Nilotinib as First-line Treatment of Ph+ CML in Early Chronic Phase

NCT00481052 | Completed Phase 2 DMC

• 1 other identifier: CML0307
• Study Type: interventional
• Target: 74
• Locations: 1 country
• Sites: 22

Brief Summary

Treating Ph pos CML with Imatinib is very effective since the majority of the patients achieve a complete cytogenetic response and a major molecular response and are alive and progression-free after 5 years. However, the great majority of responding patients are not leukemia-free and may be at risk of progression, molecular, cytogenetic and clinical, at any time. In case of disease progression due to Imatinib failure, nilotinib has been found to be very effective, as expected from the preclinical profile of the drug, that is much more potent against BCR-ABL and inhibits nearly all the imatinib-resistant BCR-ABL mutants. For these reasons, nilotinib is going to be registered for the treatment of imatinib-resistant CMl patients. For the same reasons, nilotinib is expected to be more efficient than imatinib also front-line, based on the principle that we should aim at preventing the emergence of resistance better that at treating resistance once it has emerged. This expectation can be tested safely, because the "toxicity profile" of Nilotinib may be even more convenient than that of Imatinib, due to the lower frequency of edema and fluid retention.

Conditions

Chronic Myeloid Leukemia

Keywords

Adult; CML; Philadelphia positive; Nilotinib; early chronic phase; untreated or treated only with Hydroxyurea or Anagrelide; Chronic Myeloid Leukemia

Outcome Measures

Primary Outcomes (1)

• Complete cytogenetic response (CCgR ) rate

  At 1 year

Secondary Outcomes (6)

• The complete and the partial cytogenetic response rate

  At 6 months

• The major molecular response (MMR) rate

  At 1 year

• The kinetics of haematologic, cytogenetic and molecular response to AMN107

  At 1 year

• The development of bcr-abl mutation during the treatment with AMN107 (number and type)

  At 1 year

• The safety and tolerability of nilotinib treatment at the dose of 300 mg b.i.d

  At 1 year

Interventions

Nilotinib DRUG

Eligibility Criteria

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

You may qualify if:

• Patients with a cytologic and cytogenetic confirmed diagnosis of Ph+ CML.
• Age ≥ 18 years old
• Early CP (within 6 months from diagnosis)
• No prior treatment with any antileukemic drugs with the exception of Hydroxyurea (HU) and Anagrelide.
• WHO performance status of ≤ 2
• Normal serum level of potassium, total calcium corrected for serum albumin, magnesium and phosphorus, or correctable with supplements
• ALT and AST ≤ 2.5 x ULN or ≤ 5.0 x ULN if considered due to leukaemia.
• Alkaline phosphatase ≤ 2.5 x ULN unless considered due to leukemia.
• Serum bilirubin ≤ 1.5 x ULN
• Serum creatinine ≤ 1.5 x ULN
• Serum amylase ≤ 1.5 x ULN and serum lipase ≤ 1.5 x ULN.
• Written informed consent prior to any study procedures being performed.

You may not qualify if:

• Impaired cardiac function, including LVEF \< 45% as determined by MUGA scan or echocardiogram, uncontrolled congestive heart failure, uncontrolled hypertension
• History of myocardial infarction within three months, or uncontrolled angina pectoris.
• Significant electric heart abnormalities, including history or presence of significant ventricular or atrial tachyarrhythmias, congenital long QT syndrome and/or QTc \> 450 msec on screening ECG (using the QTcF formula).
• Patients with ventricular pacemakers and clinically significant bradycardias.
• Patients with heart blocks.
• History of acute or chronic pancreatitis.
• Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of nilotinib (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection)
• Use of therapeutic coumarin derivates (i.e. warfarin, acenocoumarol, phenprocoumon).
• Acute or chronic liver or renal disease considered unrelated to leukaemia
• Other concurrent severe and/or uncontrolled medical conditions (e.g., uncontrolled diabetes, active or uncontrolled infection) that could cause unacceptable safety risks or compromise compliance with the protocol
• Patients who are currently receiving treatment with any of the medications listed in Appendix E and the treatment cannot be either discontinued or switched to a different medication prior to starting study drug. The medications listed in Appendix E have the potential to prolong QT, with the exception of HU and Anagrelide.
• Patients who have received any antileukemic agents and treatments, including HSCT, with the exception of HU and Anagrelide.
• Patients who have received any investigational drug ≤ 4 weeks.
• Patients who have undergone major surgery ≤ 2 weeks prior to starting study drug or who have not recovered from side effects of such therapy.
• Patients who are pregnant or breast feeding, or adults of reproductive potential not employing an effective method of birth control. (Women of childbearing potential must have a negative serum pregnancy test within 48 hrs prior to administration of nilotinib). Post menopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential. Male and female patients must agree to employ an effective barrier method of birth control throughout the study and for up to 3 months following discontinuation of study drug.

Sponsors & Collaborators

• Gruppo Italiano Malattie EMatologiche dell'Adulto: lead

Study Sites (22)

Dipartimento Area Medica P.O.

Ascoli Piceno, 63100, Italy

Location

Unità Operativa Ematologica - Università degli Studi di Bari

Bari, 70124, Italy

Location

Ospedali Riuniti

Bergamo, 24100, Italy

Location

stituto di Ematologia "Lorenzo e A. Seragnoli" - Università degli Studi di Bologna - Policlinico S. Orsola - Malpighi

Bologna, Italy

Location

Sezione di Ematologia e Trapianti Spedali Civili

Brescia, 21125, Italy

Location

Azienda Spedali Civili

Brescia, 25100, Italy

Location

ASL N.8 - Ospedale "A. Businco" - Struttura Complessa di Ematologia e CTMO

Cagliari, Italy

Location

Ospedale Ferrarotto

Catania, 95124, Italy

Location

Azienda Ospedaliera Pugliese Ciaccio

Catanzaro, 88100, Italy

Location

Sezione di Ematologia e Fisiopatologia delle Emostasi - Azienda Ospedaliera - Arcispedale S. Anna

Ferrara, Italy

Location

Azienda Ospedaliera Universitaria - Università degli Studi di Napoli "Federico II" - Facoltà di Medicina e Chirurgia

Napoli, Italy

Location

Ospedale S. Luigi Gonzaga

Orbassano, 10043, Italy

Location

La Maddalena Casa di Cura di Alta Specialità Dipartimento Oncologico di III Livello

Palermo, Italy

Location

Unità Operativa Ematologia e Centro Trapianti - Dipartimento di Oncologia ed Ematologia - AUSL Ospedale di Piacenza

Piacenza, Italy

Location

Ospedale S.Maria delle Croci

Ravenna, 48100, Italy

Location

Calabria Dipartimento Emato-Oncologia A.O."Bianchi-Melacrino-Morelli"

Reggio Calabria, Italy

Location

Università La Cattolica del Sacro Cuore

Roma, 00168, Italy

Location

Complesso Ospedaliero S. Giovanni Addolorata

Roma, 00184, Italy

Location

Università degli Studi "Sapienza" - Dip Biotecnologie Cellulari ed Ematologia - Divisione di Ematologia

Roma, Italy

Location

U.O. Ematologia, Azienda Ospedaliera Universitaria Senese

Siena, 53100, Italy

Location

Policlinico Universitario - Clinica Ematologia

Udine, 33100, Italy

Location

Policlinico G.B. Rossi

Verona, 37134, Italy

Location

Related Publications (13)

• Calabretta B, Perrotti D. The biology of CML blast crisis. Blood. 2004 Jun 1;103(11):4010-22. doi: 10.1182/blood-2003-12-4111. Epub 2004 Feb 24.

  PMID: 14982876 BACKGROUND

• Barnes DJ, Melo JV. Management of chronic myeloid leukemia: targets for molecular therapy. Semin Hematol. 2003 Jan;40(1):34-49. doi: 10.1053/shem.2003.50002.

  PMID: 12563610 BACKGROUND

• Goldman JM, Melo JV. Chronic myeloid leukemia--advances in biology and new approaches to treatment. N Engl J Med. 2003 Oct 9;349(15):1451-64. doi: 10.1056/NEJMra020777. No abstract available.

  PMID: 14534339 BACKGROUND

• Goldman JM, Marin D, Olavarria E, Apperley JF. Clinical decisions for chronic myeloid leukemia in the imatinib era. Semin Hematol. 2003 Apr;40(2 Suppl 2):98-103; discussion 104-13. doi: 10.1053/shem.2003.50049.

  PMID: 12783383 BACKGROUND

• Goldman JM, Marin D. Management decisions in chronic myeloid leukemia. Semin Hematol. 2003 Jan;40(1):97-103. doi: 10.1053/shem.2003.50009.

  PMID: 12563616 BACKGROUND

• Goldman JM, Druker BJ. Chronic myeloid leukemia: current treatment options. Blood. 2001 Oct 1;98(7):2039-42. doi: 10.1182/blood.v98.7.2039.

  PMID: 11567987 BACKGROUND

• Baccarani M, Russo D, Rosti G, Martinelli G. Interferon-alfa for chronic myeloid leukemia. Semin Hematol. 2003 Jan;40(1):22-33. doi: 10.1053/shem.2003.50004.

  PMID: 12563609 BACKGROUND

• Martinelli G, Soverini S, Rosti G, Cilloni D, Baccarani M. New tyrosine kinase inhibitors in chronic myeloid leukemia. Haematologica. 2005 Apr;90(4):534-41.

  PMID: 15820950 BACKGROUND

• Rosti G, Martinelli G, Bassi S, Amabile M, Trabacchi E, Giannini B, Cilloni D, Izzo B, De Vivo A, Testoni N, Cambrin GR, Bonifazi F, Soverini S, Luatti S, Gottardi E, Alberti D, Pane F, Salvatore F, Saglio G, Baccarani M; Study Committee, Italian Cooperative Study Group for Chronic Myeloid Leukemia; Writing Committee, Italian Cooperative Study Group for Chronic Myeloid Leukemia. Molecular response to imatinib in late chronic-phase chronic myeloid leukemia. Blood. 2004 Mar 15;103(6):2284-90. doi: 10.1182/blood-2003-07-2575. Epub 2003 Nov 26.

  PMID: 14645009 BACKGROUND

• Gugliotta G, Castagnetti F, Breccia M, Levato L, D'Adda M, Stagno F, Tiribelli M, Salvucci M, Fava C, Martino B, Cedrone M, Bocchia M, Trabacchi E, Cavazzini F, Usala E, Russo Rossi A, Bochicchio MT, Soverini S, Alimena G, Cavo M, Pane F, Martinelli G, Saglio G, Baccarani M, Rosti G; GIMEMA CML Working Party. Long-term outcome of a phase 2 trial with nilotinib 400 mg twice daily in first-line treatment of chronic myeloid leukemia. Haematologica. 2015 Sep;100(9):1146-50. doi: 10.3324/haematol.2015.129221. Epub 2015 Jun 25.

  PMID: 26113419 DERIVED

• Castagnetti F, Gugliotta G, Baccarani M, Breccia M, Specchia G, Levato L, Abruzzese E, Rossi G, Iurlo A, Martino B, Pregno P, Stagno F, Cuneo A, Bonifacio M, Gobbi M, Russo D, Gozzini A, Tiribelli M, de Vivo A, Alimena G, Cavo M, Martinelli G, Pane F, Saglio G, Rosti G; GIMEMA CML Working Party. Differences among young adults, adults and elderly chronic myeloid leukemia patients. Ann Oncol. 2015 Jan;26(1):185-192. doi: 10.1093/annonc/mdu490. Epub 2014 Oct 30.

  PMID: 25361995 DERIVED

• Lenaerts T, Castagnetti F, Traulsen A, Pacheco JM, Rosti G, Dingli D. Explaining the in vitro and in vivo differences in leukemia therapy. Cell Cycle. 2011 May 15;10(10):1540-4. doi: 10.4161/cc.10.10.15518. Epub 2011 May 15.

  PMID: 21478667 DERIVED

• Rosti G, Palandri F, Castagnetti F, Breccia M, Levato L, Gugliotta G, Capucci A, Cedrone M, Fava C, Intermesoli T, Cambrin GR, Stagno F, Tiribelli M, Amabile M, Luatti S, Poerio A, Soverini S, Testoni N, Martinelli G, Alimena G, Pane F, Saglio G, Baccarani M; GIMEMA CML Working Party. Nilotinib for the frontline treatment of Ph(+) chronic myeloid leukemia. Blood. 2009 Dec 3;114(24):4933-8. doi: 10.1182/blood-2009-07-232595. Epub 2009 Oct 12.

  PMID: 19822896 DERIVED

Related Links

• GIMEMA's Web page

MeSH Terms

Conditions

Leukemia, Myelogenous, Chronic, BCR-ABL Positive

Interventions

nilotinib

Condition Hierarchy (Ancestors)

Leukemia, Myeloid; Leukemia; 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

Study Officials

• Michele BACCARANI

  Azienda Ospedaliera Universitaria -Policlincio S. Orsola-Malpighi

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 31, 2007
• First Posted: June 1, 2007
• Study Start: June 23, 2007
• Primary Completion: April 30, 2018
• Study Completion: April 30, 2018
• Last Updated: January 18, 2022

Record last verified: 2022-01

Locations

IT (22)