KTE-X19 induces durable CRs, MRD negativity in ALL

Photo courtesy of ASH

SAN DIEGO—An update of the ZUMA-3 trial showed that KTE-X19—an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy—can induce high rates of undetectable minimal residual disease (MRD) and durable complete remissions (CRs) in adults with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL).

And this was particularly the case at the middle dose level of 1 x 10⁶ cells/kg.

William G. Wierda, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston, presented the update at the 2018 ASH Annual Meeting (abstract 897*).

Dr. Wierda explained that KTE-X19 is a new name for KTE-C19, also known as axicabtagene ciloleucel (Yescarta™), which is currently approved in the United States for the treatment of relapsed diffuse large B-cell lymphoma in adults and in Europe for diffuse large B-cell lymphoma and primary mediastinal large B-cell lymphoma.

“This approval was based on the ZUMA-1 clinical trial,” he said, “which showed a 54% complete remission rate and 82% overall response rate with durable remissions.”

ZUMA-3 (NCT02614066) is a phase 1/2 study of KTE-X19—a CAR T cell with CD3ζ signaling and CD28 costimulatory domains—for relapsed or refractory adults with ALL.

Dr. Wierda presented the phase 1 data available at the cutoff of August 16.

Study design

Patients underwent leukapheresis to collect their T cells for production and received bridging therapy selected by the treating physician from several prespecified regimens to maintain disease control.

Conditioning chemotherapy included fludarabine at 25 mg/m² on days -4, -3, and -2 and cyclophosphamide at 900 mg/m² on day -2.

Patients received KTE-X19 on day 0. They were monitored and released from the hospital on day 7 or upon resolution of any toxicities.

The investigators assessed response, including bone marrow evaluation, on day 28, week 8, month 3, and every 3 months for the first year as well as every 6 months for the second year of follow-up.

The dose-finding portion of the trial initially enrolled three patients. They received a dose of 2 x 10⁶ CAR T cells/kg and were monitored for dose-limiting toxicities (DLTs).

If there were no DLTs in the first three patients, phase 2 could open or investigators could further expand the 2 x 10⁶ dose level or explore lower doses of the product (1 x 10⁶ cells/kg and 0.5 x 10⁶ cells/kg).

Investigators defined DLTs as:

• KTE-X19-related events in the first 28 days, including grade 4 hematologic toxicity lasting more than 30 days and not attributable to ALL
• Grade 3 nonhematologic toxicities lasting more than 7 days
• Grade 4 nonhematologic toxicities regardless of duration, excluding grade 4 cytokine release syndrome (CRS) events lasting 7 days or less
• Neurologic events that resolve to grade 1 in 2 weeks or to baseline within 4 weeks.

Dr. Wierda said no DLTs occurred among the first 3 patients treated, and all dose levels were explored in phase 1.

Patients

As of the cutoff date, 54 patients were enrolled, confirmed eligible, and underwent leukapheresis. Six patients did not receive conditioning, three patients received conditioning but not KTE-X19, and one patient withdrew from the study after the first failed production of CAR T cells.

So 44 patients received KTE-X19. Six patients received the highest dose of CAR T cells (2 x 10⁶/kg), 22 received the middle dose (1 x 10⁶/kg), and 16 received the lowest dose (0.5 x 10⁶/kg).

The patients’ median age was 46 (range, 18 – 77). Almost half (48%) were male, and 68% had three or more prior treatment regimens. Forty-one percent had prior blinatumomab, and 14% had prior inotuzumab.

Patients had a median bone marrow blast percentage of 59% (n=44; range, 5% - 100%) at screening and 70% (n=40; range, 0 – 97%) prior to conditioning but after bridging therapy.

The safety analysis included all 44 treated patients, and the efficacy analysis included 36 patients.

“[T]he follow-up period was too short from dosing for the most recently treated eight patients,” Dr Wierda explained.

The median follow-up was 15.1 months for the 36 efficacy-evaluable patients.

Safety

All patients had a treatment-emergent adverse events (TEAEs), with 75% having grade 3/4 events.

Grade 5 TEAEs included three due to progressive disease, three due to infections, and one stroke 6 weeks after infusion.

Two patients died of KTE-X19-related AEs. One patient in the 2 x 10⁶ dose group had multiorgan failure secondary to CRS on study day 6. The other patient, in the 0.5 x 10⁶ dose group, had a stroke after infusion in the context of CRS and neurologic events (NEs) on day 7.

Investigators detected a higher incidence of grade 3 and greater CRS for the six patients treated at the highest dose. Half developed CRS of grade 3 or higher, compared with 18% in the 1 x 10⁶ dose cohort and 19% in the 0.5 x 10⁶ dose cohort.

