Ignite Creation Date:
2024-05-06 @ 7:57 PM
Last Modification Date:
2024-10-26 @ 3:17 PM
Study NCT ID:
NCT06199557
Status:
NOT_YET_RECRUITING
Last Update Posted:
2024-01-10
First Post:
2023-12-12
Brief Title:
A Study to Investigate Treatment of HU and VPA or 6-MP and VPA in Unfit AMLHR-MDS Patients
Sponsor:
Haukeland University Hospital
Organization:
Haukeland University Hospital
Study Overview
Official Title:
A Phase 12 Multicenter Open-label Study to Investigate Treatment of Hydroxyurea in Combination With Valproic Acid VPA or 6- Mercaptopurine in Combination With VPA in Patients With AML or HR-MDS Unfit for Standard Therapy
Status:
NOT_YET_RECRUITING
Status Verified Date:
2023-10
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:
HUVAMER
Brief Summary:
The purpose of this study is to investigate the safety tolerability and preliminary efficacy of the combination treatment of hydroxyurea capsules and valproic acid capsules or the combination treatment of 6-mercaptopurine tablets and valproic acid capsules in male and female patients aged 18 years or older with acute myeloid leukemia or high- risk myelodysplastic syndrome
The population to be studied is newly diagnosed AML patients who are considered unfit for standard induction chemotherapy HR-MDS unfitineligible for standard treatment and relapsedrefractory AMLHR-MDS patients who are considered unfit for standard therapy or are for some reason ineligible for another type of therapy Clinically hydroxyurea valproic acid and 6-mercaptopurine are historically very well-known therapeutic agents with low toxicity profiles The rationale for this study is that the combination of these drugs with low toxicity will be well tolerated in elderly AML patients with comorbidities or lower performance status This combination could have a beneficial therapeutic effect on overall survival and contribute to a better quality of life
The population to be studied is newly diagnosed AML patients who are considered unfit for standard induction chemotherapy HR-MDS unfitineligible for standard treatment and relapsedrefractory AMLHR-MDS patients who are considered unfit for standard therapy or are for some reason ineligible for another type of therapy Clinically hydroxyurea valproic acid and 6-mercaptopurine are historically very well-known therapeutic agents with low toxicity profiles The rationale for this study is that the combination of these drugs with low toxicity will be well tolerated in elderly AML patients with comorbidities or lower performance status This combination could have a beneficial therapeutic effect on overall survival and contribute to a better quality of life
Detailed Description:
This a two-part open-label phase 12 study that will include clinical sites in Norway and other Nordic countries
The study consists of part A and part B Part A will run in Norway only Part B will run in Norway and the Nordic countries
Both part A and part B have two different treatment combinations T combination 1 and combination 2 Part B is a cohort expansion of part A if part A proves to be positive
Treatment combination 1 T1 hydroxyurea valproic acid Treatment combination 2 T2 6-mercaptopurine valproic acid
Each patient enrolled in the trial will start and will receive at least one cycle with T1
hydroxyurea and valproic acid The first cycle in the study always constitutes of hydroxyurea 1000 mg twice a day plus valproic acid 300 mg 600 mg for 14 days this will be followed by a 14-day period with no medication Each cycle duration is 28 days
Patients who do not experience clinical benefit after the first cycle will not be eligible to continue on this regimen and they will be allocated to treatment combination 2 On the other hand patients who do experience clinical benefit after cycle 1 with combination 1 HU VPA will be further eligible to continue on this regimencombination However patients on T1 will be withdrawn after consequent cycles as soon as they do not meet the criteria for clinical benefit as defined by this protocol Each patient who does not meet the criteria of clinical benefit after the first cycle with treatment combination 1 will switch to treatment combination 2 T2 T2 constitutes of 6-mercaptopurine 50 mg once a day plus valproic acid 300 mg 600 mg for 14 days this will be followed by a 14-day period with no medication Each cycle duration is 28 days Patients will be further eligible to continue this regimencombination for as long as they experience clinical benefit otherwise they will be withdrawn from the study as soon as they do not meet the criteria for clinical benefit as defined by this protocol
There will be 8 patients allocated for the treatment combination 1 with HU VPA and up to 8 patients allocated for the treatment combination 2 with 6MP VPA For each of the two treatment combinations if one or more patients of 8 experience clinical benefit the group will be expanded with 16 more patients in Part B Part B consists of two cohort expansions where the setup is identical to part A one for HU VPA and one for 6MP VPA 16 patients in each in total up to 32 new patients
In part B the same principles will apply for response withdrawal and allocation from HU VPA to 6MP VPA Patients treated with combination 1 who do not experience clinical benefit or experience unacceptable unmanageable toxicity after cycle 1 will not be eligible to continue on this regimen and they will be allocated to combination 2 It is expected that cohort expansion of combination 2 will proceed slower than cohort expansion for combination 1
If 5 or more patients of the total of 24 part A n8 part B n16 experience clinical benefit there will be considered a phase IIIII expansion cohort for further effect assessment
The treatment duration in all groups can last to up 6 cycles in total each cycle lasts for 28 days The rationale for the flow in the study aims to ensure that the patients do not undergo prolonged periods with excessive and ineffective treatment Assessment of treatment response consecutively after each cycle will guide the treating physician to swiftly change the treatment combination or withdraw the patient from the study accordingly
The switch to a second treatment combination as a part of the study ensures that more therapy options are available for potentially all patients who enroll in the trial
The enrollment is stopped when 816 patients with HU VPA are treated or if 816 patients are treated with 6MP VPA Patients will switch over to 6MP VPA if lack of clinical benefit Some dose modifications are allowed when indicated according to the protocol At screening and during the study treatment tumor debulking with HU 6MP is required for 5 to 7 days to reduce WBC to less than 25109L 20 blasts in the peripheral blood before each cycle HU VPA or 6MP VPA Tumor debulking with HU 6MP may be repeated ahead of every cycle for both treatment combinations and in the treating physicians discretion if the patient tolerates this
The objectives of this study include
To determine the safety and tolerability of the treatment combinations of hydroxyurea valproic acid and 6-mercaptopurine valproic acid administered at established clinical doses
To establish the preliminary efficacy of the treatment combination of hydroxyurea and valproic acid administered at established clinical doses
To establish the preliminary efficacy of the treatment combination of 6-mercaptopurine and valproic acid administered at established clinical doses
To evaluate changes in patients performance status for baseline and during the study period
The adaptive study design is based on a Simon two-stage model of expanding cohorts This model tested in the TAPUR DRUP and Impress-Norway studies has been designed to effectively test a set of drugs using a minimum of number of patients see also Chapter 9 on Statistics
Each arm A1 A2 B1 and B2 will be monitored using a Simon-like two-stage admissible monitoring plan to identify patients with evidence of clinical benefit Both arms in part A will enroll 8 participants and will be considered positive if 1 patient show clinical benefit after at least 28 days on treatment for each arm In case of a positive part A arm A1 and A2 separately part B arm B1 and B2 separately will be initiated enrolling 16 additional participants in each arm into the cohort
If there are 0 patients with clinical benefit as defined by this protocol among the first 8 participants in an arm then the respective arm will not proceed to expansion Otherwise an additional 16 participants will be included in each cohort expansion B1 and B2 respectively Four or fewer responses out of 24 will suggest a lack of activity while 5 or more responses will suggest that further investigation of the drug in a phase 3 clinical trial is warranted
Study duration 5 years
Treatment duration up to 6 months for each treatment combination
Visit frequency every 7 days if applicable during the first cycle thereafter every 28 days
The study consists of part A and part B Part A will run in Norway only Part B will run in Norway and the Nordic countries
Both part A and part B have two different treatment combinations T combination 1 and combination 2 Part B is a cohort expansion of part A if part A proves to be positive
Treatment combination 1 T1 hydroxyurea valproic acid Treatment combination 2 T2 6-mercaptopurine valproic acid
Each patient enrolled in the trial will start and will receive at least one cycle with T1
hydroxyurea and valproic acid The first cycle in the study always constitutes of hydroxyurea 1000 mg twice a day plus valproic acid 300 mg 600 mg for 14 days this will be followed by a 14-day period with no medication Each cycle duration is 28 days
