Trial Outcomes & Findings for Study of CAR T-cell Therapy in Acute Myeloid Leukemia and Multiple Myeloma (NCT NCT04097301)

Results Overview

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

Recruitment status

TERMINATED

Study phase

PHASE1/PHASE2

Target enrollment

8 participants

Primary outcome timeframe

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

Results posted on

2022-01-19

Participant Flow

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

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.

Participant milestones

Participant milestones
Measure	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).
Overall Study STARTED	8
Overall Study Treated Patients	2
Overall Study COMPLETED	1
Overall Study NOT COMPLETED	7

Reasons for withdrawal

Reasons for withdrawal
Measure	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).
Overall Study Death	1
Overall Study Withdrawal by Subject	1
Overall Study Screening Failure	5

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	MLM-CAR44.1 T-cells Infusion n=8 Participants 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).
Age, Categorical <=18 years	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	7 Participants n=5 Participants
Age, Categorical >=65 years	1 Participants n=5 Participants
Age, Continuous	56 years n=5 Participants
Sex: Female, Male Female	2 Participants n=5 Participants
Sex: Female, Male Male	6 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants
Race (NIH/OMB) White	8 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants
Region of Enrollment Italy	5 participants n=5 Participants
Region of Enrollment Czechia	3 participants n=5 Participants
Confirmed diagnosis of MM	8 Participants n=5 Participants
Patients with relapse or refractory disease	8 Participants n=5 Participants

PRIMARY outcome

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

Population: Data were not collected due to early end of trial

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

Outcome measures

Outcome data not reported

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	MLM-CAR44.1 T-cells Infusion n=2 Participants 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).
Phase I: Overall Safety of Treatment With MLM-CAR44.1 T-cells	3 Number of SAEs

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	MLM-CAR44.1 T-cells Infusion n=2 Participants 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).
Phase I: Absence of Replication Competent Retrovirus (RCR) in Blood Specimens: 3 Months Post-infusion	2 Participants

PRIMARY outcome

Timeframe: 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

Outcome measures

Outcome measures
Measure	MLM-CAR44.1 T-cells Infusion n=2 Participants 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).
Phase I: Absence of Replication Competent Retrovirus (RCR) in Blood Specimens: 6 Months Post-infusion	2 Participants

PRIMARY outcome

Timeframe: 12 months after infusion (assessed as day 0)

Population: Data were not collected due to early end of trial

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

Outcome measures

Outcome data not reported

PRIMARY outcome

Timeframe: 24 months after infusion (assessed as day 0)

Population: Data were not collected due to early end of trial

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

Outcome measures

Outcome data not reported

PRIMARY outcome

Timeframe: 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

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

Outcome measures

Outcome data not reported

PRIMARY outcome

Timeframe: 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

The hematologic disease response will be classified according to IMWG criteria

Outcome measures

Outcome measures
Measure	MLM-CAR44.1 T-cells Infusion n=2 Participants 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).
Phase IIa: Hematological Disease Response to MLM-CAR44.1 T-cells in MM	0 Participants

SECONDARY outcome

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

Population: Data were not collected because no AML patients were enrolled

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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 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.

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).

Outcome measures

Outcome measures
Measure	MLM-CAR44.1 T-cells Infusion n=2 Participants 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).
Phase I: Hematologic Disease Response to MLM-CAR44.1 T-cells in MM No response detected	2 Participants
Phase I: Hematologic Disease Response to MLM-CAR44.1 T-cells in MM Hematologic disease response	0 Participants

SECONDARY outcome

Timeframe: 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).

Outcome measures

Outcome measures
Measure	MLM-CAR44.1 T-cells Infusion n=2 Participants 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).
Phase I: The Levels of Circulating MLM-CAR44.1 T-cells in Blood Samples Positive at day 14 and 21	1 Participants
Phase I: The Levels of Circulating MLM-CAR44.1 T-cells in Blood Samples Negative at all monitoring time points	1 Participants

SECONDARY outcome

Timeframe: 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

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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 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

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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 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

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

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: 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

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.

Outcome measures

Outcome data not reported

OTHER_PRE_SPECIFIED outcome

Timeframe: 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

AML: proportion of patients with a molecular complete response (CR); MM: proportion of patients with a molecular CR.

Outcome measures

Outcome data not reported

Adverse Events

MLM-CAR44.1 T-cells Infusion

Serious events: 2 serious events

Other events: 2 other events

Deaths: 1 deaths

Serious adverse events

Serious adverse events
Measure	MLM-CAR44.1 T-cells Infusion n=2 participants at risk 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).
Infections and infestations Pneumonia	100.0% 2/2 • 15 months All SAEs and AEs are collected regardless of their relationship with the experimental product. Laboratory abnormalities that constitute an AE should be recorded on the Adverse Events page of the eCRF. Whenever possible, a diagnosis, rather than a symptom should be provided. Laboratory abnormalities that meet the criteria for Adverse Events should be followed until they have returned to normal or an adequate explanation of the abnormality is found.
General disorders Disease progression	50.0% 1/2 • 15 months All SAEs and AEs are collected regardless of their relationship with the experimental product. Laboratory abnormalities that constitute an AE should be recorded on the Adverse Events page of the eCRF. Whenever possible, a diagnosis, rather than a symptom should be provided. Laboratory abnormalities that meet the criteria for Adverse Events should be followed until they have returned to normal or an adequate explanation of the abnormality is found.

Other adverse events

Other adverse events
Measure	MLM-CAR44.1 T-cells Infusion n=2 participants at risk 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).
Immune system disorders Pyrexia	100.0% 2/2 • 15 months All SAEs and AEs are collected regardless of their relationship with the experimental product. Laboratory abnormalities that constitute an AE should be recorded on the Adverse Events page of the eCRF. Whenever possible, a diagnosis, rather than a symptom should be provided. Laboratory abnormalities that meet the criteria for Adverse Events should be followed until they have returned to normal or an adequate explanation of the abnormality is found.
Blood and lymphatic system disorders Neutropenia	100.0% 2/2 • 15 months All SAEs and AEs are collected regardless of their relationship with the experimental product. Laboratory abnormalities that constitute an AE should be recorded on the Adverse Events page of the eCRF. Whenever possible, a diagnosis, rather than a symptom should be provided. Laboratory abnormalities that meet the criteria for Adverse Events should be followed until they have returned to normal or an adequate explanation of the abnormality is found.
Blood and lymphatic system disorders Anemia	100.0% 2/2 • 15 months All SAEs and AEs are collected regardless of their relationship with the experimental product. Laboratory abnormalities that constitute an AE should be recorded on the Adverse Events page of the eCRF. Whenever possible, a diagnosis, rather than a symptom should be provided. Laboratory abnormalities that meet the criteria for Adverse Events should be followed until they have returned to normal or an adequate explanation of the abnormality is found.

Additional Information

Anna Stornaiuolo

AGC Biologics

Phone: 0221277440

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The Company will keep the information related to the trial in the strictest confidence and won't disclose such confidential information to third parties without the written consent of the Sponsor. It warrants that the obligation of confidentiality will be extended to the PI, his collaborators and to any other person who may become aware of confidential data. These obligations will remain in effect until the information is released into the public domain by the by the Sponsor.
Publication restrictions are in place

Restriction type: OTHER