CD123-CD33 cCAR in Patients With Relapsed and/or Refractory, High Risk Hematologic Malignancies

Study Overview
=================
Brief Summary
-----------------
Phase I, interventional, single arm, open label, treatment study to evaluate the safety and tolerability of CD123-CD33 cCAR in patients with relapsed and/or refractory, high risk hematologic malignancies.

Detailed Description
-----------------
AML bears heterogeneous cells that can consequently offset killing by single-CAR-based therapy, which results in disease relapse. Leukemic stem cells (LSCs) associated with CD123 expression comprise a rare population that also plays an important role in disease progression and relapse for myeloid malignancies. CD33 is widely expressed in AML, high risk myelodysplastic syndromes (MDS) and myeloproliferative neoplasms. Targeting both CD33 and CD123 surface antigens together may offer two distinct benefits. First, targeting both bulk disease and leukemic stem cells together allows for a more comprehensive ablation of the disease. Second, dual targeting of myeloid malignancies by both CD33 and CLL1 directed therapy overcomes the pitfalls of single-antigen therapy by preventing relapse due to antigen loss. While loss of a single antigen under antigen-specific selection pressure is possible, loss of two antigens simultaneously is much less likely. CD123-CD33 cCAR is a compound Chimeric Antigen Receptor (cCAR) immunotherapy with two distinct functional CAR molecules expressed on a T-cell, directed against the surface proteins CLL1 and CD33. cCAR intends to target the mechanisms of single-CAR relapse, specifically antigen escape and leukemic stem cells.

Official Title
-----------------
Phase I, Interventional, Single Arm, Open Label, Treatment Study to Evaluate The Safety and Tolerability of CD123-CD33 cCAR in Patients With Relapsed and/or Refractory, High Risk Hematologic Malignancies

Conditions
-----------------
Hematologic Malignancy, Acute Myeloid Leukemia, Myelodysplastic Syndromes, Myeloproliferative Neoplasm, Chronic Myeloid Leukemia

Intervention / Treatment
-----------------
* Biological: CD123-CD33 cCAR T cells


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Prior HSCT relapse beyond 6 months without active GVHD; systematic usage of immunosuppressive drug or corticosteroid must have been stopped for more than 4 weeks De novo AML Transformed AML MDS with excess blasts (RAEB-2) MDS that is not a candidate for induction chemotherapy. Myeloproliferative neoplasms with blastic transformation Patients have exhausted standard therapeutic options Exclusion Criteria: Prior solid organ transplantation Potentially curative therapy including hematopoietic cell transplant Prior treatment with CD123xCD3 or CLL1x3 bispecific agents, T cells expressing CD123 CAR or CLL1 CAR, or toxin-conjugated to CD123 or CLL1 antibodies.
Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CD123-CD33 cCAR T cells<br>C123-CD33cCAR T cells transduced with a lentiviral vector to express two distinct units of anti-CD123 and CD33 CARs | Biological: CD123-CD33 cCAR T cells<br>* CD123-CD33 cCAR T cells transduced with a lentiviral vector to express two distinct units of anti-CD123 and CD33 CARs.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with dose limiting toxicity (DLT) as assessed by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 |  | 28 days | 
| Type of dose-limiting toxicity (DLT) |  | 28 days | 
| Number of participants with adverse event by severity as assessed by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 |  | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) | Assessment of morphologic complete remission (CR), complete remission with incomplete recovery of counts (CR1), no residual disease as analyzed by flow cytometry analysis, and molecular remission by molecular studies | 1 year | 
| Progression-free survival (PFS) |  | 1 year | 
| Overall survival |  | 1 year | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
CD123, CD33, CD123-CD33 cCAR, Leukemia, Hematologic Malignancies