Phase 1/2 Dose Escalation Study of CD19/CD22 Bicistronic Chimeric Antigen Receptor (CAR) T Cells in Children and Young Adults With Recurrent or Refractory B Cell Malignancies
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 130
- 试验地点
- 1
- 主要终点
- Safety
研究概览
简要总结
Background:
Acute lymphoblastic leukemia (ALL) is the most common cancer in children. About 90% of children and young adults who are treated for ALL can now be cured. But if the disease comes back, the survival rate drops to less than 50%. Better treatments are needed for ALL relapses.
Objective:
To test chimeric antigen receptor (CAR) therapy. CARs are genetically modified cells created from each patient s own blood cells. his trial will use a new type of CAR T-cell that is targeting both CD19 and CD22 at the same time. CD19 and CD22 are proteins found on the surface of most types of ALL.
Eligibility:
People aged 3 to 39 with ALL or related B-cell lymphoma that has not been cured by standard therapy.
Design:
Participants will be screened. This will include:
Physical exam
Blood and urine tests
Tests of their lung and heart function
Imaging scans
Bone marrow biopsy. A large needle will be inserted into the body to draw some tissues from the interior of a bone.
Lumbar puncture. A needle will be inserted into the lower back to draw fluid from the area around the spinal cord.
Participants will undergo apheresis. Their blood will circulate through a machine that separates blood into different parts. The portion containing T cells will be collected; the remaining cells and fluids will be returned to the body. The T cells will be changed in a laboratory to make them better at fighting cancer cells.
Participants will receive chemotherapy starting 4 or 5 days before the CAR treatment.
Participants will be admitted to the hospital. Their own modified T cells will be returned to their body.
Participants will visit the clinic 2 times a week for 28 days after treatment. Follow-up will continue for 15 years....
详细描述
Background:
- Despite improvements in therapy, acute lymphoblastic leukemia (ALL) contributes to significant morbidity and mortality for children and young adults with cancer. CD19-CAR and CD22-CAR therapy have proven highly effective in inducing remission in patients with relapsed/refractory disease.
- Immune escape has been observed by several groups following CD19-CAR and CD22- CAR therapy for B-ALL. Investigation of this phenomenon reveals a complex biology responsible for loss or downregulation of CD19 and/or CD22 expression observed in these cases.
- The challenges encountered with currently available CD19- and CD22-directed CAR T cells in B-ALL demonstrates the need for combinatorial treatment strategies simultaneously targeting two antigens, such as CD19 and CD22, to enhance the long-term effectiveness of CARs.
- We have previously treated patients with B-ALL on a phase 1/2 clinical trial using a bivalent CD19/22 CAR T-cell as a first combinatorial treatment strategy. This CAR T-cell construct is well-tolerated and has yielded responses however there has been limited CAR T cell expansion and persistence. Additionally, the previously tested CD19/CD22 bivalent CAR T-cell construct is limited in its ability to target CD22.
- This new CD19/22 targeted construct being tested in this clinical trial has improved dual targeting capability based on preclinical data/evaluation.
Objectives:
- Phase I: Assess the safety of administering escalating doses of autologous CD19/CD22- CAR engineered T cells in children and young adults with B cell ALL or lymphoma following a cyclophosphamide/fludarabine conditioning regimen.
- Phase II: Determine the efficacy of CD19/CD22 therapy in participants with B-ALL/ B-LBL..
Eligibility:
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 3 Years 至 39 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •INCLUSION CRITERIA:
- •Diagnosis
- •Participant must:
- •Have pathology confirmed B cell ALL (not isolated to the testis or CNS), CML with ALL transformation, or high-grade lymphoma (e.g., Burkitt's lymphoma, B-lymphoblastic lymphoma, diffuse large B-cell lymphoma, inclusive of low-grade lymphoma that has transformed to high grade disease); and
- •Have relapsed or been refractory after at least one standard chemotherapy regimen and at least one salvage treatment. Participants with Philadelphia chromosome + ALL must have failed prior tyrosine kinase inhibitor; and
- •Be ineligible for allogeneic stem cell transplant (SCT), have refused SCT, or have recurred after SCT; and
- •Be unable to access (in a timely manner), ineligible for, or have relapsed/failed after or not responded to a commercially available CD19 CAR T-cell construct; and
- •Have evidence of at least minimal residual disease or PET-avid disease (lymphoma) at the time of enrollment.
- •CD22/CD19 expression
- •Cohorts A1b, B1b, C2b
- •CD19 must be detected on >15% of the malignant cells by immunohistochemistry or > 80% by flow cytometry.
- •CD22 positivity must be confirmed.
- •Cohorts D1b, 2 B-ALL
- •CD19 or CD22 positivity must be confirmed
- •Age >= 3 years of age and <=39 years of age at time of enrollment.
- •Clinical Performance status: Participants >= 16 years of age: Karnofsky >= 50%; Participants < 16 years of age: Lansky scale >= 50%.