Grade 3 or higher NEs were more common than CRS. The lowest incidence occurred in the lowest dose cohort, at 25%, compared with 45% in the 1 x 10⁶ dose cohort and 50% in the 2 x 10⁶ dose cohort.

Due to the incidence of grade 3 and greater NEs observed in the 1 x 10⁶ dose cohort, investigators revised the management guidelines for AEs. The revisions included using tocilizumab only for CRS—and not for NEs—and initiating steroids for grade 2 NEs instead of waiting for grade 3.

Eight patients were treated under the revised recommendations, and the incidence of grade 3 NEs was 13%, with no grade 4 or 5 NEs.

“This compared favorably with the 14 patients treated at the same dose level but prior to these changes," Dr. Wierda said.

In comparison, 57% developed grade 3 NEs and 7% grade 4 with the original AE management protocol.

The incidence of grade 3 CRS remained low, with no CRS events of grade 4 or greater with the revised recommendations.

Efficacy

The best overall response in the 36 efficacy-evaluable patients was 69% CR and CR with incomplete hematologic recovery (CRi).

Seventy-five percent of these patients had undetectable MRD in the bone marrow at 10^-4 sensitivity at 3 months of follow-up.

All patients in the 1 x 10⁶ dose cohort (n=14) responded. Ninety-three percent achieved a CR/CRi, 7% had a partial response, and all had undetectable MRD in the bone marrow.

The median duration of response was 12.9 months in the 1 x 10⁶ cohort. This was the dose selected for the phase 2 trial, which is now enrolling patients.

ZUMA-3 was sponsored by Kite, a Gilead Company.

Dr. Wierda disclosed research funding from AbbVie and Genentech. 

* Data in the abstract differ from the presentation.

Photo courtesy of ASH

SAN DIEGO—An update of the ZUMA-3 trial showed that KTE-X19—an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy—can induce high rates of undetectable minimal residual disease (MRD) and durable complete remissions (CRs) in adults with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL).

And this was particularly the case at the middle dose level of 1 x 10⁶ cells/kg.

William G. Wierda, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston, presented the update at the 2018 ASH Annual Meeting (abstract 897*).

Dr. Wierda explained that KTE-X19 is a new name for KTE-C19, also known as axicabtagene ciloleucel (Yescarta™), which is currently approved in the United States for the treatment of relapsed diffuse large B-cell lymphoma in adults and in Europe for diffuse large B-cell lymphoma and primary mediastinal large B-cell lymphoma.

“This approval was based on the ZUMA-1 clinical trial,” he said, “which showed a 54% complete remission rate and 82% overall response rate with durable remissions.”

ZUMA-3 (NCT02614066) is a phase 1/2 study of KTE-X19—a CAR T cell with CD3ζ signaling and CD28 costimulatory domains—for relapsed or refractory adults with ALL.

Dr. Wierda presented the phase 1 data available at the cutoff of August 16.

Study design

Patients underwent leukapheresis to collect their T cells for production and received bridging therapy selected by the treating physician from several prespecified regimens to maintain disease control.

Conditioning chemotherapy included fludarabine at 25 mg/m² on days -4, -3, and -2 and cyclophosphamide at 900 mg/m² on day -2.

Patients received KTE-X19 on day 0. They were monitored and released from the hospital on day 7 or upon resolution of any toxicities.

The investigators assessed response, including bone marrow evaluation, on day 28, week 8, month 3, and every 3 months for the first year as well as every 6 months for the second year of follow-up.

The dose-finding portion of the trial initially enrolled three patients. They received a dose of 2 x 10⁶ CAR T cells/kg and were monitored for dose-limiting toxicities (DLTs).

If there were no DLTs in the first three patients, phase 2 could open or investigators could further expand the 2 x 10⁶ dose level or explore lower doses of the product (1 x 10⁶ cells/kg and 0.5 x 10⁶ cells/kg).

Investigators defined DLTs as:

• KTE-X19-related events in the first 28 days, including grade 4 hematologic toxicity lasting more than 30 days and not attributable to ALL
• Grade 3 nonhematologic toxicities lasting more than 7 days
• Grade 4 nonhematologic toxicities regardless of duration, excluding grade 4 cytokine release syndrome (CRS) events lasting 7 days or less
• Neurologic events that resolve to grade 1 in 2 weeks or to baseline within 4 weeks.

Dr. Wierda said no DLTs occurred among the first 3 patients treated, and all dose levels were explored in phase 1.

Patients

As of the cutoff date, 54 patients were enrolled, confirmed eligible, and underwent leukapheresis. Six patients did not receive conditioning, three patients received conditioning but not KTE-X19, and one patient withdrew from the study after the first failed production of CAR T cells.

So 44 patients received KTE-X19. Six patients received the highest dose of CAR T cells (2 x 10⁶/kg), 22 received the middle dose (1 x 10⁶/kg), and 16 received the lowest dose (0.5 x 10⁶/kg).

