Clinical trial NCT00727415: Lenalidomide, Fludarabine & Cyclophosphamide in Advanced Chronic Lymphocytic Leukemia Not Responding to Therapy
Official title: A Prospective Multicenter Pilot Trial to Evaluate the Efficacy of a Treatment With Fludarabine, Cyclophosphamide, Lenalidomide (FCL) for Advanced Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL) Patients.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Chronic Lymphocytic Leukemia
Keywords: advanced or progressive chronic lymphocytic leukemia
Lenalidomide
Fludarabine
Lead sponsor: Gruppo Italiano Malattie EMatologiche dell'Adulto
Sponsor class: OTHER
First posted: 2008-08-04
Enrollment: 42
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This is a phase I - II multicenter, non-comparative, open label study in patients with previously treated CLL aimed at defining the MTD of Lenalidomide given in combination with Fludarabine, Cyclophosphamide and at evaluating the (CR) rate of FC given in combination with the MTD of Lenalidomide (FCL).

Detailed description: OBJECTIVES:

Primary

* To define the maximum tolerated dose (MTD) of Lenalidomide given in combination with FC.(Phase I)
* To evaluate the complete remission (CR) rate of FC given in combination with the MTD of Lenalidomide (FCL). (Phase II)

Secondary

* To define the toxicity and the infection rate of patients treated with FCL and the median number of delivered courses of FCL, overall response rate and the progression-free survival and the relationship between the response and the baseline biologic factors (IgVH, FISH, ZAP-70, CD38).
* To evaluate the overall response rate (complete and partial responses).
* To evaluate the progression-free survival.

OUTLINE: This is a phase I - II multicenter, non-comparative, open label study in patients with previously treated CLL aimed at defining the MTD of Lenalidomide given in combination with Fludarabine, Cyclophosphamide and at evaluating the (CR) rate of FC given in combination with the MTD of Lenalidomide (FCL).

All patients will receive six monthly courses of FCL schedule consisting of three days of Fludarabine and Cyclophosphamide administration (d1-d3) combined with 14 days of Lenalidomide administration (d1-d14).

After completion of study treatment, patients are followed periodically for up to 18 months.

Eligibility criteria: Inclusion criteria:

* Age \>=18 years.
* Able to adhere to the study visit schedule and other protocol requirements.
* Patients with advanced stage or progressive CLL (NCI criteria) and relapsed or refractory disease.
* No more than 2 previous different treatment lines.
* No treatment with Campath-1H in the previous 6 months.
* Disease-free of prior malignancies for \>=5 years, with the exception of currently treated basal cell, squamous cell carcinoma of the skin, or carcinoma "in situ" of the cervix or breast.
* All previous cancer therapy, including chemotherapy, immunotherapy and surgery, must have been discontinued at least 4 weeks prior to treatment in this study.
* ECOG performance status of \<=2 at study entry.
* Laboratory test results within these ranges:

  * Serum creatinine \<=1.5 mg/dL and creatinine clearance ≥60mL/min
  * Total bilirubin \<=1.5 mg/dL
  * AST (SGOT) and ALT (SGPT) \<=1.5 x ULN
* Able to take low molecular weight heparin or in alternative, low- fixed-dose warfarin or, in alternative, low-dose aspirin.
* Able to understand and voluntarily sign the informed consent form.
* Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL 10 - 14 days prior to therapy and repeated within 24 hours of starting study. FCBP must agree to use two reliable forms of contraception for at least 28 days before starting study drug; while participating in the study; and for at least 4 weeks after discontinuation from the study.
* Females must agree to abstain from breastfeeding during study participation and for at least 28 days after discontinuation from the study.
* Males must agree to use a latex condom during sexual contact with females of childbearing potential while participating in the study and for at least 4 weeks following discontinuation.
* (Other details regarding pregnancy tests and contraception are reported in the chapter "Eligibility Criteria" within the study protocol).

Exclusion criteria:

* Treatment with Campath-1H during the previous 6 months.
* Concurrent use of other anti-cancer agents.
* Positive DAT with clinical and laboratory signs of hemolysis, autoimmune thrombocytopenia.
* Known positivity for HIV or active infectious hepatitis.
* Active bacterial, viral, or fungal infection requiring systemic anti-viral, antibiotic or anti-fungal therapy.
* Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent form.
* Pregnant or breast feeding females (lactating females must agree not to breast feed while taking Lenalidomide).
* Any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study or confounds the ability to interpret data from the study.
* Prior history or presence of thrombosis, thromboembolism, hearth failure or arrhythmia, neurologic disease and renal insufficiency.
* Use of any other experimental drug or therapy within 28 days of baseline.
* Known hypersensitivity to thalidomide.
* The development of erythema nodosum, desquamating rash while taking thalidomide or similar drugs.
* Any prior use of Lenalidomide
* Lactose intolerance

Primary outcomes:
measure: Maximum Tolerated Dose of Lenalidomide (Phase I)
timeFrame: The MTD of Lenalinomide will be evaluated during the two courses given with the escalated dose of Lenalinomide defined by the respective dose level.
measure: Overall Complete Response (CR) Rate (Phase II)
timeFrame: After 6 months from study entry (end of treatment).
Secondary outcomes:
measure: Number of Patients Reaching Disease-free Survival (DSF) Overall
timeFrame: After 6 months from study entry (end of treatment)
measure: Toxicity as Assessed by NCI CTCAE v3.0
timeFrame: At 24 months from study entry (end of follow-up)
measure: Number of Patients With Severe Infections
timeFrame: At 24 months from study entry (end of follow-up)
measure: Correlation Between Complete Response (CR) and Baseline Biologic Parameters (i.e., IgHV, CD38, Etc.).
timeFrame: After 6 months from study entry (end of treatment).
Other outcomes:
Locations:
city: Bari
country: Italy
facility: Unità Operativa Ematologia 1 - Università degli Studi di Bari
city: Bologna
country: Italy
facility: Istituto di Ematologia e Oncologia Medica "Lorenzo e A. Seragnoli" - Università degli Studi di Bologna - Policlinico S. Orsola - Malpighi
city: Catanzaro
country: Italy
facility: Azienda Ospedaliera Pugliese Ciaccio
city: Ferrara
country: Italy
facility: Sez.Ematologia e Dip. scienze Biomediche Arcispedale S. Anna
city: Genova
country: Italy
facility: Clinica Ematologica - Università degli Studi
city: Latina
country: Italy
facility: Divisione di Ematologia Ospedale "Santa Maria Goretti"
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"
city: Milano
country: Italy
facility: UO Centro Trapianti di Midollo - IRCCS Ospedale Maggiore Policlinico
city: Nocera Inferiore
country: Italy
facility: (SA) U.O. di Oncoematologia di Nocera Inferiore-plesso ospedaliero "A. Tortora" di Pagani del DEA Nocera-Pagani
city: Padova
country: Italy
facility: Università degli Studi di Padova - Ematologia ed Immunologia Clinica
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 di Piacenza
city: Ravenna
country: Italy
facility: Ospedale S. M. delle Croci
city: Reggio Calabria
country: Italy
facility: Azienda Ospedaliera Bianchi Melacrino Morelli
city: Rimini
country: Italy
facility: Ospedale "Infermi"
city: Roma
country: Italy
facility: Università degli Studi "Sapienza" - Dip Biotecnologie Cellulari ed Ematologia - Divisione di Ematologia
city: Rome
country: Italy
facility: Universita Degli Studi "La Sapeinza"
city: Rome
country: Italy
facility: Policlinico A. Gemelli - Universita Cattolica del Sacro Cuore
city: Rome
country: Italy
facility: U.O.C. Ematologia - Ospedale S.Eugenio
city: Siena
country: Italy
facility: U.O. Ematologia, Azienda Ospedaliera Universitaria Senese
city: Terni
country: Italy
facility: SS.C. di Oncoematologia - Dipartimento di Medicina Clinica e Sperimentale - Azienda Ospedaliera - S. Maria Di Terni
city: Udine
country: Italy
facility: Clinica Ematologica - Policlinico Universitario
Study officials:
affiliation: Universita Degli Studi "La Sapeinza"
name: Roberto Foa, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Mauro FR, Carella AM, Molica S, Paoloni F, Liberati AM, Zaja F, Belsito V, Cortellezzi A, Rizzi R, Tosi P, Spriano M, Ferretti A, Nanni M, Marinelli M, De Propris MS, Orlando SM, Vignetti M, Cuneo A, Guarini AR, Foa R. Fludarabine, cyclophosphamide and lenalidomide in patients with relapsed/refractory chronic lymphocytic leukemia. A multicenter phase I-II GIMEMA trial. Leuk Lymphoma. 2017 Jul;58(7):1640-1647. doi: 10.1080/10428194.2016.1258698. Epub 2016 Nov 23.