Study in Patients With Chronic Leukemia, Where Previous Therapy Failed, and Who Will be Treated With Ponatinib as Second Line Therapy (PONS)

• ClinicalTrials.gov Identifier: NCT03807479
• Recruitment Status: Active, not recruiting
• First Posted: January 17, 2019
• Last Update Posted: September 10, 2022
• Sponsor: GWT-TUD GmbH
• Collaborator: Incyte Biosciences International Sàrl
• Information provided by (Responsible Party): GWT-TUD GmbH

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.

Condition or disease	Intervention/treatment	Phase
Leukemia, Myeloid, Chronic-Phase	Drug: Ponatinib	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 18 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: December 11, 2018
• Estimated Primary Completion Date: July 31, 2024
• Estimated Study Completion Date: August 31, 2024

Arms and Interventions

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.	Drug: Ponatinib; 2 film-coated tablets à 15mg for oral administration on a daily basis; Other Name: Iclusig

Outcome Measures

Primary Outcome Measures :

1. 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.

Secondary Outcome Measures :

1. 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.
2. Time to response [ Time Frame: at 3, 6, 9, 12, 18 and 24 months ]
   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).
3. Durations of response [ Time Frame: at 3, 6, 9, 12, 18 and 24 month ]
   To evaluate the duration of hematologic, cytogenetic and molecular response to Ponatinib after one TKI failure.
4. Occurrence of BCR-ABL-mutations [ Time Frame: at 3, 6, 9, 12, 18 and 24 months ]
   To evaluate the occurrence of BCR-ABL-mutations in patients with failure of Ponatinib 2nd line therapy.
5. Time to progression [ Time Frame: at 3, 6, 9, 12, 18 and 24 months ]
   To define the time to progression for patients with CML in chronic phase treated with Ponatinib after one TKI failure.
6. Time to overall survival [ Time Frame: at 3, 6, 9, 12, 18 and 24 month ]
   To define the time to overall survival for patients with CML in chronic phase treated with Ponatinib after one TKI failure.

Eligibility Criteria

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

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

Contacts and Locations

Locations

Germany

University Hospital

Halle (Saale), Saxony-Anhalt, Germany, 06097

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

Aachen, Germany, 52074

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

Berlin, Germany, 13353

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

Essen, Germany, 45122

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

Greifswald, Germany, 17475

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

Hamburg, Germany, 20099

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

Mannheim, Germany, 68167

University Hospital Giessen and Marburg GmbH, Institution department Clinic for Hematology, Oncology and Immunology

Marburg, Germany, 35043

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

Minden, Germany, 32429

University Hospital Ulm - Department for internal medicine III

Ulm, Germany, 89081

Sponsors and Collaborators

GWT-TUD GmbH

Incyte Biosciences International Sàrl

Investigators

• Principal Investigator: Philipp le Coutre, Prof.; Charité Berlin - Department of Hematology, Oncology and Tumor Immunology

More Information

• Responsible Party: GWT-TUD GmbH
• ClinicalTrials.gov Identifier: NCT03807479
• Other Study ID Numbers: PONS_11272
• First Posted: January 17, 2019
• Last Update Posted: September 10, 2022
• Last Verified: September 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by GWT-TUD GmbH:

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

Additional relevant MeSH terms:

Leukemia; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Chronic-Phase; Neoplasms by Histologic Type; Neoplasms; Myeloproliferative Disorders; Bone Marrow Diseases; Hematologic Diseases; Ponatinib; Antineoplastic Agents; Protein Kinase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action