CART22 Alone or in Combination With huCART19 for ALL

• ClinicalTrials.gov Identifier: NCT03620058
• Recruitment Status: Active, not recruiting
• First Posted: August 8, 2018
• Last Update Posted: February 24, 2023
• Sponsor: University of Pennsylvania
• Information provided by (Responsible Party): University of Pennsylvania

Tracking Information

• First Submitted Date: June 25, 2018
• First Posted Date: August 8, 2018
• Last Update Posted Date: February 24, 2023
• Actual Study Start Date: September 27, 2018
• Estimated Primary Completion Date: January 2036 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 2, 2018)

• Assess the safety of CART22-65s in ALL subjects using the common terminology criteria of adverse events (CTCAE) v5.0. [ Time Frame: 15 months ]
  Frequency and severity of adverse events, including, but not limited to, cytokine release syndrome (CRS).
• Assess the safety of combination CART22-65s and huCART19 in relapsed/refractory ALL Subjects using the common terminology criteria of adverse events (CTCAE) v5.0. [ Time Frame: 15 months ]
  Frequency and severity of adverse events, including, but not limited to, cytokine release syndrome (CRS).

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: February 18, 2022)

• Tumor response. [ Time Frame: 28 Days ]
  Overall Complete Remission Rate (ORR) at Day 28 which includes CR and CR with incomplete blood count recovery (CRi).
• Tumor response. [ Time Frame: 6 months ]
  overall response rate (CR/CRi by or at Month 6) and disease response status at Month 6
• Tumor response. [ Time Frame: 1 Year ]
  overall survival (OS)
• Tumor response. [ Time Frame: 1 Year ]
  duration of remission (DOR)
• Tumor response. [ Time Frame: 1 Year ]
  relapse free survival (RFS)
• Tumor response. [ Time Frame: 1 Year ]
  event free survival (EFS)
• CAR T cell kinetics [ Time Frame: 1 Year ]
  Engraftment and persistence in blood by qPCR (or flow cytometry)
• CAR T cell kinetics [ Time Frame: 1 Year ]
  Trafficking to target tissue (bone marrow) or other tissues (cerebral spinal fluid and other tissues if available) as determined by qPCR (or flow cytometry).
• Evaluate bioactivity of CAR T cells [ Time Frame: 1 Year ]
  Measure levels of systemic soluble immune and inflammatory factors by Luminex-based analyses
• Determine antigen expression and normal B cell levels in response to CAR T cells [ Time Frame: 1 Year ]
  Measure CD22, CD19 and B cell levels pre- and post-CAR T cell infusion by flow cytometry

Original Secondary Outcome Measures (submitted: August 2, 2018)

