Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
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.
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.
Not provided
Not provided
Not provided
Not provided
Not provided
| Label | Type | Description | Intervention Names |
|---|---|---|---|
| JS212 + Capecitabine | Experimental | Participants receive JS212 in combination with Capecitabine. |
|
| JS212 +Capecitabine+ Bevacizumab | Experimental | Participants receive JS212 in combination with Capecitabine and Bevacizumab |
|
| JS212 + XELOX | Experimental | Participants receive JS212 in combination with XELOX chemotherapy (capecitabine plus oxaliplatin) |
|
| JS212 + XELOX + JS207 | Experimental | Participants receive JS212 in combination with XELOX chemotherapy and JS207 |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| JS212 | Drug | Bispecific antibody-drug conjugate targeting EGFR and HER3 |
|
| Measure | Description | Time Frame |
|---|---|---|
| Investigator-assessed objective response rate (ORR) | Proportion of participants with confirmed complete response (CR) or partial response (PR) according to RECIST v1.1. | Up to approximately 12 months |
| Safety and Tolerability(AEs) | Incidence and severity of adverse events (AEs) assessed according to CTCAE. | From first dose up to approximately 90 days after last dose |
| Safety and Tolerability(SAEs) | Incidence and severity of serious adverse events (SAEs)assessed according to CTCAE. | From first dose up to approximately 90 days after last dose |
| Safety and Tolerability(DLTs) | Incidence and severity dose-limiting toxicities (DLTs) assessed according to CTCAE. | From first dose up to approximately 90 days after last dose |
| Maximum Tolerated Dose (MTD) | Determination of MTD for JS212 combination therapy. | Up to approximately 6 months |
| Recommended Phase 3 Dose (RP3D) | Determination of RP3D for JS212 combination therapy. | Up to approximately 6 months |
| Measure | Description | Time Frame |
|---|---|---|
| Investigator-assessed objective response rate (DCR) | 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). | Up to approximately 12 months |
| Investigator-assessed Duration of Response (DoR) |
| Measure | Description | Time Frame |
|---|---|---|
| The potential biomarker EGFR | To explore the correlation between screening baseline levels of potential biomarker EGFR and clinical efficacy of JS212 combination therapy. Biomarkers will be assessed only at screening. Screening | Up to approximately 1 months |
| The potential biomarker HER3 |
Inclusion Criteria:
Exclusion Criteria:
Not provided
Not provided
Not provided
Not provided
| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Ying Zhang, Master | Contact | 86 18616904609 | ying_zhang2@junshipharma.com | |
| Huiyu Lan, Master | Contact | 86 15000239047 | huiyu_lan@junshipharma.com |
| Name | Affiliation | Role |
|---|---|---|
| Zhenyu Xu, Doctor | Medical Director | Study Director |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Shanghai East Hospital | Recruiting | Shanghai | Shanghai Municipality | 200123 | China |
Not provided
Not provided
Not provided
Not provided
Not provided
Not provided
| ID | Term |
|---|---|
| D015179 | Colorectal Neoplasms |
| ID | Term |
|---|---|
| D007414 | Intestinal Neoplasms |
| D005770 | Gastrointestinal Neoplasms |
| D004067 | Digestive System Neoplasms |
| D009371 | Neoplasms by Site |
Not provided
Not provided
| ID | Term |
|---|---|
| D000069287 | Capecitabine |
| D000068258 | Bevacizumab |
| D000077150 | Oxaliplatin |
| ID | Term |
|---|---|
| D003841 | Deoxycytidine |
| D003562 | Cytidine |
| D011741 | Pyrimidine Nucleosides |
| D011743 | Pyrimidines |
Not provided
Not provided
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.
Not provided
Not provided
Not provided
| Capecitabine | Drug | Oral fluoropyrimidine chemotherapy |
|
| Bevacizumab | Drug | Humanized anti-VEGF monoclonal antibody |
|
| Oxaliplatin | Drug | Platinum-based chemotherapy administered intravenously |
|
| JS207 | Drug | Bispecific antibody targeting PD-1 and VEGF |
|
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. |
| Up to approximately 12 months |
| Investigator-assessed Progression-Free Survival (PFS) | 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). | Up to approximately 12 months |
| Investigator-assessed overall survival (OS) | The OS is defined as the time from the first administration of the drug to death due to any cause. | Up to approximately 20 months |
| PK of Cmax | Maximum Observed Plasma Concentration (Cmax) of JS212 and JS207 | Up to approximately 12 months |
| PK of AUC | Area Under the Concentration-Time Curve of JS212 and JS207 | Up to approximately 12 months |
| PK of half-time | Terminal Elimination Half-life of JS212 and JS207 | Up to approximately 12 months |
| Immunogenicity | Incidence of anti-drug antibodies (ADA) and neutralizing antibodies. | Up to approximately 12 months |
To explore the correlation between screening baseline levels of potential biomarker HER3 and clinical efficacy of JS212 combination therapy. Biomarkers will be assessed only at screening. Screening |
| Up to approximately 1 months |
| D009369 | Neoplasms |
| D004066 | Digestive System Diseases |
| D005767 | Gastrointestinal Diseases |
| D003108 | Colonic Diseases |
| D007410 | Intestinal Diseases |
| D012002 | Rectal Diseases |
| D006573 |
| Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D005472 | Fluorouracil |
| D014498 | Uracil |
| D011744 | Pyrimidinones |
| D003853 | Deoxyribonucleosides |
| D009705 | Nucleosides |
| D009706 | Nucleic Acids, Nucleotides, and Nucleosides |
| D061067 | Antibodies, Monoclonal, Humanized |
| D000911 | Antibodies, Monoclonal |
| D000906 | Antibodies |
| D007136 | Immunoglobulins |
| D007162 | Immunoproteins |
| D001798 | Blood Proteins |
| D011506 | Proteins |
| D000602 | Amino Acids, Peptides, and Proteins |
| D012712 | Serum Globulins |
| D005916 | Globulins |
| D056831 | Coordination Complexes |
| D009930 | Organic Chemicals |