Dual-Targeting CAR-NK Cells in Biomarker-Selected Advanced Colorectal Cancer (DUO-CRC-NK-111)
A Phase 1/2, Biomarker-Assigned, Open-Label Dose Escalation and Expansion Study of Allogeneic Dual-Target CAR-NK Cells Targeting CEA (CEACAM5) and/or GUCY2C (GCC) With an Exploratory HER2/ERBB2-Positive Cohort in Subjects With Advanced or Metastatic Colorectal Cancer
Aperçu de l'étude
Statut
Les conditions
Intervention / Traitement
Description détaillée
Colorectal cancer remains a major cause of cancer-related morbidity and mortality. CAR-NK therapy is being explored as a potentially safer, 'off-the-shelf' adoptive cell therapy platform with lower risk of graft-versus-host disease and typically less severe cytokine release than CAR-T in early experiences.
Target selection for solid tumors is limited by tumor heterogeneity and on-target/off-tumor expression. To reduce antigen escape and increase tumor selectivity, this study tests dual-target recognition against CRC-associated antigens: CEA (CEACAM5) and GUCY2C (GCC), with a HER2/ERBB2-positive subset as an exploratory population. GUCY2C is frequently retained in primary and metastatic CRC and is a well-established CRC target antigen. HER2 amplification/overexpression occurs in a minority of metastatic CRC and can be identified by validated IHC/ISH or genomic assays.
Biomarker assessment and target-pair selection: Tumor tissue (archival or fresh) is tested by central laboratory immunohistochemistry (IHC) for CEA and GUCY2C, and by HER2 testing per colorectal cancer criteria (IHC with reflex amplification testing as needed). Participants must meet co-expression thresholds for one antigen pair and are assigned accordingly. After Part A (dose escalation), a prespecified selection algorithm will nominate the target pair for expansion using a composite score including DLT rate, feasibility/manufacturing success, ORR/DCR signals, CAR-NK persistence, and evidence of target engagement. Treatment plan: Participants receive lymphodepleting chemotherapy followed by infusion of the assigned dual-target CAR-NK cells. A second infusion in the same cycle may be permitted in selected dose levels if safety criteria are met. Hospitalization/close monitoring is required during the early post-infusion period.
Type d'étude
Inscription (Estimé)
Phase
- Phase 2
- La phase 1
Contacts et emplacements
Coordonnées de l'étude
- Nom: Seni S Lu, Phd
- Numéro de téléphone: +86 13076790030
- E-mail: Seni-Lu@beijing-biotech.com
Lieux d'étude
-
-
Guangdong
-
Shenzhen, Guangdong, Chine, 518036
- Recrutement
- Peking University Shenzhen Hospital
-
Contact:
- Zhen J Peng, Phd
- Numéro de téléphone: +86 13076790039
- E-mail: Zhen-Peng@beijing-biotech.com
-
-
Critères de participation
Critère d'éligibilité
Âges éligibles pour étudier
- Adulte
- Adulte plus âgé
Accepte les volontaires sains
La description
Inclusion Criteria:
- Histologically confirmed colorectal adenocarcinoma that is unresectable or metastatic and has progressed after, is intolerant to, or is ineligible for standard therapies.
- Measurable disease per RECIST v1.1 (unless in minimal residual disease (MRD) or post-resection cohorts if a future amendment is planned).
- Tumor antigen co-expression meeting central lab thresholds for one of the following pairs: CEA+GUCY2C, CEA+HER2, or GUCY2C+HER2.
- ECOG performance status 0-1.
- Adequate organ function (hematologic, renal, hepatic, and cardiac) as defined in protocol.
- Recovered to Grade ≤1 from prior therapy-related toxicities (except stable Grade 2 neuropathy or alopecia).
- Life expectancy ≥ 12 weeks.
- Willingness to use effective contraception during study and for a protocol-defined period after cell infusion.
Exclusion Criteria:
- Active, uncontrolled infection (including uncontrolled HBV/HCV) or known uncontrolled HIV infection.
- Active CNS metastases that are symptomatic or require escalating steroids. (Stable treated CNS disease may be allowed per protocol.)
- Prior gene-modified cellular therapy (CAR-T/CAR-NK/TCR-T) within 6 months, or any prior therapy that in the investigator's judgment increases risk of severe toxicity.
- Clinically significant autoimmune disease requiring systemic immunosuppression within the past 6 months.
- Concurrent anti-cancer therapy (other than protocol-permitted bridging) during the DLT window.
- Pregnant or breastfeeding.
- Significant cardiovascular disease (e.g., recent MI, uncontrolled arrhythmia), uncontrolled pulmonary disease, or other severe comorbidity that would increase risk.
- Known hypersensitivity to study chemotherapy components (fludarabine/cyclophosphamide) or required supportive medications.
- Any condition that, in the investigator's opinion, would interfere with study participation, safety monitoring, or interpretation of results.
Plan d'étude
Comment l'étude est-elle conçue ?
Détails de conception
- Objectif principal: Traitement
- Répartition: Non randomisé
- Modèle interventionnel: Affectation parallèle
- Masquage: Aucun (étiquette ouverte)
Armes et Interventions
Groupe de participants / Bras |
Intervention / Traitement |
|---|---|
|
Expérimental: Arm A: CEA+GUCY2C Dual CAR-NK
CRC with tumor co-expression of CEA (CEACAM5) and GUCY2C (GCC) above prespecified thresholds
|
ogeneic dual-target CAR-NK cells manufactured from cord blood-derived NK cells, genetically engineered to express a tandem (dual-binding) CAR, an IL-15 support element (e.g., membrane-bound IL-15 or IL-15/IL-15R fusion), and an inducible suicide switch
Lymphodepleting chemotherapy ( fludarabine and cyclophosphamide) administered pre-infusion to facilitate CAR-NK cell engraftment.
|
|
Expérimental: CEA+HER2 Dual CAR-NK
CRC with CEA expression and HER2/ERBB2 positivity
|
ogeneic dual-target CAR-NK cells manufactured from cord blood-derived NK cells, genetically engineered to express a tandem (dual-binding) CAR, an IL-15 support element (e.g., membrane-bound IL-15 or IL-15/IL-15R fusion), and an inducible suicide switch
Lymphodepleting chemotherapy ( fludarabine and cyclophosphamide) administered pre-infusion to facilitate CAR-NK cell engraftment.
|
|
Expérimental: GUCY2C+HER2 Dual CAR-NK
CRC with GUCY2C expression and HER2/ERBB2 positivity
|
ogeneic dual-target CAR-NK cells manufactured from cord blood-derived NK cells, genetically engineered to express a tandem (dual-binding) CAR, an IL-15 support element (e.g., membrane-bound IL-15 or IL-15/IL-15R fusion), and an inducible suicide switch
Lymphodepleting chemotherapy ( fludarabine and cyclophosphamide) administered pre-infusion to facilitate CAR-NK cell engraftment.
|
Que mesure l'étude ?
Principaux critères de jugement
Mesure des résultats |
Délai |
|---|---|
|
Incidence des toxicités limitant la dose (TLD) classées selon CTCAE v5.0.
Délai: 28 Jours
|
28 Jours
|
|
Dose maximale tolérée (DMT)
Délai: 28 jours
|
28 jours
|
|
Taux de réponse objective (TRO) selon RECIST v1.1 dans la cohorte d'expansion.
Délai: 12 semaines
|
12 semaines
|
Mesures de résultats secondaires
Mesure des résultats |
Délai |
|---|---|
|
Survie sans progression (PFS)
Délai: 24mois
|
24mois
|
|
Incidence et sévérité des événements indésirables (EI)
Délai: 24 mois
|
24 mois
|
|
Disease control rate (DCR) and duration of response (DoR) by RECIST v1.1.
Délai: 24 months
|
24 months
|
Collaborateurs et enquêteurs
Parrainer
Dates d'enregistrement des études
Dates principales de l'étude
Début de l'étude (Réel)
Achèvement primaire (Estimé)
Achèvement de l'étude (Estimé)
Dates d'inscription aux études
Première soumission
Première soumission répondant aux critères de contrôle qualité
Première publication (Réel)
Mises à jour des dossiers d'étude
Dernière mise à jour publiée (Réel)
Dernière mise à jour soumise répondant aux critères de contrôle qualité
Dernière vérification
Plus d'information
Termes liés à cette étude
Mots clés
Termes MeSH pertinents supplémentaires
Autres numéros d'identification d'étude
- EB-CARNK-CRC-111
Informations sur les médicaments et les dispositifs, documents d'étude
Étudie un produit pharmaceutique réglementé par la FDA américaine
Étudie un produit d'appareil réglementé par la FDA américaine
Ces informations ont été extraites directement du site Web clinicaltrials.gov sans aucune modification. Si vous avez des demandes de modification, de suppression ou de mise à jour des détails de votre étude, veuillez contacter register@clinicaltrials.gov. Dès qu'un changement est mis en œuvre sur clinicaltrials.gov, il sera également mis à jour automatiquement sur notre site Web .