Trial of Pentostatin Plus Cyclophosphamide With Ofatumumab (PCO) in Older Patients With Chronic Lymphocytic Leukemia

A Single-arm Multi-center Trial of Pentostatin Plus Cyclophosphamide With Ofatumumab (PCO) in Older Patients With Previously Untreated Chronic Lymphocytic Leukemia

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).

Study Overview

• Status: Completed
• Conditions: Chronic Lymphocytic Leukemia
• Intervention / Treatment: Drug: Pentostatin; Drug: Cyclophosphamide; Drug: Ofatumumab

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.

• Study Type: Interventional
• Enrollment (Actual): 47
• Phase: Phase 2

Contacts and Locations

Study Locations

• Italy
  • Bergamo, Italy, 24128
    • A.O. Papa Giovanni XXIII U.S.C. Ematologia
  • Brescia, Italy, 25125
    • Presidi Ospedalieri Spedali Civili di Brescia Divisione di Ematologia
  • Como, Italy, 22100
    • Ospedale Valduce S.C. Medicina Interna Sez. Ematologia
  • Milano, Italy, 20122
    • Ospedale Maggiore Policlinico Università di Milano Istituto di Ematologia
  • Milano, Italy, 20132
    • IRCCS Fondazione Centro S. Raffaele del Monte Tabor Università Vita-Salute Dipartimento di Medicina Interna
  • Milano, Italy, 20162
    • Ospedale Cà Granda - Niguarda S.C: Ematologia
  • Novara, Italy, 28100
    • Azienda ospedaliera-universitaria Maggiore della Carità SCDU Ematologia
  • Pavia, Italy, 27100
    • IRCCS Policlinico San Matteo Pavia Istituto di Ematologia
  • Torino, Italy, 10126
    • A.O.U. Città della Salute e della Scienza Ospedale Molinette Divisione di Ematologia
  • MB
    • Monza, MB, Italy, 20052
      • Azienda Ospedaliera San Gerardo di Monza U.O. Ematologia
  • MI
    • Legnano, MI, Italy, 20025
      • Azienda Ospedaliera Ospedale Civile di Legnano U.O. Medicina Interna
  • Milano
    • Rozzano, Milano, Italy, 20089
      • IRCCS Istituto clinico Humanitas di Rozzano Dipartimento di Ematologia

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 65 years and older (Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Pentostatin/Cyclophosphamide/Ofatumumab; Subjects will receive up to 6 cycles of pentostatin, cyclophosphamide, and ofatumumab given every 21 days (+/- 4 days).	Drug: Pentostatin; Lyophilized powder for intravenous administration.; Other Names: Nipent 10 mg; Drug: Cyclophosphamide; IV; Drug: Ofatumumab; Liquid concentrate for solution for infusion.; Other Names: Arzerra 100 mg

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response Rate (ORR)	To assess the overall response rate (ORR) using pentostatin, cyclophosphamide, and ofatumumab in patients with previously untreated CLL requiring therapy.	2 months after the last dose received (End of treatment period)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse Events according to CTCAE, Version 3.0 NCI CTCAE	To monitor and assess toxicity of pentostatin, cyclophosphamide, and ofatumumab in patients with previously untreated CLL.	From informed consent signed through to 28 days after the last study drug administration
Complete Response Rate (CRR)	To assess the complete response of CLL patients treated with pentostatin, cyclophosphamide, and ofatumumab	Baseline, at cycle 3 and 2 months after the last dose received
Minimal Residual Disease (MRD)	To determine the proportion of patients who achieve a minimal residual disease (MRD) negative state as assessed by flow cytometry.It will be assessed only in patients responding to PCO treatment.	Every 3 months from the last dose of treatment up to 2 years follow up.
Progression-Free Survival	To determine the progression-free survival in CLL patients treated with pentostatin,cyclophosphamide, and ofatumumab.	Measured as the time from inclusion in the trial to disease progression or death, assessed up to 2 years
Overall Survival (OS)	To assess overall survival (OS) of CLL patients treated with pentostatin, cyclophosphamide, and ofatumumab	Measured as the time from inclusion in the trial until death from any cause, assessed up to 2 years of follow up
Time To Progression (TTP)	To assess the time-to-progression (TTP) of CLL patients treated with pentostatin, cyclophosphamide, and ofatumumab	Measured as the time from inclusion in the trial until disease progression or death, assessed up to 2 years
Genetic analysis by Fish	To determine if cytogenetic abnormalities identified by FISH, relate to response to PCO therapy.	Baseline, 2 months after the last dose received and at month 12 and 24 during follow up
Ofatumumab pharmacokinetics parameter	To assess ofatumumab pharmacokinetic parameters	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
IgVH mutation status	To determine if IgVH mutation status relate to response to PCO therapy	Baseline, 2 months after the last dose received and at month 12 and 24 during follow up

Collaborators and Investigators

• Sponsor: Niguarda Hospital
• Collaborators: GlaxoSmithKline; Hospira, now a wholly owned subsidiary of Pfizer; Regione Lombardia
• Investigators: Study Director: Marco Montillo, MD, Ospedale Cà Granda - Niguarda S.C: Ematologia; Principal Investigator: Agostino Cortelezzi, MD, Ospedale Maggiore Policlinico Università di Milano Istituto di Ematologia; Principal Investigator: Giovanni Ucci, MD, ASL della provincia di Lodi Presidio Ospedaliero di Lodi Dipartimento di Medicina Interna; Principal Investigator: Ester Orlandi, MD, IRCCS Policlinico San Matteo Pavia Istituto di Ematologia; Principal Investigator: Fausto Rossini, MD, Azienda Ospedaliera San Gerardo di Monza U.O. Ematologia; Principal Investigator: Armando Santoro, MD, IRCCS Istituto clinico Humanitas di Rozzano Dipartimento di Ematologia; Principal Investigator: Paolo Ghia, MD, IRCCS Ospedale S. Raffaele Università Vita-Salute Dipartimento di Medicina Interna; Principal Investigator: Marina Motta, MD, Presidi Ospedalieri Spedali Civili di Brescia Divisione di Ematologia; Principal Investigator: Gianluca Gaidano, MD, Azienda Ospedaliero-Universitaria Maggiore della Carità - Struttura Complessa a Direzione Universitaria (SCDU Ematologia); Principal Investigator: Mauro Turrini, MD, Ospedale Valduce S.C. Medicina Interna Sezione di Ematologia; Principal Investigator: Pierangelo Spedini, MD, Istituti Ospitalieri di Cremona U.O.Complessa di Ematologia e CTMO; Principal Investigator: Marta Coscia, MD, AOU Città della Salute e della Scienza Ospedale Molinette Divisione di Ematologia; Principal Investigator: Antonino Mazzone, MD, Azienda Ospedaliera Ospedale Civile di Legnano U.O. Medicina Interna; Principal Investigator: Alessandro Rambaldi, MD, A.O. Papa Giovanni XXIII di Bergamo USC Ematologia

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: September 1, 2011
• Primary Completion (Actual): November 1, 2015
• Study Completion (Actual): December 1, 2016

Study Registration Dates

• First Submitted: June 18, 2012
• First Submitted That Met QC Criteria: September 5, 2012
• First Posted (Estimate): September 10, 2012

Study Record Updates

• Last Update Posted (Estimate): December 28, 2016
• Last Update Submitted That Met QC Criteria: December 27, 2016
• Last Verified: December 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Leukemia, B-Cell; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Lymphoid; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Adenosine Deaminase Inhibitors; Cyclophosphamide; Ofatumumab; Pentostatin
• Other Study ID Numbers: PCO; 2010-022332-37 (EudraCT Number)