User login
ORLANDO – A gamma secretase inhibitor could enhance the efficacy of B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T cells in patients with relapsed or refractory multiple myeloma, a phase 1 trial suggests.
The inhibitor, JSMD194, increased BCMA expression in all 10 patients studied. All patients responded to anti-BCMA CAR T-cell therapy, including three patients who had previously failed BCMA-directed therapy.
Nine patients remain alive and in response at a median follow-up of 20 weeks, with two patients being followed for more than a year. One patient experienced dose-limiting toxicity and died, which prompted a change to the study’s eligibility criteria.
Andrew J. Cowan, MD, of the University of Washington and Fred Hutchinson Cancer Research Center in Seattle, presented these results at the annual meeting of the American Society of Hematology.
Dr. Cowan and colleagues previously showed that treatment with a gamma secretase inhibitor increased BCMA expression on tumor cells and improved the efficacy of BCMA-targeted CAR T cells in a mouse model of multiple myeloma. The team also showed that a gamma secretase inhibitor could “markedly” increase the percentage of BCMA-positive tumor cells in myeloma patients (Blood. 2019 Nov 7;134[19]:1585-97).
To expand upon these findings, the researchers began a phase 1 trial of BCMA-directed CAR T cells and the oral gamma secretase inhibitor JSMD194 in patients with relapsed/refractory multiple myeloma.
Ten patients have been treated, five men and five women. The patients’ median age at baseline was 66 years (range, 44-74 years). They received a median of 10 prior therapies (range, 4-23). Nine patients had received at least one autologous stem cell transplant, and one patient had two. One patient underwent allogeneic transplant (as well as autologous transplant).
Three patients had received prior BCMA-directed therapy. Two patients had received BCMA-directed CAR T cells. One of them did not respond, and the other responded but relapsed. The third patient received a BCMA-targeted bispecific T-cell engager and did not respond.
Study treatment
Patients had BCMA expression measured at baseline, then underwent apheresis for CAR T-cell production.
Patients received JSMD194 at 25 mg on days 1, 3, and 5. Then, they received cyclophosphamide at 300 mg and fludarabine at 25 mg for 3 days.
Next, patients received a single CAR T-cell infusion at a dose of 50 x 106 (n = 5), 150 x 106 (n = 3), or 300 x 106 (n = 2). They also received JSMD194 at 25 mg three times a week for 3 weeks.
Safety
“Nearly all patients had a serious adverse event, which was typically admission to the hospital for neutropenic fever,” Dr. Cowan said.
One patient experienced dose-limiting toxicity and died at day 33. The patient had a disseminating fungal infection, grade 4 cytokine release syndrome (CRS), and neurotoxicity. The patient’s death prompted the researchers to include performance status in the study’s eligibility criteria.
All patients developed CRS. Only the aforementioned patient had grade 4 CRS, and three patients had grade 3 CRS. Six patients experienced neurotoxicity. There were no cases of tumor lysis syndrome.
Efficacy
“All patients experienced an increase of cells expressing BCMA,” Dr. Cowan said. “While there was significant variability in BCMA expression at baseline, all cells expressed BCMA after three doses of the gamma secretase inhibitor.”
The median BCMA expression after JSMD194 treatment was 99% (range, 96%-100%), and there was a median 20-fold (range, 8- to 157-fold) increase in BCMA surface density.
The overall response rate was 100%. Two patients achieved a stringent complete response (CR), one achieved a CR, five patients had a very good partial response, and two had a partial response.
The patient with a CR received the 50 x 106 dose of CAR T cells, and the patients with stringent CRs received the 150 x 106 and 300 x 106 doses.
Of the three patients who previously received BCMA-directed therapy, two achieved a very good partial response, and one had a partial response.
Nine of the 10 patients are still alive and in response, with a median follow-up of 20 weeks. The longest follow-up is 444 days.
“To date, all patients have evidence of durable responses,” Dr. Cowan said. “Moreover, all patients had dramatic reductions in involved serum free light chain ... and serum monoclonal proteins.”
Dr. Cowan noted that longer follow-up is needed to assess CAR T-cell persistence and the durability of response.
This trial is sponsored by the Fred Hutchinson Cancer Research Center in collaboration with the National Cancer Institute. Two researchers involved in this work are employees of Juno Therapeutics. Dr. Cowan reported relationships with Juno Therapeutics, Janssen, Celgene, AbbVie, Cellectar, and Sanofi.
SOURCE: Cowan AJ et al. ASH 2019. Abstract 204.
