Esophageal Squamous Cell Carcinoma
Conditions
Brief summary
This study is an open-label, biomarker-integrated umbrella trial designed to evaluate the clinical efficacy of molecular subtype- and genomic biomarker-guided precision therapies in patients with advanced esophageal cancer refractory to prior immunotherapy. Conducted in a two-step process, the study first enrolls patients with locally advanced or metastatic esophageal squamous cell carcinoma (ESCC) who have progressed on prior immunotherapy, performing circulating tumor DNA (ctDNA) sequencing to stratify them into three distinct treatment cohorts, after which patients receive tailored combination regimens matched to their specific molecular profiling in the second step. Specifically, Cohort 1 includes patients with high EGFR expression or activation of EGFR-related signaling pathways, who will receive Afatinib (40 mg, p.o., Q.D.) combined with Toripalimab (240 mg, i.v., Q21D) in a 21-day treatment cycle, continuing until radiographic disease progression (PD), unacceptable toxicity, loss to follow-up, death, or other investigator-determined criteria for discontinuation, with a maximum toripalimab treatment duration of 24 months. Cohort 2 comprises patients harboring genomic alterations directly associated with cell cycle regulation or activation of cell cycle signaling pathways, who will be treated with Dalpiciclib (125 mg, p.o., Q.D. for 21 consecutive days followed by a 7-day off period in a 28-day cycle \[Q4W\]) combined with Pyrotinib maleate (320 mg, p.o., Q.D., administered within 30 minutes post-meal, Q4W) until disease progression, unacceptable toxicity, initiation of a new anti-tumor therapy, withdrawal of consent, or investigator's decision for treatment discontinuation. Cohort 3 includes patients with other molecular profiles who do not fit Cohorts 1 or 2, who will receive Camrelizumab (200 mg, i.v., Q3W) and Apatinib (250 mg, p.o., Q.D.), with clinical efficacy evaluations performed every 6 weeks, continuing until radiographic PD, unacceptable toxicity, death, or treatment discontinuation, whichever occurs first. The study aims to recruit an estimated maximum of 90 subjects, enrolling up to 30 subjects per cohort, with the final sample size dependent on the observed toxicities and the prevalence of each molecular cohort within the screened population.
Interventions
DRUGCamrelizumab + Apatinib
Patients in this cohort will receive a triple-combination therapy consisting of Camrelizumab (200 mg i.v. every 3 weeks \[Q3W\]), and Apatinib (250 mg p.o. Q.D.). Efficacy evaluations will be performed every 6 weeks. Treatment will continue until radiographic disease progression, unacceptable toxicity, death, or treatment discontinuation, whichever occurs first.
DRUGAfatinib + Toripalimab
Patients in this cohort will receive Afatinib at a dose of 40 mg orally (p.o.) once daily (Q.D.) combined with Toripalimab at a dose of 240 mg intravenously (i.v.) every 3 weeks (Q21D). Treatment will continue in 21-day cycles until radiographic disease progression, unacceptable toxicity, withdrawal of consent, or other discontinuation criteria are met. Toripalimab administration is capped at a maximum duration of 24 months.
Patients will receive Dalpiciclib at a dose of 125 mg p.o. Q.D. for 21 consecutive days followed by a 7-day off period in a 28-day cycle (Q4W), in combination with Pyrotinib maleate at a dose of 320 mg p.o. Q.D. administered within 30 minutes post-meal (Q4W). Treatment will continue until disease progression, unacceptable toxicity, initiation of a new anti-tumor therapy, or withdrawal of consent.
Sponsors
Peking University Cancer Hospital & Institute
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Signed written informed consent from previous studies and age ≥18 years. 2. Histologically or cytologically confirmed esophageal squamous cell carcinoma (ESCC). 3. Locally advanced, unresectable, or metastatic ESCC that progressed on or after standard second-line or later therapy containing immunotherapy (including but not limited to PD-1, PD-L1, CTLA-4 antibodies, or bispecific antibodies). 4. At least one measurable lesion per RECIST 1.1. 5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 6. Anticipated life expectancy ≥12 weeks. 7. Adequate organ and bone marrow function within 14 days prior to the first dose (without blood transfusion, EPO, G-CSF, or other hematologic supports), as defined by: * Absolute neutrophil count (ANC) ≥1.5×109/L * Platelet count ≥100×109/L * Hemoglobin ≥9 g/dL (or ≥5.6 mmol/L) * Serum albumin \>30 g/L * Serum creatinine ≤1.5×ULN (Upper Limit of Normal) or calculated creatinine clearance ≥60 mL/min (using the Cockcroft-Gault formula) * Total bilirubin ≤1.5×ULN * AST and ALT ≤2.5×ULN (≤5.0×ULN for patients with documented liver metastases, provided total bilirubin is within normal limits) * International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5×ULN, and activated Partial Thromboplastin Time (aPTT) ≤1.5×ULN 8. Female patients of childbearing potential (WOCBP) must have a negative pregnancy test within 7 days prior to the first dose. WOCBP and male patients with WOCBP partners must agree to use highly effective contraception from signing the informed consent throughout the treatment period and for at least 6 months after the last dose. (Highly effective methods include oral/implanted hormonal contraceptives, intrauterine devices \[IUDs\], or barrier methods combined with spermicide. Postmenopausal women aged \>50 years must have been amenorrheic for ≥12 months to be considered postmenopausal). 9. Required washout periods prior to the first dose of study treatment are as follows: * Systemic anticancer therapies (chemotherapy, targeted therapy, immunotherapy, biological therapy, or hormonal therapy) or participation in clinical trials: \>4 weeks. * Systemic small-molecule targeted therapies: \>2 weeks or 5 half-lives (whichever is longer). * Prior Chinese herbal medicine with anti-tumor activity: \>2 weeks. * Prior major surgery or radiotherapy: \>4 weeks (palliative radiotherapy for bone metastases: \>2 weeks).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) | 1 year | Progression-Free Survival (PFS) defined as the time from the first dose to the first documented disease progression per RECIST v1.1 or death from any cause, whichever occurs first. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | 1 year | Overall Survival (OS) defined as the time from the first dose to death from any cause. |
| Objective Response Rate (ORR) | 1 year | Objective Response Rate (ORR) as assessed by RECIST v1.1 |
Contacts
CONTACTzhihao Lu
Outcome results
None listed