Study of CAR T-cell Therapy in Acute Myeloid Leukemia and Multiple Myeloma

The purpose of this first-in-man Phase I-IIa study is to evaluate the safety and antitumor activity of autologous CD44v6 CAR T-cells in patients with acute myeloid leukemia (AML) and multiple myeloma (MM).

The study is a seamless Phase I/IIa, open-label, multicenter clinical trial that combines Phase I dose escalation based on toxicity with Phase IIa dose expansion based on antitumor activity. Considering the "first in human" nature of this clinical study, the Bayesian Optimal Interval Design (BOIN) has been chosen to minimize any risks of exposure to the novel CD44v6 CAR T-cells during dose escalation. The study population is made up of patients with relapsed/refractory AML or MM expressing CD44v6.

The medicinal product under investigation (MLM-CAR44.1 T-cells) is patient specific as it is prepared starting from lymphocytes of the patient collected through lymphocyte apheresis. These autologous T-cells are expanded in vitro in large numbers and genetically modified to express the CAR CD44v6ΔNL gene and thus acquire antitumor functions. As a safety feature, the MLM-CAR44.1 T-cells are genetically modified to also express the HSV-TK Mut2 gene (suicide gene), which can be selectively activated in case of severe toxicity through the administration of ganciclovir (GCV), leading to the death of proliferating CAR T-cells.

The aim of this study is to assess the safety, antitumor activity and feasibility of CD44v6 CAR T cell immunotherapy in AML and MM.

Eligibility Criteria:
Inclusion Criteria:

Patients must meet all the following inclusion criteria to be eligible for the study.

1. Written informed consent before any study-related procedure.
2. Adults and children:

   1. Adults 18 to 75 (65) years old with AML or MM.
   2. Children 1 to 17 years old with AML, only in Phase IIa.
3. Confirmed diagnosis of AML or MM as follows:

   1. AML: Primary or secondary AML (any subtype except acute promyelocytic leukemia) according to World Health Organization (WHO) classification.
   2. MM with measurable disease as defined by the International Myeloma Working Group (IMWG).
4. Patients with relapse or refractory disease:

   1. AML patients must be unlikely to benefit from cytotoxic chemotherapy as follows:

      * Leukemia refractory to at least 2 induction attempts.
      * Leukemia in relapse within 1 year following complete response (CR) after at least 2 induction attempts.
      * High-risk leukemia in adults according to 2017 European LeukemiaNet (ELN) in first relapse after a hypomethylating agent or a cycle containing cytarabine at a dose ≥ 1g/sqm a day (e.g. FLAG-IDA), except for FLT3-mutated AML.
      * High-risk leukemia in children as defined by the Italian Association of Pediatric Hematology and Oncology (AIEOP).
   2. Patients with MM must have a relapse or refractory disease after at least 4 different prior treatments in 3 treatment lines, or 4 treatments in 2 treatment lines in case of early relapsing patients (relapse in less than 1.5 years). Treatments include:

      * Proteasome inhibitor
      * High-dose alkylating agent if patients less than 70 years old
      * Immunomodulatory drug (IMID)
      * A monoclonal antibody (i.e. anti CD38 monoclonal antibody)
5. Positive CD44v6 expression on tumor cells by flow cytometry.
6. Eastern Cooperative Oncology Group (ECOG) performance status 0-2.
7. Life expectancy of at least 12 weeks.
8. Adequate organ function (hepatic, cardiac, pulmonary).
9. Recovery from toxicities of clinical consequence attributed to previous chemotherapy to CTCAE v5.0 Grade 1 (i.e., certain toxicities such as alopecia will not be considered in this category).
10. Ability to comply with study procedures, including hospitalization and protocol-specified acquisition of blood and/or bone marrow specimens.
11. Willing to be followed up long term, i.e. a 15-year follow up as required by health authorities for cell and gene therapy products.
12. Women of childbearing potential must test negative for pregnancy at enrolment and during the study.

Exclusion Criteria:

At screening: patients must meet none of the following exclusion criteria to be eligible for the study:

1. History of or candidate for allogeneic stem cell transplantation.
2. Cardiovascular, pulmonary, renal, and hepatic functions that in the judgment of the investigator are insufficient for the patient to undergo investigational CAR T-cell therapy.
3. Any history of or suspected current autoimmune disorders (apart from vitiligo, resolved childhood atopic dermatitis, Graves' disease clinically controlled).
4. History of rheumatologic disorders requiring specific treatment at any time in the patient's medical history.