Lymphoma
Conditions
Keywords
CD70, Relapsed/Refractory
Brief summary
In this single-center, single-arm,prospective, open-label, phase 1/2 study, the safety and efficacy of autologous CD70 targeted chimeric antigen receptor modified T (CAR-T) cell therapy will be evaluated in patients with CD70 antigen positive Relapsed/Refractory Lymphoma . In this clinical trial, at least 12 eligible patients in dose escalation period will be enrolled to receive 3 doses of CD70-CAR cell therapy according to the 3+3 principle. In dose expansion period, additional at most 21 eligible patients will be enrolled to receive CD70-CAR-T cell therapy at dose of recommended phase 2 dose(RP2D).
Detailed description
CAR-T cell therapy has been identified as a breakthrough therapy in hematologic malignancies,especially anti-CD19 CAR-T cell therapy in the treatment of r/r B-NHL has achieved remarkable efficacy.However, relapse with CD19-negative tumor after treatment with anti-CD19 CAR-T cells has been reported in different types of B-cell lymphoid malignancies, with a percentage up to 38% in patients with non-Hodgkin lymphoma (NHL).At present, the CAR-T cell treatment for HL is mainly confined to CD30 antigen,with an objective response rate (ORR) only 38%\ 62%. Therefore, a more effective treatment strategy is needed for these patients. CD70, the membrane-binding ligand of the CD27 (a tumor necrosis factor receptor superfamily), has been reported to mediate tumour cell proliferation and be expressed on the malignant cells of diffuse large B-cell lymphoma (DLBCL)，mantle cell lymphoma (MCL) and follicular lymphomas (FL), as well as Hodgkin lymphoma, etc,but rarely on normal B cells or T cells,indicating CD70 targeted treament has emerged as potentialnovel immunotherapeutic strategy.Preclinical study demonstrated CD70-CAR-T cells represent a new therapeutic option for the treatment of patients with CD19-negative recurrence of lymphoma.Based on the preclinical data, we conduct this clinical trial in order to test the the safety profiles and anti-tumor activities of CD70-CAR-T cells in vivo. In dose escalation period, at least 12 eligible patients will be enrolled and receive 3 doses of CD70-CAR-T cell therapy (1 × 10\^6 cells/kg, 3 × 10\^6 cells/kg, 1 × 10\^7 cells/kg) according to the 3+3 principle. In dose expansion period, additional at most 21 eligible patients will be enrolled to receive CD70-CAR-T cell infusion at dose of RP2D, which is determined by data from dose escalation period, including occurrence of dose limiting toxicities(DLT), pharmacokinetics/pharmacodynamics, efficacy and other parameters, to furtherly evaluate the safety and efficacy profiles of CD70-CAR-T cell therapy.
Interventions
BIOLOGICALCD70-targeting CAR-T cells
Dose escalation: Dose1 (1×10\^6 cells/kg) ,Dose 2(3×10\^6 cells/kg) ,Dose 3 (1×10\^7 cells/kg) Doseexpansion: RP2D Drug: Fludarabine Intravenous fludarabine 25-30 mg/m\^2/day on days 5, -4, and -3. Drug: Cyclophosphamide Intravenous cyclophosphamide 300-500 mg/m\^2/day on days -5, -4, and -3.
Sponsors
UTC Therapeutics Inc.
Chinese PLA General Hospital
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
Patients eligible for inclusion in this study had to meet all of the following criteria: 1. Age 18-75 (inclusive); 2. ECOG performance status ≤2 and Estimated life expectancy of more than 3 months; 3. Patients with histologically confirmed lymphoma including the following types defined by the World Health Organization(WHO) 2016:HL,Aggressive B-cell non-Hodgkin's lymphoma(Diffuse large B-cell lymphoma,High grade B-cell lymphoma,burkitt's lymphoma,Mantle cell lymph,Anaplastic large cell lymphoma, etc.) and Indolent lymphoma（Including but not limited to follicular lymphoma, marginal zone lymphoma, chronic lymphocytic leukemia, etc.） 4. Relapse after treatment with ≥2 lines systemic therapy for all the above disease types. Relapse disease is defined as disease progression after last regimen. Refractory disease is defined as no CR tofirst-line therapy: * PD as best response to first-line therapy, or * SD as best response after at least 4 cycles of first-line therapy (eg, 4 cycles of R- CHOP), or * PR as best response after at least 6 cycles and biopsy-proven residual disease or disease progression ≤ 6 months of therapy, or * Refractory post-autologous stem cell transplant (ASCT) i. Disease progression or relapsed less than or equal to 12 months of ASCT (must have biopsy prove recurrence in relapsed individuals) ii. If salvage therapy is given post-ASCT, the individual must have had no response to or relapsed after the last line of therapy. * Individuals must have received adequate prior therapy. 5. CD70 antigen expression percentage ≥ 10%. 6. Successful leukapheresis assessment and preculture of T cells; 7. According to Lugano response criteria 2014, there should be at least one evaluable tumor focus. Evaluable tumor focus was defined as that with the longest diameter of intranodal focus \> 1.5cm, the longest diameter of extranodal focus \> 1.0cm assessed by computed tomography (CT) ormagnetic resonance imaging (MRI). 8. Functions of important organs meet the following requirements:ANC≥≥1×10\^9/L; Platelet count ≥50×10\^9/L; Hemoglobin ≥80 g/L;Serum AST and serum ALT, ≤3.0 x ULN (≤5 x ULN for patients with liver metastases); Total serum bilirubin ≤3.0 x ULN); Serum creatinine ≤1.5xULN ; Echocardiography showed left ventricular ejection fraction ≥50%.Pulmonary function: oxygen saturation of blood (SaO2) ≥92% in indoor air environment. 9. Toxicity from previous antitumor therapy ≤ grade 1 (according to CTCAE version 5.0) or to an acceptable level of inclusion/
Exclusion criteria
(other toxicities such as alopecia and vitiligo considered by the investigator to pose no safety risk to the subject). 10. Pregnancy tests for women of childbearing age shall be negative;Both men and women agreed to use effective contraception during treatment and during the subsequent 1 year. 11. Ability to understand and sign a written informed consent documen.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of treatment related adverse events（AEs） | Up to 12 months since the initiation of CD70-CAR-T cell therapy. | AE is defined as any adverse medical event from the date of randomization to 12 months after CD70-CAR-T cells infusion. Among them, CRS and ICANS were graded according to American Society for Transplantation and Cellular Therapy (ASTCT) criteria. Other AEs were graded according to common terminology criteria for adverse events (CTCAE) v5.0. |
| Incidence of dose limiting toxicities (DLTs) | Up to 28 days since the initiation of CD70-CAR-T cell therapy | DLT was defined as CD70-CAR-T cells-related events with onset within first 28 days following infusion: Thedevelopment of Grade (G) 3 or higher grade CRS lasting \> 2 weeks; All G4 non-hematologic toxicities. |
| Maximum tolerated dose (MTD) | Up to 28 days since the initiation of CD70-CAR-T cell therapy | MTD is defined as the highest dose level of less than or equal to 2 DLT among the 6 subjects finally determined. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to response (TTR) | Up to 3 years | TTR is defined as the time from CD70-CAR-T cell infusion to first assessed CR or PR by investigators and based on the Lugano 2014 assessment criterion. |
| Duration of response (DOR) | Up to 3 years | Duration of response is defined as the time from objective response until documented tumor progression among responders. |
| Number and copy number of CD70-CAR-T cells | Up to 3 years | Number and copy number of CD70-CAR-T cells are evaluated by number in peripheral blood and tumor tissue. |
| Pharmacodynamics: Peak level of cytokines in serum (phase 1 and phase 2) | Up to 28 days since the initiation of CD70-CAR-T cell therapy | The cytokines mainly include interleukin-2 (IL-2 ), IL-6, IL-8, IL-10, tumor necrosis factor-α (TNF-α), C reactive protein (CRP), ferritin. Peak was defined as the maximum post-baseline level of the cytokine. |
| Overall Survival (OS) | Up to 3 years | Overall Survival is defined as the time from the initiation of CD70-CAR-T cell therapy to documented disease progression or death. |
| Objective response rate (ORR) | Up to 3 years | The incidence of complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD), or unevaluable (UE) as the best response to treatment assessed by investigators and based on the Lugano 2014. assessment criterion |
| Progression Free Survival (PFS) | Up to 3 years | Progression Free Survival is defined as the time from the initiation of CD70-CAR-T cell therapy to documented disease progression or death. |
Countries
China
Contacts
Primary ContactWeidong Han, Ph.D
Backup ContactYang Liu, M.D
Outcome results
None listed