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

NCT04097301 | Terminated Phase 1 Results DMC

• 2 other identifiers: EURE-CART-12018-000813-19
• Study Type: interventional
• Target: 8
• Locations: 2 countries
• Sites: 3

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).

Conditions

Acute Myeloid Leukemia; Multiple Myeloma

Outcome Measures

Primary Outcomes (8)

• Phase I: Maximum Tolerated Dose (MTD) and the Recommended Phase IIa Dose of MLM-CAR44.1 T-cells in AML and MM

  MTD established through BOIN design and the dose-limiting toxicities (DLTs) occurring following CAR T-cell infusion.

  Within 30 days following CAR T-cell infusion, assessed as day 0

• Phase I: Overall Safety of Treatment With MLM-CAR44.1 T-cells

  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). Overall, 3 study emergent serious adverse events (SAEs) were reported in patients treated with MLM-CAR44.1 T-cells.

  For 30 days following CAR T-cell infusion, assessed as day 0.

• Phase I: Absence of Replication Competent Retrovirus (RCR) in Blood Specimens: 3 Months Post-infusion

  The absence of replication competent retrovirus (RCR) in blood specimens: 3 months post-infusion will be monitored by DNA PCR for the Galv gene. RCR search was conducted centrally using a quantitative molecular test, (real time quantitative PCR, q-PCR analysis) determining the absence of RCR by DNA PCR for the Galv and gag-pol genes on genomic DNA from patient's peripheral blood lymphocytes. The objective of this q-PCR analysis is to exclude the presence of RCR originated by recombination with PG13 packaging cell sequences by detecting the Galv and gag-pol transcripts in the transduced cells. The absence of the Galv and gag-pol transcripts can exclude the presence of an RCR, while its presence is not sufficient to indicate the presence of an RCR, and in this case further analysis is required.

  3 months after infusion (assessed as day 0)

• Phase I: Absence of Replication Competent Retrovirus (RCR) in Blood Specimens: 6 Months Post-infusion

  The absence of replication competent retrovirus (RCR) in blood specimens will be monitored by DNA PCR for the Galv gene. RCR search was conducted centrally using a quantitative molecular test, (real time quantitative PCR, q-PCR analysis) determining the absence of RCR by DNA PCR for the Galv and gag-pol genes on genomic DNA from patient's peripheral blood lymphocytes. The objective of this q-PCR analysis is to exclude the presence of RCR originated by recombination with PG13 packaging cell sequences by detecting the Galv and gag-pol transcripts in the transduced cells. The absence of the Galv and gag-pol transcripts can exclude the presence of an RCR, while its presence is not sufficient to indicate the presence of an RCR, and in this case further analysis is required

  6 months after infusion (assessed as day 0)

• Phase I: Absence of Replication Competent Retrovirus (RCR) in Blood Specimens: 12 Months Post-infusion

  The absence of replication competent retrovirus (RCR) in blood specimens will be monitored by DNA PCR for the Galv gene.

  12 months after infusion (assessed as day 0)

• Phase I: Absence of Replication Competent Retrovirus (RCR) in Blood Specimens: 24 Months Post-infusion

  The absence of replication competent retrovirus (RCR) in blood specimens will be monitored by DNA PCR for the Galv gene.

  24 months after infusion (assessed as day 0)

• Phase IIa: Hematological Disease Response to MLM-CAR44.1 T-cells in AML.

  The hematologic disease response will be classified according to ELN criteria.

  2 months after MLM-CAR44.1 T-cell infusion, assessed as day 0

• Phase IIa: Hematological Disease Response to MLM-CAR44.1 T-cells in MM

  The hematologic disease response will be classified according to IMWG criteria

  3 months after T-cell infusion, assessed as day 0

Secondary Outcomes (7)

• Phase I: Hematologic Disease Response to MLM-CAR44.1 T-cells in AML

  1 and 2 months following T-cell infusion, assessed as day 0

• Phase I: Hematologic Disease Response to MLM-CAR44.1 T-cells in MM

  1 and 3 months following T-cell infusion, assessed as day 0

• Phase I: The Levels of Circulating MLM-CAR44.1 T-cells in Blood Samples

  At day 7, 14, 21, 28, 60, 90, 180 from infusion, assessed as day 0

• Phase I: The Percentage of Patients for Whom Activation of Suicide Gene Was Needed

  At day 7, 14, 21, 28, 60, 90, 180 from infusion, assessed as day 0

• Phase IIa: Hematologic Disease Response in AML

  1, 2 and 6 months after MLM-CAR44.1 T-cell infusion, assessed as day 0.

