Metastatic Colorectal Cancer
Conditions
Brief summary
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.
Detailed description
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.
Interventions
Sponsors
Shanghai Junshi Bioscience Co., Ltd.
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Intervention model description
This is a phaseII, open-label, multicenter study in previously untreated MSS/pMMR advanced colorectal cancer, evaluating JS212+Capecitabine (Cohort 1), JS212+Capecitabine+Bevacizumab (Cohort 2), JS212 + XELOX (Cohort 3) and JS212 + XELOX + JS207 (Cohort 4). Cohort 1: A dose-escalation phase (JS212 Q3W +Capecitabine) will select 1-2 RP2Ds, followed by a dose-expansion phase to assess safety, efficacy. Cohort 2: After confirming Cohort 1's RP2D, a safety lead-in phase will evaluate JS212 (RP2D) + Capecitabine + Bevacizumab Q3W. A dose-expansion phase will further assess safety, efficacy. Cohort 3: After confirming Cohort 1's RP2D, a safety lead-in phase will evaluate JS212 (RP2D) + XELOX Q3W. A dose-expansion phase will further assess safety, efficacy. Cohort 4: After confirming Cohort 1's RP2D, a safety lead-in phase will evaluate JS212 (RP2D) + XELOX + JS207 Q3W. A dose-expansion phase will further assess safety, efficacy.
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* 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
Exclusion criteria
* 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Investigator-assessed objective response rate (ORR) | Up to approximately 12 months | Proportion of participants with confirmed complete response (CR) or partial response (PR) according to RECIST v1.1. |
| Safety and Tolerability(AEs) | From first dose up to approximately 90 days after last dose | Incidence and severity of adverse events (AEs) assessed according to CTCAE. |
| Safety and Tolerability(SAEs) | From first dose up to approximately 90 days after last dose | Incidence and severity of serious adverse events (SAEs)assessed according to CTCAE. |
| Safety and Tolerability(DLTs) | From first dose up to approximately 90 days after last dose | Incidence and severity dose-limiting toxicities (DLTs) assessed according to CTCAE. |
| Maximum Tolerated Dose (MTD) | Up to approximately 6 months | Determination of MTD for JS212 combination therapy. |
| Recommended Phase 3 Dose (RP3D) | Up to approximately 6 months | Determination of RP3D for JS212 combination therapy. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Investigator-assessed objective response rate (DCR) | Up to approximately 12 months | The DCR is defined as the proportion of subjects whose Best Overall Response (BOR) is Complete Response (CR), Partial Response (PR), or Stable Disease (SD). |
| Investigator-assessed Duration of Response (DoR) | Up to approximately 12 months | The DoR is defined as the time from the first occurrence of CR or PR to the first occurrence of Progressive Disease (PD) or death (whichever occurs first). The DoR is only applicable to subjects whose BOR is CR or PR. |
| Investigator-assessed Progression-Free Survival (PFS) | Up to approximately 12 months | The PFS is defined as the time from the first administration of the drug to the first documented disease progression (PD) according to the RECIST v1.1 criteria or death due to any disease (whichever occurs first). |
| Investigator-assessed overall survival (OS) | Up to approximately 20 months | The OS is defined as the time from the first administration of the drug to death due to any cause. |
| PK of Cmax | Up to approximately 12 months | Maximum Observed Plasma Concentration (Cmax) of JS212 and JS207 |
| PK of AUC | Up to approximately 12 months | Area Under the Concentration-Time Curve of JS212 and JS207 |
| PK of half-time | Up to approximately 12 months | Terminal Elimination Half-life of JS212 and JS207 |
| Immunogenicity | Up to approximately 12 months | Incidence of anti-drug antibodies (ADA) and neutralizing antibodies. |
Countries
China
Contacts
CONTACTYing Zhang, Master
CONTACTHuiyu Lan, Master
STUDY_DIRECTORZhenyu Xu, Doctor
Medical Director
Outcome results
None listed