Clinical trial NCT03153514: Obinutuzumab Containing Conditioning Regimen for Patients With Poor Risk CLL or Richter's Transformation Requiring Allogeneic Stem Cell Transplantation
Official title: Obinutuzumab Containing Conditioning Regimen for CLL Patients and Patients With Richter's Transformation Requiring an Allogeneic Stem Cell Transplantation
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Chronic Lymphocytic Leukemia
Richter's Transformation
Keywords: CLL
Lead sponsor: German CLL Study Group
Sponsor class: OTHER
Collaborators: name: Hoffmann-La Roche
First posted: 2017-05-15
Enrollment: 3
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The primary objective of the study is to evaluate the feasibility, efficacy and safety of an obinutuzumab containing conditioning regimen for poor risk CLL patients and patients with Richter's transformation requiring an allogeneic stem cell transplantation.

Detailed description: CLL is the most common haematological malignancy in the western world. Though in the majority it behaves like a chronic disease with minimal impact on life expectancy, in around 15-20% of the patients it takes a very aggressive course. Patients who experience a high grade transformation, i.e., Richter's transformation also have a poor prognosis. Despite the advent of new therapeutic agents like Bcl-2 and BTK inhibitors which are revolutionising the outlook for this particular patient cohort, allogeneic stem cell transplantation is the only currently available therapy with the potential to cure. The non relapse mortality associated with this treatment is a major deterrent for physicians and patients alike to opt this intervention. We propose a trial to study the use of a B-cell depleting agent, obinutuzumab to simultaneously reduce tumour bulk control and offer GvHD prophylaxis in the peri-transplant setting and thereby analyse its impact on non relapse morbidity and mortality as well as maximum minimum residual disease (MRD) eradication. All patients with poor risk CLL (current EBMT criteria) and Richter's transformation with the best possible response to available therapies will be considered for the trial. Due to the poor disease control associated with peri-transplant T-cell depletion, obinutuzumab will be used instead of T-cell depleting agents as GvHD prophylaxis.

Eligibility criteria: Inclusion Criteria:

1. Have documented CLL according to iwCLL criteria
2. a) CLL requiring transplant according to the consensus statement 2014

   * Non-response or early relapse within 24 months after purine analogue combination therapy or treatment of similar efficacy plus high risk CLL TP53 deletion/mutation (del 17p-) and/or del 11 plus response to kinase inhibitors or other small molecules or
   * Non-response or early relapse within 24 months after purine analogue combination therapy or treatment of similar efficacy and refractory to or non-tolerating kinase inhibitors or other small molecules or b) