- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT03807479
Study in Patients With Chronic Leukemia (PONS)
Phase 2 Clinical Trial With Ponatinib as a Second Line Therapy for Patients With Chronic Myeloid Leukemia in Chronic Phase Resistant or Intolerant to Prior First Line Tyrosine Kinase Inhibitor Treatment
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
Despite significant progress in the treatment of patients with chronic phase CML, there is still need to further optimize therapy to reach the goal of disease eradication for almost all patients. In case of imatinib failure, dasatinib and nilotinib are effective treatment options after an individualized treatment selection. Although MMR rates of around 30% after 2 years of therapy are a significant achievement, options that may improve response rates in depth are still desirable. Ponatinib is a third generation TKI with very high anti-clonal activity in all CML phases. Moreover, it also eradicates most of the known and problematic mutations and only very few (compound) mutations may induce ponatinib-resistance.
Based on its favourable target spectrum, it is expected that Ponatinib may be more effective than 2nd line dasatinib or nilotinib in achieving early (i.e., at 6 months) cytogenetic and molecular responses in patients after inappropriate response to imatinib, and more effective as 2nd line treatment after failure of initial treatment with dasatinib or nilotinib than a cross-over between the 2nd generation TKIs. The basic hypothesis underlying therapeutic programs in CML is to be able to achieve meaningful and long-lasting suppression of the Philadelphia chromosome and breakpoint cluster region-abelson fusion gen (BCR-ABL). Complete cytogenetic responses have been associated with improved survival in CML, while major molecular responses are associated with improved event-free survival.
Study Type
Enrollment (Actual)
Phase
- Phase 2
Contacts and Locations
Study Locations
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Aachen, Germany, 52074
- University Hospital RWTH Aachen,Clinic for Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Medical Department IV
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Berlin, Germany, 13353
- Charité University Medicine Berlin - Medical Clinic, Department of Hematology, Oncology and Tumor Immunology
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Essen, Germany, 45122
- University Hospital Essen gGmbH, Westdeutsches Tumorzentrum; Internal Medicine (Tumor Research)
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Greifswald, Germany, 17475
- University Medicine Greifswald, Clinic and Policlinic - Internal Medicine C - Hematology and Oncology
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Hamburg, Germany, 20099
- Asklepios Clinic St. Georg - Department of Oncology, Section Hematology
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Mannheim, Germany, 68167
- University Hospital Mannheim GmbH, III. Medical Clinic for Hematology and Oncology
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Marburg, Germany, 35043
- Clinic for Hematologie
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Minden, Germany, 32429
- UKRUB University Hospital of Ruhr-University Bochum, Clinic for Hematology and Oncology
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Ulm, Germany, 89081
- University Hospital Ulm - Department for internal medicine III
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Saxony-Anhalt
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Halle (Saale), Saxony-Anhalt, Germany, 06097
- University Hospital
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-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Description
Inclusion Criteria:
- Male or female patients ≥18 years old
- Diagnosis of Ph-positive (by cytogenetics) or BCR-ABL-positive (by PCR) CP-CML
Patients should have demonstrated to have
a failure of a prior 1st line TKI treatment with either imatinib, dasatinib or nilotinib. Failure is defined as per European LeukemiaNet (ELN) recommendations:
- Less than Complete Hematologic Response (CHR) and/or Ph+ > 95% at or beyond 3 months
- No cytogenetic response (Ph+>35%) and/or Abelson murine leukemia viral oncogene homolog 1 (BCR-ABL1) >10% at or beyond 6 months
- BCR-ABL (on international scale) >1% and/or PH+ >0%
- Less than MMR at or beyond 18 months
- Loss of response or development of mutations or other clonal chromosomal abnormalities at any time during the first line TKI treatment
- or intolerance to prior TKI treatment defined as grade 3 or 4 toxicity, or persistent grade 2 toxicity despite optimal management including dose adjustment, or in a patient where dose reductions are considered to be not in the patient's best interest to obtain an adequate response. Intolerant patients should not have achieved or have lost major molecular response at the time of enrollment
- Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
Exclusion Criteria:
- Any 1st line anti-CML treatment other than TKI (apart from therapy with hydroxyurea)
- Any 2nd line therapy with a tyrosine kinase inhibitor (>1 European Medicines Agency (EMA) approved TKI for CML, or any investigational non EMA-approved TKI)
- Concurrent participation in any other clinical trial involving another investigational drug within 4 weeks prior to enrollment and throughout participation in PONS-Study
- New York Heart Association (NYHA) cardiac class 3-4 heart disease
- Cardiac Symptoms within the past 12 months prior recruitment
Study Plan
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: Ponatinib
Patients in this treatment arm receive Ponatinib: starting dose 30 mg once-daily.
Doses may be increased in case of inappropriate response and reduced to manage drug-related adverse events (AEs) and may be re-escalated once events resolve.
|
2 film-coated tablets à 15mg for oral administration on a daily basis
Other Names:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Major Molecular Response (MMR) of treatment
Time Frame: by 12 moths
|
To estimate the proportion of CP-CML patients with tyrosine kinase inhibitor (TKI)-resistance or intolerance to first line therapy with TKI, attaining MMR by 12 months of treatment with second line Ponatinib therapy.
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by 12 moths
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Time to toxicity
Time Frame: up to 24 months
|
To evaluate the toxicity profile of ponatinib in patients with CML in chronic phase after one TKI failure toxicities will be followed up at each visit during the treatment phase and will be assessed using CTCAE v.5.0.
Type of toxicity (hematologic or non-hematologic) along with the grading will be followed up on.
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up to 24 months
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Time to response
Time Frame: at 3, 6, 9, 12, 18 and 24 months
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To estimate the time to CCyR, MMR, MCyR and MR4 for patients treated with Ponatinib as second line therapy for CP-CML (chronic phase-chronic myelogenous leukemia).
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at 3, 6, 9, 12, 18 and 24 months
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Durations of response
Time Frame: at 3, 6, 9, 12, 18 and 24 month
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To evaluate the duration of hematologic, cytogenetic and molecular response to Ponatinib after one TKI failure.
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at 3, 6, 9, 12, 18 and 24 month
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Occurrence of BCR-ABL-mutations
Time Frame: at 3, 6, 9, 12, 18 and 24 months
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To evaluate the occurrence of BCR-ABL-mutations in patients with failure of Ponatinib 2nd line therapy.
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at 3, 6, 9, 12, 18 and 24 months
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Time to progression
Time Frame: at 3, 6, 9, 12, 18 and 24 months
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To define the time to progression for patients with CML in chronic phase treated with Ponatinib after one TKI failure.
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at 3, 6, 9, 12, 18 and 24 months
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Time to overall survival
Time Frame: at 3, 6, 9, 12, 18 and 24 month
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To define the time to overall survival for patients with CML in chronic phase treated with Ponatinib after one TKI failure.
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at 3, 6, 9, 12, 18 and 24 month
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Collaborators and Investigators
Sponsor
Collaborators
Investigators
- Principal Investigator: Philipp le Coutre, Prof., Charité Berlin - Department of Hematology, Oncology and Tumor Immunology
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Pathologic Processes
- Neoplasms by Histologic Type
- Neoplasms
- Disease Attributes
- Bone Marrow Diseases
- Hematologic Diseases
- Myeloproliferative Disorders
- Chronic Disease
- Leukemia
- Leukemia, Myeloid
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive
- Leukemia, Myeloid, Chronic-Phase
- Molecular Mechanisms of Pharmacological Action
- Enzyme Inhibitors
- Antineoplastic Agents
- Protein Kinase Inhibitors
- Ponatinib
Other Study ID Numbers
- PONS_11272
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
product manufactured in and exported from the U.S.
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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