Advanced or Metastatic Clear Cell Renal Cell Carcinoma
Conditions
Keywords
RCC, kidney cancer, clear cell renal cell carcinoma
Brief summary
Phase 1/2 study evaluates the safety, feasibility, and preliminary antitumor activity of allogeneic dual-target CD70/CAIX CAR-NK cells after fludarabine/cyclophosphamide lymphodepletion in adults with advanced or metastatic clear cell RCC that has progressed after standard therapy. The study is designed to determine a recommended dose and schedule, characterize hepatobiliary safety, and explore whether CD70-high, CAIX-high, or dual-high tumors derive the greatest benefit. Biomarker-defined activity signals will be used to guide whether later development should prioritize CD70, CAIX/CA9, or continued dual-targeting.
Detailed description
Advanced clear cell RCC remains difficult to treat after immune checkpoint blockade and VEGF-pathway therapy. Both CD70 and CAIX are attractive RCC targets: CAIX is broadly expressed in clear cell RCC, while CD70 is frequently overexpressed and has already generated encouraging clinical cell-therapy signals in RCC \[3-11\]. The investigational product in this example is an allogeneic, cord blood-derived NK cell product engineered to express a dual CAR recognizing CD70 and CAIX/CA9, membrane-bound IL-15 to enhance persistence, and an inducible caspase-9 safety switch to improve controllability. The allogeneic CAR-NK strategy is intended to provide an off-the-shelf platform with lower theoretical risk of graft-versus-host disease than allogeneic T-cell products and with innate NK killing as a complementary antitumor mechanism \[1, 2, 11\]. The study uses a standard dose-escalation phase followed by a biomarker-guided expansion phase. All participants receive lymphodepletion with fludarabine and cyclophosphamide and then one infusion of dual-target CAR-NK cells on Day 0; an optional second infusion on Day 15 is allowed for participants without doselimiting toxicity, uncontrolled cytokine-mediated toxicity, or rapid progression. During expansion, participants remain in a single treatment arm but are prospectively analyzed in CD70-high, CAIX-high, and dual-high subgroups. Because earlier CAIX CAR-T studies in metastatic RCC reported on-target hepatobiliary toxicity related to low-level CAIX expression in biliary epithelium, this example protocol incorporates enhanced liver screening, exclusion of significant biliary disease, staggered first-patient dosing at each dose level, frequent liver function monitoring, and an explicit early stopping rule for recurrent protocoldefined hepatobiliary toxicity \[5, 6\]. The translational objective is not only to identify a recommended phase 2 dose but also to learn which antigen context appears most actionable in patients. If activity clusters in CD70-high tumors with cleaner safety, later development may pivot toward a CD70-led construct. If CAIX-high tumors uniquely benefit without meaningful hepatobiliary toxicity, CAIX/CA9 may remain central. If dual-high tumors clearly outperform single-high tumors without added risk, the dual-target program should continue.
Interventions
BIOLOGICALEB-701/CA9-NK
dual-target allogeneic CAR-NK cells (single infusion on Day 0; optional second infusion on Day 15 if safety criteria are met)
DRUGFludarabine
lymphodepletion
Sponsors
Beijing Biotech
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Masking description
The trial is open-label because the main objectives are dose finding, real-time toxicity review, cell-product release management, and intensive translational monitoring.
Intervention model description
Up to 36 participants will be treated. Phase 1 uses a 3+3 dose-escalation design with three planned dose levels of dual-target CAR-NK cells following lymphodepletion. Dose level review is performed after Day 28 safety assessment for each cohort. After the recommended phase 2 dose / schedule (RP2D / RP2S) is declared, an expansion phase enrolls additional participants into biomarker-defined analytic subgroups (CD70-high, CAIX-high, dual-high) within the same single treatment arm. These subgroups are used for exploratory target-selection analysis rather than for randomization. Staggered enrollment is required for the first two participants at each dose level. Optional repeat infusion on Day 15 is permitted at investigator and sponsor discretion if predefined safety criteria are met.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Written informed consent and willingness to comply with protocol procedures. * Age \>= 18 years at the time of consent. * Histologically confirmed unresectable or metastatic clear cell RCC, or RCC with a clear-cell component, with radiographic progression after standard therapy. * Prior exposure to at least one PD-1 / PD-L1-based regimen and at least one VEGF-pathway targeted regimen, or documented intolerance / unsuitability for available standard systemic options. * At least one measurable lesion by RECIST 1.1. * Available archival tumor tissue or willingness to undergo fresh biopsy for central biomarker testing; protocoldefined tumor positivity for CD70 and/or CAIX is required. Dual-positive cases are preferred for the biomarkerexpansion portion. * ECOG performance status 0-1. * Adequate marrow, liver, cardiac, pulmonary, and renal function as defined by the protocol (for example, ANC, platelets, bilirubin, AST/ALT, creatinine clearance, oxygen saturation, and left ventricular function within protocoldefined limits). * Life expectancy of at least 12 weeks. * Negative pregnancy test for participants of childbearing potential and agreement to highly effective contraception during protocol-defined risk windows. * Previously treated brain metastases are allowed if clinically stable and off escalating corticosteroids for at least 14 days before lymphodepletion.
Exclusion criteria
* Active, untreated, or symptomatic central nervous system metastases, leptomeningeal disease, or uncontrolled seizure disorder. * Prior gene-modified cellular therapy (including prior CAR-T, CAR-NK, CAR-NKT, or TCR-engineered therapy) within the protocol-defined washout window. * Prior allogeneic stem cell transplant or solid organ transplant with ongoing clinically significant immunosuppression. * Active autoimmune disease requiring systemic immunosuppressive treatment; physiologic replacement doses are permitted. * Active uncontrolled infection, including uncontrolled hepatitis B, hepatitis C, HIV, tuberculosis, or sepsis. * Clinically significant hepatobiliary disease that could increase risk from CAIX-directed therapy, such as active cholangitis, primary sclerosing cholangitis, biliary obstruction, Child-Pugh B/C cirrhosis, or prior hepatic venoocclusive disease. * Clinically significant cardiovascular disease (for example, unstable angina, recent myocardial infarction, uncontrolled arrhythmia, or clinically meaningful heart failure). * Systemic corticosteroid use greater than 10 mg prednisone equivalent daily within 7 days before lymphodepletion, unless required as physiologic replacement. * Pregnancy or breastfeeding. * Another active invasive malignancy requiring systemic treatment, except for protocol-defined low-risk exceptions. * Known hypersensitivity to fludarabine, cyclophosphamide, or a critical study-product excipient.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of dose-limiting toxicities (DLTs) | 28 Days | Incidence of dose-limiting toxicities (DLTs) during the DLT window, graded by CTCAE v5.0 |
| Determination of recommended phase 2 dose | 8 weeks | — |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective response rate (ORR) per RECIST 1.1 by independent radiologic review | 6 months | — |
| Overall Survival (OS) | 12 months | Overall Survival (OS) is the length of time from diagnosis or treatment start that patients remain alive |
Countries
China
Contacts
CONTACTshan S Lu, Phd
Outcome results
None listed