Acute Lymphoblastic Leukemia (ALL) Philadelphia Chromosome-positive (Ph+), Childhood Leukemia, Acute Lymphoblastic
Conditions
Keywords
olverembatinib, Blinatumomab, venetoclax
Brief summary
This prospective clinical trial evaluates the effectiveness and safety of chemotherapy-light regimen incorporating the third-generation TKI olverembatinib, the bi-specific CD3/CD19 T cell engager blinatumomab, and the BCL-2 selective inhibitor venetoclax for newly diagnosed pediatric/adolescent patients with Ph+ ALL. The CCCG-Ph+ B-ALL-2025 protocol will be modified as following compared to the CCCG-ALL-2020 protocol
Detailed description
1. All Ph+-ALL patients will uniformly use the 3rd generation of TKI olverembatinib (OVB) instead of dasatinib throughout the regimen. 2. OVB is combined with Vincristine and Prednisone (VP) during the first 2 weeks and with blinatumomab during the last 4 weeks of remission induction in this protocol. 3. Patients will receive blinatumomab for 28 days as induction instead of CAT to improve induction response and avoid toxicity. 4. All patients will receive two cycles of HDMTX+Blina-14 and 4 times of triple intrathecal therapy (TIT) throughout the consolidation 1 phase. 5. To decrease the toxicities of high-dose AraC, the dosage will be reduced to 1 g/m2 in the consolidation 2 phase in contrast to 2 g/m2 in 2020 protocol. 6. Throughout the early Maintenance Therapy, dexamethasone and vincristine combination will be added with either venetoclax or daunorubicin alternatively for five cycles, given after MTX and 6-MP. 7. Cyclophosphamide and asparaginase are totally omitted from the entire treatment to mitigate toxicities. 8. Olverembatinib concentrations are recommended to be examined (cerebrospinal fluid and peripheral blood in parallel) before OVB given, after full dosing of OVB, and/or Blina+OVB, best to match lumbar puncture assessments timepoints. 9. IgH rearrangement by NGS MRD will be added as an evaluation indicator, with testing frequency matching bone marrow aspiration assessments. 10. Pharmarcotyping studies are recommended at baseline if condition permits. 11. For patients who cannot use full-dose blinatumomab, we will adopt the CCCG-Ph+ALL2020 protocol. complications.
Interventions
DRUGolverembatinib
All Ph+-ALL patients will uniformly use the 3rd generation of TKI olverembatinib (OVB) instead of dasatinib throughout the regimen. OVB is combined with Vincristine and Prednisone (VP) during the first 2 weeks and with blinatumomab during the last 4 weeks of remission induction in this protocol. Patients will receive blinatumomab for 28 days as induction instead of CAT to improve induction response and avoid toxicity. All patients will receive two cycles of HDMTX+Blina-14 and 4 times of triple intrathecal therapy (TIT) throughout the consolidation 1 phase. To decrease the toxicities of high-dose AraC, the dosage will be reduced to 1 g/m2 in the consolidation 2 phase in contrast to 2 g/m2 in 2020 protocol. Throughout the early Maintenance Therapy, dexamethasone and vincristine combination will be added with either venetoclax or daunorubicin alternatively for five cycles, given after MTX and 6-MP.
Sponsors
Institute of Hematology & Blood Diseases Hospital, China
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Months to 18 Years
Healthy volunteers
No
Inclusion criteria
Must meet all items below: 1. Age older than 1 month to younger 18 years. 2. Newly diagnosed Philadelphia chromosome-positive or BCR::ABL1-positive B-ALL. 3. Written informed consent of the parents or other legally authorized guardian of the patient according to local law and regulations.
