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
Overview
- Phase
- Phase 1
- Intervention
- MLM-CAR44.1 T-cells at day 0 Single intravenous infusion
- Conditions
- Acute Myeloid Leukemia
- Sponsor
- AGC Biologics S.p.A.
- Enrollment
- 8
- Locations
- 3
- Primary Endpoint
- Phase I: Absence of Replication Competent Retrovirus (RCR) in Blood Specimens: 6 Months Post-infusion
- Status
- Terminated
- Last Updated
- 4 years ago
Overview
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).
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Patients must meet all the following inclusion criteria to be eligible for the study.
- •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:
Exclusion Criteria
- •At screening: patients must meet none of the following exclusion criteria to be eligible for the study:
- •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.
Arms & Interventions
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. 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
Intervention: MLM-CAR44.1 T-cells at day 0 Single intravenous infusion
Outcomes
Primary Outcomes
Phase I: 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 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
Phase I: 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.
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.
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
Phase I: 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 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.
Phase I: Overall 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). Overall, 3 study emergent serious adverse events (SAEs) were reported in patients treated with MLM-CAR44.1 T-cells.
Phase I: 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 replication competent retrovirus (RCR) in blood specimens will be monitored by DNA PCR for the Galv gene.
Phase I: 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 replication competent retrovirus (RCR) in blood specimens will be monitored by DNA PCR for the Galv gene.
Secondary Outcomes
- 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 IIa: Hematologic Disease Response in AML(1, 2 and 6 months after MLM-CAR44.1 T-cell infusion, assessed as day 0.)
- Phase IIa: Overall Survival (OS)(At the date of the early study termination)
- 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 IIa: Hematologic Disease Response in MM(1, 2 and 6 months after T-cell 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)