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Basic Trial Information
Trial Description
     Summary
     Further Trial Information
     Eligibility Criteria
Trial Contact Information

Basic Trial Information

Phase	Type	Status	Age	Sponsor	Protocol IDs
Phase III, Phase II	Treatment	Active	18 to 65	Other	NILG-ALL 10/07 NCT00795756

Trial Description

Summary

The aim of this clinical study in adult ALL is to compare by risk category (1) the feasibility of two different CNS prophylaxis regimens and (2) the overall disease-free survival in relation to the achievement of an early MRD negative status and following consolidation with lineage-targeted methotrexate infusions and other disease-specific therapeutic elements, with or without the application of allogeneic or autologous SCT depending on risk class and MRD study results.

In this multicentric prospective pilot randomized phase II trial on CNS prophylaxis, all patients receive induction/consolidation therapy incorporating lineage-targeted high-dose methotrexate plus other drugs (with additional imatinib in Ph/BCR-ABL+ ALL), for the achievement of an early negative MRD status. The MRD study supports a risk/MRD-oriented final consolidation phase.

Further Study Information

A) Risk Classification Newly diagnosed patients are hierarchically clustered into very high, high and standard risk cases (VHR, HR, SR) using international risk criteria modified according to NILG: A1) VHR (any criterium): B-precursor: WBC count >100x109/L; adverse cytogenetics/molecular biology such as t(9;22)/BCR-ABL, t(4;11)/MLL rearrangement at 11q23, +8, -7, del6q, t(8;14), low hypodiploidy with 30-39 chromosomes, near triploidy with 60-78 chromosomes, complex with >5 unrelated anomalies.

T-precursor: WBC count >100x109/L; early/late non-cortical immunophenotype (CD1a-); adverse cytogenetics/molecular biology (as above).

A2) HR (any criterium, VHR excluded): B-precursor: WBC count >30x109/L; pro-B immunophenotype; complete remission after cycle 2. T-precursor: complete remission after cycle 2. A3) SR (all criteria, VHR/HR excluded): B-precursor: WBC count <30x109/L; T-precursor: WBC count <100x109/L; cortical immunophenotype (CD1a+).

B) CNS Prophylaxis Stratification before randomisation

1. by immunophenotype, i.e. B-precursor vs. T-precursor

2. by risk class, i.e. SR vs. non-SR (using only known factors) Randomisation: intrathecal (IT) CNS prophylaxis with standard triple therapy (TIT, 12 total injections) vs. DepoCyte (6-8 total injections by disease subset). Cranial irradiation is omitted in both arms, and all patients receive the same chemotherapy program including CNS-crossing agents.

C)Induction/Early Consolidation and MRD Study Randomised patients receive homogeneous induction/early consolidation chemotherapy, including subset-specific elements for B-precursor ALL (3x targeted-infusion methotrexate 2.5 g/m2), T-precursor ALL (3x targeted-infusion methotrexate 5 g/m2), age >55 years (methotrexate reduced to 1.5 g/m2), Ph/BCR-ABL+ ALL (imatinib, reduced-intensity chemotherapy), radiation therapy (LL). Patients not in CR after cycles 1-2 are off study. For CR evaluation bone marrow is checked on days 28 and/or 56. Consolidation cycles are administered at 21-28 day intervals Concurrent MRD analysis is performed at four timepoints (weeks 4, 10, 16 and 22 of induction/consolidation), to optimize risk classification and support risk/MRD-oriented therapy: C1) MRD negative (M-NEG): negative MRD study (<10-4 at timepoints #2 and #3, and negative at timepoint #4) C2) MRD positive (M-POS): positive MRD study (>10-4 at timepoints #2 or #3, or positive at timepoint #4)

D)MRD/Risk-Oriented Final Therapy D1) VHR patients are candidate to an early allogeneic SCT (related/unrelated donor/cord blood; ablative/non-ablative conditioning according to current protocols/guidelines) after CR, regardless MRD study results. D2) M-POS as well as HR patients with unknown MRD are allocated to allogeneic SCT after MRD timepoint 2 (M-POS >10-4) or MRD timepoint 4 (others).

When an allogeneic SCT is not possible, patients complete consolidation and receive autologous-type SCT followed by maintenance.

D3) M-NEG as well as SR patients with unknown MRD are allocated to maintenance therapy.

