Clinical trial NCT01392079: Subcutaneous Alemtuzumab Combined With Oral Dexamethasone, Followed by Alemtuzumab Maintenance or Allo-SCT in CLL With 17p- or Refractory to Fludarabine
Official title: A Prospective, Multi-center Phase II Study of Subcutaneous Alemtuzumab Combined With Oral Dexamethasone, Followed by Alemtuzumab Maintenance or Allogeneic Stem-cell Transplantation, in Chronic Lymphocytic Leukemia Which is Associated With 17p Deletion or is Refractory to Fludarabine
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Chronic Lymphocytic Leukemia
Keywords: CLL
17p deletion
refractory to fludarabine
subcutaneous alemtuzumab
CLL with 17p- or refractory to fludarabine
Lead sponsor: University of Ulm
Sponsor class: OTHER
Collaborators: name: Technical University of Munich
name: WiSP Wissenschaftlicher Service Pharma GmbH
name: German CLL Study Group
First posted: 2011-07-12
Enrollment: 135
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: Aims and objectives

* Assessment of the efficacy of the study treatment in the study population in terms of response rate, progression-free survival, failure-free survival and overall survival.
* Acquisition of further data to expand the data base on the toxicity of the study treatment.
* Assessment of the efficacy of the study treatment in biological risk groups.
* Assessment of response in terms of minimal residual disease. Number of patients and estimated duration Total no. of patients: 122 (\~29 with 17p deletion for first-line therapy, \~29 with 17p deletion for second- or higher-line treatment, \~65 fludarabine-refractory irrespective of 17p status).

Duration for each patient: Max. 12 weeks of treatment in three 4-week cycles, then up to two years maintenance treatment.

Detailed description: 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:

* Start of recruitment: January 2008
* End of recruitment: September 2011
* End of study procedures (conclusion of maintenance therapy): December 2013 (plus eventual additional follow-up)

Eligibility criteria: Inclusion Criteria:

1. The patient has CLL requiring treatment (Binet C or A/B with "active disease" according to the NCI criteria).
2. One or both of the following is true:

   * The patient's disease is refractory to a previous fludarabine-containing regimen, defined as no CR or PR according to NCI criteria, or progression within 6 months after a fludarabine-containing regime. (N.B.: Within the framework of this trial, the term "fludarabine-refractory" is synonymous to a refractory status to any established purine analogue (i.e. pentostatin, cladribine); this also encompasses bendamustine, as this drug molecule contains both an alkylating and a purine analogue moiety. Acc. to experimental findings and clinical experience, its mechanism of action differs distinctly from that of a pure alkylator (Cheson et al., 2009, Leoni et al., 2008)).
   * 17p deletion is present (irrespective of whether previously treated or untreated).
3. The patient is at least 18 years of age.
4. The patient's performance status is 0, 1 or 2 on the WHO/ECOG scale.
5. Any previous chemotherapy and/or immunotherapy ended at least four weeks before the first study treatment with alemtuzumab.
6. The patient has recovered from all previous chemotherapy and/or immunotherapy.
7. For fertile men and for women of childbearing potential: Adequate contraception (oral contraceptives, intrauterine device or barrier method in conjunction with spermicidal jelly).
8. The patient has given written informed consent to participate in the study.

Exclusion Criteria:

1. The patient has received more than five different prior therapeutic regimens.
2. Any major organ dysfunction is present (e.g. unstable angina pectoris, NYHA III/IV heart insufficiency, significant coronary stenoses, uncontrolled diabetes mellitus, uncontrolled hypertension, pulmonary disease with hypoxemia, renal failure).
3. Any of the following laboratory values are found at the screening visit to be \>2 × the upper limit of the normal range: serum creatinine, serum bilirubin, ASAT, ALAT.
4. Any active infection is present.
5. B-PLL or Richter transformation is diagnosed or suspected (e.g. symptoms or cytology).
6. There is involvement of the central nervous system.
7. The patient is known to be positive for human immunodeficiency virus (HIV).
8. CMV viremia is present, as demonstrated by pp65 EA or CMV-DNA.
9. The patient has previously been treated with alemtuzumab. (Exception: alemtuzumab used in a "non-therapeutic" context, i.e. administered as part of a conditioning regimen prior to SCT).
10. The patient has received autologous or allogeneic SCT within the past six months.
11. The patient is receiving long-term systemic treatment with corticosteroids or has received such treatment in the four weeks before first treatment with alemtuzumab.
12. Any additional active malignancy is present.
13. The patient has ever had an anaphylactic response to humanized antibodies.
14. For female patients: The patient is pregnant or lactating.
15. The patient has a history of drug or alcohol abuse that might lead to inability to comply with the protocol.