Patients who do not experience clinical benefit after the first cycle will not be eligible to continue on this regimen and they will be allocated to treatment combination 2 On the other hand patients who do experience clinical benefit after cycle 1 with combination 1 HU VPA will be further eligible to continue on this regimencombination However patients on T1 will be withdrawn after consequent cycles as soon as they do not meet the criteria for clinical benefit as defined by this protocol Each patient who does not meet the criteria of clinical benefit after the first cycle with treatment combination 1 will switch to treatment combination 2 T2 T2 constitutes of 6-mercaptopurine 50 mg once a day plus valproic acid 300 mg 600 mg for 14 days this will be followed by a 14-day period with no medication Each cycle duration is 28 days Patients will be further eligible to continue this regimencombination for as long as they experience clinical benefit otherwise they will be withdrawn from the study as soon as they do not meet the criteria for clinical benefit as defined by this protocol
There will be 8 patients allocated for the treatment combination 1 with HU VPA and up to 8 patients allocated for the treatment combination 2 with 6MP VPA For each of the two treatment combinations if one or more patients of 8 experience clinical benefit the group will be expanded with 16 more patients in Part B Part B consists of two cohort expansions where the setup is identical to part A one for HU VPA and one for 6MP VPA 16 patients in each in total up to 32 new patients
In part B the same principles will apply for response withdrawal and allocation from HU VPA to 6MP VPA Patients treated with combination 1 who do not experience clinical benefit or experience unacceptable unmanageable toxicity after cycle 1 will not be eligible to continue on this regimen and they will be allocated to combination 2 It is expected that cohort expansion of combination 2 will proceed slower than cohort expansion for combination 1
If 5 or more patients of the total of 24 part A n8 part B n16 experience clinical benefit there will be considered a phase IIIII expansion cohort for further effect assessment
The treatment duration in all groups can last to up 6 cycles in total each cycle lasts for 28 days The rationale for the flow in the study aims to ensure that the patients do not undergo prolonged periods with excessive and ineffective treatment Assessment of treatment response consecutively after each cycle will guide the treating physician to swiftly change the treatment combination or withdraw the patient from the study accordingly
The switch to a second treatment combination as a part of the study ensures that more therapy options are available for potentially all patients who enroll in the trial
The enrollment is stopped when 816 patients with HU VPA are treated or if 816 patients are treated with 6MP VPA Patients will switch over to 6MP VPA if lack of clinical benefit Some dose modifications are allowed when indicated according to the protocol At screening and during the study treatment tumor debulking with HU 6MP is required for 5 to 7 days to reduce WBC to less than 25109L 20 blasts in the peripheral blood before each cycle HU VPA or 6MP VPA Tumor debulking with HU 6MP may be repeated ahead of every cycle for both treatment combinations and in the treating physicians discretion if the patient tolerates this
The objectives of this study include
To determine the safety and tolerability of the treatment combinations of hydroxyurea valproic acid and 6-mercaptopurine valproic acid administered at established clinical doses
To establish the preliminary efficacy of the treatment combination of hydroxyurea and valproic acid administered at established clinical doses
To establish the preliminary efficacy of the treatment combination of 6-mercaptopurine and valproic acid administered at established clinical doses
To evaluate changes in patients performance status for baseline and during the study period
The adaptive study design is based on a Simon two-stage model of expanding cohorts This model tested in the TAPUR DRUP and Impress-Norway studies has been designed to effectively test a set of drugs using a minimum of number of patients see also Chapter 9 on Statistics
Each arm A1 A2 B1 and B2 will be monitored using a Simon-like two-stage admissible monitoring plan to identify patients with evidence of clinical benefit Both arms in part A will enroll 8 participants and will be considered positive if 1 patient show clinical benefit after at least 28 days on treatment for each arm In case of a positive part A arm A1 and A2 separately part B arm B1 and B2 separately will be initiated enrolling 16 additional participants in each arm into the cohort
If there are 0 patients with clinical benefit as defined by this protocol among the first 8 participants in an arm then the respective arm will not proceed to expansion Otherwise an additional 16 participants will be included in each cohort expansion B1 and B2 respectively Four or fewer responses out of 24 will suggest a lack of activity while 5 or more responses will suggest that further investigation of the drug in a phase 3 clinical trial is warranted
Study duration 5 years
Treatment duration up to 6 months for each treatment combination
Visit frequency every 7 days if applicable during the first cycle thereafter every 28 days
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