The patients’ median age was 46 (range, 18 – 77). Almost half (48%) were male, and 68% had three or more prior treatment regimens. Forty-one percent had prior blinatumomab, and 14% had prior inotuzumab.

Patients had a median bone marrow blast percentage of 59% (n=44; range, 5% - 100%) at screening and 70% (n=40; range, 0 – 97%) prior to conditioning but after bridging therapy.

The safety analysis included all 44 treated patients, and the efficacy analysis included 36 patients.

“[T]he follow-up period was too short from dosing for the most recently treated eight patients,” Dr Wierda explained.

The median follow-up was 15.1 months for the 36 efficacy-evaluable patients.

Safety

All patients had a treatment-emergent adverse events (TEAEs), with 75% having grade 3/4 events.

Grade 5 TEAEs included three due to progressive disease, three due to infections, and one stroke 6 weeks after infusion.

Two patients died of KTE-X19-related AEs. One patient in the 2 x 10⁶ dose group had multiorgan failure secondary to CRS on study day 6. The other patient, in the 0.5 x 10⁶ dose group, had a stroke after infusion in the context of CRS and neurologic events (NEs) on day 7.

Investigators detected a higher incidence of grade 3 and greater CRS for the six patients treated at the highest dose. Half developed CRS of grade 3 or higher, compared with 18% in the 1 x 10⁶ dose cohort and 19% in the 0.5 x 10⁶ dose cohort.

Grade 3 or higher NEs were more common than CRS. The lowest incidence occurred in the lowest dose cohort, at 25%, compared with 45% in the 1 x 10⁶ dose cohort and 50% in the 2 x 10⁶ dose cohort.

Due to the incidence of grade 3 and greater NEs observed in the 1 x 10⁶ dose cohort, investigators revised the management guidelines for AEs. The revisions included using tocilizumab only for CRS—and not for NEs—and initiating steroids for grade 2 NEs instead of waiting for grade 3.

Eight patients were treated under the revised recommendations, and the incidence of grade 3 NEs was 13%, with no grade 4 or 5 NEs.

“This compared favorably with the 14 patients treated at the same dose level but prior to these changes," Dr. Wierda said.

In comparison, 57% developed grade 3 NEs and 7% grade 4 with the original AE management protocol.

The incidence of grade 3 CRS remained low, with no CRS events of grade 4 or greater with the revised recommendations.

Efficacy

The best overall response in the 36 efficacy-evaluable patients was 69% CR and CR with incomplete hematologic recovery (CRi).

Seventy-five percent of these patients had undetectable MRD in the bone marrow at 10^-4 sensitivity at 3 months of follow-up.

All patients in the 1 x 10⁶ dose cohort (n=14) responded. Ninety-three percent achieved a CR/CRi, 7% had a partial response, and all had undetectable MRD in the bone marrow.

The median duration of response was 12.9 months in the 1 x 10⁶ cohort. This was the dose selected for the phase 2 trial, which is now enrolling patients.

ZUMA-3 was sponsored by Kite, a Gilead Company.

Dr. Wierda disclosed research funding from AbbVie and Genentech. 

* Data in the abstract differ from the presentation.

Photo courtesy of ASH

SAN DIEGO—An update of the ZUMA-3 trial showed that KTE-X19—an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy—can induce high rates of undetectable minimal residual disease (MRD) and durable complete remissions (CRs) in adults with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL).

And this was particularly the case at the middle dose level of 1 x 10⁶ cells/kg.

William G. Wierda, MD, PhD, of The University of Texas MD Anderson Cancer Center in Houston, presented the update at the 2018 ASH Annual Meeting (abstract 897*).

Dr. Wierda explained that KTE-X19 is a new name for KTE-C19, also known as axicabtagene ciloleucel (Yescarta™), which is currently approved in the United States for the treatment of relapsed diffuse large B-cell lymphoma in adults and in Europe for diffuse large B-cell lymphoma and primary mediastinal large B-cell lymphoma.

“This approval was based on the ZUMA-1 clinical trial,” he said, “which showed a 54% complete remission rate and 82% overall response rate with durable remissions.”

ZUMA-3 (NCT02614066) is a phase 1/2 study of KTE-X19—a CAR T cell with CD3ζ signaling and CD28 costimulatory domains—for relapsed or refractory adults with ALL.

Dr. Wierda presented the phase 1 data available at the cutoff of August 16.

Study design

Patients underwent leukapheresis to collect their T cells for production and received bridging therapy selected by the treating physician from several prespecified regimens to maintain disease control.

Conditioning chemotherapy included fludarabine at 25 mg/m² on days -4, -3, and -2 and cyclophosphamide at 900 mg/m² on day -2.

Patients received KTE-X19 on day 0. They were monitored and released from the hospital on day 7 or upon resolution of any toxicities.

The investigators assessed response, including bone marrow evaluation, on day 28, week 8, month 3, and every 3 months for the first year as well as every 6 months for the second year of follow-up.

The dose-finding portion of the trial initially enrolled three patients. They received a dose of 2 x 10⁶ CAR T cells/kg and were monitored for dose-limiting toxicities (DLTs).

If there were no DLTs in the first three patients, phase 2 could open or investigators could further expand the 2 x 10⁶ dose level or explore lower doses of the product (1 x 10⁶ cells/kg and 0.5 x 10⁶ cells/kg).

Investigators defined DLTs as:

• KTE-X19-related events in the first 28 days, including grade 4 hematologic toxicity lasting more than 30 days and not attributable to ALL
• Grade 3 nonhematologic toxicities lasting more than 7 days
• Grade 4 nonhematologic toxicities regardless of duration, excluding grade 4 cytokine release syndrome (CRS) events lasting 7 days or less
• Neurologic events that resolve to grade 1 in 2 weeks or to baseline within 4 weeks.

Dr. Wierda said no DLTs occurred among the first 3 patients treated, and all dose levels were explored in phase 1.

Patients

As of the cutoff date, 54 patients were enrolled, confirmed eligible, and underwent leukapheresis. Six patients did not receive conditioning, three patients received conditioning but not KTE-X19, and one patient withdrew from the study after the first failed production of CAR T cells.

So 44 patients received KTE-X19. Six patients received the highest dose of CAR T cells (2 x 10⁶/kg), 22 received the middle dose (1 x 10⁶/kg), and 16 received the lowest dose (0.5 x 10⁶/kg).

The patients’ median age was 46 (range, 18 – 77). Almost half (48%) were male, and 68% had three or more prior treatment regimens. Forty-one percent had prior blinatumomab, and 14% had prior inotuzumab.

Patients had a median bone marrow blast percentage of 59% (n=44; range, 5% - 100%) at screening and 70% (n=40; range, 0 – 97%) prior to conditioning but after bridging therapy.

The safety analysis included all 44 treated patients, and the efficacy analysis included 36 patients.

“[T]he follow-up period was too short from dosing for the most recently treated eight patients,” Dr Wierda explained.

The median follow-up was 15.1 months for the 36 efficacy-evaluable patients.

Safety

All patients had a treatment-emergent adverse events (TEAEs), with 75% having grade 3/4 events.

Grade 5 TEAEs included three due to progressive disease, three due to infections, and one stroke 6 weeks after infusion.

Two patients died of KTE-X19-related AEs. One patient in the 2 x 10⁶ dose group had multiorgan failure secondary to CRS on study day 6. The other patient, in the 0.5 x 10⁶ dose group, had a stroke after infusion in the context of CRS and neurologic events (NEs) on day 7.

Investigators detected a higher incidence of grade 3 and greater CRS for the six patients treated at the highest dose. Half developed CRS of grade 3 or higher, compared with 18% in the 1 x 10⁶ dose cohort and 19% in the 0.5 x 10⁶ dose cohort.

Grade 3 or higher NEs were more common than CRS. The lowest incidence occurred in the lowest dose cohort, at 25%, compared with 45% in the 1 x 10⁶ dose cohort and 50% in the 2 x 10⁶ dose cohort.

Due to the incidence of grade 3 and greater NEs observed in the 1 x 10⁶ dose cohort, investigators revised the management guidelines for AEs. The revisions included using tocilizumab only for CRS—and not for NEs—and initiating steroids for grade 2 NEs instead of waiting for grade 3.

Eight patients were treated under the revised recommendations, and the incidence of grade 3 NEs was 13%, with no grade 4 or 5 NEs.

“This compared favorably with the 14 patients treated at the same dose level but prior to these changes," Dr. Wierda said.

In comparison, 57% developed grade 3 NEs and 7% grade 4 with the original AE management protocol.

The incidence of grade 3 CRS remained low, with no CRS events of grade 4 or greater with the revised recommendations.

Efficacy

The best overall response in the 36 efficacy-evaluable patients was 69% CR and CR with incomplete hematologic recovery (CRi).

Seventy-five percent of these patients had undetectable MRD in the bone marrow at 10^-4 sensitivity at 3 months of follow-up.

All patients in the 1 x 10⁶ dose cohort (n=14) responded. Ninety-three percent achieved a CR/CRi, 7% had a partial response, and all had undetectable MRD in the bone marrow.

The median duration of response was 12.9 months in the 1 x 10⁶ cohort. This was the dose selected for the phase 2 trial, which is now enrolling patients.

ZUMA-3 was sponsored by Kite, a Gilead Company.

Dr. Wierda disclosed research funding from AbbVie and Genentech. 

* Data in the abstract differ from the presentation.