Other Outcomes (1)

• Exploratory Outcome of Phase IIa: Percentages of Patients With Minimal Residual Disease

  AML: 2 months after infusion, assessed as day 0. MM: 3 months after infusion, assessed as day 0

Study Arms (1)

MLM-CAR44.1 T-cells infusion

EXPERIMENTAL

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. single dose of MLM-CAR44.1 T-cells corresponding to the maximum tolerated dose (MTD). Phase I and IIa Pre-treatment: lymphodepleting chemotherapy with cyclophosphamide (500 mg/m2) and fludarabine (30 mg/m2) daily from day -5 to day -3

Drug: MLM-CAR44.1 T-cells at day 0 Single intravenous infusion

Interventions

MLM-CAR44.1 T-cells at day 0 Single intravenous infusion DRUG

Lymphodepleting chemotherapy with cyclophosphamide (500 mg/m2) and fludarabine (30 mg/m2) daily from day -5 to day -3.

Also known as: CAR-T cells

MLM-CAR44.1 T-cells infusion

Eligibility Criteria

• Age: 1 Year - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Written informed consent before any study-related procedure.
• Adults and children:
• Adults 18 to 75 (65) years old with AML or MM.
• Children 1 to 17 years old with AML, only in Phase IIa.
• Confirmed diagnosis of AML or MM as follows:
• AML: Primary or secondary AML (any subtype except acute promyelocytic leukemia) according to World Health Organization (WHO) classification.
• MM with measurable disease as defined by the International Myeloma Working Group (IMWG).
• Patients with relapse or refractory disease:
• 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).
• 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

You may not qualify if:

• History of or candidate for allogeneic stem cell transplantation.
• 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.
• Any history of or suspected current autoimmune disorders (apart from vitiligo, resolved childhood atopic dermatitis, Graves' disease clinically controlled).
• History of rheumatologic disorders requiring specific treatment at any time in the patient's medical history.

Sponsors & Collaborators

• AGC Biologics S.p.A.: lead
• Horizon 2020 - European Commission: collaborator

Study Sites (3)

Department of Haematooncology, Fakultni Nemocnice

Ostrava, Czech Republic, Czechia

Location

IRCCS San Raffaele

Milan, Italy

Location

IRCCS Ospedale Pediatrico Bambino Gesù

Roma, Italy

Location

Related Publications (1)

• Stornaiuolo A, Valentinis B, Sirini C, Scavullo C, Asperti C, Zhou D, Martinez De La Torre Y, Corna S, Casucci M, Porcellini S, Traversari C. Characterization and Functional Analysis of CD44v6.CAR T Cells Endowed with a New Low-Affinity Nerve Growth Factor Receptor-Based Spacer. Hum Gene Ther. 2021 Jul;32(13-14):744-760. doi: 10.1089/hum.2020.216. Epub 2021 May 5.

  PMID: 33554732 DERIVED

MeSH Terms

Conditions

Leukemia, Myeloid, Acute; Multiple Myeloma

Interventions

Immunotherapy, Adoptive

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Hematologic Diseases; Hemic and Lymphatic Diseases; Neoplasms, Plasma Cell; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Adoptive Transfer; Immunization, Passive; Immunization; Immunotherapy; Immunomodulation; Biological Therapy; Therapeutics; Immunologic Techniques; Investigative Techniques

Limitations and Caveats

The early termination of this study is due to the analysis of its feasibility, based on the low patient recruitment rate (due to the lower-than-expected proportion of myeloma and leukemia expressing the CD44v6). A further decrease in the recruitment occurred with the diffusion of the COVID-19 emergency and the availability of new drugs for the treatment of myeloma and leukemia. These reasons make impossible to foresee the conclusion of the study in a clinically relevant time frame.

Results Point of Contact

• Title: Anna Stornaiuolo
• Organization: AGC Biologics

astornaiuolo@agcbio.com

0221277440

Study Officials

• Fabio Ciceri, MD

  IRCCS San Raffaele

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 5, 2019
• First Posted: September 20, 2019
• Study Start: August 27, 2019
• Primary Completion: June 18, 2021
• Study Completion: June 18, 2021
• Last Updated: January 19, 2022
• Results First Posted: January 19, 2022

Record last verified: 2021-12

Locations

CZ (1); IT (2)