Consolidation Treatment With Ponatinib 15 mg on Treatment Free-Remission Rate in Patients With Chronic Myeloid Leukemia

NCT04043676 | Unknown Phase 2

• 2 other identifiers: PonaZero_study2017-004565-27
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 9

Brief Summary

Ponatinib has shown to induce deeper molecular responses compared with imatinib. Therefore, ponatinib treatment could increase the proportion of patients who could discontinue treatment successfully. This strategy that includes treatment change to a more powerful treatment before treatment discontinuation has not been evaluated in any of the previous clinical trials, and will be explored in the current study. In this framework, the purpose is to determine the rate of successful treatment-free remission (TFR) within the first 48 weeks following cessation of treatment in patients who achieved Molecular Response 4 (MR4) on imatinib and maintained MR4 on ponatinib after a switch from imatinib. Eligible patients have been previously treated with imatinib as unique tyrosine kinase inhibitor (at least 4 years) and have documented MR4 (at least 12 months) at the time of switch to ponatinib to study entry.

Conditions

Chronic Myeloid Leukemia

Keywords

Leukemia; BCR-ABL positive; Myeloide; Philadelphia-positive; Chronic

Outcome Measures

Primary Outcomes (1)

• Loss MR4

  Proportion of patients without confirmed loss of MR4 or loss of MMR (don't require confirmation) within 48 weeks following ponatinib therapy cessation.

  96 weeks (48 weeks ponatinib consolidation phase plus 48 weeks ponatinib treatment-free remission)

Study Arms (1)

Ponatinib Treatment

EXPERIMENTAL

Patients will be treated with 15 mg/day of ponatinib during 48 weeks. If a patient maintains MR4 throughout the 48 weeks, he/she will be eligible to start the ponatinib TFR phase. If a patient has confirmed loss of MR4 (two consecutive BCR-ABL \> 0.01% IS) or loss of MMR (no confirmation needed), he/she will not be eligible for the TFR phase. Instead, he/she will restart imatinib treatment.

Drug: Ponatinib

Interventions

Ponatinib DRUG

All patient will take 15 mg/day ponatinib oral during 48 weeks.

Ponatinib Treatment

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or female patients ≥ 18 years of age.
• ECOG performance status of 0, 1, or 2.
• Patient with diagnosis of BCR-ABL positive CML-CP.
• Patient has received a minimum of 4 years of imatinib treatment, as unique TKI therapy.
• Patient has achieved MR4 during at least 12 months with imatinib treatment, and determined by PCR lab assessment at screening.
• Adequate end organ function.
• Patients must have the following electrolyte values ≥ LLN limits or corrected to within normal limits with supplements prior to the first dose of study medication: Potassium, Magnesium, Total calcium (corrected for serum albumin).
• Patients must have normal marrow function
• Patients with preexisting, well-controlled, diabetes are not excluded.
• Have normal QTcF interval on screening ECG evaluation, defined as QTcF of ≤ 450 ms in males or ≤ 470 ms in females.
• Have a negative pregnancy test documented prior to enrollment
• Be willing and able to comply with scheduled visits and study procedures.
• Written informed consent obtained prior to any screening procedures.

You may not qualify if:

• Prior AP, BC or autologous or allogenic transplant.
• Patients with known atypical transcript.
• CML treatment resistant mutation(s).
• Are taking medications with a known risk of torsades de pointes (Appendix A)
• Patient ever attempted to permanently discontinue imatinib or ponatinib treatment.
• Severe and/or uncontrolled concurrent medical disease that in the opinion of the investigator could cause unacceptable safety risks.
• Have clinically significant, uncontrolled, or active cardiovascular disease.
• Have uncontrolled hypertension (diastolic blood pressure \> 90 mmHg; systolic \> 150 mmHg).
• Have a history of alcohol abuse.
• History of acute pancreatitis within 1 year prior to study entry or past medical history of chronic pancreatitis.
• Have malabsorption syndrome or other gastrointestinal illness that could affect oral absorption of study drug.
• Known presence of a significant congenital or acquired bleeding disorder unrelated to cancer.
• Have a history of another malignancy; the exception is if patients have been disease-free for at least 5 years.
• Have undergone surgery within 14 days prior to first dose of ponatinib.
• Treatment with other investigational within 4 weeks of Day 1.

