Safety and antitumor activity of autologous CD44v6 CAR T-cells in acute myeloid leukemia and multiple myeloma expressing CD44v6.

Phase 1

Conditions: Acute myeloid leukemia and Multiple myeloma
MedDRA version: 20.0Level: LLTClassification code 10028228Term: Multiple myelomaSystem Organ Class: 100000004864
MedDRA version: 20.0Level: LLTClassification code 10000886Term: Acute myeloid leukemiaSystem Organ Class: 100000004864
Therapeutic area: Diseases [C] - Cancer [C04]

Registration Number: EUCTR2018-000813-19-CZ

Lead Sponsor: MolMed S.p.A.

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: 68

Inclusion Criteria

1. Written informed consent before any study-related procedure.
2. Adults and children:
a) Adults 18 to 75 years old with AML or MM
b) Children 1 to 17 years old with AML, only in Phase IIa
3. Confirmed diagnosis of AML or MM as follows:
a) AML: Primary or secondary AML (any subtype except acute promyelocytic leukemia) according to World Health Organization (WHO) classification
b) MM with measurable disease as defined by the International Myeloma Working Group (IMWG).
4. Patients with relapse or refractory disease:
a) AML patients must be unlikely to benefit from cytotoxic chemotherapy as follows:
• Leukemia refractory to at least 2 induction attempts (use of a hypomethylating agent for at least 4 cycles can be considered a line of treatment).
• Leukemia in relapse within 1 year following complete response (CR) after at least 2 induction attempts (use of a hypomethylating agent for at least 4 cycles can be considered a first line of treatment).
• 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).
b) 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 patient 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:
a) Alanine aminotransferase (ALT) level within 2.5 times the institutional upper limit of normal (ULN).
b) aspartate aminotransferase (AST) level = 2.5 x ULN.
c) Total bilirubin level = 1.5 x ULN, or = 2.5 x ULN in case of history of Gilbert’s disease.?
d) Serum creatinine = 2.0 mg/dL or a calculated or measured creatinine clearance = 45mL/min.
e) Corrected Diffusing Capacity of Carbon Monoxide (DLCO) (via Dinakara Equation) or FEV1 of ? 66% without dyspnea on slight activity after hemoglobin correction.
f) Left ventricular ejection fraction ? 45%.
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 (15 years) as required by health authorities for cell and gene therapy products
12. Women of childbearing potential must have test negative for pregnancy at enrolment and during the study and agree to use an effective method of contraception.
Are the trial subjects under 18? yes
Number of subjects for this age range: 7
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 58
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 3

Exclusion Criteria

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 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.
5. Second primary malignancy that requires active therapy. Adjuvant hormonal therapy is allowed. ??
6. Known or suspected central nervous system (CNS) leukemia. ?
7. Presence or history of myeloid sarcoma or any extramedullary mass.
8. Any medical or psychiatric condition that may limit compliance or increase safety risks, such as:
a) Active uncontrolled infection (including, but not limited to viral, bacterial, fungal, or mycobacterial infection).?
b) Patients with known multiple antibiotic resistant infections in their clinical history.
c) Known human immunodeficiency virus infection, active or chronic hepatitis B or C infection. ?
d) Grade 3 or 4 bleeding. ??
e) Uncontrolled hypertension (systolic pressure > 180 mm Hg or diastolic pressure > 100 mm Hg). ?
f) Clinically significant arrhythmia, clinically significant baseline QTcF, or QTcF > 480 msec. ?
g) Unstable angina. ?
h) Myocardial infarction within 6 months prior to study drug administration. ?
i) Clinically significant heart disease (e.g. CHF NYHA III or IV, unstable coronary artery disease, myocardial infarction < 6 mo. prior to study entry).
j) Pregnancy or breast feeding.
k) Major surgery or trauma within 4 weeks before enrollment. ?
l) Dementia or altered mental status that would preclude sufficient understanding to provide informed consent.
Once all the above eligibility criteria are confirmed, a lymphocyte apheresis product of non-mobilized cells must be received and accepted by the manufacturing site. Note: the lymphocyte apheresis product will not be shipped or assessed for acceptance by the manufacturing site until documented confirmation of all other inclusion/exclusion criteria have been satisfied.

Prior to lymphocyte apheresis (week -9 to -7), the following criteria must be met:
1. Peripheral blast count = 20,000/mm3 (AML).
2. No treatment with any other investigational agent in the previous 4 weeks.
3. No treatment with an immunostimulatory agent (IMIDs are allowed) or any cell therapy in the previous 30 days.
4. Negative to the following tests: HCV (Antibody, NAT), HIV 1-2 (p24, AB, Ag and NAT), total Ig Treponema Pallidum (if positive perform specific test), Australia HBsAg, total anti HB core Ab (if positive perform HBV DNA NAT), mycoplasma (PCR or IgM) and HTLV I-II.

Prior to lymphodepleting chemotherapy and MLM-CAR44.1 T-cell infusion (day -5 to day -3), the following criteria must be met:
1. Evidence of active disease at the beginning of lympho-depleting chemotherapy.
2. The following medications are excluded and should not be administered concomitantly or following lymphodepleting chemotherapy:
a) Monoclonal antibodies in the 8 weeks prior to MLM-CAR44.1 T-cell infusion are prohibited.
b) Salvage chemotherapy (e.g. clofarabine, cytosine arabinoside > 100 mg/m2, anthracyclines, cyclophosphamide, proteasome inhibitors, IMIDs) must be stopped > 2 weeks prior to lymphodepleting chemotherapy
c) Granulocyte colony stimulati

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method

Secondary Outcome Measures

Name	Time	Method

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