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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Chronic Lymphocytic Leukemia

Intervention / Treatment
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* Drug: Pentostatin
* Drug: Cyclophosphamide
* Drug: Ofatumumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of B-CLL defined by: 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 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: Unintentional Weight loss ³ 10% within the previous six months Fevers > 38.0 °C for ≥ 2 weeks without evidence of infection 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: Creatinine Clearance < 60 mL/min Total bilirubin > 2.0 times upper normal limit (unless due to liver involvement of BCLL) 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

Ages Eligible for Study
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Minimum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

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

What is the study measuring?
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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 |