Ignite Creation Date:
2024-05-06 @ 8:26 PM
Last Modification Date:
2024-10-26 @ 3:28 PM
Study NCT ID:
NCT06387069
Status:
RECRUITING
Last Update Posted:
2024-05-30
First Post:
2024-04-16
Brief Title:
A Study to Evaluate HMPL-306 in Patients With IDH1- and IDH2-mutated Acute Myeloid Leukemia
Sponsor:
Hutchmed
Organization:
Hutchmed
Study Overview
Official Title:
A Multicenter Randomized Open-Label Phase III Clinical Study to Evaluate the Efficacy and Safety of HMPL-306 vs Salvage Chemotherapy Regimens in Patients With IDH1- and IDH2-mutated RelapsedRefractory Acute Myeloid Leukemia RR AML
Status:
RECRUITING
Status Verified Date:
2024-05
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
An open-label design is adopted in this study All patients will first undergo pre-screening to determine the mutation status of IDH and all patients will be assigned to the registry study of the corresponding cohorts of IDH1 and IDH2 based on the pre-screening results Patients with both IDH1 and IDH2 mutations will be enrolled in the IDH2 cohort This study is divided into two cohorts Cohort 1 includes RR AML patients with IDH1-R132 mutations Cohort 2 includes RR AML patients with IDH2-R140 and R172 mutations The two cohorts are designed independently and will be analyzed separately for statistical hypothesis testing Patients in both cohorts will be randomized in a 11 ratio according to the central Interactive Web Response System IWRS into the test or control group patients in the test group will receive HMPL-306 monotherapy at a dose of 250 mg once daily QD Cycle 1 C1 150 mg QD starting from Cycle 2 C2 Patients in the control group will receive salvage chemotherapy one of four options consisting of two intensive chemotherapy regimens MEC regimen and FLAG Ida regimen and two non-intensive chemotherapy regimens azacitidine and LoDAC
Detailed Description:
Study overview This is a multicenter randomized open-label phase III clinical study to evaluate the efficacy safety and pharmacokinetic PK of HMPL-306 vs salvage chemotherapy in patients with IDH1- and IDH2-mutated RR AML
An open-label design is adopted in this study All patients will first undergo pre-screening to determine the mutation status of IDH and all patients will be assigned to the registry study of the corresponding cohorts of IDH1 and IDH2 based on the pre-screening results Patients with both IDH1 and IDH2 mutations will be enrolled in the IDH2 cohort This study is divided into two cohorts Cohort 1 includes RR AML patients with IDH1-R132 mutations Cohort 2 includes RR AML patients with IDH2-R140 and R172 mutations The two cohorts are designed independently and will be analyzed separately for statistical hypothesis testing Patients in both cohorts will be randomized in a 11 ratio according to the central Interactive Web Response System IWRS into the test or control group patients in the test group will receive HMPL-306 monotherapy at a dose of 250 mg once daily QD Cycle 1 C1 150 mg QD starting from Cycle 2 C2 Patients in the control group will receive salvage chemotherapy one of four options consisting of two intensive chemotherapy regimens MEC regimen and FLAG Ida regimen and two non-intensive chemotherapy regimens azacitidine and LoDAC Before randomization the investigator will preselect a salvage chemotherapy regimen based on the patients condition Patients will then be stratified and randomized based on their prior first-line treatment response recurrence within 6 months after allogeneic Hematopoietic stem cell transplantation HSCT recurrence beyond 6 months after allogeneic HSCT primary refractory disease without HSCT recurrence within 6 months after achieving CRCRh without HSCT recurrence beyond 6 months after achieving complete response CRCR with partial hematologic recovery CRh without HSCT and the intensity of preselected chemotherapy regimen intensive chemotherapy non-intensive chemotherapy
After the patient signs the pre-screening informed consent form ICF pre-screening genetic testing will be performed to determine the mutation status of IDH so as to clarify the subsequent enrollment of the cohorts Patients who meet the inclusion criteria will receive treatment in the test group or the control group Each treatment cycle lasts for 28 days Treatment will continue until progression of disease PDrecurrence death intolerable toxicity initiation of a new anti-tumor therapy the patient no longer benefits from the treatment as judged by the investigator the patient or hisher legal representative requests to withdraw from the study loss to follow-up or end of study whichever occurs first the treatment cycle of MEC regimen and FLAG Ida regimen in the chemotherapy group will be adjusted based on the actual dosing and a maximum of two treatment cycles is allowed
Patients with PD in the control group should not be crossed over to the test group and patients in the control group should not be crossed over to other salvage treatment regimens
The information of treatment groups is as follows consistent between the two cohorts
Test group Patients will receive HMPL-306 monotherapy
- HMPL-306 PO at 250 mg QD C1 150 mg QD starting from C2 28 days as a cycle
Control group Patients will receive treatment with one of the following regimens and the regimen will be selected by the investigator based on the patients condition
MEC regimen etoposide injection 100 mgm2 cytarabine injection 1000 mgm2 mitoxantrone injection 8 mgm2 QD IV for 5 consecutive days Days 1-5
FLAG Ida regimen granulocyte colony stimulating factor G-CSF injection 300 mcgm2 QD subcutaneous injectionSC for 5 consecutive days Days 1-5 fludarabine injection 30 mgm2 QD IV for 5 consecutive days Days 2-6 cytarabine injection 2000 mgm2 QD IV for 5 consecutive days Days 2-6 idarubicin injection 10 mgm2 QD IV for 3 consecutive days Days 2-4 This regimen can be given with or without Ida which will be determined by the investigator based on the actual condition of the patient After the completion of chemotherapy the investigator will determine whether it is necessary to continue G-CSF administration If necessary G-CSF may be administered again until absolute neutrophil count ANC 05 109L
LoDAC cytarabine injection 20 mg q12h SC or IV for 10 consecutive days Days 1-10
Azacitidine azacitidine injection 75 mgm2 QD SC or IV for 7 consecutive days Days 1-7
Phase of study
The study phase includes a pre-screening period a screening period a treatment period and a follow-up period including end-of-treatment EOT follow-up EFS follow-up and OS follow-up
Pre-screening period The pre-screening period is defined as the period from signing the pre-screening ICF to obtaining test reports on IDH1 and IDH2 mutations For patients without a previous report of IDH1 or IDH2 testing specimens can be sent to the central laboratory for IDH1 and IDH2 mutation and other concomitant gene testing before screening and after signing the pre-screening ICF Patients previously reported to be positive for IDH1IDH2 mutation test can enter the screening period directly without pre-screening if permitted by the investigator Patients should not be enrolled until the test results are confirmed by the central laboratory
The screening period is defined as the time from signing the main screening ICF until pre-dose on C1D1
The treatment period is defined as the time from the first dose to EOT EOT visit Patients at EOT are required to return to the study site for an EOT follow-up visit within 30 7 days after the last dose of investigational product or before starting any other anti-tumor therapy whichever occurs first
EFS follow-up Patients at EOT except for PDrecurrence and lack of efficacy will be retained in the study and enter the EFS follow-up stage EFS follow-up will be conducted every 8 weeks from the day of entering the EFS follow-up stage until progression of diseaserecurrence death withdrawal by the patient or hisher legal representative loss to follow-up or end of study whichever occurs first Subsequent new transplant conditioning regimens or new anti-tumor regimens should be recorded during the EFS follow-up period According to the Guidelines for Clinical Development of New Drugs for Acute Myeloid Leukemia issued by the Center for Drug Evaluation CDE lack of efficacy is defined as failure to achieve CR or CRhCR with incomplete hematologic recovery CRimorphological leukemia-free status MLFSpartial response PR after 2 cycles of treatment under the protocol of the intensive chemotherapy group In the reduced intensity chemotherapy group if CR or CRhCRiMLFSPR is not achieved after 180 days of treatment it will be judged as lack of efficacy Lack of efficacy in the test group is defined as failure to achieve CR or CRhCRiMLFSPR from the day of HMPL-306 treatment until C5D1 including C5D1 visit Whether patients are considered lack of efficacy during the study will be determined by the investigator based on the actual clinical condition For patients who are deemed as having experienced an event-free survival EFS event due to meeting the definition of lack of efficacy among EFS events but who could still potentially benefit from continued treatment as judged by the investigator they may continue to receive treatment after being fully informed without changing the conclusion that an EFS event has occurred
OS follow-up After the end of EFS follow-up patients will enter the overall survival OS follow-up stage OS follow-ups will be conducted every 8 weeks from the day of OS follow-up until death request for withdrawal from the study by the patient or herhis legal representative loss to follow-up or end of study whichever occurs first
End of study The two cohorts may vary in the time of end of study The end of study for each cohort is defined as the number of target OS events for which the final analysis is observed in that cohort The actual study duration for each cohort depends on the actual enrollment rate dropout rate and median OS of each group
Efficacy assessment Efficacy assessment will be based on the European Leukemia Collaboration ELN 2022 criteria Efficacy assessment will be conducted once every cycle during the first 6 treatment cycles ie C2D1 C3D1 C4D1 C5D1 C6D1 and C7D1 and once every 2 cycles thereafter ie C9D1 C11D1 C13D1 efficacy evaluation will also be conducted at EOT follow-up and at each EFS follow-up
