Clinical trial NCT03807479: Study in Patients With Chronic Leukemia
Official title: 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 type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Leukemia, Myeloid, Chronic-Phase
Keywords: CP-CML
CML in chronic phase
Chronic Myelogenous Leukemia
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Lead sponsor: GWT-TUD GmbH
Sponsor class: OTHER
Collaborators: name: Incyte Biosciences International Sàrl
First posted: 2019-01-17
Enrollment: 18
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This study will include patients suffering from chronic myeloid leukemia (CP-CML), who were treated with tyrosine kinase inhibitor (TKI, a substance that blocks the action of enzymes) in a previous therapy but which has not been effective. Patients will be treated with Ponatinib 30 mg in in this study. The aim of the study is to evaluate the safety and efficacy of Ponatinib as a second line treatment in patients failing or not tolerating first line therapy with any other approved TKIs. It is expected that Ponatinib, due to its efficacy, may be more effective as second line therapy than other approved TKIs and lead to improved overall survival. The effect will be determined by the molecular response rate (MMR) as the primary objective after 12 months of treatment. The safety of the drug will be evaluated on the basis if routine medical and laboratory examinations.

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.

Eligibility criteria: Inclusion Criteria:

1. Male or female patients ≥18 years old
2. Diagnosis of Ph-positive (by cytogenetics) or BCR-ABL-positive (by PCR) CP-CML
3. 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
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2

Exclusion Criteria:

1. Any 1st line anti-CML treatment other than TKI (apart from therapy with hydroxyurea)
2. 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)
3. Concurrent participation in any other clinical trial involving another investigational drug within 4 weeks prior to enrollment and throughout participation in PONS-Study
4. New York Heart Association (NYHA) cardiac class 3-4 heart disease
5. Cardiac Symptoms within the past 12 months prior recruitment

Primary outcomes:
measure: Major Molecular Response (MMR) of treatment
timeFrame: by 12 moths
Secondary outcomes:
measure: Time to toxicity
timeFrame: up to 24 months
measure: Time to response
timeFrame: at 3, 6, 9, 12, 18 and 24 months
measure: Durations of response
timeFrame: at 3, 6, 9, 12, 18 and 24 month
measure: Occurrence of BCR-ABL-mutations
timeFrame: at 3, 6, 9, 12, 18 and 24 months
measure: Time to progression
timeFrame: at 3, 6, 9, 12, 18 and 24 months
measure: Time to overall survival
timeFrame: at 3, 6, 9, 12, 18 and 24 month
Other outcomes:
Locations:
city: Halle (Saale)
country: Germany
facility: University Hospital
state: Saxony-Anhalt
city: Aachen
country: Germany
facility: University Hospital RWTH Aachen,Clinic for Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Medical Department IV
city: Berlin
country: Germany
facility: Charité University Medicine Berlin - Medical Clinic, Department of Hematology, Oncology and Tumor Immunology
city: Essen
country: Germany
facility: University Hospital Essen gGmbH, Westdeutsches Tumorzentrum; Internal Medicine (Tumor Research)
city: Greifswald
country: Germany
facility: University Medicine Greifswald, Clinic and Policlinic - Internal Medicine C - Hematology and Oncology
city: Hamburg
country: Germany
facility: Asklepios Clinic St. Georg - Department of Oncology, Section Hematology
city: Mannheim
country: Germany
facility: University Hospital Mannheim GmbH, III. Medical Clinic for Hematology and Oncology
city: Marburg
country: Germany
facility: Clinic for Hematologie
city: Minden
country: Germany
facility: UKRUB University Hospital of Ruhr-University Bochum, Clinic for Hematology and Oncology
city: Ulm
country: Germany
facility: University Hospital Ulm - Department for internal medicine III
Study officials:
affiliation: Charité Berlin - Department of Hematology, Oncology and Tumor Immunology
name: Philipp le Coutre, Prof.
role: PRINCIPAL_INVESTIGATOR
References: