A Phase II Study on Allogeneic Stem Cell Transplantation in Patients With Active Acute Leukemia (Gandalf-01)

March 9, 2023 updated by: Gruppo Italiano Trapianto di Midollo Osseo

A Phase II Multicentre Open-label Study on Allogeneic Stem Cell Transplantation From Unrelated, Cord-blood and Family Haploidentical Donors in Patients With Active Acute Leukemia

The experimental treatment consists in the application of a therapeutic strategy of allogeneic transplantation as a potential curative procedure in a population of patients with chemoresistant acute leukemias.

Therapeutic intervention, namely the conditioning regimen as well as GVHD prophylaxis, are based on regimens currently in standard use in the context of allogeneic transplantation.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

The experimental treatment consists in the application of a therapeutic strategy of allogeneic transplantation using either a Marrow Unrelated Donor (MUD) or a Cord Blood (CB) unit or a family Haploidentical (Haplo) donor as a potential curative procedure in a population of patients with chemoresistant acute leukemias for increase the overall survival in this patients.

Therapeutic intervention, namely the conditioning regimen as well as GVHD prophylaxis, are based on regimens currently in standard use in the context of allogeneic transplantation.

The Data Safety Monitoring Board (DSMB) in collaboration with the Steering Committee (SC) will make periodic monitoring to ensure the safety of patients enrolled in to the study. In particular, DSMB will check the periodic safety reports of serious adverse events, the primary or secondary graft failure and treated related mortality (TRM) data generated by the Data Management Center. A safety report will be generated every 30 enrolled patients completed 100 days of follow-up.

The population for analysis in the trial will be the Intention to Treat (ITT) population. All patients enrolled in the study will be included in the ITT analysis.

This study will explore the feasibility, safety and efficacy of allogeneic stem cell transplantation from unrelated, cord-blood and haploidentical donor in patients with an active leukemia. Due to the lack of detailed information from literature and the absence of alternative curative options in this patient population, criteria for sample size assessment do not refer to a formal statistical power calculation. Therefore, GITMO will promote enrollment of all patients with active leukemia eligible to allogeneic SCT in all Italian centres with the aim to collect outcome variables in ITT in the widest and most representative cohort of this specific patient population.

The choice of 80 patients transplanted is based on feasibility reasons and the expected patient population with these characteristics referred to the main Italian Transplant Centres in two year. GITMO survey data on transplant activity points to an estimated accrual of 40 patients per year over a 24 months enrolment period. Criteria for defining sample size do not follow statistical power estimates in order to demonstrate difference between the alternative donor options.

Study Type

Interventional

Enrollment (Actual)

101

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Italy
      • Alessandria, Italy
        • Azienda Ospedaliera SS Antonio e Biagio
      • Bari, Italy
        • Policlinico
      • Bergamo, Italy
        • Divisione di Ematologia - Ospedali Papa Giovanni XXIII
      • Bologna, Italy
        • Ospedale San Orsola
      • Bolzano, Italy
        • Ospedale Regionale Generale- Divisione Ematologia
      • Cagliari, Italy
        • Ospedale Binaghi
      • Cagliari, Italy
        • Ospedale Oncologico Businco
      • Catania, Italy
        • Ospedale Ferrarotto - Ematologia
      • Cuneo, Italy
        • S.C. Ematologia - Azienda Ospedaliera S. Croce e Carle
      • Firenze, Italy
        • Cattedra di Ematologia - Azienda Ospedaliera di Careggi
      • Genova, Italy
        • Ospedale Policlinico San Martino - IST
      • Milano, Italy
        • Ospedale San Raffaele
      • Milano, Italy
        • Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico
      • Milano, Italy
        • Ospedale Niguarda Ca' Grande
      • Modena, Italy
        • Divisione Ematologia - Azienda Ospedaliera Universitaria - Policlinico -
      • Monza, Italy
        • Cattedra di Medicina Interna ed Ematologia - Ospedale S. Gerardo de' i Tintori - Università degli Studi di Milano
      • Palermo, Italy
        • AO Ospedali Riuniti Villa Sofia - Cervello
      • Palermo, Italy
        • Dipartimento Oncologico La Maddalena
      • Pavia, Italy, 27100
        • Fondazione Irccs San Matteo
      • Pescara, Italy
        • Dip. di Ematologia - Unità di Terapia Intensiva Ematologica per il Trapianto Emopoietico - Ospedale Civile di Pescara
      • Piacenza, Italy
        • Ospedale G. Da Saliceto di Piacenza
      • Roma, Italy
        • Policlinico Universitario Tor Vergata
      • Roma, Italy
        • Cattedra di Ematologia - Policlinico
      • Roma, Italy
        • U.O. di Ematologia e Trapianti di Midollo Osseo - Azienda Osp. S. Camillo-Forlanini / Padiglione Morgagni
      • Roma, Italy
        • Policlinico A. Gemelli
      • San Giovanni Rotondo, Italy
        • Ematologia e Centro Trapianti Midollo Osseo - Ospedale IRCCS Casa Sollievo della Sofferenza
      • Taranto, Italy
        • Ospedale San Giuseppe Moscato
      • Torino, Italy
        • Azienda Ospedaliera Citta della Salute e della Scienza
      • Torino, Italy
        • Centro Trapianti Metropolitano
      • Udine, Italy
        • A.O. Santa Maria della Misericordia

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 70 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

Diagnosis of Primary induction Failure or chemoresistant relapse in Acute Myeloid Leukemia (AML) or Acute Lymphoblastic Leukemia (ALL) patients

Activation of an alternative donor search by the Italian Bone Marrow Donor Registry (IBMDR)

Age >=18<=70

Unavailability of a HLA-matched related donor (MRD)

Performance status: ECOG<=3

Written and signed informed consent

Life expectancy not severely limited by concomitant illness.

Exclusion Criteria:

Previous allogeneic transplant (autologous transplant is accepted)

Positive pregnancy test

Any active, uncontrolled infection.

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Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: allogenic transplant
The experimental treatment consists in the application of a therapeutic strategy of allogeneic transplantation as a potential curative procedure in a population of patients with chemoresistant acute leukemias. Therapeutic intervention, namely the conditioning regimen as well as GVHD prophylaxis, are based on regimens currently in standard use in the context of allogeneic transplantation.
Procedure: allogeneic transplant

Allogenic transplant using either a Marrow Unrelated Donor or a Cord Blood unit or a family Haploidentical donor.

The conditioning regimen in standard use is:

Thiotepa (Tepadina) i.v. 5 mg/kg/daily (total dose 10 mg/kg) day -7 and -6;

Busulfan (Busilvex) i.v. 3,2 mg/kg/day (total dose 9,6 mg/kg) as a single daily dose day -5, -4, -3;

Fludarabine i.v. 50 mg/m2 (total dose150 mg/m2) day -5, -4, -3.

Primary antifungal prophylaxis is Micafungin 50 mg/die i.v. (1 mg/kg if <40 kg) day 0 to engraftment. After engraftment continue antifungal prophylaxis according to local practice.

Other Names:
  • Marrow Unrelated or Cord Blood or family Haploidentical donor

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Overall Survival (OS)
Time Frame: 2 years from time of enrolment

The overall survival at 2 years (from time of enrolment) of all patients enrolled in to the study (either transplanted or not).