ORLANDO – A gamma secretase inhibitor could enhance the efficacy of B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T cells in patients with relapsed or refractory multiple myeloma, a phase 1 trial suggests.
The inhibitor, JSMD194, increased BCMA expression in all 10 patients studied. All patients responded to anti-BCMA CAR T-cell therapy, including three patients who had previously failed BCMA-directed therapy.
Nine patients remain alive and in response at a median follow-up of 20 weeks, with two patients being followed for more than a year. One patient experienced dose-limiting toxicity and died, which prompted a change to the study’s eligibility criteria.
Andrew J. Cowan, MD, of the University of Washington and Fred Hutchinson Cancer Research Center in Seattle, presented these results at the annual meeting of the American Society of Hematology.
Dr. Cowan and colleagues previously showed that treatment with a gamma secretase inhibitor increased BCMA expression on tumor cells and improved the efficacy of BCMA-targeted CAR T cells in a mouse model of multiple myeloma. The team also showed that a gamma secretase inhibitor could “markedly” increase the percentage of BCMA-positive tumor cells in myeloma patients (Blood. 2019 Nov 7;134[19]:1585-97).
To expand upon these findings, the researchers began a phase 1 trial of BCMA-directed CAR T cells and the oral gamma secretase inhibitor JSMD194 in patients with relapsed/refractory multiple myeloma.
Ten patients have been treated, five men and five women. The patients’ median age at baseline was 66 years (range, 44-74 years). They received a median of 10 prior therapies (range, 4-23). Nine patients had received at least one autologous stem cell transplant, and one patient had two. One patient underwent allogeneic transplant (as well as autologous transplant).
Three patients had received prior BCMA-directed therapy. Two patients had received BCMA-directed CAR T cells. One of them did not respond, and the other responded but relapsed. The third patient received a BCMA-targeted bispecific T-cell engager and did not respond.
Study treatment
Patients had BCMA expression measured at baseline, then underwent apheresis for CAR T-cell production.
Patients received JSMD194 at 25 mg on days 1, 3, and 5. Then, they received cyclophosphamide at 300 mg and fludarabine at 25 mg for 3 days.
Next, patients received a single CAR T-cell infusion at a dose of 50 x 106 (n = 5), 150 x 106 (n = 3), or 300 x 106 (n = 2). They also received JSMD194 at 25 mg three times a week for 3 weeks.
Safety
“Nearly all patients had a serious adverse event, which was typically admission to the hospital for neutropenic fever,” Dr. Cowan said.
One patient experienced dose-limiting toxicity and died at day 33. The patient had a disseminating fungal infection, grade 4 cytokine release syndrome (CRS), and neurotoxicity. The patient’s death prompted the researchers to include performance status in the study’s eligibility criteria.
All patients developed CRS. Only the aforementioned patient had grade 4 CRS, and three patients had grade 3 CRS. Six patients experienced neurotoxicity. There were no cases of tumor lysis syndrome.
Efficacy
“All patients experienced an increase of cells expressing BCMA,” Dr. Cowan said. “While there was significant variability in BCMA expression at baseline, all cells expressed BCMA after three doses of the gamma secretase inhibitor.”
The median BCMA expression after JSMD194 treatment was 99% (range, 96%-100%), and there was a median 20-fold (range, 8- to 157-fold) increase in BCMA surface density.
The overall response rate was 100%. Two patients achieved a stringent complete response (CR), one achieved a CR, five patients had a very good partial response, and two had a partial response.
The patient with a CR received the 50 x 106 dose of CAR T cells, and the patients with stringent CRs received the 150 x 106 and 300 x 106 doses.
Of the three patients who previously received BCMA-directed therapy, two achieved a very good partial response, and one had a partial response.
Nine of the 10 patients are still alive and in response, with a median follow-up of 20 weeks. The longest follow-up is 444 days.
“To date, all patients have evidence of durable responses,” Dr. Cowan said. “Moreover, all patients had dramatic reductions in involved serum free light chain ... and serum monoclonal proteins.”
Dr. Cowan noted that longer follow-up is needed to assess CAR T-cell persistence and the durability of response.
This trial is sponsored by the Fred Hutchinson Cancer Research Center in collaboration with the National Cancer Institute. Two researchers involved in this work are employees of Juno Therapeutics. Dr. Cowan reported relationships with Juno Therapeutics, Janssen, Celgene, AbbVie, Cellectar, and Sanofi.
SOURCE: Cowan AJ et al. ASH 2019. Abstract 204.
ORLANDO – A gamma secretase inhibitor could enhance the efficacy of B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T cells in patients with relapsed or refractory multiple myeloma, a phase 1 trial suggests.
The inhibitor, JSMD194, increased BCMA expression in all 10 patients studied. All patients responded to anti-BCMA CAR T-cell therapy, including three patients who had previously failed BCMA-directed therapy.
Nine patients remain alive and in response at a median follow-up of 20 weeks, with two patients being followed for more than a year. One patient experienced dose-limiting toxicity and died, which prompted a change to the study’s eligibility criteria.
Andrew J. Cowan, MD, of the University of Washington and Fred Hutchinson Cancer Research Center in Seattle, presented these results at the annual meeting of the American Society of Hematology.
Dr. Cowan and colleagues previously showed that treatment with a gamma secretase inhibitor increased BCMA expression on tumor cells and improved the efficacy of BCMA-targeted CAR T cells in a mouse model of multiple myeloma. The team also showed that a gamma secretase inhibitor could “markedly” increase the percentage of BCMA-positive tumor cells in myeloma patients (Blood. 2019 Nov 7;134[19]:1585-97).
To expand upon these findings, the researchers began a phase 1 trial of BCMA-directed CAR T cells and the oral gamma secretase inhibitor JSMD194 in patients with relapsed/refractory multiple myeloma.
Ten patients have been treated, five men and five women. The patients’ median age at baseline was 66 years (range, 44-74 years). They received a median of 10 prior therapies (range, 4-23). Nine patients had received at least one autologous stem cell transplant, and one patient had two. One patient underwent allogeneic transplant (as well as autologous transplant).
Three patients had received prior BCMA-directed therapy. Two patients had received BCMA-directed CAR T cells. One of them did not respond, and the other responded but relapsed. The third patient received a BCMA-targeted bispecific T-cell engager and did not respond.
Study treatment
Patients had BCMA expression measured at baseline, then underwent apheresis for CAR T-cell production.
Patients received JSMD194 at 25 mg on days 1, 3, and 5. Then, they received cyclophosphamide at 300 mg and fludarabine at 25 mg for 3 days.
Next, patients received a single CAR T-cell infusion at a dose of 50 x 106 (n = 5), 150 x 106 (n = 3), or 300 x 106 (n = 2). They also received JSMD194 at 25 mg three times a week for 3 weeks.
Safety
“Nearly all patients had a serious adverse event, which was typically admission to the hospital for neutropenic fever,” Dr. Cowan said.
One patient experienced dose-limiting toxicity and died at day 33. The patient had a disseminating fungal infection, grade 4 cytokine release syndrome (CRS), and neurotoxicity. The patient’s death prompted the researchers to include performance status in the study’s eligibility criteria.
All patients developed CRS. Only the aforementioned patient had grade 4 CRS, and three patients had grade 3 CRS. Six patients experienced neurotoxicity. There were no cases of tumor lysis syndrome.
Efficacy
“All patients experienced an increase of cells expressing BCMA,” Dr. Cowan said. “While there was significant variability in BCMA expression at baseline, all cells expressed BCMA after three doses of the gamma secretase inhibitor.”
The median BCMA expression after JSMD194 treatment was 99% (range, 96%-100%), and there was a median 20-fold (range, 8- to 157-fold) increase in BCMA surface density.
The overall response rate was 100%. Two patients achieved a stringent complete response (CR), one achieved a CR, five patients had a very good partial response, and two had a partial response.
The patient with a CR received the 50 x 106 dose of CAR T cells, and the patients with stringent CRs received the 150 x 106 and 300 x 106 doses.
Of the three patients who previously received BCMA-directed therapy, two achieved a very good partial response, and one had a partial response.
Nine of the 10 patients are still alive and in response, with a median follow-up of 20 weeks. The longest follow-up is 444 days.
“To date, all patients have evidence of durable responses,” Dr. Cowan said. “Moreover, all patients had dramatic reductions in involved serum free light chain ... and serum monoclonal proteins.”
Dr. Cowan noted that longer follow-up is needed to assess CAR T-cell persistence and the durability of response.
This trial is sponsored by the Fred Hutchinson Cancer Research Center in collaboration with the National Cancer Institute. Two researchers involved in this work are employees of Juno Therapeutics. Dr. Cowan reported relationships with Juno Therapeutics, Janssen, Celgene, AbbVie, Cellectar, and Sanofi.
SOURCE: Cowan AJ et al. ASH 2019. Abstract 204.
REPORTING FROM ASH 2019