- •Participants must have adequate organ and marrow function as defined below:
- •leukocytes >= 750/mcL*
- •platelets >= 50,000/mcL*
- •total bilirubin <=2 X ULN (except in the case of participants with documented Gilbert's disease > 3x ULN)
- •AST(SGOT)/ALT(SGPT) <=10 X institutional upper limit of normal
- •creatinine <= the maximum for age listed in the table below OR
- •measured creatinine clearance >=60 mL/min/1.73 m^2 for participants with creatinine levels above the max listed below per age.
- •Age (Years) <= 5 / Maximum Serum Creatinine (mg/dL) <= 0.8
- •Age (Years) 6 to <= 10 / Maximum Serum Creatinine (mg/dL) <= 1.0
- •Age (Years) >10 / Maximum Serum Creatinine (mg/dL) <= 1.2
- •a participant will not be excluded because of pancytopenia >= Grade 3 if it is due to underlying bone marrow involvement by leukemia
- •Central nervous system (CNS) Status
- •Participants with leukemia with CNS 1 and 2 disease are eligible in the absence of
排除标准
- •Participants of child-bearing or child-fathering potential must be willing to practice effective birth control from the time of enrollment until 12 months following completion of study treatment for women and for 4 months following completion of study treatment for men.
- •Participants who are breastfeeding or plan to breastfeed must agree to discontinue/postpone breastfeeding while on study therapy and until 1 month after the administration of CAR.
- •Cardiac function: Left ventricular ejection fraction >= 45% or fractional shortening >=28%
- •Pulmonary Function
- •Baseline oxygen saturation >92% on room air at rest
- •Ability of participant or Legally Authorized Representative (LAR) to understand and the willingness to sign a written informed consent document.
- •Ability and willingness of participant or Legally Authorized Representative (LAR) to co- enroll on 15-C-0028: Follow-up Evaluation for Gene-Therapy Related Delayed Adverse Events after Participation in Pediatric Oncology Branch Clinical Trials.
- •EXCLUSION CRITERIA:
- •Participants meeting any of the following criteria are not eligible for participation in the study:
- •Participants with CNS3 disease, progressing neurologic signs* of CNS disease, radiologically detected active CNS lymphoma (*resolving manifestation or persistent and/or irreversible findings from prior CNS involvement (e.g., blindness) is not exclusionary)
- •Hyperleukocytosis (>= 50,000 blasts/microL)
- •Positive serum or urine beta-HCG pregnancy test performed at screening.
- •Participants will be excluded based on prior therapy if they fail to meet following washout criteria:
- •Therapy: Systemic Chemotherapy, anti-neoplastic agents, antibody- based therapies
- •Washout*: >=2 weeks
- •Exceptions: 6 weeks for clofarabine or nitrosoureas; No washout for prior intrathecal chemotherapy, steroid therapy, hydroxyurea (no dose increases within prior 2 weeks) or ALL maintenance-type chemotherapy (vincristine, 6-mercaptopurine, oral methotrexate, or a tyrosine kinase inhibitor for participants with Ph+ ALL) provided there is recovery from any acute toxic effects
- •Therapy: Radiation
- •Washout*: >=3 weeks
- •Exceptions: No time restriction with radiation therapy if the volume of bone marrow treated is less than 10% and the participant has measurable/evaluable disease outside the radiation window
- •Therapy: Allogeneic Stem Cell Transplant
- •Washout*: >= 100 days since SCT; >= 30 days since completion of immunosuppression; >= 6 weeks since donor lymphocyte infusion (DLI)
- •Exceptions: Cannot have evidence of active graft-versus-host disease (GVHD) requiring systemic immunosuppression
- •Therapy: CAR T-Cell Therapy or other Adoptive Cell Therapy
- •Washout*: > 30 days post infusion
- •Washout: Time between therapy and apheresis
- •Positive HIV antibodies consistent with active HIV.
- •Positive hepatitis C antibodies or positive Hepatitis B surface antigen (HbsAG) indicative of current/active HCV/HBV.
- •Active second malignancy other than in situ carcinoma of the cervix, unless the tumor was treated with curative intent at least two years previously and participant is in remission.
- •History of severe, immediate hypersensitivity reaction attributed to compounds of similar chemical or biologic composition to any agents used in study or in the manufacturing of the cells.
- •Uncontrolled, symptomatic, intercurrent illness or social situations that would limit compliance with study requirements or in the opinion of the PI would pose an unacceptable risk to the participant.