Age-limited therapeutic procedures: Patients aged >55 years are treated with age-adapted therapy, and when indicated will be included in SCT programs whenever possible and according to performance status and comorbidity.

Eligibility Criteria

Inclusion Criteria:

• Age 18-65 years.

• Diagnosis of untreated ALL with B-/T-precursor phenotype or B-cell lymphoblastic lymphoma (B-LL), either de novo or secondary to chemo-radiotherapy for other cancer.

• Full cytological, cytochemical, cytogenetic and immunobiological disease characterization by revised FAB, EGIL and WHO criteria.

• Bone marrow and peripheral blood sampling (ALL) or biopsy specimen (LL) for MRD study.

• ECOG performance status 0-2 or reversible ECOG 3 score following intensive care of complications.

• Signed informed consent.

Exclusion Criteria:

• Diagnosis of B-ALL (FAB L3 ALL/Burkitt's leukemia or lymphoma) and T-LL (T-cell lymphoblastic lymphoma).

• Down's syndrome.

• Pre-existing, uncontrolled pathology such as cardiac disease (congestive/ischemic, acute myocardial infarction within the past 3 months, untreatable arrythmias, NYHA classes III and IV), severe liver disease with serum bilirubin >3 mg/dL and/or ALT >3 x upper normal limit (unless attributable to ALL/LL), kidney function impairment with serum creatinine >2 mg/dL (unless attributable to ALL/LL), and severe neurological or psychiatric disorder that impairs the patient's ability to understand and sign the informed consent, or to cope with the intended treatment plan.

• Known HIV positive serology.

• Other active hematological or non-hematological cancer with life expectancy <1 year.

• Pregnancy (fertile women will be advised not to become pregnant while on treatment; and male patients to adopt contraceptive methods), unless therapeutic aborption/early discharge is carried out.

Trial Contact Information

Trial Lead Organizations/Sponsors

Northern Italy Leukemia Group

Renato Bassan

Study Chair

Roberto Marchioli, MD		Ph: 0039-(0)872-570250
		Email: marchioli@negrisud.it

Italy
	Bergamo
	Ospedali Riuniti di Bergamo
		Renato Bassan, MD	Ph: 0039-(0)35-269492
			Email: rbassan@ospedaliriuniti.bergamo.it
		Renato Bassan	Principal Investigator
		Tamara Intermesoli, MD	Sub-Investigator
		Alessandro Rambaldi	Sub-Investigator
		Orietta Spinelli, B. Sci.	Sub-Investigator
	Bolzano
	Ospedale San Maurizio
		Sergio Cortelazzo, MD
		Sergio Cortelazzo, MD	Principal Investigator
		Irene Cavattoni, MD	Sub-Investigator
		Vincenzo Cassibba, MD	Sub-Investigator
	Cuneo
	Ospedale Santa Croce
		Daniele Mattei, MD
		Daniele Mattei, MD	Principal Investigator
		Andrea Gallamini	Sub-Investigator
	Milano
	Istituto Scientifico H. San Raffaele
		Fabio Ciceri, MD
		Fabio Ciceri, MD	Principal Investigator
		Stefania Trinca, MD	Sub-Investigator
	Ospedale Maggiore Policlinico
		Giorgio Lambertenghi-Deliliers, MD
		Giorgio Lambertenghi-Deliliers, MD	Principal Investigator
		Agostino Cortelezzi, MD	Sub-Investigator
		Angelo Cardellini, MD	Sub-Investigator
	Monza
	Ospedale San Gerardo
		Enrico Pogliani, MD
		Enrico M. Pogliani	Principal Investigator
		Elisabetta Terruzzi, MD	Sub-Investigator
		Monica Fumagalli, MD	Sub-Investigator
		Luisa Verga, MD	Sub-Investigator
	Torino
	Azienda Sanitaria Ospedale San Giovanni Battista Molinette di Torino
		Filippo Marmont, MD
		Filippo Marmont, MD	Principal Investigator
		Ernesta Audisio, MD	Sub-Investigator
	Vicenza
	Ospedale San Bortolo
		Eros Di Bona, MD
		Eros Di Bona, MD	Principal Investigator

Link to the current ClinicalTrials.gov record.
NLM Identifer NCT00795756
Information obtained from ClinicalTrials.gov on March 18, 2009