This is the simplest outcome, defined as the probability of survival irrespective of disease state at any point in time. Patients alive at their last follow-up are censored. It is analyzed by the Kaplan-Meier method, Log-Rank Test and parametric or semiparametric survival models.
2 years from time of enrolment
Disease-Free Survival (DFS)
Time Frame: 2 years from enrolment
DFS is defined as the probability of being alive free of disease at any point in time. Thus, death or disease relapse are treated as events (1). Patients alive and free of disease at their last follow-up are censored. The statistical methods for the analysis of DFS are the same as for OS (Kaplan-Meier curve, Log-Rank Test and survival models).
2 years from enrolment
Relapse Incidence (RI)
Time Frame: 2 years from enrolment
RI is defined as the probability of having had a relapse before time t. Death without experiencing a relapse is a competing event. The correct method of analysis is therefore the estimation of the Cumulative Incidence curve, comparable by the Gray Test and, for the multivariate analysis, the application of the proportional hazard model for the sub-distribution of competing risks, by Fine and Gray. In studying relapse, sometimes the interest is not only in the estimation of the cumulative incidence curve, but also in the estimation of the hazard ratios for comparing groups of patients. It is therefore common to apply also a survival (Cox or parametric) model considering relapse as an event and death without relapse as a censoring (the response time is given by the minimum between time to relapse and time to death without relapse; as usual, a patient who is alive and free of relapse is also censored).
2 years from enrolment
Non-Relapse Mortality (NRM)
Time Frame: 2 years from enrolment
It is defined as the probability of dying without previous occurrence of a relapse, which is a competing event. The same indications as for the analysis of RI apply.
2 years from enrolment
Progression-Free Survival (PFS)
Time Frame: 2 years from enrolment
It is defined as the probability of being alive with no indication of disease progression (relapse is considered as progression for patients in CR). It is analyzed by KaplanMeier curve, Log-Rank Test and parametric or non-parametric survival models.
2 years from enrolment

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Haematopoietic Recovery
Time Frame: participants will be followed for the duration of hospital stay, an expected average of 30 days

The day of engraftment is defined as the first day of 3 consecutive days with a persistent blood cell count above a predefined level:

WBC 1 x 109/l PMN 0.5 x 109/l Platelets 50 x109 /l or 20x 10 9 /l Death without recovery is a competing event, while no engraftment at the last followup is to be considered as a censored observation. Relapse or disease progression could be considered (depending on the disease being studied) as further competing events: this must be discussed with the responsible physician.
participants will be followed for the duration of hospital stay, an expected average of 30 days
Acute Graft-versus-Host Disease (aGvHD)
Time Frame: from date of transplant to until the date of first event of aCGVD assessed up to 100 days post transplant
The available information in the EBMT data regard the date of onset and the maximum grade of aGvHD. It is therefore possible to estimate the probability of aGvHD in a competing risks setting (death is a competing event; whether relapse/progression is a competing event must be discussed with the physician). By definition, patients alive (relapse/progression-free) at day 100 without having experienced aGvHD are censored. If the dates of onset are missing for the majority of patients, the analysis can focus only on the occurrence of aGvHD, which is analyzed by a logistic regression model. This method would however be incorrect if there is a (non negligible) percentage of censored observations or if competing events occurred before day 100.
from date of transplant to until the date of first event of aCGVD assessed up to 100 days post transplant
Chronic Graft-versus-Host Disease (cGvHD)
Time Frame: from day +100 post transplant to until the date of first event to cGVHD assessed up to 2 years post enrolment
When possible, if information on the date of 1°occurrence of cGvHD is available, it should be analyzed as a time-to-event outcome, being death (and possibly relapse/progression) the competing event; data are censored for patients alive (relapse/progression-free) without episodes of cGvHD at last follow-up. Since cGvHD is defined only for patients surviving at least 100 days, the survival model should consider a left truncation at 100 days; alternatively, the time of occurrence of cGvHD must be computed from 100 days. If information on the timing of cGvHD is not available, the outcome considered is the occurrence, and the statistical model to be used is the logistic regression. Only patients surviving at least 100 days are considered to be at risk of developing cGvHD, therefore the analysis must be restricted to these patients. This analysis is of course not satisfactory because it does not take into account the occurrence of death and censoring.
from day +100 post transplant to until the date of first event to cGVHD assessed up to 2 years post enrolment

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Gruppo Italiano Trapianto di Midollo Osseo

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

July 1, 2013

Primary Completion (Actual)

June 30, 2017

Study Completion (Actual)

June 30, 2017

Study Registration Dates

First Submitted

March 14, 2013

First Submitted That Met QC Criteria

March 16, 2013

First Posted (Estimate)

March 20, 2013

Study Record Updates

Last Update Posted (Estimate)

March 10, 2023

Last Update Submitted That Met QC Criteria

March 9, 2023

Last Verified

March 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2012-004008-37 Gandalf-01

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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