Exclusion criteria
Should be excluded if had any item below: 1. ALL evolved from CML. 2. Known underlying congenital immunodeficiency or metabolic disease. 3. Congenital heart disease with cardiac insufficiency. 4. Gastrointestinal dysfunction or gastrointestinal diseases that may significantly alter the absorption of study drug. 5. Severe malnutrition, uncontrolled active infections, or serious cardiovascular diseases. 6. Subjects with significant CNS disorder (e.g., uncontrolled seizure disorder, autoimmune disease involving CNS). 7. Treated with glucocorticoids for ≥14 days, or targeted inhibitor for \> 7 days within one month before enrollment, or any chemotherapy or any systemic anticancer therapy (including but not limited to any TKI) or radiotherapy within 3 months before enrollment (except for emergency radiotherapy to relieve airway compression). 8. Any significant comorbidities or psychiatric disorders that may impact patient safety, compliance, informed consent, study participation, follow-up, or the interpretation of study results. In such cases, all participating sites must report directly to the PI to determine whether the patient meets
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Day 48 end-of-induction measurable residual diseases (MRD48) after induction remission with olverembatinib and blinatumomab, compared to MRD46 of those treated with dasatinib plus chemotherapy induction (CCCG-ALL-2015 /2020) or from historical cohorts . | Up to approximately 4.5 years. | Primary analysis will be performed by one-sided (Monte-Carlo-) exact chi-square test because the objective calls for testing if the proportion of patients in the \<0.01% Day 48 MRD group is higher than the historical control. The historical control of Day 46 MRD of dasatinib combination with intensive chemotherapy is 80%. It is estimated that VPO+Blinatumomab can increase the negative rate of Day 48 MRD by 10%. a total sample size of 135 provides sufficient power for the planned analyses outlined above if the true D48 MRD negativity probability is 0.90 or higher based on a one-sided alpha of 0.05. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Day 19 measurable residual diseases (MRD19) during induction remission with olverembatinib plus VP (VOP), compared to MRD19 of those treated with dasatinib plus 4-drug chemotherapy induction (CCCG-ALL-2015 /2020) or from historical cohorts | Approximately 4.5 years. | For this objective a one-sided comparison of probabilities and historical control rate of 40% will be made. Let p2 be the probability of achieving negative D19 MRD on the current study, then the one-sided alternative hypothesis H0: p2=40% vs. H1: p2\>40% will be tested. This analysis will be performed by one-sample one-sided exact binomial test, based on a one-sided alpha of 0.025. The historical control is based on the MRD of patients treated on CCCG-ALL-2015. |
| Event-free survival (EFS) of patients treated with this therapy, in comparison to historical regimens. | Approximately 7 years. | The EFS functions will be estimated by the Kaplan-Meier method along with 95% confidence intervals at specified timepoints (e.g., 2, 3 years since diagnosis). Standard error will be estimated using the default procedure in R. Follow up of the historical comparison cohort (CCCG-ALL-2020 and 2015) will continue during the course of the current trial. Comparisons of EFS will be performed using two-sided log-rank test. Multivariable regression modeling including trial (CAMS-Ph+B-ALLRegimen 2025 vs. CCCG-Ph-ALL 2020 or 2015) and other known prognostic factors as main effects may also be performed, using the Cox models. |
| Overall survival (OS) of patients treated with this therapy, in comparison to historical regimens | Approximately 7 years. | The OS functions will be estimated by the Kaplan-Meier method along with 95% confidence intervals at specified timepoints (e.g., 2, 3 years since diagnosis). Comparison of OS functions will be conducted using the two-sided log-rank test. Standard error will be estimated using the default procedure in R. Follow up of the historical comparison cohort (CCCG-ALL-2020 and 2015) will continue during the course of the current trial. Comparisons of OS will be performed using two-sided log-rank test. Multivariable regression modeling including trial (CAMS-Ph+B-ALL-2025 vs. CCCGALL-2020 or 2015) and other known prognostic factors as main effects may also be performed, using the Cox models. |
| Cumulative incidence of relapse (CIR) of this therapy, in comparison to historical regimens. | Approximately 7 years. | CIR functions of relapse will be estimated by the Kalbafleisch-Prentice method. Follow up of the historical comparison cohort (CCCG-ALL-2020 and 2015) will continue during the course of the current trial. Comparisons of CIR will be performed by Gray's test. Multivariable regression modeling including trial (CAMS-Ph+B-ALLALL-2025 vs. CCCGALL-2020 or 2015) and other known prognostic factors as main effects may also be performed, using the Fine-Gray models. |
Other
| Measure | Time frame | Description |
|---|---|---|
| To explore the pharmacokinetic profiles as Maximum Plasma Concentration [Cmax] in blood paired with cerebrospinal fluid of olverembatinib given alone and in combination with blinatumomab or with prednisone plus vincristine | Up to 30 days after last dose of study treatment | In pharmacokinetic (PK) studies of Cmax, descriptive statistics (mean, standard deviation, median, range) will be used to summarize the data. Visualizations, such as box plots and line graphs, will be used to depict the drug's concentration over time in blood and cerebrospinal fluid. Centers with the appropriate resources may conduct these analyses. |
| To explore the pharmacokinetic profiles as Time to Reach Maximum Plasma Concentration (Tmax) in blood paired with cerebrospinal fluid of olverembatinib given alone and in combination with blinatumomab or with prednisone plus vincristine | Up to 30 days after last dose of study treatment | In pharmacokinetic (PK) studies as Tmax, descriptive statistics (e.g., mean, standard deviation, five-number summary) are used to summarize the data, while visualizations like box plots and line graphs are employed to depict the drug's behavior in the body. It is recommended that centers with the appropriate resources and interest consider undertaking these studies. |
| To correlate measurable residual diseases (MRD) during remission induction and after consolidation by Ig-NGS, qPCR of BCR::ABL1 and FCM-MRD with cumulative incidence of event-free survival (EFS) | Approximately 7 years | Proportions of patients with positive MRD by NGS, qPCR and FCM on Days 19 and 48 will be estimated by the sample proportion along with the 95% confidence interval. The EFS functions will be estimated by the Kaplan-Meier method along with 95% confidence intervals at specified timepoints (e.g., 2 3 years since diagnosis). Comparisons of OS and EFS will be done by log-trank test, and comparison of CIR will be done by Gray's test. Multivariable regression modeling including trial (CAMS-Ph+B-ALL-2025 vs. CCCGALL-2020 or 2015) and other known prognostic factors as main effects may also be performed, using the Cox models. |
| To explore the pharmacokinetic profiles as Half-Life (t½) in blood paired with cerebrospinal fluid of olverembatinib given alone and in combination with blinatumomab or with prednisone plus vincristine | Up to 30 days after last dose of study treatment | In pharmacokinetic (PK) studies of t½, descriptive statistics (e.g., mean, standard deviation, five-number summary) are used to summarize the data, while visualizations like box plots and line graphs are employed to depict the drug's behavior in the body. It is recommended that centers with the appropriate resources and interest consider undertaking these studies. |
| To explore the pharmacokinetic profiles as Clearance (CL) in blood paired with cerebrospinal fluid of olverembatinib given alone and in combination with blinatumomab or with prednisone plus vincristine | Up to 30 days after last dose of study treatment | In pharmacokinetic (PK) studies of CL, descriptive statistics (e.g., mean, standard deviation, five-number summary) are used to summarize the data, while visualizations like box plots and line graphs are employed to depict the drug's behavior in the body. It is recommended that centers with the appropriate resources and interest consider undertaking these studies. |
| To explore the pharmacokinetic profiles as Area Under the Plasma Concentration-Time Curve (AUC) in blood paired with cerebrospinal fluid of olverembatinib given alone and in combination with blinatumomab or with prednisone plus vincristine | Up to 30 days after last dose of study treatment | In pharmacokinetic (PK) studies of AUC, descriptive statistics (e.g., mean, standard deviation, five-number summary) are used to summarize the data, while visualizations like box plots and line graphs are employed to depict the drug's behavior in the body. It is recommended that centers with the appropriate resources and interest consider undertaking these studies. |
| To correlate measurable residual diseases (MRD) during remission induction and after consolidation by Ig-NGS, qPCR of BCR::ABL1 and FCM-MRD with cumulative incidence of relapse(CIR) | Approximately 7 years | Proportions of patients with positive MRD by NGS, qPCR and FCM on Days 19 and 48 will be estimated by the sample proportion along with the 95% confidence interval. The CIR curve will be estimated by Kalbafleisch-Prentice method, along with 95% confidence intervals at specified timepoints (e.g., 2 3 years since diagnosis). Comparisons of CIR will be done by Gray's test. Multivariable regression modeling including trial (CAMS-Ph+B-ALL-2025 vs. CCCGALL2020 or 2015) and other known prognostic factors as main effects may also be performed, using the Fine-Gray models(CIR). |
| To correlate measurable residual diseases (MRD) during remission induction and after consolidation by Ig-NGS, qPCR of BCR::ABL1 and FCM-MRD with overall survival (OS) | Approximately 7 years | Proportions of patients with positive MRD by NGS, qPCR and FCM on Days 19 and 48 will be estimated by the sample proportion along with the 95% confidence interval. The OS functions will be estimated by the Kaplan-Meier method along with 95% confidence intervals at specified timepoints (e.g., 2 3 years since diagnosis). Comparisons of OS will be done by log-rank test. Multivariable regression modeling including trial (CAMS-Ph+B-ALL-2025 vs. CCCGALL-2020 or 2015) and other known prognostic factors as main effects may also be performed, using the Cox models. |
| Incidence of Grade 3 or higher Treatment-Emergent Adverse Events (TEAE) associated with olverembatinib, venetoclax and blinatumomab, and compared with the historical controls treated with dasatinib plus intensive chemotherapy. | Up to 30 days after last dose of study treatment | Proportions of grade-3 or higher TEAEs in each treatment phase will be estimated by the sample proportions along with exact 95% confidence intervals. Cumulative incidences of various grade-3 or higher AEs throughout therapy will be estimated by the Kalbafleisch-Prentice method; death, relapse and other events rendering off therapy before completion are regarded as competing risks. |
| To explore the relationship between cellular immunity dynamics during olverembatinib treatment and the efficacy of blinatumomab-contained therapy. | Approximately 7 years | Descriptive statistics including correlation coefficients (Pearson's or Spearman's) and regression modeling including possibly longitudinal data models will be applied as appropriate to analyze the biological associations. Associations between cellular immunity dynamics and relapse will be analysed using Gray's test or Fine-Gray regression models, as appropriate. |
Countries
China, Hong Kong
Contacts
Primary ContactJingliao Zhang, MD
Backup ContactXiaofan Zhu, MD
Outcome results
None listed