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The present pharmacokinetic (PK)-pharmacodynamic (PD) study will explore the toxicity and antileukemic response during the initial 3 months of individualised therapy of children and young adults with acute lymphoblastic leukemia (ALL). The investigators will on an individual toxicity-titrated basis attempt to increase the dose intensity of the 6-mercaptopurine used in the two-months post-remission treatment phase of lower risk childhood ALL. This will be performed together with continuous PEG-ASP (every 2nd week) and interspersed HD-MTX (5 g/m^2) every 3rd week. Thus, the trial will also test the feasibility of this particular drug combination.
In addition to the details above we will also explore
The study could improve the understanding of the pharmacodynamics of the 6MP/HD-MTX interaction in combination with PEG-ASP.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 6 mercaptopurine arm | Experimental | All patients received basic daily 6MP (6-mercaptopurine) (25 mg/m^2) and in addition high-dose methotrexate(HDM) every 3rd week (3 times HDM in total) and PEG-asparaginase every 14th day. Patients increased the dose of 6MP 2 weeks after each HDM if if the myelotoxicity had been acceptable. This means 2 increments since the study stopped 2 weeks after the last HDM |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| 6-mercaptopurine | Drug | Standard dose 25 mg/m^2/day. Can be increased up to 75 mg/m^2/day if the myelosuppression is acceptable (ANC>0.5 T-count >50) |
|
| Measure | Description | Time Frame |
|---|---|---|
| Toxicity of Treatment in Terms of Number of Participants With Serious Adverse Events or Adverse Events, Reported | Number of participants following the protocol treatment for the full consolidation therapy with toxicity in this pilot study trying to individually titrate 6-mercaptopurine to the highest tolerable level during Consolidation. | 3 months ( 79 days ) |
| Measure | Description | Time Frame |
|---|---|---|
| Incorporation of 6-thioguanine Nucleotides (6TGN) Into Leukocyte DNA, Development of Asparaginase Antibody Production | Biweekly bloodsamples during the 3 months are analyzed for 6TGN incorporation into leucocyte DNA. In addition Methylated Mercaptopurine (MeMP) and Erythrocyte-Methotrexate level is measured | During the 3 months consolidation therapy |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Kjeld Schmiegelow, M.D. | Pediatric Clinic II, RIgshospitalet, Copenhagen, DK-2100 | Study Chair |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Department of Pediatrics, Rigshospitalet | Copenhagen | Denmark | ||||
| Department of Pediatrics, University Hospital |
Data published (Frandsen et al, Br J Haematol Oct 2011) Anonymised data on individual patients can be provided by study chair (kschmiegelow@rh.dk) including studyno, gender, age, thiopurine methyltransferase status, immunophenotype, white blood cell count at diagnosis, dose increments at time point 1 and 2 for dose adjustment, and dose-limiting toxicities
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38 patients were recruited in 3 different countries. Recruitment period 12/01/2007 - 12/21/2008. All recruitments were done in departments of Pediatric Hematology/oncology
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| ID | Title | Description |
|---|---|---|
| FG000 | 6-mercaptopurine | All patients received basic 6-mercaptopurine and in addition high-dose methotrexate(HDM) at 3 week intervals ((3 3-week intervals) in total) and PEG-asparaginase at 2 week intervals(5 dosis in total) . Patients received dose increments of 6-mercaptopurine 14 days after High-dose methotrexate if the myelotoxicity was acceptable |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | 6-mercaptopurine | All patients received basic 6-mercaptopurine and in addition high-dose methotrexate(HDM) at 3 week intervals ((3 3-week intervals) in total) and PEG-asparaginase at 2 week intervals(5 dosis in total) . Patients received dose increments of 6-mercaptopurine 14 days after High-dose methotrexate if the myelotoxicity was acceptable |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Toxicity of Treatment in Terms of Number of Participants With Serious Adverse Events or Adverse Events, Reported | Number of participants following the protocol treatment for the full consolidation therapy with toxicity in this pilot study trying to individually titrate 6-mercaptopurine to the highest tolerable level during Consolidation. | Posted | Number | Participants | 3 months ( 79 days ) |
|
Adverse events were reported for each patient for a period of 3 months
Adverse events were recorded in a bi-weekly questionaire to be filled by physician and patient/parents.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 6-mercaptopurine | All patients received basic 6-mercaptopurine and in addition high-dose methotrexate(HDM) at 3 week intervals ((3 3-week intervals) in total) and PEG-asparaginase at 2 week intervals(5 dosis in total) . Patients received dose increments of 6-mercaptopurine 14 days after High-dose methotrexate if the myelotoxicity was acceptable |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Hypoglycemia | Hepatobiliary disorders | Non-systematic Assessment | 2 patients had hypoglycemia due to liver toxicity. Not an unusual event during 6MP treatment, but somewhat early in the treatment. Both had to be hospitalized longer due to this adverse event. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| pain | Gastrointestinal disorders | Systematic Assessment | pain is also expected during treatment of leukemia in childhool. Most common pain from abdomen or legs or mouth (stomatitis) |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Thomas Frandsen | Rigshospitalet, Juliane Marie Centret | +45 35458364 | thomas.leth.frandsen@rh.regionh.dk |
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| ID | Term |
|---|---|
| D054198 | Precursor Cell Lymphoblastic Leukemia-Lymphoma |
| D007938 | Leukemia |
| ID | Term |
|---|---|
| D007945 | Leukemia, Lymphoid |
| D009370 | Neoplasms by Histologic Type |
| D009369 | Neoplasms |
| D006402 | Hematologic Diseases |
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| ID | Term |
|---|---|
| D015122 | Mercaptopurine |
| ID | Term |
|---|---|
| D013438 | Sulfhydryl Compounds |
| D013457 | Sulfur Compounds |
| D009930 | Organic Chemicals |
| D011687 | Purines |
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|
| Odense |
| Denmark |
| Department of Pediatrics, Drottning Sylvias Pediatric Hospital | Gothenburg | Sweden |
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Gender | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Units | Counts |
|---|
| Participants |
|
|
| Secondary | Incorporation of 6-thioguanine Nucleotides (6TGN) Into Leukocyte DNA, Development of Asparaginase Antibody Production | Biweekly bloodsamples during the 3 months are analyzed for 6TGN incorporation into leucocyte DNA. In addition Methylated Mercaptopurine (MeMP) and Erythrocyte-Methotrexate level is measured | Not Posted | Feb 2018 | During the 3 months consolidation therapy | Participants |
| 26 |
| 38 |
| 23 |
| 38 |
|
| neutropenic fever | Congenital, familial and genetic disorders | Systematic Assessment | admission to hospital for neutropenic fever is expected during leukemia treatment in the consolidation phase. Usually patients are admitted for i.v. antibiotic treatment for 5-10 days depending on neutropenia and agent. |
|
| pancreatitis | Gastrointestinal disorders | Non-systematic Assessment | grade 4 pancreatitis |
|
| PRES (Posterior Reversible Encephalopathy Syndrome) | Nervous system disorders | Non-systematic Assessment | Hypertension and PRES in connection with High Dose Methotrexate. |
|
|
| mucositis | Gastrointestinal disorders | Systematic Assessment | Mucositis following chemotherapy-mostly high dose Methotrexate in combination with 6MP |
|
| nausea and vomiting | Gastrointestinal disorders | Systematic Assessment |
|
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| D006425 |
| Hemic and Lymphatic Diseases |
| D008232 | Lymphoproliferative Disorders |
| D008206 | Lymphatic Diseases |
| D007160 | Immunoproliferative Disorders |
| D007154 | Immune System Diseases |
| D006574 |
| Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |