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

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ClinicalTrials.gov Identifier: NCT04097301
Recruitment Status : Recruiting
First Posted : September 20, 2019
Last Update Posted : September 20, 2019
Sponsor:
Collaborator:
Horizon 2020 - European Commission
Information provided by (Responsible Party):
MolMed S.p.A.

Brief Summary:
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).

Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia Multiple Myeloma Drug: MLM-CAR44.1 T-cells, cyclophosphamide and fludarabine from -5 to -3 Phase 1 Phase 2

Detailed Description:

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 58 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I-IIa Trial to Assess the Safety and Antitumor Activity of Autologous CD44v6 CAR T-cells in Acute Myeloid Leukemia and Multiple Myeloma Expressing CD44v6
Actual Study Start Date : August 27, 2019
Estimated Primary Completion Date : June 28, 2023
Estimated Study Completion Date : June 28, 2023


Arm Intervention/treatment
Experimental: MLM-CAR44.1 T-cells infusion

PHASE I: i.v. single dose of MLM-CAR44.1 T-cells: 0.5 x 10E6/Kg or 1 x 10E6/Kg or 2 x10E6/Kg according to the BOIN design.

PHASE IIa: i.v. dose of MLM-CAR44.1 T-cells corresponding to the maximum tolerated dose (MTD).

Drug: MLM-CAR44.1 T-cells, cyclophosphamide and fludarabine from -5 to -3
Single intravenous infusion
Other Name: CAR-T cells




Primary Outcome Measures :
  1. The maximum tolerated dose (MTD) and the recommended phase IIa dose of MLM-CAR44.1 T-cells in AML and MM [ Time Frame: Within 30 days following CAR T-cell infusion, assessed as day 0 ]
    MTD established through BOIN design and the dose-limiting toxicities (DLTs) occurring following CAR T-cell infusion.

  2. Phase I: The safety of treatment with MLM-CAR44.1 T-cells [ Time Frame: For 30 days following CAR T-cell infusion, assessed as day 0. ]
    Safety will be evaluated by analyzing the type, frequency and severity of adverse events (AE) and by monitoring for systemic reactions (fever, tachycardia, nausea and vomiting, joint pain, skin rash).

  3. Phase I: The absence of replication competent retrovirus (RCR) in blood specimens: 3 months post-infusion [ Time Frame: 3 months after infusion (assessed as day 0) ]
    The absence of RCR will be monitored by DNA PCR for the Galv gene.

  4. Phase I: The absence of replication competent retrovirus (RCR) in blood specimens: 6 months post-infusion [ Time Frame: 6 months after infusion (assessed as day 0) ]
    The absence of RCR will be monitored by DNA PCR for the Galv gene.

  5. Phase I: The absence of replication competent retrovirus (RCR) in blood specimens: 12 months post-infusion [ Time Frame: 12 months after infusion (assessed as day 0) ]
    The absence of RCR will be monitored by DNA PCR for the Galv gene.

  6. Phase I: The absence of replication competent retrovirus (RCR) in blood specimens: 24 months post-infusion [ Time Frame: 24 months after infusion (assessed as day 0) ]
    The absence of RCR will be monitored by DNA PCR for the Galv gene.

  7. Phase IIa: Hematological disease response to MLM-CAR44.1 T-cells in AML. [ Time Frame: 2 months after MLM-CAR44.1 T-cell infusion, assessed as day 0 ]
    The hematologic disease response will be classified according to ELN criteria.

  8. Phase IIa: Hematological disease response to MLM-CAR44.1 T-cells in MM [ Time Frame: 3 months after T-cell infusion, assessed as day 0 ]
    The hematologic disease response will be classified according to IMWG criteria


Secondary Outcome Measures :
  1. Phase I: Hematologic disease response to MLM-CAR44.1 T-cells in AML [ Time Frame: 1 and 2 months following T-cell infusion, assessed as day 0 ]
    The hematologic disease response will be classified with the following response criteria: complete response (CR), incomplete response (CRi) and partial response (PR) according to ELN criteria.