• Evaluate the percentage of CART22-65s and huCART19 manufacturing products that do not meet release criteria. [ Time Frame: 3 months ]
• Evaluate CART22-65s efficacy as a single agent through Overall Complete Remission Rate (ORR) at Day 28 which includes CR and CR with incomplete blood count recovery (CRi). [ Time Frame: 1 months ]
• Evaluate CART22-65s efficacy as a single agent through overall response rate (CR/CRi by or at Month 6) and disease response status at Month 6. [ Time Frame: 6 months ]
• Evaluate CART22-65s efficacy as a single agent through overall survival (OS). [ Time Frame: 15 months ]
• Evaluate CART22-65s efficacy as a single agent through duration of remission (DOR). [ Time Frame: 15 months ]
• Evaluate CART22-65s efficacy as a single agent through relapse free survival (RFS). [ Time Frame: 15 months ]
• Evaluate CART22-65s efficacy as a single agent through event free survival (EFS). [ Time Frame: 15 months ]
• Evaluate CART22-65s efficacy as a single agent by determining cause of death (COD) when appropriate. [ Time Frame: 15 months ]
• Evaluate CART22-65s efficacy as a single agent by describing response in terms of minimal residual disease (MRD). [ Time Frame: 15 months ]
  Percentage of subjects who achieve a CR associated with minimal residual disease (MRD) negative bone marrow as determined by high sensitivity flow cytometry.
• Evaluate CART22-65s efficacy in combination with huCART19 through Overall Complete Remission Rate (ORR) at Day 28 which includes CR and CR with incomplete blood count recovery (CRi). [ Time Frame: 1 months ]
• Evaluate CART22-65s efficacy in combination with huCART19 through overall response rate (CR/CRi by or at Month 6) and disease response status at Month 6. [ Time Frame: 6 months ]
• Evaluate CART22-65s efficacy in combination with huCART19 through overall survival (OS). [ Time Frame: 15 months ]
• Evaluate CART22-65s efficacy in combination with huCART19 through duration of remission (DOR). [ Time Frame: 15 months ]
• Evaluate CART22-65s efficacy in combination with huCART19 through relapse free survival (RFS). [ Time Frame: 15 months ]
• Evaluate CART22-65s efficacy in combination with huCART19 through event free survival (EFS). [ Time Frame: 15 months ]
• Evaluate CART22-65s efficacy in combination with huCART19 by determining cause of death (COD) when appropriate. [ Time Frame: 15 months ]
• Evaluate CART22-65s efficacy in combination with huCART19 by describing response in terms of minimal residual disease (MRD). [ Time Frame: 15 months ]
  Percentage of subjects who achieve a CR associated with minimal residual disease (MRD) negative bone marrow as determined by high sensitivity flow cytometry.
• Characterize CART22-65s pharmacokinetic (PK) profile when given as a single agent through engraftment of CART22-65s in blood as determined by qPCR (or flow cytometry). [ Time Frame: 12 Months ]
• Characterize CART22-65s pharmacokinetic (PK) profile when given as a single agent through persistence of CART22-65s in blood as determined by qPCR (or flow cytometry). [ Time Frame: 12 Months ]
• Characterize CART22-65s pharmacokinetic (PK) profile when given as a single agent through trafficking to target tissue as determined by qPCR (or flow cytometry). [ Time Frame: 15 Months ]
• Characterize the PK profile of CART22-65s and huCART19 when given as dual agents through engraftment of CART22-65s and huCART19 in blood as determined by qPCR (or flow cytometry). [ Time Frame: 15 Months ]
• Characterize the PK profile of CART22-65s and huCART19 when given as dual agents through persistence of CART22-65s and huCART19 in blood as determined by qPCR (or flow cytometry). [ Time Frame: 15 Months ]
• Characterize the PK profile of CART22-65s and huCART19 when given as dual agents through trafficking to target tissue as determined by qPCR (or flow cytometry). [ Time Frame: 15 Months ]
• Evaluate bioactivity of CART22-65s cells by systemic soluble immune and inflammatory factors pre-CART22 infusion as determined by Luminex-based analyses. [ Time Frame: 15 Months ]
• Evaluate bioactivity of CART22-65s cells by systemic soluble immune and inflammatory factors post-CART22 infusion as determined by Luminex-based analyses. [ Time Frame: 15 Months ]
• Determine CD22 levels pre-CAR T cell infusion as determined by multi-parametric flow cytometry. [ Time Frame: 15 Months ]
• Determine CD22 levels post-CAR T cell infusion as determined by multi-parametric flow cytometry. [ Time Frame: 15 Months ]
• Determine CD19 levels pre-CAR T cell infusion as determined by multi-parametric flow cytometry. [ Time Frame: 15 Months ]
• Determine CD19 levels post-CAR T cell infusion as determined by multi-parametric flow cytometry. [ Time Frame: 15 Months ]
• Determine B cell levels pre-CAR T cell infusion as determined by multi-parametric flow cytometry. [ Time Frame: 15 Months ]
• Determine B cell levels post-CAR T cell infusion as determined by multi-parametric flow cytometry. [ Time Frame: 15 Months ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: CART22 Alone or in Combination With huCART19 for ALL
• Official Title: Phase 1 Study of Autologous Anti-CD22 Chimeric Antigen Receptor Redirected T Cells (CART22-65s) Alone and When Co-administered With Humanized Anti-CD19 Chimeric Antigen Receptor Redirected T Cells (huCART19) In Patients With Chemotherapy Resistant Or Refractory Acute Lymphoblastic Leukemia
• Brief Summary: This is a single center, open-label, phase 1 study to determine the safety and feasibility of infusing CART22-65s with or without huCART19 after administration of lymphodepleting chemotherapy in adult patients with relapsed or refractory B-ALL.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: Non-Randomized; Intervention Model: Sequential Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Chemotherapy Resistant Acute Lymphoblastic Leukemia
• Refractory Acute Lymphoblastic Leukemia

Intervention

• Biological: CART22-65s cells
  Autologous T cells transduced with a lentiviral vector to express anti-CD22 scFv TCRz:41BB
• Biological: huCART19 Cells
  Autologous T cells transduced with lentiviral vector to express anti-CD19 scFv TCRζ:4-1BB

Study Arms

• Experimental: CART22-65s monotherapy
  Intervention: Biological: CART22-65s cells
• Experimental: CART22-65s in combination with huCART19
  Interventions:

  • Biological: CART22-65s cells
  • Biological: huCART19 Cells

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: December 16, 2020): 23
• Original Estimated Enrollment (submitted: August 2, 2018): 18
• Estimated Study Completion Date: January 2036
• Estimated Primary Completion Date: January 2036 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

- 1. Patients with relapsed or refractory B cell ALL:

a. Patients with 2nd or greater relapse or refractory to 1st salvage as defined by: i. Recurrent disease in the bone marrow identified morphologically, by immunohistochemistry or by Flow cytometry.

ii. Patients with extramedullary relapse only (no bone marrow involvement) will be eligible if disease response can be assessed radiographically b. Patients with refractory disease as defined by: i. Failure to achieve remission (<5% bone marrow blasts) after 2 cycles of induction chemotherapy ii. Patients that achieve remission but remain MRD+ after ≥2 cycles of induction chemotherapy.

c. Patients with Ph+ ALL are eligible provided they are intolerant to or have failed tyrosine kinase inhibitor therapy.

d. Patients with prior or current history of CNS3 disease* will be eligible only if CNS disease is responsive to therapy.

i. *CNS disease definitions:

1. CNS1 - no blasts seen on cytocentrifuge (CNS negative);
2. CNS2 - total nucleated cell count <5x106/L, but blasts seen on cytocentrifuge;

3. CNS3 - total nucleated cell count 5x106/L with blasts on cytocentrifuge and/or signs of CNS leukemia (i.e. cranial nerve palsy).

   • 2. For Cohort 1: Documentation of CD22 expression on malignant cells at relapse. For Cohort 2: Documentation of CD22 and/or CD19

   • 3. Adequate vital organ function defined as:

     1. Creatinine ≤ 1.6 mg/dl
     2. ALT/AST ≤ 3x upper limit of normal range
     3. Total or Direct bilirubin ≤ 2.0 mg/dl. If Total bilirubin is ≤2.0, Direct bilirubin does not need to be assessed.
     4. Left Ventricle Ejection Fraction (LVEF) ≥ 40% confirmed by ECHO/MUGA
   • 4. Male or female age ≥ 18 years.
   • 5. ECOG Performance Status that is either 0 or 1.
   • 6. No contraindications for leukapheresis.
   • 7. Subjects of reproductive potential must agree to use acceptable birth control methods.

Exclusion Criteria:

• 1. Active hepatitis B or active hepatitis C.
• 2. HIV Infection.
• 3. Class III/IV cardiovascular disability according to the New York Heart Association Classification.
• 4. Subjects with clinically apparent arrhythmia or arrhythmias who are not stable on medical management within two weeks of eligibility confirmation by physician-investigator.
• 5. Active acute or chronic graft-versus-host disease (GVHD) requiring systemic therapy.
• 6. Planned concurrent treatment with systemic steroids or immunosuppressant medications. Patients may be on a stable low dose of steroids (<10mg equivalent of prednisone) for chronic respiratory conditions or adrenal insufficiency. For additional details regarding use of steroid and immunosuppressant medications.
• 7. CNS3 disease that is progressive on therapy, or with CNS parenchymal lesions that might increase the risk of CNS toxicity.
• 8. Pregnant or nursing (lactating) women.
• 10. Patients with a known history or prior diagnosis of optic neuritis or other immunologic or inflammatory disease affecting the central nervous system.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03620058
• Other Study ID Numbers: IRB # 830049; UPCC #12418
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: University of Pennsylvania
• Original Responsible Party: Same as current
• Current Study Sponsor: University of Pennsylvania
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Noelle Frey, MD; University of Pennsylvania

• PRS Account: University of Pennsylvania
• Verification Date: February 2023