Safety assessment All adverse events AEs will be graded as per the National Cancer Institute NCI Common Terminology Criteria for Adverse Events CTCAE V50 AEs will be coded using the Medical Dictionary for Regulatory Activities MedDRA The number and frequency of treatment emergent adverse events TEAEs will be summarized by system organ class SOC and preferred term PT
In this study all serious adverse events SAEs related to study procedures reported from the date of signing the informed consent form for pre-screening to the date of signing the master informed consent form will be collected all SAEs need to be collected from the date of signing the master informed consent form to the date of the first dose all AESAEs need to be collected from the first dose to 30 days after the last dose or the initiation of a new anti-tumor therapy whichever occurs first SAEs confirmed by investigators as having a reasonable possibility of correlation with the investigational product need to be collected 30 days after the last dose or after the initiation of a new anti-tumor therapy whichever occurs earliest
An open-label design is adopted in this study All patients will first undergo pre-screening to determine the mutation status of IDH and all patients will be assigned to the registry study of the corresponding cohorts of IDH1 and IDH2 based on the pre-screening results Patients with both IDH1 and IDH2 mutations will be enrolled in the IDH2 cohort This study is divided into two cohorts Cohort 1 includes RR AML patients with IDH1-R132 mutations Cohort 2 includes RR AML patients with IDH2-R140 and R172 mutations The two cohorts are designed independently and will be analyzed separately for statistical hypothesis testing Patients in both cohorts will be randomized in a 11 ratio according to the central Interactive Web Response System IWRS into the test or control group patients in the test group will receive HMPL-306 monotherapy at a dose of 250 mg once daily QD Cycle 1 C1 150 mg QD starting from Cycle 2 C2 Patients in the control group will receive salvage chemotherapy one of four options consisting of two intensive chemotherapy regimens MEC regimen and FLAG Ida regimen and two non-intensive chemotherapy regimens azacitidine and LoDAC Before randomization the investigator will preselect a salvage chemotherapy regimen based on the patients condition Patients will then be stratified and randomized based on their prior first-line treatment response recurrence within 6 months after allogeneic Hematopoietic stem cell transplantation HSCT recurrence beyond 6 months after allogeneic HSCT primary refractory disease without HSCT recurrence within 6 months after achieving CRCRh without HSCT recurrence beyond 6 months after achieving complete response CRCR with partial hematologic recovery CRh without HSCT and the intensity of preselected chemotherapy regimen intensive chemotherapy non-intensive chemotherapy
After the patient signs the pre-screening informed consent form ICF pre-screening genetic testing will be performed to determine the mutation status of IDH so as to clarify the subsequent enrollment of the cohorts Patients who meet the inclusion criteria will receive treatment in the test group or the control group Each treatment cycle lasts for 28 days Treatment will continue until progression of disease PDrecurrence death intolerable toxicity initiation of a new anti-tumor therapy the patient no longer benefits from the treatment as judged by the investigator the patient or hisher legal representative requests to withdraw from the study loss to follow-up or end of study whichever occurs first the treatment cycle of MEC regimen and FLAG Ida regimen in the chemotherapy group will be adjusted based on the actual dosing and a maximum of two treatment cycles is allowed
Patients with PD in the control group should not be crossed over to the test group and patients in the control group should not be crossed over to other salvage treatment regimens
The information of treatment groups is as follows consistent between the two cohorts
Test group Patients will receive HMPL-306 monotherapy
- HMPL-306 PO at 250 mg QD C1 150 mg QD starting from C2 28 days as a cycle
Control group Patients will receive treatment with one of the following regimens and the regimen will be selected by the investigator based on the patients condition
MEC regimen etoposide injection 100 mgm2 cytarabine injection 1000 mgm2 mitoxantrone injection 8 mgm2 QD IV for 5 consecutive days Days 1-5
FLAG Ida regimen granulocyte colony stimulating factor G-CSF injection 300 mcgm2 QD subcutaneous injectionSC for 5 consecutive days Days 1-5 fludarabine injection 30 mgm2 QD IV for 5 consecutive days Days 2-6 cytarabine injection 2000 mgm2 QD IV for 5 consecutive days Days 2-6 idarubicin injection 10 mgm2 QD IV for 3 consecutive days Days 2-4 This regimen can be given with or without Ida which will be determined by the investigator based on the actual condition of the patient After the completion of chemotherapy the investigator will determine whether it is necessary to continue G-CSF administration If necessary G-CSF may be administered again until absolute neutrophil count ANC 05 109L
LoDAC cytarabine injection 20 mg q12h SC or IV for 10 consecutive days Days 1-10
Azacitidine azacitidine injection 75 mgm2 QD SC or IV for 7 consecutive days Days 1-7
