A Phase 2 interventional study of Alemtuzumab in Chronic Lymphocytic Leukemia, sponsored by University of Ulm. Completed at 38 sites in 3 countries. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2019-10-24.
Sponsored by University of Ulm · Phase 2, Interventional, and Treatment
Aims and objectives
Duration for each patient: Max. 12 weeks of treatment in three 4-week cycles, then up to two years maintenance treatment.
CLL refractory to therapy based on fludarabine or with 17p deletion has a poor prognosis. Patients with F-refractory CLL have a remission rate of 20% after various salvage regimens and a median overall survival (OS) of \<12 months (Keating et al., 2002a). CLL patients with 17p deletion have a median OS of 16 months after first-line treatment with fludarabine or FC in the CLL4 trial of the GCLLSG (Figure 2; Stilgenbauer et al., 2005b; Eichhorst et al., 2006).
Alemtuzumab is the most active single agent in fludarabine-refractory CLL, with remission rates of 30-40% and median OS of 16-28 months (Keating et al., 2002b, Rai et al., 2002). Furthermore, alemtuzumab is of proven efficacy in CLL with 17p deletion and the subcutaneous administration is as effective as the intravenous application (Stilgenbauer \& Döhner, 2002, Lozanski et al., 2004, Stilgenbauer et al., 2004).
However, the outcome of fludarabine-refractory CLL is still poor, owing to the facts that the majority of patients do not achieve a remission and that the average duration of remission is short. Therefore, the current trial aims at achieving: (i) a higher remission rate, by adding high-dose dexamethasone to alemtuzumab, and (ii) prolongation of remission duration and survival by alemtuzumab maintenance or allogeneic stem-cell transplantation (SCT). High-dose steroids have shown activity independently of 17p and p53 status, and are effective in debulking large lymph nodes, a weakness of alemtuzumab (Bellosillo et al., 2002, Thornton et al., 2003, Pettitt et al., 2006). Maintenance treatment with alemtuzumab improved remission duration in the CLL4B trial and allogeneic SCT resulted in disease control in high-risk CLL in the CLL3X trial (Wendtner et al., 2004, Dreger et al., 2005).
This is a prospective, open, multi-center Phase II study conducted by the Deutsche CLL Studiengruppe (DCLLSG; German CLL Study Group, GCLLSG). There will be only one treatment group and thus no randomization. The study will be conducted at approximately 40 investigation sites in Germany, Austria and France.
The study will be conducted according to the EG Directive on Good Clinical Practice, the German Arzneimittelgesetz (AMG, 12. Novelle) as well as - with respect to the local activities and regulations - to the corresponding laws in France and Austria.
A total of 122 patients (adults, males and females, in-patients and out-patients; 2 to 10 patients are expected to be recruited by each of the centers) will be recruited, with stratification by detailed diagnosis. The distribution of female and male patients is not relevant for the study as both sexes are affected by CLL and treatment effects are not different in both groups (GCP-V § 7, 2). Recruiting will stop when the 122th. patient has completed the first four-week cycle of treatment. The study will be concluded when the last patient has completed treatment with alemtuzumab according to this protocol. The retrieval of additional follow-up data may be appropriate to achieve mature data in the survival endpoints.
Subcutaneous alemtuzumab (30 mg) will be administered three times weekly (days 1, 3 and 5) along with oral dexamethasone (40 mg/day, days 1-4, every 2 weeks) for at least 4 weeks (corresponding to 12 doses of alemtuzumab, in case of treatment interruption this may take longer than 4 weeks) and, for patients who show at least SD, a maximum of 12 weeks (36 doses of alemtuzumab, in case of treatment interruption this may take longer than 12 weeks). Thereafter, maintenance therapy with alemtuzumab will be instituted for a maximum of two years. If CR (including bone marrow histology and imaging (chest X-ray and ultrasound, CT if indicated) is documented before week 12, i.e. after week 4 (12 doses of 30 mg alemtuzumab) or 8 (24 doses of 30 mg alemtuzumab), maintenance treatment with alemtuzumab will be instituted at this time point.
In this study it is recommended to start the dose of alemtuzumab directly at 30 mg. However, the dose of alemtuzumab can be increased gradually (3 mg day -2, 10 mg day -1 and 30 mg day 1, as in earlier studies), according to the investigators discretion.
Staging will be performed at inclusion to the study and after 12 doses of alemtuzumab (aim: at the end of Week 4), after 24 doses of alemtuzumab (aim: at the end of Week 8), and after 36 doses of alemtuzumab (aim: at the end of Week 12) of treatment. Patients showing progressive disease (PD) (according to NCI criteria) will be withdrawn from the study. If hematological or other toxicity is seen, treatment will be interrupted and the dose will be reduced according to the prescription information.
If after 12 weeks there is stable disease (SD), partial response (PR) or complete response (CR), then maintenance treatment will be given, with continued subcutaneous alemtuzumab (30 mg every 14 days). Patients for whom stem-cell transplantation is a realistic treatment option will be offered the possibility of receiving allogeneic stem-cell treatment in another clinical trial (CLLX2 or other GCLLSG trial). The latter will however only be offered if (1) the patient is eligible according to protocol and (2) a HLA-compatible donor is available who has given his/her informed consent. There should be a treatment-free period of at least 2 months before SCT, details are specified in the corresponding protocol.
Appropriate premedication and infection prophylaxis will be administered. After each disease staging (i.e. every three months during the maintenance phase), if there is SD, PR or CR, then patients will continue study therapy (alemtuzumab maintenance). Maintenance therapy will be stopped after two years.
During the study, continual monitoring of efficacy and toxicity will be performed. Early stopping rules will be applied if major intolerability is observed.
Response will be assessed by clinical examination, blood counts, clinical chemistry, chest X-ray (plain radiograph of the chest), ultrasound of the abdomen, CT scanning (if indicated), bone marrow cytology and histology (only in cases of possible CR), and assessment of MRD (for molecular response rate only). Time points for response evaluation according to NCI criteria will be after 12 doses, 24 doses, and 36 doses of alemtuzumab. For an uninterrupted treatment course, this will be after 4, 8 and 12 weeks respectively. (If treatment with alemtuzumab is interrupted, then the time points for all subsequent doses, assessments and other procedures will be delayed correspondingly; i.e., the number of doses is the determining factor for elapsed treatment time, and not the calendar date; see above, "Staging will be performed...".) Follow-up assessment will continue at three-month intervals for at least three years.
The following time schedule is anticipated for the study:
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Exclusion Criteria:
30 mg alemtuzumab will be administered subcutaneously 3 times weekly for 4 weeks (total of 12 doses of 30 mg alemtuzumab) with premedication (as needed) and infection prophylaxis; combined with oral dexamethasone 40 mg total dose for 4 days every 2 weeks; evaluation at end of cycle (i.e. after 12 doses of 30 mg alemtuzumab). If CR is documented after week 4 (12 doses of 30 mg alemtuzumab) or 8 (24 doses of 30 mg alemtuzumab), maintenance treatment with alemtuzumab or withdrawal from the study and stem cell transplantation will be instituted at this time point. After a maximum of three 4-week cycles (total of 36 doses of 30 mg alemtuzumab, in case of interruptions this may take longer than 12 weeks), maintenance treatment with alemtuzumab or withdrawal from the study and stem cell transplantation will be instituted. Maintenance treatment with alemtuzumab will continue for a maximum of two years, with evaluation every three months, unless there is PD.
Drug: Alemtuzumab
Alemtuzumab 30 mg s.c. 3 × weekly for 28 days (Days 1, 3, 5; 8, 10, 12; etc.)
Response rate
Time points for response evaluation according to NCI criteria will be: * The end of each treatment cycle: after 12 doses (4 weeks actual treatment), 24 doses (8 weeks actual treatment), and 36 doses (12 weeks actual treatment) of alemtuzumab * During maintenance therapy, every three months * During follow-up, every three months * A final response assessment will be made at the end of study treatment if the patient's participation is ended at a point other than one of those specified above.
Time frame: 2.5 years
Progression-free-survival
Progression-free survival: time from study entry to the detection of progressive disease according to NCI criteria or death of any cause, whichever occurs first.
Time frame: up to five years
Failure-free survival
Failure-free survival: time from study entry until next treatment, detection of progressive disease according to NCI criteria or death of any cause, whichever occurs first.
Time frame: up to five years
Overall survival
Time from study entry to death of any cause.
Time frame: up to five years
Number of participants with Adverse Events as a measure of safety and tolerability
Acquisition of further data to expand the data base on the toxicity of the study treatment. (Type, frequency, severity, timing and relatedness of AEs and laboratory abnormalities observed during different treatment cycles)
Time frame: up to 2.5 years
This study is completed, as verified in Oct 2019. You cannot join it, but the record below documents what was studied.
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