Sponsors & Collaborators

• Fundación Teófilo Hernando, Spain: lead

Study Sites (9)

Hospital Trials i Pujol

Badalona, Barcelona, 08916, Spain

RECRUITING

Hospital Vall D'Hebron

Barcelona, 08035, Spain

RECRUITING

Hospital Universitario de Gran Canarias Dr. Negrin

Las Palmas de Gran Canaria, 35010, Spain

RECRUITING

Hospital Unversitario de la Princesa

Madrid, 28006, Spain

RECRUITING

Hospital Universitario Ramon y Cajal

Madrid, 28034, Spain

RECRUITING

Hospital Universitario Doce de Octubre

Madrid, 28041, Spain

RECRUITING

Hospital Regional de Malaga

Málaga, 29010, Spain

RECRUITING

Hospital Universitario de Salamanca

Salamanca, 37007, Spain

RECRUITING

Hospital Clinico Universitario de Valencia

Valencia, 46010, Spain

RECRUITING

Related Publications (9)

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  PMID: 11756187 RESULT

• Hochhaus A, Masszi T, Giles FJ, Radich JP, Ross DM, Gomez Casares MT, Hellmann A, Stentoft J, Conneally E, Garcia-Gutierrez V, Gattermann N, Wiktor-Jedrzejczak W, le Coutre PD, Martino B, Saussele S, Menssen HD, Deng W, Krunic N, Bedoucha V, Saglio G. Treatment-free remission following frontline nilotinib in patients with chronic myeloid leukemia in chronic phase: results from the ENESTfreedom study. Leukemia. 2017 Jul;31(7):1525-1531. doi: 10.1038/leu.2017.63. Epub 2017 Feb 20.

  PMID: 28218239 RESULT

• Imagawa J, Tanaka H, Okada M, Nakamae H, Hino M, Murai K, Ishida Y, Kumagai T, Sato S, Ohashi K, Sakamaki H, Wakita H, Uoshima N, Nakagawa Y, Minami Y, Ogasawara M, Takeoka T, Akasaka H, Utsumi T, Uike N, Sato T, Ando S, Usuki K, Morita S, Sakamoto J, Kimura S; DADI Trial Group. Discontinuation of dasatinib in patients with chronic myeloid leukaemia who have maintained deep molecular response for longer than 1 year (DADI trial): a multicentre phase 2 trial. Lancet Haematol. 2015 Dec;2(12):e528-35. doi: 10.1016/S2352-3026(15)00196-9. Epub 2015 Nov 10.

  PMID: 26686407 RESULT

• Mahon FX, Rea D, Guilhot J, Guilhot F, Huguet F, Nicolini F, Legros L, Charbonnier A, Guerci A, Varet B, Etienne G, Reiffers J, Rousselot P; Intergroupe Francais des Leucemies Myeloides Chroniques. Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: the prospective, multicentre Stop Imatinib (STIM) trial. Lancet Oncol. 2010 Nov;11(11):1029-35. doi: 10.1016/S1470-2045(10)70233-3. Epub 2010 Oct 19.

  PMID: 20965785 RESULT

• Mahon FX, Etienne G. Deep molecular response in chronic myeloid leukemia: the new goal of therapy? Clin Cancer Res. 2014 Jan 15;20(2):310-22. doi: 10.1158/1078-0432.CCR-13-1988. Epub 2013 Oct 28.

  PMID: 24166905 RESULT

• Mori S, Vagge E, le Coutre P, Abruzzese E, Martino B, Pungolino E, Elena C, Pierri I, Assouline S, D'Emilio A, Gozzini A, Giraldo P, Stagno F, Iurlo A, Luciani M, De Riso G, Redaelli S, Kim DW, Pirola A, Mezzatesta C, Petroccione A, Lodolo D'Oria A, Crivori P, Piazza R, Gambacorti-Passerini C. Age and dPCR can predict relapse in CML patients who discontinued imatinib: the ISAV study. Am J Hematol. 2015 Oct;90(10):910-4. doi: 10.1002/ajh.24120. Epub 2015 Sep 10.

  PMID: 26178642 RESULT

• Ross DM, Branford S, Seymour JF, Schwarer AP, Arthur C, Yeung DT, Dang P, Goyne JM, Slader C, Filshie RJ, Mills AK, Melo JV, White DL, Grigg AP, Hughes TP. Safety and efficacy of imatinib cessation for CML patients with stable undetectable minimal residual disease: results from the TWISTER study. Blood. 2013 Jul 25;122(4):515-22. doi: 10.1182/blood-2013-02-483750. Epub 2013 May 23.

  PMID: 23704092 RESULT

• Rousselot P, Charbonnier A, Cony-Makhoul P, Agape P, Nicolini FE, Varet B, Gardembas M, Etienne G, Rea D, Roy L, Escoffre-Barbe M, Guerci-Bresler A, Tulliez M, Prost S, Spentchian M, Cayuela JM, Reiffers J, Chomel JC, Turhan A, Guilhot J, Guilhot F, Mahon FX. Loss of major molecular response as a trigger for restarting tyrosine kinase inhibitor therapy in patients with chronic-phase chronic myelogenous leukemia who have stopped imatinib after durable undetectable disease. J Clin Oncol. 2014 Feb 10;32(5):424-30. doi: 10.1200/JCO.2012.48.5797. Epub 2013 Dec 9.

  PMID: 24323036 RESULT

• Lee SE, Choi SY, Bang JH, Kim SH, Jang EJ, Byeun JY, Park JE, Jeon HR, Oh YJ, Kim HJ, Kim YK, Park JS, Jeong SH, Kim SH, Zang DY, Oh S, Koo DH, Kim H, Do YR, Kwak JY, Kim JA, Kim DY, Mun YC, Mauro MJ, Kim DW. Predictive factors for successful imatinib cessation in chronic myeloid leukemia patients treated with imatinib. Am J Hematol. 2013 Jun;88(6):449-54. doi: 10.1002/ajh.23427. Epub 2013 Mar 28.

  PMID: 23440689 RESULT

MeSH Terms

Conditions

Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia; Bronchiolitis Obliterans Syndrome

Interventions

ponatinib

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Neoplasms by Histologic Type; Neoplasms; Myeloproliferative Disorders; Bone Marrow Diseases; Hematologic Diseases; Hemic and Lymphatic Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Organizing Pneumonia; Bronchiolitis Obliterans; Bronchiolitis; Bronchitis; Bronchial Diseases; Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases; Graft vs Host Disease; Immune System Diseases

Study Officials

• Juan Luis Steegmann, MD PhD

  Fundación de Investigación Biomédica - Hospital Universitario de La Princesa

  PRINCIPAL INVESTIGATOR

• Valentin Garcia Gutierrez, MD PhD

  Hospital Universitario Ramon y Cajal

  PRINCIPAL INVESTIGATOR

• Rosa Ayala, MD PhD

  Hospital Universitario Doce de Octubre

  PRINCIPAL INVESTIGATOR

• Luis Felipe Casado, Dr.

  Hospital Universitario Virgen del Rocio

  PRINCIPAL INVESTIGATOR

• Fermin Sanchez-Guijo, MD PhD

  University of Salamanca

  PRINCIPAL INVESTIGATOR

• Juan Carlos Hernandez, Dr.

  Hospital Clínico Universitario de Valencia

  PRINCIPAL INVESTIGATOR

• Guillermo Orti, Dr.

  Hospital Vall d'Hebron

  PRINCIPAL INVESTIGATOR

• Blanca Xicoy, Dr.

  Hospital German Trials i Pujol

  PRINCIPAL INVESTIGATOR

• Antonio Jimenez, Dr.

  Hospital Regional Universitario de Malaga

  PRINCIPAL INVESTIGATOR

• Maria Teresa Gomez, Dr.

  Hospital Universitario de Gran Canarias Dr. Negrin

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Begonya Maestro, PhD

CONTACT

(0034) 911923700; ponazero@ifth.es

Rocio Prieto, PhD

CONTACT

(0034) 911923700; ponazero@ifth.es

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Masking Details: This is a single-arm, open label study designed to determine the rate of successful treatment free remission (TFR) in patients who achieved and maintained molecular response 4 (MR4) on ponatinib. This study has 2 main phases: ponatinib consolidation (48 weeks), and ponatinib TFR phases (96 weeks). All patients who have received a minimum of 4 years of imatinib therapy as unique TKI therapy, he/she has documented MR4 at least 12 months for study entry, and he/she shall continue with MR4 before the discontinuation of the ponatinib treatment.
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 40 patients of both genders with chronic myeloid leukemia in MR4. Each patient will enter in the ponatinib consolidation phase (48 weeks) and them in the ponatinib treatment-free remission (96 weeks).

Study Record Dates

• First Submitted: July 31, 2019
• First Posted: August 2, 2019
• Study Start: April 30, 2019
• Primary Completion: April 30, 2022
• Study Completion: April 30, 2023
• Last Updated: August 2, 2019

Record last verified: 2019-08

Locations

ES (9)