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Antibody-drug conjugate (ADC) connects target-specific monoclonal antibodies with highly lethal cytotoxic drugs through a specific connector, and uses monoclonal antibodies as a carrier to efficiently target small-molecule cytotoxic drugs.
It is transported to the target tumor cells to achieve the purpose of killing tumor cells efficiently.
In recent years, ADC drugs have become one of the research hotspots in the field of tumor precision treatment.
At present, 8 ADC drugs worldwide have been approved for clinical treatment.
Among them, Inotuzumab Ozogamicin (IO), which targets CD22, has been approved for the treatment of adult relapsed or refractory (R/R) precursor B-cell acute lymphoblastic leukemia (ALL).
The key study that IO was approved for clinical use was the INO-VATE ALL trial, which included 326 patients with R/R ALL.
The results showed that IO significantly improved the complete remission (CR) rate of patients compared with standard chemotherapy, which were 80.
7% and 80.
7% respectively.
29.
4% (P<0.
001), the median progression-free survival (PFS) was 5.
0 months and 1.
8 months (P<0.
001), and the median overall survival (OS) was 7.
7 months and 6.
7 months, respectively ( P=0.
04).
ALL is a common malignant disease in children.
In the past 20 years, the therapeutic effect of childhood ALL has made great progress.
At present, the use of multi-drug combination first-line treatment can make the cure rate of children's ALL reach 85%.
However, the remaining 15% of patients with ineffective conventional treatments or recurrence have a poor prognosis, and there are still unmet clinical needs.
It is not clear whether ADC drug IO, which has achieved excellent efficacy in adult R/R ALL patients, is equally safe and effective in children.
Recently, Professor Erica Brivio and others reported the results of a phase I clinical study (ITCC-059 trial) on the efficacy and safety of CD22-targeted ADC drug IO in the treatment of CD22+ children with R/R ALL.
Research methods The ITCC-059 trial included children with R/R ALL patients aged ≥1 year and <18 years.
All patients expressed CD22 and received IO therapy to determine the recommended phase 2 dose of IO (RP2D).
The patients received a total of 3 doses of IO treatment on the 1, 8, and 15 days of each treatment cycle.
The dose increase of IO is based on the dose limiting toxicity (DLT) in the first treatment cycle, dose level 1 (DL1) is 1.
4 mg/m2 (0.
6, 0.
4, 0.
4 mg/m2), and DL2 is 1.
8 mg/m2 (0.
8 , 0.
5, 0.
5 mg/m2).
Secondary endpoints include safety, anti-leukemia efficacy and pharmacokinetics.
Results of the study A total of 25 patients were enrolled in the study (23 of them can be assessed for DLT).
In the first treatment cycle, 1 out of 6 patients in the DL1 group in the first cohort study, and 2 out of 5 patients in the DL2 group experienced DLT; however, 2 DLTs in the DL2 group were considered in the subsequent review It is not dose limited.
In the second cohort study, the dose was downgraded to DL1 while waiting for the protocol revision to re-evaluate DL2.
Among them, none of the 6 patients in the DL1 group experienced DLT, and 1 of the 6 patients in the DL2 group experienced DLT.
During the study, all patients experienced ≥1 adverse events (AEs), among which the most common AEs were fever (64%), thrombocytopenia (60%), neutropenia (56%), Vomiting (48%) and anemia (44%).
A total of 23 patients had grade 3-4 AEs, of which 4 patients had grade 5 AEs but they were all considered to be unrelated to IO.
No cases of sinusoidal obstruction syndrome (SOS) were reported during IO treatment; however, 2 patients developed SOS after subsequent chemotherapy.
After the first course of treatment, the patient’s overall response rate (ORR) was 80% (95% confidence interval [CI], 59%-93%), and the CR rate was 60%.
Among the patients who obtained treatment response, 84% (95% CI, 60%-97%) of patients with minimal residual disease (MRD) test negative (<0.
01%) using flow cytometry.
The median duration of response (DOR) for patients was 8 months (range 1-19 months).
The OS rate at 6 months from the IO treatment was 63% (95% CI, 46%-85%), and the OS rate at 12 months was 40% (95% CI, 25%-66%).
After IO treatment, 9 patients received hematopoietic stem cell transplantation or chimeric antigen receptor (CAR)-T cell therapy.
Pharmacokinetic studies have shown that after multiple administrations, the median maximum concentration of IO in patients under DL1 (n=9) is 217 ng/mL, and the median maximum concentration of IO under DL2 (n=5) is 246 ng/mL is equivalent to a simulated adult concentration of 234 ng/mL of 1.
8 mg/m2 per treatment course; therefore, as in adults, IO in children is determined to be 1.
8 mg/m2 RP2D per treatment cycle.
Research conclusions The research shows that IO has good tolerability and excellent anti-leukemia activity in CD22+ children with R/R ALL patients who have undergone multi-line therapy.
In addition, like adults, RP2D for children is 1.
8 mg/m2 per course of treatment. References: Erica Brivio, Franco Locatelli, Marta Lopez-Yurda, et al.
A phase 1 study of inotuzumab ozogamicin in pediatric relapsed/refractory acute lymphoblastic leukemia (ITCC-059 study).
Blood.
2021 Mar 25;137(12): 1582-1590.
Stamp "read the original text", we will make progress together
It is transported to the target tumor cells to achieve the purpose of killing tumor cells efficiently.
In recent years, ADC drugs have become one of the research hotspots in the field of tumor precision treatment.
At present, 8 ADC drugs worldwide have been approved for clinical treatment.
Among them, Inotuzumab Ozogamicin (IO), which targets CD22, has been approved for the treatment of adult relapsed or refractory (R/R) precursor B-cell acute lymphoblastic leukemia (ALL).
The key study that IO was approved for clinical use was the INO-VATE ALL trial, which included 326 patients with R/R ALL.
The results showed that IO significantly improved the complete remission (CR) rate of patients compared with standard chemotherapy, which were 80.
7% and 80.
7% respectively.
29.
4% (P<0.
001), the median progression-free survival (PFS) was 5.
0 months and 1.
8 months (P<0.
001), and the median overall survival (OS) was 7.
7 months and 6.
7 months, respectively ( P=0.
04).
ALL is a common malignant disease in children.
In the past 20 years, the therapeutic effect of childhood ALL has made great progress.
At present, the use of multi-drug combination first-line treatment can make the cure rate of children's ALL reach 85%.
However, the remaining 15% of patients with ineffective conventional treatments or recurrence have a poor prognosis, and there are still unmet clinical needs.
It is not clear whether ADC drug IO, which has achieved excellent efficacy in adult R/R ALL patients, is equally safe and effective in children.
Recently, Professor Erica Brivio and others reported the results of a phase I clinical study (ITCC-059 trial) on the efficacy and safety of CD22-targeted ADC drug IO in the treatment of CD22+ children with R/R ALL.
Research methods The ITCC-059 trial included children with R/R ALL patients aged ≥1 year and <18 years.
All patients expressed CD22 and received IO therapy to determine the recommended phase 2 dose of IO (RP2D).
The patients received a total of 3 doses of IO treatment on the 1, 8, and 15 days of each treatment cycle.
The dose increase of IO is based on the dose limiting toxicity (DLT) in the first treatment cycle, dose level 1 (DL1) is 1.
4 mg/m2 (0.
6, 0.
4, 0.
4 mg/m2), and DL2 is 1.
8 mg/m2 (0.
8 , 0.
5, 0.
5 mg/m2).
Secondary endpoints include safety, anti-leukemia efficacy and pharmacokinetics.
Results of the study A total of 25 patients were enrolled in the study (23 of them can be assessed for DLT).
In the first treatment cycle, 1 out of 6 patients in the DL1 group in the first cohort study, and 2 out of 5 patients in the DL2 group experienced DLT; however, 2 DLTs in the DL2 group were considered in the subsequent review It is not dose limited.
In the second cohort study, the dose was downgraded to DL1 while waiting for the protocol revision to re-evaluate DL2.
Among them, none of the 6 patients in the DL1 group experienced DLT, and 1 of the 6 patients in the DL2 group experienced DLT.
During the study, all patients experienced ≥1 adverse events (AEs), among which the most common AEs were fever (64%), thrombocytopenia (60%), neutropenia (56%), Vomiting (48%) and anemia (44%).
A total of 23 patients had grade 3-4 AEs, of which 4 patients had grade 5 AEs but they were all considered to be unrelated to IO.
No cases of sinusoidal obstruction syndrome (SOS) were reported during IO treatment; however, 2 patients developed SOS after subsequent chemotherapy.
After the first course of treatment, the patient’s overall response rate (ORR) was 80% (95% confidence interval [CI], 59%-93%), and the CR rate was 60%.
Among the patients who obtained treatment response, 84% (95% CI, 60%-97%) of patients with minimal residual disease (MRD) test negative (<0.
01%) using flow cytometry.
The median duration of response (DOR) for patients was 8 months (range 1-19 months).
The OS rate at 6 months from the IO treatment was 63% (95% CI, 46%-85%), and the OS rate at 12 months was 40% (95% CI, 25%-66%).
After IO treatment, 9 patients received hematopoietic stem cell transplantation or chimeric antigen receptor (CAR)-T cell therapy.
Pharmacokinetic studies have shown that after multiple administrations, the median maximum concentration of IO in patients under DL1 (n=9) is 217 ng/mL, and the median maximum concentration of IO under DL2 (n=5) is 246 ng/mL is equivalent to a simulated adult concentration of 234 ng/mL of 1.
8 mg/m2 per treatment course; therefore, as in adults, IO in children is determined to be 1.
8 mg/m2 RP2D per treatment cycle.
Research conclusions The research shows that IO has good tolerability and excellent anti-leukemia activity in CD22+ children with R/R ALL patients who have undergone multi-line therapy.
In addition, like adults, RP2D for children is 1.
8 mg/m2 per course of treatment. References: Erica Brivio, Franco Locatelli, Marta Lopez-Yurda, et al.
A phase 1 study of inotuzumab ozogamicin in pediatric relapsed/refractory acute lymphoblastic leukemia (ITCC-059 study).
Blood.
2021 Mar 25;137(12): 1582-1590.
Stamp "read the original text", we will make progress together
