Study in Patients With Chronic Leukemia

Leukemia, Myeloid, Chronic-Phase Clinical Trial

— PONS  

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03807479
• Other study ID #: PONS_11272
• Status: Terminated
• Phase: Phase 2
• Start date: December 11, 2018
• Est. completion date: August 31, 2023

Study information

• Verified date: September 2022
• Source: GWT-TUD GmbH
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 18
• Est. completion date: August 31, 2023
• Est. primary completion date: February 28, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Leukemia
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive
• Leukemia, Myeloid
• Leukemia, Myeloid, Chronic-Phase

Intervention

Drug:
• Ponatinib
2 film-coated tablets à 15mg for oral administration on a daily basis

Locations

Country	Name	City	State
Germany	University Hospital RWTH Aachen,Clinic for Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Medical Department IV	Aachen
Germany	Charité University Medicine Berlin - Medical Clinic, Department of Hematology, Oncology and Tumor Immunology	Berlin
Germany	University Hospital Essen gGmbH, Westdeutsches Tumorzentrum; Internal Medicine (Tumor Research)	Essen
Germany	University Medicine Greifswald, Clinic and Policlinic - Internal Medicine C - Hematology and Oncology	Greifswald
Germany	University Hospital	Halle (Saale)	Saxony-Anhalt
Germany	Asklepios Clinic St. Georg - Department of Oncology, Section Hematology	Hamburg
Germany	University Hospital Mannheim GmbH, III. Medical Clinic for Hematology and Oncology	Mannheim
Germany	Clinic for Hematologie	Marburg
Germany	UKRUB University Hospital of Ruhr-University Bochum, Clinic for Hematology and Oncology	Minden
Germany	University Hospital Ulm - Department for internal medicine III	Ulm

Sponsors (2)

Lead Sponsor	Collaborator
GWT-TUD GmbH	Incyte Biosciences International Sàrl

Country where clinical trial is conducted

Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Major Molecular Response (MMR) of treatment	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.	by 12 moths
Secondary	Time to toxicity	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.	up to 24 months
Secondary	Time to response	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).	at 3, 6, 9, 12, 18 and 24 months
Secondary	Durations of response	To evaluate the duration of hematologic, cytogenetic and molecular response to Ponatinib after one TKI failure.	at 3, 6, 9, 12, 18 and 24 month
Secondary	Occurrence of BCR-ABL-mutations	To evaluate the occurrence of BCR-ABL-mutations in patients with failure of Ponatinib 2nd line therapy.	at 3, 6, 9, 12, 18 and 24 months
Secondary	Time to progression	To define the time to progression for patients with CML in chronic phase treated with Ponatinib after one TKI failure.	at 3, 6, 9, 12, 18 and 24 months
Secondary	Time to overall survival	To define the time to overall survival for patients with CML in chronic phase treated with Ponatinib after one TKI failure.	at 3, 6, 9, 12, 18 and 24 month