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

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

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.

Study Overview

• Status: Completed
• Conditions: Chronic Myeloid Leukemia
• Intervention / Treatment: Drug: Imatinib mesylate

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 Type: Interventional
• Enrollment (Actual): 112
• Phase: Phase 4

Contacts and Locations

Study Locations

• Canada
  • Quebec
    • Montréal, Quebec, Canada, H3T 1E2
      • McGill University - Jewish General Hospital Division of Hematology and Department of Oncology
• Germany
  • Berlin, Germany, 13353
    • Charité University of Berlin - Clinic of Medicine - Hematology and Oncology
• Israel
  • Tel Hashomer, Israel, 52621
    • Chaim Sheba Medical Center - Division of Hematology, BMT and CBB
• Italy
  • Genova, Italy, 16132
    • IRCCS A.O.U. San Martino
  • Italy/Catania
    • Catania, Italy/Catania, Italy, 95124
      • Azienda Ospedaliero-Universitaria "Policlinico-Vittorio Emanuele"
  • Italy/Firenze
    • Firenze, Italy/Firenze, Italy, 50134
      • Università di Firenze Azienda Ospedaliera - Universitaria Careggi
  • Italy/MB
    • Monza, Italy/MB, Italy, 20052
      • Azienda Ospedaliera San Gerardo di Monza
  • Italy/Milano
    • Milano, Italy/Milano, Italy, 20162
      • Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico UOC di Ematologia
  • Italy/Pavia
    • Pavia, Italy/Pavia, Italy, 27100
      • IRCCS Policlinico San Matteo Pavia - Istituto di Ematologia
  • Italy/Reggio Calabria
    • Reggio Calabria, Italy/Reggio Calabria, Italy, 89124
      • A.O. Bianchi-Melacrino-Morelli U.O. Ematologia
  • Italy/Rome
    • Rome, Italy/Rome, Italy, 00142
      • Universita di Tor Vergata Ospedale S. Eugenio
  • Italy/Vicenza
    • Vicenza, Italy/Vicenza, Italy, 36100
      • Ospedale S. Bortolo (USSL 6)
  • MI
    • Milano, MI, Italy, 20162
      • Ospedale Niguarda Ca' Granda - U.O. Ematologia
• Spain
  • Zaragoza, Spain
    • Hospital Universitario Miguel Servet - Hematologia

Participation Criteria

Eligibility Criteria

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

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

1

Arms and Interventions

Participant Group / 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 Names: Glivec, Gleevec

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Negative Predicted Value Ratio (rNPV) of dPCR over Q-RT-PCR	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	At 36 months.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of molecular and cytogenetic relapse	Rate of molecular and cytogenetic relapse after discontinuation of imatinib treatment out of total number of patients enrolled	At 36 months
Rate of dPCR positive patients	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.	At 36 months
Rate of dPCR negative patients	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.	At 36 months
Rate of patients who are maintaining dPCR negativity for 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.	At 36 months
Time to molecular relapse	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.	At 36 months
Overall Survival	Overall Survival	At the end of the study
Quality of Life Assessment	Quality of Life, as measured by the Global Health Status\QOL and other subscales scores of EORTC-QLQ-C30 questionnaire	At 36 months
Rate of patients progressing or developing resistance	Rate of patients progressing or developing resistance after imatinib resumption out of total number of patients enrolled	At 36 months

Collaborators and Investigators

• Sponsor: 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: 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 Miguel Servet; Principal Investigator: Micaela Bergamaschi, MD, IRCCS A.O.U. San Martino

Study record dates

Study Major Dates

• Study Start: November 9, 2011
• Primary Completion (Actual): November 28, 2018
• Study Completion (Actual): November 28, 2018

Study Registration Dates

• First Submitted: April 13, 2012
• First Submitted That Met QC Criteria: April 13, 2012
• First Posted (Estimate): April 16, 2012

Study Record Updates

• Last Update Posted (Actual): December 3, 2019
• Last Update Submitted That Met QC Criteria: November 28, 2019
• Last Verified: November 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Bone Marrow Diseases; Hematologic Diseases; Myeloproliferative Disorders; Leukemia; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Imatinib Mesylate
• Other Study ID Numbers: ISAV; 2011-002749-37 (EudraCT Number)