Combined Immunochemotherapy in Patients With T-Prolymphocytic Leukemia (T-PLL)

Study Overview
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Brief Summary
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Study hypothesis: Simultaneous FMC-Alemtuzumab administration followed by Alemtuzumab maintenance therapy in patients with T-PLL is feasible, safe and efficient.

Detailed Description
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As the median survival time of patients with T-PLL is less than 12 months, the treatment of T-PLL is a special challenge. The overall response rates with conventional chemotherapy or Deoxycoformycin were low (about 30% and 40%), with the monoclonal antibody Alemtuzumab response rates of 50% to 70% were achieved, but the duration of the response was short. In the previous trial (T PLL 1), the efficacy of the FMC regimen (FMC = Fludarabine, Mitoxantrone and Cyclophosphamide) was tested, a preliminary analysis of 16 patients revealed a response rate of more than 60% after FMC-polychemotherapy and 83% after the subsequent administration of Alemtuzumab. The goal of the T-PLL2-protocol is to assess if the simultaneous administration of FMC-polychemotherapy and Alemtuzumab with a subsequent Alemtuzumab maintenance therapy is capable of improving the remission rate and the disease-free survival time in patients with T-PLL.

Official Title
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Phase II Trial of Combined Immunochemotherapy With Fludarabine, Mitoxantrone, Cyclophosphamide and Alemtuzumab (FMC-Alemtuzumab) in Patients With Previously Treated or Untreated T-Prolymphocytic Leukemia

Conditions
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T-cell-prolymphocytic Leukemia

Intervention / Treatment
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* Drug: Fludarabine, Mitoxantrone, Cyclophosphamide and Alemtuzumab
* Drug: Alemtuzumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Untreated patients with T-prolymphocytic leukemia (T-PLL) according to WHO criteria or pretreated patients (max. one previous treatment) with T-PLL Age ≥ 18 years WHO performance status of 0-2 Life expectancy > 6 months CIRS score >= 6 Left ventricular ejection fraction ≥50% confirmed by echo-cardiogram performed < 6 months before inclusion to the trial and after the end of a possible anthracycline containing pretreatment Adequate liver function as indicated by a total bilirubin, AST and ALT >= 2 the institutional ULN value, unless directly attributable to the T-PLL Creatinine clearance >= 70 ml/min calculated according to the formula of Cockcroft and Gault Seronegativity for HIV, HBV or HCV confirmed by serological testing within 6 weeks prior to registration Willingness of fertile male and female patients to use a highly effective contraceptive method with a Pearl-Index < 1 during and at least six months after the end of the study treatment (e.g. implants, injectables, oral contraceptives in combination with another contraceptive method, some IUDs, sexual abstinence or vasectomised partner) Negative serum pregnancy test one week prior to treatment (required for female patients before and <2 years after onset of menopause) Patient's written informed consent Exclusion Criteria: Clinically significant auto-immune cytopenia or clinically significant hemolytic anaemia with suspicion of immune origin, even if Coombs test is negative Active secondary malignancy requiring treatment (except basal cell carcinoma or tumour curatively treated by surgery) Medical condition requiring prolonged use of oral corticosteroids (> 1 month) Cerebral dysfunction, legal incapacity Any circumstance at the time of study entry that would preclude completion of the study and required follow-up Active infection or severe infection (WHO 4th degree) within the last three months before inclusion to the study Participation in any other clinical trial during this study Known hypersensitivity to any of the study medications (Fludarabine, Cyclophosphamide, Mitoxantrone or Alemtuzumab) Patients who have already received more than 60% of the recommended maximum cumulative dose of an anthracycline (Epirubicine, Adriamycine or Mitoxantrone). This maximum cumulative dose is defined for the individual substances as follows: Epirubicin 900 mg/m² Daunorubicin 550 mg/m², (or 400 mg/m² if the patient received mediastinal irradiation) Adriamycine (Doxorubicine) 550 mg/m² Mitoxantrone 200 mg/m² Patients who already received Fludarabine in combination with Cyclophosphamide or Mitoxantrone Patients who received prior treatment with Alemtuzumab alone or in combination with a purine analogue and who did not achieve a PR that lasted at least 6 months Patients who are employees of the Sponsor (University of Cologne) or the study sites.

Ages Eligible for Study
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Minimum Age: 18 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: FCM-A followed by A-maintenance<br>First treatment phase: Chemoimmunotherapy A-FMC maximum 4 cycles. Second treatment phase: Maintenance-treatment with 30mg Alemtuzumab s.c. | Drug: Fludarabine, Mitoxantrone, Cyclophosphamide and Alemtuzumab<br>* I. First treatment phase: Chemoimmunotherapy A-FMC Alemtuzumab: Cycle 1+2: 10 mg s.c., days 1-3 Cycle 3+4: CR: 10 mg s.c., days 1-3 PR/SD: 30 mg s.c., days 1-3 Fludarabine: 20 mg/m2 i.v., days 1-3 Mitoxantrone: 6 mg/m2 i.v., day 1 Cyclophosphamide: 200 mg/m2 i.v., days 1-3 Repeat day 29, maximum 4 cycles. II. Second treatment phase: Maintenance-treatment with 30mg Alemtuzumab s.c. The maintenance therapy will start one month after the Final Staging and will be administered monthly during the first six months plus once in month 10 and 13.<br>* Other names: Novantron;Drug: Alemtuzumab<br>* maintenance with Alemtuzumab following a induction with combined immunochemotherapy consisting of Fludarabine, cyclophosphamide, mitoxantrone and alemtuzumab<br>* Other names: Mabcampath;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Remission Rate | Efficacy of the FMC therapy and Alemtuzumab Percentage and 95%-confidence-interval of response rates (CR, CRi, nPR, PR, SD and PD) will be provided. | 2 years after trial started | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival Time | OS will be calculated from the patient´s time of recruitment to death from any cause. | 4 years after start of trial | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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T-PLL, Polychemotherapy, Alemtuzumab, Efficacy