NOPHO ALL-2008 Pilot Study on Consolidation Therapy for Children and Adolescents With Acute Lymphoblastic Leukemia

• Sponsor: Rigshospitalet, Denmark (Other)
• Overall Status: Completed
• CT.gov ID: NCT00548431
• Collaborator: (none)
• Enrollment: 38
• Locations: 3
• Arm: 1
• Duration (Months): 17
• Patients Per Site: 12.7
• Patients Per Site Per Month: 0.7

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Leukemia, Lymphocytic, Acute	Drug: 6-mercaptopurine	Phase 2

Detailed Description

In addition to the details above we will also explore

• the relationship of the post-HD-MTX MRD-levels with the dose of 6MP, TPMT-activity, DNA-6TGN, E-6TGN, E-MeMP, E-MTX, and presence of ASP-antibodies,

• the early development of anti-ASP antibodies during continuous PEG-ASP therapy.

The study could improve the understanding of the pharmacodynamics of the 6MP/HD-MTX interaction in combination with PEG-ASP.

Study Design

• Study Type: Interventional
• Actual Enrollment: 38 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Study of Individual 6-mercaptopurine(6MP) Dose Increments in Children With Acute Lymphoblastic Leukemia (ALL) Receiving High-dose Methotrexate (HDM) and PEG-asparaginase
• Study Start Date: Dec 1, 2007
• Actual Primary Completion Date: Jan 1, 2009
• Actual Study Completion Date: May 1, 2009

Arms and Interventions

Arm

Intervention/Treatment

Experimental: 6 mercaptopurine arm 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

Drug: 6-mercaptopurine; 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); Other Names: PURINETHOL

Outcome Measures

Primary Outcome Measures

1. Toxicity of Treatment in Terms of Number of Participants With Serious Adverse Events or Adverse Events, Reported [3 months ( 79 days )]

   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.

Secondary Outcome Measures

1. Incorporation of 6-thioguanine Nucleotides (6TGN) Into Leukocyte DNA, Development of Asparaginase Antibody Production [During the 3 months consolidation therapy]

   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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 1 Year to 18 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• B-lineage ALL

• 1-17.9 years

• WBC <100, clinical remission obtained day 2

• Written consent to participation.

Exclusion Criteria:

• t(9;22)

• Hypodiploidy

• 11q23-aberrations

• TPMT-deficiency

• Intolerance to MTX or 6MP

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Department of Pediatrics, Rigshospitalet	Copenhagen		Denmark
2	Department of Pediatrics, University Hospital	Odense		Denmark
3	Department of Pediatrics, Drottning Sylvias Pediatric Hospital	Gothenburg		Sweden

Sponsors and Collaborators

• Rigshospitalet, Denmark

Investigators

• Study Chair: Kjeld Schmiegelow, M.D., Pediatric Clinic II, RIgshospitalet, Copenhagen, DK-2100

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Kjeld Schmiegelow, Professor, Rigshospitalet, Denmark
• ClinicalTrials.gov Identifier: NCT00548431
• Other Study ID Numbers: NOPHO HDM-6MP pilot study
• First Posted: Oct 24, 2007
• Last Update Posted: Jan 9, 2017
• Last Verified: Nov 1, 2016

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by Kjeld Schmiegelow, Professor, Rigshospitalet, Denmark: Leukemia, Lymphocytic, Acute [C04.557.337.428.511]; 6-mercaptopurine; methotrexate; asparaginase
• Additional relevant MeSH terms: Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Leukemia, Lymphoid; Mercaptopurine

Study Results

Participant Flow

Recruitment Details	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

Arm/Group Title	6-mercaptopurine
Arm/Group Description	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
Period Title: Overall Study
STARTED	38
COMPLETED	38
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	6-mercaptopurine
Arm/Group Description	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
Overall Participants	38
Age (Count of Participants)
<=18 years	38 100%
Between 18 and 65 years	0 0%
>=65 years	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	7 (3)
Gender (Count of Participants)
Female	21 55.3%
Male	17 44.7%
Region of Enrollment (participants) [Number]
Denmark	12 31.6%
Sweden	21 55.3%
Finland	5 13.2%

Outcome Measures

1. Primary Outcome

Title	Toxicity of Treatment in Terms of Number of Participants With Serious Adverse Events or Adverse Events, Reported
Description	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.
Time Frame	3 months ( 79 days )

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	6-mercaptopurine
Arm/Group Description	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
Measure Participants	38
Number [Participants]	26 68.4%

2. Secondary Outcome

Title	Incorporation of 6-thioguanine Nucleotides (6TGN) Into Leukocyte DNA, Development of Asparaginase Antibody Production
Description	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
Time Frame	During the 3 months consolidation therapy

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	Adverse events were reported for each patient for a period of 3 months
Adverse Event Reporting Description	Adverse events were recorded in a bi-weekly questionaire to be filled by physician and patient/parents.
Arm/Group Title	6-mercaptopurine
Arm/Group Description	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
All Cause Mortality
	6-mercaptopurine
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	6-mercaptopurine
	Affected / at Risk (%)	# Events
Total	26/38 (68.4%)
Congenital, familial and genetic disorders
neutropenic fever	22/38 (57.9%)	30
Gastrointestinal disorders
pancreatitis	1/38 (2.6%)	1
Hepatobiliary disorders
Hypoglycemia	2/38 (5.3%)	2
Nervous system disorders
PRES (Posterior Reversible Encephalopathy Syndrome)	1/38 (2.6%)	1
Other (Not Including Serious) Adverse Events
	6-mercaptopurine
	Affected / at Risk (%)	# Events
Total	23/38 (60.5%)
Gastrointestinal disorders
pain	23/38 (60.5%)	55
mucositis	22/38 (57.9%)	30
nausea and vomiting	21/38 (55.3%)	68

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.