Clinical trial NCT01681563: Trial of Pentostatin Plus Cyclophosphamide With Ofatumumab (PCO) in Older Patients With Chronic Lymphocytic Leukemia
Official title: A Single-arm Multi-center Trial of Pentostatin Plus Cyclophosphamide With Ofatumumab (PCO) in Older Patients With Previously Untreated Chronic Lymphocytic Leukemia
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Chronic Lymphocytic Leukemia
Lead sponsor: Niguarda Hospital
Sponsor class: OTHER
Collaborators: name: Regione Lombardia
name: GlaxoSmithKline
name: Hospira, now a wholly owned subsidiary of Pfizer
First posted: 2012-09-10
Enrollment: 47
Sex: ALL
Minimum age (years): 65
Standard ages: OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This is a phase II multicenter, non-comparative, open label study in older previously untreated Chronic Lymphocytic Leukaemia patients, requiring therapy, aimed at defining the efficacy profile (ORR, CRR and TTP) of pentostatin and cyclophosphamide given in combination with Ofatumumab (PCO).

Detailed description: Chronic lymphocytic leukemia (CLL) is the most common of the chronic lymphoid leukemias, comprising 30% of all adult leukemias. The majority of CLL patients are of advanced age. Currently, immunochemotherapy with Rituximab, Fludarabine and Cyclophosphamide (RFC) is the standard of care in previously untreated patients with CLL requiring treatment. The combination of Pentostatin and Cyclophosphamide has generated excellent clinical response rates in pretreated B-CLL patients. Early data on the use of Ofatumumab as a single agent in Fludarabine-refractory CLL patients have been reported. Given the reported efficacy of chemo-immunotherapy combinations in CLL and the promising activity and toxicity profile of Pentostatin combinations, we designed a trial of Pentostatin, Cyclophosphamide, and Ofatumumab for previously untreated older patients with CLL. The aim is improving efficacy, in Rituximab resistant CLL, and toxicity considering the good profile of tolerability showed using Ofatumumab as single agent.

Eligibility criteria: Inclusion Criteria:

* Diagnosis of B-CLL defined by:

  1. Circulating lymphocytes of more than or equal to 5 x109/L B lymphocytes (5000/mL) in the peripheral blood for the duration of at least 3 months. AND
  2. Flow cytometry confirmation of immunophenotype: CD5, CD19, CD20, CD23, CD79b, and surface Ig
* Age ≥ 65 years
* Active disease and indication for treatment based on modified NCI-WG guidelines defined by presenting at least any one of the following conditions:
* Evidence of progressive marrow failure as manifested by development of, or worsening of anemia and/or thrombocytopenia
* Massive (i.e. \> 6 cm below the left costal margin) or progressive or symptomatic splenomegaly
* Massive nodes (i.e. \> 10 cm in longest diameter) or progressive or symptomatic lymphadenopathy
* Progressive lymphocytosis with an increase of \> 50% over a two month period or an lymphocyte doubling time \< 6 months
* A minimum of any one of the following disease-related symptoms must be present:

  1. Unintentional Weight loss ³ 10% within the previous six months
  2. Fevers \> 38.0 °C for ≥ 2 weeks without evidence of infection
  3. Night sweats for more than 1 month without evidence of infection
* Not been previously treated for B-CLL (prior autoimmune hemolytic anemia treatment permitted)
* ECOG Performance Status of 0-2
* Signed written informed consent prior to performing any study-specific procedures

Exclusion Criteria:

* Prior therapy for B-CLL with any agent except corticosteroids used to treat autoimmune hemolytic anemia
* Active autoimmune hemolytic anemia (AIHA) requiring corticosteroid therapy \> 100 mg equivalent to hydrocortisone, or chemotherapy
* Known Richter transformation
* Known CNS involvement of B-CLL
* Any radiation therapy ≤ 4 weeks prior to registration;
* Any major surgery ≤ 4 weeks prior to registration;
* 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 and active Hepatitis C
* Past or current malignancy with the exception of basal cell carcinoma of the skin or in situ carcinoma of the cervix or the breast unless the tumor was successfully treated with curative intend at least 2 years prior to trial entry.
* Clinically significant cardiac disease including unstable angina, acute myocardial infarction within 6 months prior to Visit 1, congestive heart failure, and arrhythmia requiring therapy, with the exception of extra systoles or minor conduction abnormalities
* History of significant cerebrovascular disease
* Glucocorticoid unless given in doses ≤ 100 mg/day hydrocortisone (or equivalent dose of other glucocorticoid) if for exacerbations other than B-CLL (e.g. asthma)
* Known HIV positive
* Positive serology for Hepatitis B (HB), defined as a positive test for HBsAg. In addition if negative for HBsAg but HBcAb positive and HBsAb negative a HB DNA test will be performed and if positive the subject will be excluded. Note: if HBcAb positive and HBsAb positive, which is indicative of a past infection, the subject can be included.
* Screening laboratory values:

  1. Creatinine Clearance \< 60 mL/min
  2. Total bilirubin \> 2.0 times upper normal limit (unless due to liver involvement of BCLL)
  3. ALT \> 3.0 times upper normal limit (unless due to liver involvement of B-CLL)
* Treatment with any non-marketed drug substance or experimental therapy within 4 weeks prior to Visit 1 or currently participating in any other interventional clinical study
* Known or suspected inability to comply with the study protocol

Primary outcomes:
measure: Overall Response Rate (ORR)
timeFrame: 2 months after the last dose received (End of treatment period)
Secondary outcomes:
measure: Adverse Events according to CTCAE, Version 3.0 NCI CTCAE
timeFrame: From informed consent signed through to 28 days after the last study drug administration
measure: Complete Response Rate (CRR)
timeFrame: Baseline, at cycle 3 and 2 months after the last dose received
measure: Minimal Residual Disease (MRD)
timeFrame: Every 3 months from the last dose of treatment up to 2 years follow up.
measure: Progression-Free Survival
timeFrame: Measured as the time from inclusion in the trial to disease progression or death, assessed up to 2 years
measure: Overall Survival (OS)
timeFrame: Measured as the time from inclusion in the trial until death from any cause, assessed up to 2 years of follow up
measure: Time To Progression (TTP)
timeFrame: Measured as the time from inclusion in the trial until disease progression or death, assessed up to 2 years
measure: Genetic analysis by Fish
timeFrame: Baseline, 2 months after the last dose received and at month 12 and 24 during follow up
measure: Ofatumumab pharmacokinetics parameter
timeFrame: Cycle1: Day 1, 2, 3, 8, 9, 15. Cycles 2-5: Day 1, 2, 3, 8,15. Cycle 6: Day 1, 2, 3, 8, 15, 21
measure: IgVH mutation status
timeFrame: Baseline, 2 months after the last dose received and at month 12 and 24 during follow up
Other outcomes:
Locations:
city: Monza
country: Italy
facility: Azienda Ospedaliera San Gerardo di Monza U.O. Ematologia
state: MB
city: Rozzano
country: Italy
facility: IRCCS Istituto clinico Humanitas di Rozzano Dipartimento di Ematologia
state: Milano
city: Legnano
country: Italy
facility: Azienda Ospedaliera Ospedale Civile di Legnano U.O. Medicina Interna
state: MI
city: Bergamo
country: Italy
facility: A.O. Papa Giovanni XXIII U.S.C. Ematologia
city: Brescia
country: Italy
facility: Presidi Ospedalieri Spedali Civili di Brescia Divisione di Ematologia
city: Como
country: Italy
facility: Ospedale Valduce S.C. Medicina Interna Sez. Ematologia
city: Milano
country: Italy
facility: Ospedale Maggiore Policlinico Università di Milano Istituto di Ematologia
city: Milano
country: Italy
facility: IRCCS Fondazione Centro S. Raffaele del Monte Tabor Università Vita-Salute Dipartimento di Medicina Interna
city: Milano
country: Italy
facility: Ospedale Cà Granda - Niguarda S.C: Ematologia
city: Novara
country: Italy
facility: Azienda ospedaliera-universitaria Maggiore della Carità SCDU Ematologia
city: Pavia
country: Italy
facility: IRCCS Policlinico San Matteo Pavia Istituto di Ematologia
city: Torino
country: Italy
facility: A.O.U. Città della Salute e della Scienza Ospedale Molinette Divisione di Ematologia
Study officials:
affiliation: Ospedale Cà Granda - Niguarda S.C: Ematologia
name: Marco Montillo, MD
role: STUDY_DIRECTOR
affiliation: Ospedale Maggiore Policlinico Università di Milano Istituto di Ematologia
name: Agostino Cortelezzi, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: ASL della provincia di Lodi Presidio Ospedaliero di Lodi Dipartimento di Medicina Interna
name: Giovanni Ucci, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: IRCCS Policlinico San Matteo Pavia Istituto di Ematologia
name: Ester Orlandi, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Azienda Ospedaliera San Gerardo di Monza U.O. Ematologia
name: Fausto Rossini, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: IRCCS Istituto Clinico Humanitas di Rozzano Dipartimento di Ematologia
name: Armando Santoro, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: IRCCS Ospedale S. Raffaele Università Vita-Salute Dipartimento di Medicina Interna
name: Paolo Ghia, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Presidi Ospedalieri Spedali Civili di Brescia Divisione di Ematologia
name: Marina Motta, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Azienda Ospedaliero-Universitaria Maggiore della Carità - Struttura Complessa a Direzione Universitaria (SCDU Ematologia)
name: Gianluca Gaidano, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Ospedale Valduce S.C. Medicina Interna Sezione di Ematologia
name: Mauro Turrini, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Istituti Ospitalieri di Cremona U.O.Complessa di Ematologia e CTMO
name: Pierangelo Spedini, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: AOU Città della Salute e della Scienza Ospedale Molinette Divisione di Ematologia
name: Marta Coscia, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Azienda Ospedaliera Ospedale Civile di Legnano U.O. Medicina Interna
name: Antonino Mazzone, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: A.O. Papa Giovanni XXIII di Bergamo USC Ematologia
name: Alessandro Rambaldi, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Tedeschi A, Rossi D, Motta M, Quaresmini G, Rossi M, Coscia M, Anastasia A, Rossini F, Cortelezzi A, Nador G, Scarfo L, Cairoli R, Frustaci AM, Dalceggio D, Picardi P, De Paoli L, Orlandi E, Rambaldi A, Massaia M, Gaidano G, Montillo M; Rete Ematologica Lombarda-CLL Workgroup. A phase II multi-center trial of pentostatin plus cyclophosphamide with ofatumumab in older previously untreated chronic lymphocytic leukemia patients. Haematologica. 2015 Dec;100(12):e501-4. doi: 10.3324/haematol.2015.132035. Epub 2015 Aug 20. No abstract available.