研究组 & 干预措施
4/Phase II Dose Expansion- with high disease burden - CLOSED
CD19/CD22-CAR-transduced T cells at MTD/or highest dose administered with LD regimen #2
干预措施: cyclophosphamide (Drug)
3b Phase I Dose Escalation: Either CD19 or CD22 positivity
CD19/CD22-CAR-transduced T cells
干预措施: fludarabine (Drug)
2/Phase I Dose Escalation- with intensified LD - CLOSED
CD19/CD22-CAR-transduced T cells + standard LD (120 mg/m2 Flu + 1200 mg/m2 Cy)
干预措施: fludarabine (Drug)
2b/Phase 1 Dose Escalation - high disease burden
CD19/CD22-CAR-transduced T cells
干预措施: CD19/CD22-CAR-transduced T cells (Biological)
1/Phase I Dose Escalation-with standard LD - CLOSED
CD19/CD22-CAR-transduced T cells at escalating dose + standard LD (75 mg/mg2 Flu+ 900 mg/m2 Cy)
干预措施: CD19/CD22-CAR-transduced T cells (Biological)
1b/Phase 1 Dose Escalation - low disease burden
CD19/CD22-CAR-transduced T cells
干预措施: CD19/CD22-CAR-transduced T cells (Biological)
2/Phase I Dose Escalation- with intensified LD - CLOSED
CD19/CD22-CAR-transduced T cells + standard LD (120 mg/m2 Flu + 1200 mg/m2 Cy)
干预措施: CD19/CD22-CAR-transduced T cells (Biological)
1/Phase I Dose Escalation-with standard LD - CLOSED
CD19/CD22-CAR-transduced T cells at escalating dose + standard LD (75 mg/mg2 Flu+ 900 mg/m2 Cy)
干预措施: cyclophosphamide (Drug)
2b/Phase 1 Dose Escalation - high disease burden
CD19/CD22-CAR-transduced T cells
干预措施: fludarabine (Drug)
2b/Phase 1 Dose Escalation - high disease burden
CD19/CD22-CAR-transduced T cells
干预措施: cyclophosphamide (Drug)
A/Pre-treatment
All participants enrolled on the study prior to treatment initiation.
1b/Phase 1 Dose Escalation - low disease burden
CD19/CD22-CAR-transduced T cells
干预措施: cyclophosphamide (Drug)
3/Phase II Dose Expansion- with low disease burden - CLOSED
CD19/CD22-CAR-transduced T cells at MTD/or highest dose administered with LD
干预措施: CD19/CD22-CAR-transduced T cells (Biological)
1b/Phase 1 Dose Escalation - low disease burden
CD19/CD22-CAR-transduced T cells
干预措施: fludarabine (Drug)
1/Phase I Dose Escalation-with standard LD - CLOSED
CD19/CD22-CAR-transduced T cells at escalating dose + standard LD (75 mg/mg2 Flu+ 900 mg/m2 Cy)
干预措施: fludarabine (Drug)
3/Phase II Dose Expansion- with low disease burden - CLOSED
CD19/CD22-CAR-transduced T cells at MTD/or highest dose administered with LD
干预措施: fludarabine (Drug)
4/Phase II Dose Expansion- with high disease burden - CLOSED
CD19/CD22-CAR-transduced T cells at MTD/or highest dose administered with LD regimen #2
干预措施: CD19/CD22-CAR-transduced T cells (Biological)
4b Phase II Dose Expansion in B-ALL/B-LBL
CD19/CD22-CAR-transduced T cells at RP2D
干预措施: CD19/CD22-CAR-transduced T cells (Biological)
3b Phase I Dose Escalation: Either CD19 or CD22 positivity
CD19/CD22-CAR-transduced T cells
干预措施: CD19/CD22-CAR-transduced T cells (Biological)
2/Phase I Dose Escalation- with intensified LD - CLOSED
CD19/CD22-CAR-transduced T cells + standard LD (120 mg/m2 Flu + 1200 mg/m2 Cy)
干预措施: cyclophosphamide (Drug)
4/Phase II Dose Expansion- with high disease burden - CLOSED
CD19/CD22-CAR-transduced T cells at MTD/or highest dose administered with LD regimen #2
干预措施: fludarabine (Drug)
4b Phase II Dose Expansion in B-ALL/B-LBL
CD19/CD22-CAR-transduced T cells at RP2D
干预措施: cyclophosphamide (Drug)
3/Phase II Dose Expansion- with low disease burden - CLOSED
CD19/CD22-CAR-transduced T cells at MTD/or highest dose administered with LD
干预措施: cyclophosphamide (Drug)
4b Phase II Dose Expansion in B-ALL/B-LBL
CD19/CD22-CAR-transduced T cells at RP2D
干预措施: fludarabine (Drug)
3b Phase I Dose Escalation: Either CD19 or CD22 positivity
CD19/CD22-CAR-transduced T cells
干预措施: cyclophosphamide (Drug)
结局指标
主要结局
Safety
时间窗: 30 days post CAR T infusion
Assess the safety of administering escalating doses of autologous CD19/CD22-CAR engineered T cells in children and young adult with B cell ALL or lymphoma following a cyclophosphamide/fludarabine LD.
Efficacy
时间窗: Monthly until 3 months post CAR T infusion and then at 6 months and every 6 months after that, for 2 years post-infusion for each participant, up to 2 years after the entry date of the last participant.
Determine the efficacy of CD19/CD22 therapy in participants with B-ALL/B-LBL.
次要结局
- Feasibility(Up to two years after the last participant has entered.)
- Assess response and toxicity (CRS grade)(Up to two years after last participant has entered)
- Persistence and expansion(Up to two years after the last participant has entered.)
- Progression free survival (PFS) and Overall survival (OS)(Up to two years after the last participant has entered.)
- Overall response rate(Monthly until 3 months post infusion and then at 6 months and every 6 months after that, for 2 years post-infusion for each participant, for up to two years from the entry date of the last participant)
- Adverse Events(30 days post CAR T infusion)