Validation of Digital-PCR Analysis Through Programmed Imatinib Interruption in PCR Negative CML Patients (ISAV)

• ClinicalTrials.gov Identifier: NCT01578213
• Recruitment Status: Completed
• First Posted: April 16, 2012
• Last Update Posted: December 3, 2019
• Sponsor: University of Milano Bicocca
• Information provided by (Responsible Party): University of Milano Bicocca

Study Description

Brief Summary:

The purpose of this study is to assess the capability of the dPCR technique to predict the absence of disease relapses after imatinib discontinuation in CML patients with negative Q-RT-PCR results for longer than 18 months.

Condition or disease	Intervention/treatment	Phase
Chronic Myeloid Leukemia	Drug: Imatinib mesylate	Phase 4

Detailed Description:

This study will recruit approximately 100 CML patients under imatinib therapy in complete molecular remission with a history of at least 18 months of consecutive negative standard Q-RT-PCR as performed in their own centers. After signing the informed consent form (ICF), the patients will be tested for dPCR and will discontinue imatinib therapy. Then they will be monitored by standard Q-RT-PCR to assess the maintenance of the molecular remission; collection of data will be prospective as each center will collect the data for 36 months. At the end of this period, a peripheral blood sample for dPCR analysis will be obtained from those patients who will still have undetectable BCR-ABL transcripts by Q-RT-PCR to verify CML eradication. The maintenance of molecular remission by Q-RT-PCR and the survival will be monitored every six months during an additional follow-up of 24 months. Patients found to be positive to BCR-ABL transcripts by standard Q-RTPCR will repeat the test every 2 to 4 weeks until the loss of molecular remission, defined as two consecutive BCR-ABL positive tests with at least one with BCR-ABL/BCR value above 0.1%, or until the end of the study, whichever come first.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 112 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Other
• Official Title: Validation of Digital-PCR Analysis Through Programmed Imatinib Interruption in PCR Negative CML Patients (ISAV)
• Study Start Date: November 9, 2011
• Actual Primary Completion Date: November 28, 2018
• Actual Study Completion Date: November 28, 2018

Arms and Interventions

Arm	Intervention/treatment
Experimental: Imatinib	Drug: Imatinib mesylate; Capsules, hard 50 or 100 mg/Film-coated Tablets 100 or 400 mg; Total dosage per day: 800 mg; Oral use; Other Name: Glivec, Gleevec

Outcome Measures

Primary Outcome Measures :

1. The Negative Predicted Value Ratio (rNPV) of dPCR over Q-RT-PCR [ Time Frame: At 36 months. ]
   The capability of the dPCR method to predict relapse-free patients relative to the standard method. NPV of each method will be computed as the number of patients who are negative according to either method at the time of imatinib discontinuation and remain relapse-free 36 months later over the total of negative patients according to either method, respectively

Secondary Outcome Measures :

1. Rate of molecular and cytogenetic relapse [ Time Frame: At 36 months ]
   Rate of molecular and cytogenetic relapse after discontinuation of imatinib treatment out of total number of patients enrolled
2. Rate of dPCR positive patients [ Time Frame: At 36 months ]
   Rate of patients who are dPCR positive before discontinuation of imatinib and who do not relapse within the following 36 months (false positive) out of the total number of relapse-free patients at month 36.
3. Rate of dPCR negative patients [ Time Frame: At 36 months ]
   Rate of patients who are dPCR negative before discontinuation of imatinib and who relapse (false negative) out of the total number of patients relapsing within the following 36 months.
4. Rate of patients who are maintaining dPCR negativity for 36 months [ Time Frame: At 36 months ]
   Rate of patients who are maintaining dPCR negativity for 36 months over the patients who are Q-RT-PCR negative at the end of the interval.
5. Time to molecular relapse [ Time Frame: At 36 months ]
   Time to molecular relapse, both from the first PCR-negative and from the discontinuation of imatinib to the time of loss of molecular response, respectively.
6. Overall Survival [ Time Frame: At the end of the study ]
   Overall Survival
7. Quality of Life Assessment [ Time Frame: At 36 months ]
   Quality of Life, as measured by the Global Health Status\QOL and other subscales scores of EORTC-QLQ-C30 questionnaire
8. Rate of patients progressing or developing resistance [ Time Frame: At 36 months ]
   Rate of patients progressing or developing resistance after imatinib resumption out of total number of patients enrolled

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Signed and dated IRB/IEC-approved Informed Consent
2. Age>=18 years
3. Male or female patients with CML diagnosed in chronic or accelerated phase and who have been treated for more than 2 consecutive years with imatinib therapy
4. Sustained Complete Molecular Response (as defined by the treating center) for at least 18 months with imatinib treatment
5. A minimum of 3 CMR determined by Q-RT-PCR analysis to support disease status, with the list one performed within 3 calendar months prior to enrollment date
6. Willingness and ability to comply with scheduled visits laboratory tests and other study procedures

Exclusion Criteria:

1. Allogenic hematopoietic stem cell transplantation
2. Known active infections including human immunodeficiency virus (HIV) positivity
3. Current enrollment another clinical trial
4. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration or may interfere with the interpretation of study results

Contacts and Locations

Locations

Canada, Quebec

McGill University - Jewish General Hospital Division of Hematology and Department of Oncology

Montréal, Quebec, Canada, H3T 1E2

Germany

Charité University of Berlin - Clinic of Medicine - Hematology and Oncology

Berlin, Germany, 13353

Israel

Chaim Sheba Medical Center - Division of Hematology, BMT and CBB

Tel Hashomer, Israel, 52621

Italy

Azienda Ospedaliero-Universitaria "Policlinico-Vittorio Emanuele"

Catania, Italy/Catania, Italy, 95124

Università di Firenze Azienda Ospedaliera - Universitaria Careggi

Firenze, Italy/Firenze, Italy, 50134

Azienda Ospedaliera San Gerardo di Monza

Monza, Italy/MB, Italy, 20052

Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico UOC di Ematologia

Milano, Italy/Milano, Italy, 20162

IRCCS Policlinico San Matteo Pavia - Istituto di Ematologia

Pavia, Italy/Pavia, Italy, 27100

A.O. Bianchi-Melacrino-Morelli U.O. Ematologia

Reggio Calabria, Italy/Reggio Calabria, Italy, 89124

Universita di Tor Vergata Ospedale S. Eugenio

Rome, Italy/Rome, Italy, 00142

Ospedale S. Bortolo (USSL 6)

Vicenza, Italy/Vicenza, Italy, 36100

Ospedale Niguarda Ca' Granda - U.O. Ematologia

Milano, MI, Italy, 20162

IRCCS A.O.U. San Martino

Genova, Italy, 16132

Spain

Hospital Universitario Miguel Servet - Hematologia

Zaragoza, Spain

Sponsors and Collaborators

University of Milano Bicocca

Investigators

• Study Director: Carlo Gambacorti-Passerini, MD; Azienda Ospedaliera San Gerardo di Monza
• Principal Investigator: Eros Di Bona, MD; Ospedale S. Bortolo (USSL 6)
• Principal Investigator: Francesco Di Raimondo, MD; Azienda Ospedaliero-Universitaria "Policlinico - Vittorio Emanuele"
• Principal Investigator: Elisabetta Abruzzese, MD; Università di Tor Vergata Ospedale di S. Eugenio
• Principal Investigator: Luca Arcaini, MD; IRCCS Policlinico San Matteo Pavia
• Principal Investigator: Valeria Santini, MD; Università di Firenze Azienda Ospedaliera-Universitaria Careggi
• Principal Investigator: Bruno Martino, MD; A.O. Bianchi-Melacrino-Morelli
• Principal Investigator: Alessandra Iurlo, MD; Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico
• Principal Investigator: Arnon Nagler, MD; Chaim Sheba Medical Center
• Principal Investigator: Ester Pungolino, MD; Ospedale Niguarda Ca' Granda
• Principal Investigator: Philipp le Coutre, MD; Charité University of Berlin
• Principal Investigator: Sarit Assouline, MD; McGill University - Jewish General Hospital
• Principal Investigator: Onno Leeskma, MD; Onze Lieve Vrouwe Gasthuis
• Principal Investigator: Marcio Andrade, MD; Hospital Universitario Miguel Servet
• Principal Investigator: Micaela Bergamaschi, MD; IRCCS A.O.U. San Martino

More Information

• Responsible Party: University of Milano Bicocca
• ClinicalTrials.gov Identifier: NCT01578213
• Other Study ID Numbers: ISAV; 2011-002749-37 ( EudraCT Number )
• First Posted: April 16, 2012
• Last Update Posted: December 3, 2019
• Last Verified: November 2019

Additional relevant MeSH terms:

Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid; Leukemia; Neoplasms by Histologic Type; Neoplasms; Myeloproliferative Disorders; Bone Marrow Diseases; Hematologic Diseases; Imatinib Mesylate; Antineoplastic Agents; Protein Kinase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action