Clinical trial NCT02582320: Clinical-biological Characteristics and Outcome of Chronic Lymphocytic Leukemia Under Ibrutinib-named Patient Program
Official title: A Retrospective Study to Evaluate the Clinical-Biologic Characteristics and Outcome of Patients Treated in Italy According to the Ibrutinib-Named Patient Program for Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Chronic Lymphocytic Leukemia
Lead sponsor: Gruppo Italiano Malattie EMatologiche dell'Adulto
Sponsor class: OTHER
First posted: 2015-10-21
Enrollment: 264
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: RETROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Patients with R/R CLL or 17p deleted CLL fulfilling the eligibility criteria required by the NPP who received at least 1 dose of Ibrutinib 420 mg daily before November, 30th 2014

Brief summary: This is a retrospective observational study aimed at describing the characteristics and outcome of CLL patients included in the NPP in Italy in a period of time ranging from the start of the NPP until November, 30th 2014. A longitudinal survey will be carried out by collecting data of patients who received at least 1 dose of Ibrutinib. All patients will be observed for at least 12 months from the treatment start.

Detailed description: Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults. The disease is characterized by the progressive accumulation of phenotypically mature malignant B lymphocytes, primarily in the peripheral blood, bone marrow, and lymph nodes. Over the last 10-15 years several biological prognostic markers have been identified, starting from the immunoglobulin gene mutational analysis to CD38, ZAP70, CD49d expression, and many others. The very recent discovery of several new genes that carry point mutations in CLL, including NOTCH1, SF3B1 and BIRC3, has added more markers that seem to correlate with resistance to treatment and with transformation into Richter syndrome. A large number of chemoimmunotherapy regimens are currently considered for the treatment of CLL patients.

NPP program The Named Patient Program (NPP) is a program intended to provide early access to ibrutinib in Italy. This program is specifically for patients who have relapsed or refractory chronic lymphocytic leukaemia (CLL)/small lymphocytic lymphoma (SLL), mantle cell lymphoma.

Rationale In patients with CLL Ibrutinib, given as single agent has shown marked activity and a good safety profile. Data from patients treated with ibrutinib outside a controlled clinical trial within a National Patient Program (NPP) could give additional information about the clinical use, treatment duration, efficacy, and toxicity of ibrutinib given to CLL patients in a real life context.

Eligibility criteria: NPP Inclusion Criteria:

1. Patients ≥18 years of age.
2. Eastern Cooperative Oncology Group (ECOG) performance status of ≤2.
3. A minimum of one prior line of systemic chemotherapy, chemo-immunotherapy, or an alemtuzumab-based regimen, consisting of at least two cycles of therapy.
4. Relapsed or refractory CLL with one or more of the following criteria:

   * Presence of deletion of the short-arm of chromosome 17 (ie 17p deletion).
   * Relapsed: Failed two or more previous treatments, at least one with a purine analogue such as fludarabine.
   * Relapsed: Progression-free interval of less than 24 months from completing treatment with a nucleoside analogue, or bendamustine-containing regimen in combination with an anti-CD20 monoclonal antibody such as rituximab.
   * Refractory: Failure to respond to a prior chemotherapy-based treatment, stable disease, or disease progression while on treatment.
5. Patient has active CLL requiring treatment as defined by the IWCLL 2008 criteria. A minimum of one of the following criteria is required:

   * Evidence of progressive marrow failure, as manifested by the development of, or worsening of, anemia or thrombocytopenia.
   * Massive (at least 6 cm below the left costal margin), progressive, or symptomatic splenomegaly.

     c. Massive nodes (at least 10 cm in longest diameter), progressive, or symptomatic lymphadenopathy.
   * Progressive lymphocytosis with an increase of more than 50% over a 2-month period or a lymphocyte doubling time of less than 6 months (which may be extrapolated). For patients with initial blood lymphocyte counts of less than 30 x 109/L (30,000/mL), lymphocyte doubling time should not be used as a single parameter to define indication for treatment. Factors contributing to lymphocytosis or lymphadenopathy other than CLL (e.g., infections) should be excluded.
   * Constitutional symptoms, defined as 1 or more of the following disease-related symptoms or signs:

     i. Unintentional weight loss \>10% within the previous 6 months prior to screening.

   ii. Significant fatigue (inability to work or perform usual activities). iii. Fever higher than 38.0°C for 2 or more weeks without evidence of infection.

   iv. Night sweats for more than 1 month without evidence of infection.
6. Haematology values within the following parameters:

   * Absolute neutrophil count (ANC) of ≥0.75 x109/L independent of growth factor support.
   * Platelet count of ≥30 x109/L independent of platelet support.
7. Biochemical values within the following limits:

   * Serum creatinine ≤2 times the upper limit of normal (ULN) or estimated glomerular filtration rate (GFR \[Crockcoft-Gault\]) ≥30 mL/minute.
   * Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 times ULN.
   * Total bilirubin ≤1.5 times ULN (unless the bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin) for whom the upper limit of serum bilirubin is 3 mg/dl.
8. No problems to swallowing regularly capsules.
9. Agreed to practice a highly effective method of birth control during and after participation in the NPP if they are of childbearing potential and sexually active.
10. Signed informed consent document (if feasible) indicating that they understand the purpose of the study, they agree to give complete access to their medical records.

NPP Exclusion criteria

1. Previous treatment with ibrutinib or participation to an ibrutinib clinical trial (ibrutinib or comparator arm).
2. Eligible to participate in a currently recruiting ibrutinib clinical trial.
3. Previously received ibrutinib as part of a clinical trial.
4. Previously received a Bruton's tyrosine kinase (BTK) inhibitor other than ibrutinib.
5. Currently enrolled in an interventional clinical trial.
6. Currently receiving chemotherapy, anticancer immunotherapy, or experimental therapy.
7. Currently recovering from acute toxicities of prior treatment for CLL.
8. Received stem cell transplantation within the past 6 months.
9. Evidence of graft-versus-host disease and/or requires immunosuppressant therapy.
10. Major surgery within the past 4 weeks or a major wound that has not fully healed.
11. History of human immunodeficiency virus (HIV) or active infection with Hepatitis C or B.
12. Ongoing uncontrolled active systemic infection.
13. Uncontrolled autoimmune haemolytic anemia (AIHA).
14. Uncontrolled idiopathic thrombocytopenic purpura (ITP).
15. Central nervous system leukemia/lymphoma or Richter's transformation.
16. Diagnosed or treated for another malignancy, other than CLL, except for:

    * Malignancy treated with curative intent and with no known active disease present for ≥3 years prior to entering this named patient program and considered to be at low risk for recurrence.
    * Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease.
    * Adequately treated cervical carcinoma in situ without evidence of disease.
17. Stroke within the past 6 months.
18. Intracranial haemorrhage within the past 6 months.
19. Requires anticoagulation with warfarin or equivalent vitamin K antagonist (e.g. phenprocoumon).
20. Requires treatment with a strong CYP3A inhibitor.
21. Clinically significant cardiovascular disease such as:

    * Uncontrolled or symptomatic arrhythmias.
    * Congestive heart failure.
    * Myocardial infarction within the past 6 months.
    * Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification.
22. Patient has any life-threatening illness, medical condition, clinically significant.

Primary outcomes:
measure: Number of patients who progress
timeFrame: At 12 months from the start of Ibrutinib
Secondary outcomes:
measure: Number of patients who respond to treatment
timeFrame: At 12 months from enrolment
measure: Treatment duration
timeFrame: At 12 months from enrolment
measure: Time to next treatment in terms of number of days needed
timeFrame: At 12 months from treatment start
measure: Number of patients surviving
timeFrame: At 12 months from treatment start
measure: Number of patients who reach normal values in the immunoglobulin levels
timeFrame: At 3, 6 and 12 months from treatment start
measure: Number of patients with toxic events
timeFrame: At 12 months from treatment start
measure: Number of patients who develop Richter's syndrome and secondary malignancies
timeFrame: At 12 months from treatment start
measure: Number of patients who require added assistance
timeFrame: At 12 months from treatment start
measure: Number of patients who fail to treatment.
timeFrame: At 12 months from treatment start
Other outcomes:
Locations:
city: Ascoli Piceno
country: Italy
facility: U.O.C. Ematologia e Terapia Cellulare - Ospedale "C. e G. Mazzoni" di Ascoli Piceno
city: Aversa
country: Italy
facility: U.O.C di Ematologia P.O. "S.Giuseppe Moscati" - 2° piano
city: Bari
country: Italy
facility: UO Ematologia con trapianto-Università degli Studi di Bari Aldo Moro
city: Bologna
country: Italy
facility: Istituto di Ematologia "Lorenzo e A. Seragnoli" - Università degli Studi di Bologna - Policlinico S. Orsola - Malpighi
city: Brescia
country: Italy
facility: Spedali Civili - Brescia - Azienda Ospedaliera - U.O. Ematologia
city: Brindisi
country: Italy
facility: Divisione di Ematologia Ospedale A. Perrino
city: Cagliari
country: Italy
facility: ASL N.8 - Ospedale "A. Businco" - Struttura Complessa di Ematologia e CTMO
city: Castelfranco Veneto
country: Italy
facility: US Dipartimentale - Centro per le malattie del sangue - Ospedale Civile - S.Giacomo
city: Catanzaro
country: Italy
facility: Azienda Ospedaliera Pugliese Ciaccio - Presidio Ospedaliero A.Pugliese - Unità Operativa di Ematologia
city: Civitanova Marche
country: Italy
facility: U.O. di Medicina Interna - ASUR Marche 8 - Ospedale Civile
city: Cona
country: Italy
facility: Azienda Ospedaliero Universitaria Arcispedale Sant'Anna Dipartimento di Scienze Mediche Sezione di Ematologia e Fisiopatologia dell'Emostasi
city: Firenze
country: Italy
facility: Unità di Ricerca e di Malattie del sangue - Ematologia San Luca Vecchio Pad. 16 - 1° Piano
city: Genova
country: Italy
facility: IRCCS_AOU San Martino-IST.Clinica Ematologica
city: Lecce
country: Italy
facility: ASL Le/1 P.O. Vito Fazzi - U.O. di Ematologia ed UTIE
city: Milano
country: Italy
facility: Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico UOC Oncoematologia- Padiglione Marcora 2° piano
city: Milano
country: Italy
facility: Ospedale Niguarda " Ca Granda" - SC Ematologia Blocco SUD, Ponti Est, Scala E, 4° piano
city: Milano
country: Italy
facility: U.O. Ematologia e Trapianto di MIdollo - Ist.Scientifico Ospedale San Raffaele
city: Milano
country: Italy
facility: Unità Trapianto di Midollo Ist. Nazionale Tumori
city: Modena
country: Italy
facility: UO Ematologia - AOU Policlinico di Modena
city: Napoli
country: Italy
facility: Ospedale San Gennaro - ASL Napoli 1
city: Novara di Sicilia
country: Italy
facility: S.C.D.U. Ematologia - DIMECS e Dipartimento Oncologico - Università del Piemonte Orientale Amedeo Avogadro
city: Padova
country: Italy
facility: Università degli Studi di Padova - Ematologia ed Immunologia Clinica
city: Pagani
country: Italy
facility: U.O. di Oncoematologia di Nocera Inferiore-plesso ospedaliero "A. Tortora" di Pagani del DEA Nocera-Pagani
city: Parma
country: Italy
facility: Cattedra di Ematologia CTMO Università degli Studi di Parma
city: Pavia
country: Italy
facility: S.C. Ematologia - Fondazione IRCCS Policlinico S. Matteo
city: Perugia
country: Italy
facility: Sezione di Ematologia ed Immunologia Clinica - Ospedale S.Maria della Misericordia
city: Pescara
country: Italy
facility: U.O. Ematologia Clinica - Azienda USL di Pescara
city: Piacenza
country: Italy
facility: Unità Operativa Ematologia e Centro Trapianti - Dipartimento di Oncologia ed Ematologia - AUSL Ospedale G. da Saliceto
city: Potenza
country: Italy
facility: Ematologia - Ospedale San Carlo
city: Ravenna
country: Italy
facility: Dipartimento Oncologico - Ospedale S.Maria delle Croci
city: Reggio Calabria
country: Italy
facility: Dipartimento Emato-Oncologia A.O."Bianchi-Melacrino-Morelli"
city: Reggio Emilia
country: Italy
facility: Unità Operativa Complessa di Ematologia - Arcispedale S. Maria Nuova
city: Rimini
country: Italy
facility: Ospedale "Infermi"
city: Rionero in Vulture
country: Italy
facility: U.O.C. Ematologia - IRCCS Centro oncologico della Basilicata
city: Roma
country: Italy
facility: S.C. di Ematologia e Trapianti - I.F.O. Istituto Nazionale Tumori Regina Elena
city: Roma
country: Italy
facility: U.O.C. Ematologia - Ospedale S.Eugenio
city: Roma
country: Italy
facility: U.O.S.A. Ematologia ASL RMA Presidio Nuovo Regina Margherita
city: Roma
country: Italy
facility: Università Cattolica del Sacro Cuore - Policlinico A. Gemelli
city: Roma
country: Italy
facility: Università degli Studi "Sapienza" - Dip Biotecnologie Cellulari ed Ematologia - Divisione di Ematologia
city: Rome
country: Italy
facility: Policlinico Umberto I, Hematology Department - Sapienza
city: Rozzano
country: Italy
facility: Sezione di Ematologia Cancer Center Humanitas
city: San Giovanni Rotondo
country: Italy
facility: Istituto di Ematologia - IRCCS Ospedale Casa Sollievo della Sofferenza
city: Siena
country: Italy
facility: U.O.C. Ematologia e Trapianti - A.O. Senese - Policlinico " Le Scotte"
city: Terni
country: Italy
facility: A.O. Santa Maria - Terni S.C Oncoematologia
city: Torino
country: Italy
facility: Dipartimento di Oncologia ed Ematologia S.C. Ematologia 2 A.O. Città della Salute e della Scienza di Torino San Giovanni Battista
city: Torino
country: Italy
facility: Divisione di Ematologia dell' Università degli Studi di Torino - "Città della Salute e della Scienza di Torino"
city: Vicenza
country: Italy
facility: ULSS N.6 Osp. S. Bortolo
Study officials:
affiliation: Policlinico Umberto I, Hematology Department.
name: Roberto Foà
role: STUDY_CHAIR
References: