proficient (pMMR) disease
• No prior systemic therapy for advanced or metastatic disease
• At least one measurable lesion according to RECIST v1.1
• ECOG performance status 0-1
• Adequate hematologic, hepatic, renal, and coagulation function
• Life expectancy ≥12 weeks
• Willingness to provide tumor tissue samples for biomarker analyses
• Ability to provide written informed consent

Критерии исключения

• Participants meeting any of the following criteria will be excluded
• Prior treatment with EGFR- or HER3-targeted antibody-drug conjugates or topoisomerase I inhibitor-based ADCs
• Recent major surgery, radiotherapy, or systemic anticancer therapy prior to study treatment
• Active or uncontrolled infections or significant cardiovascular disease
• Known active central nervous system metastases
• History of autoimmune disease requiring systemic therapy
• Significant bleeding disorders or high risk of hemorrhage
• Active viral infections such as uncontrolled hepatitis B, hepatitis C, or HIV
• Any other serious medical or psychiatric condition that may interfere with study participation

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Нерандомизированное

Модель

Параллельные группы

Маскирование

Простое слепое

Основная цель

Лечение

Центры проведения

Китай · 1 центр

• Shanghai East Hospital — Шанхай

Идентификаторы

NCT: NCT07503756 · JS212-005-II-CRC

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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