Primary outcomes:
measure: Response rate
timeFrame: 2.5 years
Secondary outcomes:
measure: Progression-free-survival
timeFrame: up to five years
measure: Failure-free survival
timeFrame: up to five years
measure: Overall survival
timeFrame: up to five years
measure: Number of participants with Adverse Events as a measure of safety and tolerability
timeFrame: up to 2.5 years
Other outcomes:
Locations:
city: Wien
country: Austria
facility: Hanuschkrankenhaus Wien
city: Wien
country: Austria
facility: University Hospital
city: Bayonne
country: France
facility: Centre Hospitalier de la Côte Basque
city: Bobigny Cedex
country: France
facility: Hopital Avicenne
city: Clermont-Ferrand
country: France
facility: CHU Estaing
city: CRETEIL Cedex
country: France
facility: Hôpital Henri Mondor, Creteil -APHP
city: Grenoble
country: France
facility: CHU de Grenoble
city: Lille
country: France
facility: CHU Claude Huriez
city: Lyon
country: France
facility: Hôpital Edouard Herriot Lyon
city: NANCY Cedex
country: France
facility: CHU de Nancy
city: Nantes
country: France
facility: CHU Nantes
city: Paris
country: France
facility: Hôpital Pitié Salpêtrière Paris-APHP
city: Paris
country: France
facility: Hôpital Saint-Louis Paris -APHP
city: PERPIGNAN Cedex
country: France
facility: Centre Hospitalier Marechal Joffre Hôpital Saint-Jean Perpignan
city: POITIERS Cedex
country: France
facility: CHU de Poitiers
city: Reims
country: France
facility: CHU Robert-Debre
city: Tours
country: France
facility: CHU de Tours
city: Berlin
country: Germany
facility: Charité CBF Berlin
city: Cologne
country: Germany
facility: University of Cologne
city: Dresden
country: Germany
facility: Dresden Universtiy Hospital
city: Essen
country: Germany
facility: Essen University
city: Freiburg
country: Germany
facility: Freiburg University
city: Grosshadern
country: Germany
facility: LMU Munich
city: Göttingen
country: Germany
facility: Goettingen University
city: Hamburg
country: Germany
facility: AK St. Georg Hamburg
city: Hannover
country: Germany
facility: Hannover medical school (MHH)
city: Heidelberg
country: Germany
facility: Heidelberg University
city: Homburg/Saar
country: Germany
facility: Homburg/Saar University
city: Kassel
country: Germany
facility: Dr. Soeling Kassel
city: Kiel
country: Germany
facility: Kiel University
city: Mainz
country: Germany
facility: Mainz University
city: Munich
country: Germany
facility: TU Munich
city: Nuernberg
country: Germany
facility: Nuernberg University Hospital
city: Regensburg
country: Germany
facility: OncoProGbR Regensburg
city: Tuebingen
country: Germany
facility: Universtiy of Tuebingen
city: Ulm
country: Germany
facility: University of ulm
city: Wuerzburg
country: Germany
facility: Dr. Schlag Wuerzburg
city: Wuerzburg
country: Germany
facility: University Hospital Wuerzburg
Study officials:
affiliation: University of Ulm
name: Stephan Stilgenbauer, Prof Dr med
role: PRINCIPAL_INVESTIGATOR
References:
citation: Edelmann J, Holzmann K, Tausch E, Saunderson EA, Jebaraj BMC, Steinbrecher D, Dolnik A, Blatte TJ, Landau DA, Saub J, Estenfelder S, Ibach S, Cymbalista F, Leblond V, Delmer A, Bahlo J, Robrecht S, Fischer K, Goede V, Bullinger L, Wu CJ, Mertens D, Ficz G, Gribben JG, Hallek M, Dohner H, Stilgenbauer S. Genomic alterations in high-risk chronic lymphocytic leukemia frequently affect cell cycle key regulators and NOTCH1-regulated transcription. Haematologica. 2020 May;105(5):1379-1390. doi: 10.3324/haematol.2019.217307. Epub 2019 Aug 29.
citation: Steinbrecher D, Jebaraj BMC, Schneider C, Edelmann J, Cymbalista F, Leblond V, Delmer A, Ibach S, Tausch E, Scheffold A, Bloehdorn J, Hallek M, Dreger P, Dohner H, Stilgenbauer S. Telomere length in poor-risk chronic lymphocytic leukemia: associations with disease characteristics and outcome. Leuk Lymphoma. 2018 Jul;59(7):1614-1623. doi: 10.1080/10428194.2017.1390236. Epub 2017 Oct 24.