Phase of study
The study phase includes a pre-screening period a screening period a treatment period and a follow-up period including end-of-treatment EOT follow-up EFS follow-up and OS follow-up
Pre-screening period The pre-screening period is defined as the period from signing the pre-screening ICF to obtaining test reports on IDH1 and IDH2 mutations For patients without a previous report of IDH1 or IDH2 testing specimens can be sent to the central laboratory for IDH1 and IDH2 mutation and other concomitant gene testing before screening and after signing the pre-screening ICF Patients previously reported to be positive for IDH1IDH2 mutation test can enter the screening period directly without pre-screening if permitted by the investigator Patients should not be enrolled until the test results are confirmed by the central laboratory
The screening period is defined as the time from signing the main screening ICF until pre-dose on C1D1
The treatment period is defined as the time from the first dose to EOT EOT visit Patients at EOT are required to return to the study site for an EOT follow-up visit within 30 7 days after the last dose of investigational product or before starting any other anti-tumor therapy whichever occurs first
EFS follow-up Patients at EOT except for PDrecurrence and lack of efficacy will be retained in the study and enter the EFS follow-up stage EFS follow-up will be conducted every 8 weeks from the day of entering the EFS follow-up stage until progression of diseaserecurrence death withdrawal by the patient or hisher legal representative loss to follow-up or end of study whichever occurs first Subsequent new transplant conditioning regimens or new anti-tumor regimens should be recorded during the EFS follow-up period According to the Guidelines for Clinical Development of New Drugs for Acute Myeloid Leukemia issued by the Center for Drug Evaluation CDE lack of efficacy is defined as failure to achieve CR or CRhCR with incomplete hematologic recovery CRimorphological leukemia-free status MLFSpartial response PR after 2 cycles of treatment under the protocol of the intensive chemotherapy group In the reduced intensity chemotherapy group if CR or CRhCRiMLFSPR is not achieved after 180 days of treatment it will be judged as lack of efficacy Lack of efficacy in the test group is defined as failure to achieve CR or CRhCRiMLFSPR from the day of HMPL-306 treatment until C5D1 including C5D1 visit Whether patients are considered lack of efficacy during the study will be determined by the investigator based on the actual clinical condition For patients who are deemed as having experienced an event-free survival EFS event due to meeting the definition of lack of efficacy among EFS events but who could still potentially benefit from continued treatment as judged by the investigator they may continue to receive treatment after being fully informed without changing the conclusion that an EFS event has occurred
OS follow-up After the end of EFS follow-up patients will enter the overall survival OS follow-up stage OS follow-ups will be conducted every 8 weeks from the day of OS follow-up until death request for withdrawal from the study by the patient or herhis legal representative loss to follow-up or end of study whichever occurs first
End of study The two cohorts may vary in the time of end of study The end of study for each cohort is defined as the number of target OS events for which the final analysis is observed in that cohort The actual study duration for each cohort depends on the actual enrollment rate dropout rate and median OS of each group
Efficacy assessment Efficacy assessment will be based on the European Leukemia Collaboration ELN 2022 criteria Efficacy assessment will be conducted once every cycle during the first 6 treatment cycles ie C2D1 C3D1 C4D1 C5D1 C6D1 and C7D1 and once every 2 cycles thereafter ie C9D1 C11D1 C13D1 efficacy evaluation will also be conducted at EOT follow-up and at each EFS follow-up
Safety assessment All adverse events AEs will be graded as per the National Cancer Institute NCI Common Terminology Criteria for Adverse Events CTCAE V50 AEs will be coded using the Medical Dictionary for Regulatory Activities MedDRA The number and frequency of treatment emergent adverse events TEAEs will be summarized by system organ class SOC and preferred term PT
In this study all serious adverse events SAEs related to study procedures reported from the date of signing the informed consent form for pre-screening to the date of signing the master informed consent form will be collected all SAEs need to be collected from the date of signing the master informed consent form to the date of the first dose all AESAEs need to be collected from the first dose to 30 days after the last dose or the initiation of a new anti-tumor therapy whichever occurs first SAEs confirmed by investigators as having a reasonable possibility of correlation with the investigational product need to be collected 30 days after the last dose or after the initiation of a new anti-tumor therapy whichever occurs earliest
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
False
Is an FDA AA801 Violation?:
None