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Study in Patients With Chronic Leukemia (PONS)

Primary Purpose

Leukemia, Myeloid, Chronic-Phase

Status

Terminated

Phase

Phase 2

Locations

Germany

Study Type

Interventional

Intervention

Ponatinib

About this trial

This is an interventional treatment trial for Leukemia, Myeloid, Chronic-Phase focused on measuring CP-CML, CML in chronic phase, Chronic Myelogenous Leukemia, Leukemia, Myelogenous, Chronic, BCR-ABL Positive

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

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

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Ponatinib

Arm Description

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.

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).

Durations of response

To evaluate the duration of hematologic, cytogenetic and molecular response to Ponatinib after one TKI failure.

Occurrence of BCR-ABL-mutations

To evaluate the occurrence of BCR-ABL-mutations in patients with failure of Ponatinib 2nd line therapy.

Time to progression

To define the time to progression for patients with CML in chronic phase treated with Ponatinib after one TKI failure.

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.

Full Information

NCT ID

NCT03807479

First Posted

November 7, 2018

Last Updated

September 12, 2023

Sponsor

GWT-TUD GmbH

Collaborators

Incyte Biosciences International Sàrl

1. Study Identification

Unique Protocol Identification Number

NCT03807479

Brief Title

Study in Patients With Chronic Leukemia

Acronym

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

Study Type

Interventional

2. Study Status

Record Verification Date

September 2022

Overall Recruitment Status

Terminated

Why Stopped

less recruting

Study Start Date

December 11, 2018 (Actual)

Primary Completion Date

February 28, 2023 (Actual)

Study Completion Date

August 31, 2023 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

GWT-TUD GmbH

Collaborators

Incyte Biosciences International Sàrl

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Leukemia, Myeloid, Chronic-Phase

Keywords

CP-CML, CML in chronic phase, Chronic Myelogenous Leukemia, Leukemia, Myelogenous, Chronic, BCR-ABL Positive

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

18 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Ponatinib

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Ponatinib

Other Intervention Name(s)

Iclusig

Intervention Description

2 film-coated tablets à 15mg for oral administration on a daily basis

Primary Outcome Measure Information:

Title

Major Molecular Response (MMR) of treatment

Description

Time Frame

by 12 moths

Secondary Outcome Measure Information:

Title

Time to toxicity

Description

Time Frame

up to 24 months

Title

Time to response

Description

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).

Time Frame

at 3, 6, 9, 12, 18 and 24 months

Title

Durations of response

Description

To evaluate the duration of hematologic, cytogenetic and molecular response to Ponatinib after one TKI failure.

Time Frame

at 3, 6, 9, 12, 18 and 24 month

Title

Occurrence of BCR-ABL-mutations

Description

To evaluate the occurrence of BCR-ABL-mutations in patients with failure of Ponatinib 2nd line therapy.

Time Frame

at 3, 6, 9, 12, 18 and 24 months

Title

Time to progression

Description

To define the time to progression for patients with CML in chronic phase treated with Ponatinib after one TKI failure.

Time Frame

at 3, 6, 9, 12, 18 and 24 months

Title

Time to overall survival

Description

To define the time to overall survival for patients with CML in chronic phase treated with Ponatinib after one TKI failure.

Time Frame

at 3, 6, 9, 12, 18 and 24 month

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Philipp le Coutre, Prof.

Organizational Affiliation

Charité Berlin - Department of Hematology, Oncology and Tumor Immunology

Official's Role

Principal Investigator

Facility Information:

Facility Name

University Hospital

City

Halle (Saale)

State/Province

Saxony-Anhalt

ZIP/Postal Code

06097

Country

Germany

Facility Name

University Hospital RWTH Aachen,Clinic for Hematology, Oncology, Hemostaseology and Stem Cell Transplantation, Medical Department IV

City

Aachen

ZIP/Postal Code

52074

Country

Germany

Facility Name

Charité University Medicine Berlin - Medical Clinic, Department of Hematology, Oncology and Tumor Immunology

City

Berlin

ZIP/Postal Code

13353

Country

Germany

Facility Name

University Hospital Essen gGmbH, Westdeutsches Tumorzentrum; Internal Medicine (Tumor Research)

City

Essen

ZIP/Postal Code

45122

Country

Germany

Facility Name

University Medicine Greifswald, Clinic and Policlinic - Internal Medicine C - Hematology and Oncology

City

Greifswald

ZIP/Postal Code

17475

Country

Germany

Facility Name

Asklepios Clinic St. Georg - Department of Oncology, Section Hematology

City

Hamburg

ZIP/Postal Code

20099

Country

Germany

Facility Name

University Hospital Mannheim GmbH, III. Medical Clinic for Hematology and Oncology

City

Mannheim

ZIP/Postal Code

68167

Country

Germany

Facility Name

Clinic for Hematologie

City

Marburg

ZIP/Postal Code

35043

Country

Germany

Facility Name

UKRUB University Hospital of Ruhr-University Bochum, Clinic for Hematology and Oncology

City

Minden

ZIP/Postal Code

32429

Country

Germany

Facility Name

University Hospital Ulm - Department for internal medicine III

City

Ulm

ZIP/Postal Code

89081

Country

Germany

12. IPD Sharing Statement

Plan to Share IPD

Learn more about this trial

Study in Patients With Chronic Leukemia

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