  2. Phase I: Hematologic disease response to MLM-CAR44.1 T-cells in MM [ Time Frame: 1 and 3 months following T-cell infusion, assessed as day 0 ]
    The hematologic disease response will be defined based on the overall response rate (ORR): stringent complete response (sCR), complete response (CR), very good partial response (VGPR), and partial response (PR) according to IMWG criteria

  3. Phase I: The levels of circulating MLM-CAR44.1 T-cells in blood samples [ Time Frame: At day 7, 14, 21, 28, 60, 90, 180 from infusion, assessed as day 0 ]
    The levels will be evaluated by flow cytometry (in vivo pharmacokinetic profile).

  4. Phase I: The percentage of patients for whom activation of suicide gene was needed [ Time Frame: At day 7, 14, 21, 28, 60, 90, 180 from infusion, assessed as day 0 ]
    Suicide gene activation and elimination of transduced cells will be established through administration of ganciclovir in case of cytokine-release syndrome (CRS) and other MLM-CAR44.1 T-cell related toxicities.

  5. Phase IIa: Hematologic disease response in AML [ Time Frame: 1, 2 and 6 months after MLM-CAR44.1 T-cell infusion, assessed as day 0. ]
    The hematologic disease response will be classified with the following response criteria: complete response (CR), incomplete response (CRi) and partial response (PR) according to ELN criteria.

  6. Phase IIa: Hematologic disease response in MM [ Time Frame: 1, 2 and 6 months after T-cell infusion, assessed as day 0 ]
    The hematologic disease response will be defined based on the overall response rate (ORR): stringent complete response (sCR), complete response (CR), very good partial response (VGPR), and partial response (PR) according to IMWG criteria

  7. Phase IIa: Overall Survival (OS) [ Time Frame: At 2 year: time from MLM-CAR44.1 T-cell infusion to death due to any cause ]
    Overall Survival (OS) is defined as the time from the date of MLM-CAR44.1 T-cell infusion to the date of last follow-up or death due to any cause, whichever occurs first. A description of the overall survival time will be performed using median and range


Other Outcome Measures:
  1. Exploratory outcome of Phase IIa: Percentages of patients with Minimal Residual Disease [ Time Frame: AML: 2 months after infusion, assessed as day 0. MM: 3 months after infusion, assessed as day 0 ]
    AML: proportion of patients with a molecular complete response (CR); MM: proportion of patients with a molecular CR.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   1 Year to 75 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04097301


Contacts
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Contact: MolMed S.p.A
Contact: MolMed S.p.A eurecart.1@molmed.com

Locations
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Italy
IRCCS San Raffaele Recruiting
Milan, Italy
Contact: Fabio Ciceri, Prof.    0    ciceri.fabio@hsr.it   
IRCCS Ospedale Pediatrico Bambino Gesù Recruiting
Roma, Italy
Contact: Franco Locatelli, Prof.    0    franco.locatelli@opbg.net   
Sponsors and Collaborators
MolMed S.p.A.
Horizon 2020 - European Commission
Investigators
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Principal Investigator: Fabio Ciceri, MD IRCCS San Raffaele

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Responsible Party: MolMed S.p.A.
ClinicalTrials.gov Identifier: NCT04097301     History of Changes
Other Study ID Numbers: EURE-CART-1
2018-000813-19 ( EudraCT Number )
First Posted: September 20, 2019    Key Record Dates
Last Update Posted: September 20, 2019
Last Verified: September 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Leukemia
Leukemia, Myeloid
Multiple Myeloma
Neoplasms, Plasma Cell
Leukemia, Myeloid, Acute
Neoplasms by Histologic Type
Neoplasms
Hemostatic Disorders
Vascular Diseases
Cardiovascular Diseases
Paraproteinemias
Blood Protein Disorders
Hematologic Diseases
Hemorrhagic Disorders
Lymphoproliferative Disorders
Immunoproliferative Disorders
Immune System Diseases
Cyclophosphamide
Fludarabine
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists