Acute Myeloid Leukemia, Multiple Myeloma
Conditions
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.
Interventions
DRUGMLM-CAR44.1 T-cells at day 0 Single intravenous infusion
Lymphodepleting chemotherapy with cyclophosphamide (500 mg/m2) and fludarabine (30 mg/m2) daily from day -5 to day -3.
Sponsors
Horizon 2020 - European Commission
AGC Biologics S.p.A.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Years to 75 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase IIa: Hematological Disease Response to MLM-CAR44.1 T-cells in MM | 3 months after T-cell infusion, assessed as day 0 | The hematologic disease response will be classified according to IMWG criteria |
| Phase I: Maximum Tolerated Dose (MTD) and the Recommended Phase IIa Dose of MLM-CAR44.1 T-cells in AML and MM | 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 I: Overall Safety of Treatment With MLM-CAR44.1 T-cells | 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: 3 Months Post-infusion | 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: Absence of Replication Competent Retrovirus (RCR) in Blood Specimens: 6 Months Post-infusion | 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: Absence of Replication Competent Retrovirus (RCR) in Blood Specimens: 12 Months Post-infusion | 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 | 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. |
| Phase IIa: Hematological Disease Response to MLM-CAR44.1 T-cells in AML. | 2 months after MLM-CAR44.1 T-cell infusion, assessed as day 0 | The hematologic disease response will be classified according to ELN criteria. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase IIa: Overall Survival (OS) | At the date of the early study termination | 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. One patients out of the 2 treated was still alive at the date of the early study termination. One patient died after EURE-CART-1 cell infusion, at day 121, for disease progression. |
| 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 | 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. |
| 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 | Hematologic disease response evaluated at Day 28 following CART-cell infusion, as overall response rate (ORR), stringent complete response (sCR), CR, very good partial response (VGPR) and partial response (PR). |
| 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 | The levels will be evaluated by flow cytometry and qPCR (in vivo pharmacokinetic profile). |
| 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 | 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. |
| Phase IIa: Hematologic Disease Response in AML | 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. |
| Phase IIa: Hematologic Disease Response in MM | 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 |
Other
| Measure | Time frame | Description |
|---|---|---|
| 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 | AML: proportion of patients with a molecular complete response (CR); MM: proportion of patients with a molecular CR. |
Countries
Czechia, Italy
Participant flow
Recruitment details
The study population originally planned is made up of: Adult patients 18 to 75 years old or 18 to 63 years old for CZ site, with relapsed/refractory AML or MM expressing CD44v6; Children 1 to 17 years old with AML, only in Phase IIa, except for CZ site. Up to the early termination of the study only adult patients 18 to 75 years old or 18 to 63 years old for CZ site, with relapsed/refractory MM expressing CD44v6 were recruited
Pre-assignment details
The recruited patient population, due to the early termination of the clinical study, was made up only of patients affected by multiple myeloma (MM), whereas AML patients were not enrolled. Eight patients, 6 males and 2 females were enrolled in 2 centers. Two patients received the investigational product (MLM-CAR44.1 T-cells), while 6 patients did not. Age ranged from 41 to 66 years, with a median of 56 years.
Participants by arm
| Arm | Count |
|---|---|
| MLM-CAR44.1 T-cells Infusion Patients were scheduled to receive a single intravenous (iv) infusion of CD44v6.CAR-transduced autologous lymphocytes at day 0, after lymphodepleting chemotherapy with cyclophosphamide iv (500 mg/m2) and fludarabine iv (30 mg/m2) performed daily from day -5 to day -3
The dose of iv infused MLM-CAR44.1 T-cells is:
PHASE I: 0.5x10E6/Kg or 1x10E6/Kg or 2x10E6/Kg according to the BOIN design. PHASE IIa: a dose of MLM-CAR44.1 T-cells corresponding to the maximum tolerated dose (MTD). | 8 |
| Total | 8 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Death | 1 |
| Overall Study | Screening Failure | 5 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | MLM-CAR44.1 T-cells Infusion |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 1 Participants |
| Age, Categorical Between 18 and 65 years | 7 Participants |
| Age, Continuous | 56 years |
| Confirmed diagnosis of MM | 8 Participants |
| Patients with relapse or refractory disease | 8 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 8 Participants |
| Region of Enrollment Czechia | 3 participants |
| Region of Enrollment Italy | 5 participants |
| Sex: Female, Male Female | 2 Participants |
| Sex: Female, Male Male | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 2 |
| other Total, other adverse events | 2 / 2 |
| serious Total, serious adverse events | 2 / 2 |
Outcome results
Primary
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.
Time frame: 12 months after infusion (assessed as day 0)
Population: Data were not collected due to early end of trial
Primary
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.
Time frame: 24 months after infusion (assessed as day 0)
Population: Data were not collected due to early end of trial
Primary
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.
Time frame: 3 months after infusion (assessed as day 0)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| MLM-CAR44.1 T-cells Infusion | Phase I: Absence of Replication Competent Retrovirus (RCR) in Blood Specimens: 3 Months Post-infusion | 2 Participants |
Primary
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
Time frame: 6 months after infusion (assessed as day 0)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| MLM-CAR44.1 T-cells Infusion | Phase I: Absence of Replication Competent Retrovirus (RCR) in Blood Specimens: 6 Months Post-infusion | 2 Participants |
Primary
Phase IIa: Hematological Disease Response to MLM-CAR44.1 T-cells in AML.
The hematologic disease response will be classified according to ELN criteria.
Time frame: 2 months after MLM-CAR44.1 T-cell infusion, assessed as day 0
Population: Data were not collected because Phase IIa was not performed due to early end of trial
Primary
Phase IIa: Hematological Disease Response to MLM-CAR44.1 T-cells in MM
The hematologic disease response will be classified according to IMWG criteria
Time frame: 3 months after T-cell infusion, assessed as day 0
Population: Data were not collected because Phase IIa was not performed due to early end of trial
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| MLM-CAR44.1 T-cells Infusion | Phase IIa: Hematological Disease Response to MLM-CAR44.1 T-cells in MM | 0 Participants |
Primary
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.
Time frame: Within 30 days following CAR T-cell infusion, assessed as day 0
Population: Data were not collected due to early end of trial
Primary
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.
Time frame: For 30 days following CAR T-cell infusion, assessed as day 0.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MLM-CAR44.1 T-cells Infusion | Phase I: Overall Safety of Treatment With MLM-CAR44.1 T-cells | 3 Number of SAEs |
Secondary
Phase I: Hematologic Disease Response to MLM-CAR44.1 T-cells in AML
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.
Time frame: 1 and 2 months following T-cell infusion, assessed as day 0
Population: Data were not collected because no AML patients were enrolled
Secondary
Phase I: Hematologic Disease Response to MLM-CAR44.1 T-cells in MM
Hematologic disease response evaluated at Day 28 following CART-cell infusion, as overall response rate (ORR), stringent complete response (sCR), CR, very good partial response (VGPR) and partial response (PR).
Time frame: 1 and 3 months following T-cell infusion, assessed as day 0
Population: Hematologic disease response of the two treated patients was evaluated at Day 28 following CART-cell infusion. Both patients showed a progressive disease (PD) and no sign of response.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| MLM-CAR44.1 T-cells Infusion | Phase I: Hematologic Disease Response to MLM-CAR44.1 T-cells in MM | No response detected | 2 Participants |
| MLM-CAR44.1 T-cells Infusion | Phase I: Hematologic Disease Response to MLM-CAR44.1 T-cells in MM | Hematologic disease response | 0 Participants |
Secondary
Phase IIa: Hematologic Disease Response in AML
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.
Time frame: 1, 2 and 6 months after MLM-CAR44.1 T-cell infusion, assessed as day 0.
Population: Data were not collected because Phase IIa was not performed due to early end of trial
Secondary
Phase IIa: Hematologic Disease Response in MM
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
Time frame: 1, 2 and 6 months after T-cell infusion, assessed as day 0
Population: Data were not collected because Phase IIa was not performed due to early end of trial
Secondary
Phase IIa: Overall Survival (OS)
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. One patients out of the 2 treated was still alive at the date of the early study termination. One patient died after EURE-CART-1 cell infusion, at day 121, for disease progression.
Time frame: At the date of the early study termination
Population: Data were not collected because Phase IIa was not performed due to early end of trial
Secondary
Phase I: The Levels of Circulating MLM-CAR44.1 T-cells in Blood Samples
The levels will be evaluated by flow cytometry and qPCR (in vivo pharmacokinetic profile).
Time frame: At day 7, 14, 21, 28, 60, 90, 180 from infusion, assessed as day 0
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| MLM-CAR44.1 T-cells Infusion | Phase I: The Levels of Circulating MLM-CAR44.1 T-cells in Blood Samples | Negative at all monitoring time points | 1 Participants |
| MLM-CAR44.1 T-cells Infusion | Phase I: The Levels of Circulating MLM-CAR44.1 T-cells in Blood Samples | Positive at day 14 and 21 | 1 Participants |
Secondary
Phase I: The Percentage of Patients for Whom Activation of Suicide Gene Was Needed
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.
Time frame: At day 7, 14, 21, 28, 60, 90, 180 from infusion, assessed as day 0
Population: Data were not collected because no MLM-CAR44.1 T-cell related toxicities occurred
Other Pre-specified
Exploratory Outcome of Phase IIa: Percentages of Patients With Minimal Residual Disease
AML: proportion of patients with a molecular complete response (CR); MM: proportion of patients with a molecular CR.
Time frame: AML: 2 months after infusion, assessed as day 0. MM: 3 months after infusion, assessed as day 0
Population: Data were not collected because Phase IIa was not performed due to early end of trial