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
調査の概要
詳細な説明
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.
研究の種類
入学 (推定)
段階
- フェーズ2
- フェーズ 1
連絡先と場所
研究連絡先
- 名前：Seni S Lu, Phd
- 電話番号：+86 13076790030
- メール：Seni-Lu@beijing-biotech.com
研究場所
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Guangdong
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Shenzhen、Guangdong、中国、518036
- 募集
- Peking University Shenzhen Hospital
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コンタクト：
- Zhen J Peng, Phd
- 電話番号：+86 13076790039
- メール：Zhen-Peng@beijing-biotech.com
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-
参加基準
適格基準
就学可能な年齢
- 大人
- 高齢者
健康ボランティアの受け入れ
説明
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.
研究計画
研究はどのように設計されていますか？
デザインの詳細
- 主な目的：処理
- 割り当て：非ランダム化
- 介入モデル：並列代入
- マスキング：なし（オープンラベル）
武器と介入
参加者グループ / アーム |
介入・治療 |
|---|---|
|
実験的：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.
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実験的：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.
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|
実験的：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.
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この研究は何を測定していますか？
主要な結果の測定
結果測定 |
時間枠 |
|---|---|
|
CTCAE v5.0で評価された用量制限毒性（DLT）の発現率。
時間枠：28日
|
28日
|
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最大耐用量（MTD）
時間枠：28日
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28日
|
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拡張コホートにおけるRECIST v1.1による客観的奏効率（ORR）。
時間枠：12週間
|
12週間
|
二次結果の測定
結果測定 |
時間枠 |
|---|---|
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無増悪生存期間 (PFS)
時間枠：24ヶ月
|
24ヶ月
|
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有害事象（AEs）の発生率と重症度
時間枠：24か月
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24か月
|
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Disease control rate (DCR) and duration of response (DoR) by RECIST v1.1.
時間枠：24 months
|
24 months
|
協力者と研究者
スポンサー
研究記録日
主要日程の研究
研究開始 (実際)
一次修了 (推定)
研究の完了 (推定)
試験登録日
最初に提出
QC基準を満たした最初の提出物
最初の投稿 (実際)
学習記録の更新
投稿された最後の更新 (実際)
QC基準を満たした最後の更新が送信されました
最終確認日
詳しくは
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