Clinical trial NCT02388048: Ofatumumab & Ibrutinib + Allogeneic Bone Marrow Transplant or Consolidation in High Risk Chronic Lymphocytic Leukemia
Official title: A Phase II Study of the Combination of Ofatumumab and Ibrutinib Followed by Allogeneic Bone Marrow Transplant or Consolidation for Pretreated High Risk Patients With Chronic Lymphocytic Leukemia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Leukemia, Lymphoblastic, Chronic
Keywords: Leukemia
Chronic
High-risk
ofatumumab
ibrutinib
Lymphoblastic
Lead sponsor: Gruppo Italiano Malattie EMatologiche dell'Adulto
Sponsor class: OTHER
First posted: 2015-03-13
Enrollment: 19
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: A clinical study to evaluate a treatment with two drugs, named Ofatumumab and Ibrutinib, in patients with lymphoblastic acute leukemia who have been already treated with other therapies.

Detailed description: This is a phase II multicenter, non-comparative, open label study for high risk previously treated patients with CLL, requiring therapy, aimed at evaluating the efficacy of the Ofatumumab and Ibrutinib combination.

Eligibility criteria: Inclusion Criteria:

1. Male or female, age 18 years or until 65 years;
2. Confirmation of B-CLL previously treated with no more than 1 previous line of treatment .
3. Risk patients with CLL defined as follows:

   * treated patients showing 17p deletion in \>20% of the cells by FISH, or TP53 mutation or,
   * resistant (SD/PD) to fludarabine containing combination therapy or relapse within 12 months from a fludarabine-containing combination therapy.
4. Active disease meeting at least 1 of the following IWCLL criteria for requiring treatment:

   * Evidence of progressive marrow failure as manifested by the development of, or worsening of anemia (Hb\< 10 g/dL) and/or thrombocytopenia (platelets \< 100,000/mL).
   * Massive (≥ 6 cm below the left costal margin), progressive, or symptomatic splenomegaly.
   * Massive nodes (at least 10 cm longest diameter), or progressive or symptomatic lymphadenopathy.
   * Progressive lymphocytosis with an increase of more than 50% over a 2-month period or a lymphocyte doubling time (LDT) of \< 6 months.
   * Autoimmune hemolytic anemia and/or immune thrombocytopenia that is poorly responsive to corticosteroids or other standard therapy.
   * One or more disease-related symptoms:
   * unintentional weight loss \> 10% within 6 months prior to screening;
   * significant fatigue (inability to work or perform usual activities);
   * fevers \>38.0°C for 2 or more weeks prior to screening;
   * night sweats for more than 1 month prior to screening.
5. Stage B or C of CLL according to Binet staging system;
6. Stage A disease fitting the criteria for treatment according to the IWCLL-NCI criteria (2008) are also included.
7. WHO performance status 0-II.
8. Life expectancy ≥ 6 months.
9. Hematology values must be within the following limits:

   * Absolute neutrophil count (ANC) ≥ 750/mm3 independent of growth factor support;
   * Platelets ≥100,000/mm3 or ≥ 30.000/mm3 if bone marrow involvement independent of transfusion support in either situation.
10. Biochemical values within the following limits:

    * Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x upper limit of normal (ULN).
    * Total bilirubin ≤ 1.5 x ULN unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin.
    * Serum creatinine ≤ 2 x ULN or estimated Glomerular Filtration Rate (Cockroft Gault) ≥ 30 mL/min/1.73m2.
11. Women of childbearing potential and men who are sexually active must be practicing a highly effective method of birth control during and after the study For females, these restrictions apply for 1 month after the last dose of ibrutinib and for 12 months after the last dose of Ofatumumab. For males, these restrictions apply for 3 months after the last dose of ibrutinib. Men must agree to not donate sperm during and after the study.
12. Women of childbearing potential must have a negative serum (beta-human chorionic gonadotropin \[β-hCG\]) or urine pregnancy test at Screening. Women who are pregnant or breastfeeding are ineligible for this study.
13. Sign an informed consent document indicating that they understand the purpose of and procedures required for the study, including biomarkers, and are willing to participate in the study.

Exclusion Criteria:

1. Major surgery within 3 weeks before registration.
2. Known central nervous system lymphoma.
3. History of stroke or intracranial hemorrhage within 6 months prior to registration.
4. Requires anticoagulation with warfarin or equivalent vitamin K antagonists (eg, phenprocoumon).
5. Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of Screening, or any Class 3 (moderate) or Class 4 (severe) cardiac disease as defined by the New York Heart Association Functional Classification.
6. Vaccinated with live, attenuated vaccines within 4 weeks of registration.
7. Known history of human immunodeficiency virus (HIV) or active Hepatitis C Virus or active Hepatitis B Virus infection or any uncontrolled active systemic infection requiring intravenous (IV) antibiotics.
8. Any life-threatening illness, medical condition, or organ system dysfunction which, in the investigator's opinion, could compromise the subject's safety, interfere with the absorption or metabolism of ibrutinib capsules, or put the study outcomes at undue risk.
9. Positive serology for Hepatitis B (HB) defined as a positive test for HBsAg. In addition, if negative for HBsAg but HBcAb positive (regardless of HBsAb status), a HBDNA test will be performed and if positive the subject will be excluded. \*\*\*see attached monitoring criteria for HBcAb+ and HBV DNA negative subjects.
10. Other past or current malignancy. Subjects who have been free of malignancy for at least 5 years, or have a history of completely resected non-melanoma skin cancer, or successfully treated in situ carcinoma are eligible.
11. Requirement for treatment with a strong CYP3A4/5 and/or CYP2D6 inhibitor.
12. Significant concurrent, uncontrolled medical condition including, but not limited to, renal, hepatic, gastrointestinal, endocrine, pulmonary, neurological, cerebral or psychiatric disease which in the opinion of the investigator may represent a risk for the patient.
13. Inability to swallow capsules or tablets, or disease significantly affecting gastrointestinal function and/or inhibiting small intestine absorption.
14. Chronic or current infectious disease requiring systemic antibiotics, antifungal, or antiviral treatment such as, but not limited to, chronic renal infection, chronic chest infection with bronchiectasis, tuberculosis.
15. Uncontrolled autoimmune hemolytic anemia or idiopathic thrombocytopenic purpura.
16. Central nervous system involvement with CLL.
17. Subjects who have current active hepatic or biliary disease (with exception of patients with Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic liver disease per investigator assessment).
18. Treatment with any known non-marketed drug substance or experimental therapy within 5 terminal half lives or 4 weeks prior to enrollment, whichever is longer, or currently participating in any other interventional clinical study.
19. Prior treatment with anti-CD20 monoclonal antibody or alemtuzumab within 3 months prior to the start of therapy.
20. History of significant cerebrovascular disease in the past 6 months or ongoing event with active symptoms or sequelae.

    * If HBV DNA is negative, subject may be included but must undergo at least every 2 month HBV DNA PCR testing from the start of treatment during the treatment course. Prophylactic antiviral therapy may be initiated at the discretion of the investigator.

Primary outcomes:
measure: The number of pretreated patients with high risk CLL who achieve a Complete Response (CR) after the induction therapy with Ibrutinib plus Ofatumumab.
timeFrame: After 6.5 years from treatment start
Secondary outcomes:
measure: Number of patients in Complete Response (CR)/Partial Response (PR)
timeFrame: After 28 weeks from treatment start
measure: Number of patients without progression of the disease.
timeFrame: At 60 months from treatment start
measure: Number of patients alive
timeFrame: At 60 months from treatment start
measure: Number of patients without events
timeFrame: At 60 months from treatment start
measure: Number of Minimal Residual Disease-negative Complete Responses
timeFrame: At 28 weeks from treatment start
measure: Number of adverse events
timeFrame: At 6.5 years after treatment start
Other outcomes:
Locations:
city: Roma
country: Italy
facility: Università degli Studi "Sapienza" - Dip Biotecnologie Cellulari ed Ematologia - Divisione di Ematologia
state: Provincia
city: Alessandria
country: Italy
facility: S.O.C. di Ematologia - Azienda Ospedaliera - SS. Antonio e Biagio e Cesare Arrigo
city: Ascoli Piceno
country: Italy
facility: Area Vasta N. 5 Ascoli Piceno - S. Benedetto Del Tronto, Presidio Ospedaliero Av5 Osp. Gen. Prov.Le "C.G.Mazzoni" - Uoc Ematologia
city: Bologna
country: Italy
facility: Nuovo Record Esporta in Excel Stampa Esporta in file di testo Mostra Informazioni Record Multi edit Stato dello studio presso il centro records: 28 Record 1/28 su 28 direzione di ordinamento Centro (CIC) direzione di ordinamento Sperimentatore Pri
city: Cagliari
country: Italy
facility: ASL N.8 - Ospedale "A. Businco" - Struttura Complessa di Ematologia e CTMO
city: Catania
country: Italy
facility: Università di Catania - Cattedra di Ematologia - Ospedale "Ferrarotto"
city: Catanzaro
country: Italy
facility: Azienda Ospedaliera Pugliese Ciaccio - Presidio Ospedaliero A.Pugliese - Unità Operativa di Ematologia
city: Cona
country: Italy
facility: Nuovo Record Esporta in Excel Stampa Esporta in file di testo Mostra Informazioni Record Multi edit Stato dello studio presso il centro records: 28 Record 1/28 su 28 direzione di ordinamento Centro (CIC) direzione di ordinamento Sperimentatore Pri
city: Cosenza
country: Italy
facility: U.O. Ematologia - P.O. Annunziata - A.O. di Cosenza
city: Firenze
country: Italy
facility: Policlinico di Careggi
city: Genova
country: Italy
facility: IRCCS_AOU San Martino-IST-Ematologia 1-Monoblocco 11°piano- lato ponente
city: Lecce
country: Italy
facility: ASL Le/1 P.O. Vito Fazzi - U.O. di Ematologia ed UTIE
city: Meldola
country: Italy
facility: Istituto Scientifico Romagnoli per lo Studio e la Cura dei Tumori- IRST
city: Messina
country: Italy
facility: Divisione di Ematologia - Azienda Ospedaliera Ospedali Riuniti "Papardo Piemonte" P.O. Papardo
city: Mestre
country: Italy
facility: Aulss 3 Serenissima, Ospedale Dell'Angelo - Mestre - Uo Ematologia
city: Milano
country: Italy
facility: Fondazione Irccs "Istituto Nazionale Tumori" - Milano - Sc Ematologia
city: Milano
country: Italy
facility: Ospedale Niguarda " Ca Granda" - SC Ematologia Blocco SUD, Ponti Est, Scala E, 4° piano
city: Novara
country: Italy
facility: S.C.D.U. Ematologia - DIMECS e Dipartimento Oncologico - Università del Piemonte Orientale Amedeo Avogadro
city: Padova
country: Italy
facility: Aou Di Padova - Uo Ematologia
city: Pagani
country: Italy
facility: Sl Salerno, Presidio Ospedaliero Tortora Pagani - Ematologia
city: Palermo
country: Italy
facility: U.O. di Ematologia con trapianto - Centro di Riferimento Regionale per le coagulopatie rare nel bambino e nell'adulto Dipart. Biomedico di Medicina Interna - A.U. Policlinico "Paolo Giaccone"
city: Parma
country: Italy
facility: Cattedra di Ematologia CTMO Università degli Studi di Parma
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: Asl Di Piacenza, Ospedale "Guglielmo Da Saliceto" - Ematologia E Centro Trapianti
city: Reggio Emilia
country: Italy
facility: Unità Operativa Complessa di Ematologia - Arcispedale S. Maria Nuova
city: Rimini
country: Italy
facility: Ospedale "Infermi"
city: Roma
country: Italy
facility: Università Cattolica del Sacro Cuore - Policlinico A. Gemelli
city: Roma
country: Italy
facility: Università degli Studi - Policlinico di Tor Vergata
city: Roma
country: Italy
facility: Università Degli Studi Di Roma "Sapienza" - Dipartimento Di Medicina Traslazionale E Di Precisione - U.O.C. Ematologia
city: Terni
country: Italy
facility: A.O. Santa Maria - Terni S.C Oncoematologia
city: Torino
country: Italy
facility: A.O. Mauriziano Umberto I
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: Verona
country: Italy
facility: Università degli Studi di Verona - A. O. - Istituti Ospitalieri di Verona- Div. di Ematologia - Policlinico G.B. Rossi
Study officials:
affiliation: Department of Hematology, Niguarda Ca' Granda, Milan
name: Marco Montillo
role: STUDY_CHAIR
affiliation: Department of Hematology, Policlinico Umberto I di Roma
name: Francesca R. Mauro
role: STUDY_DIRECTOR
References: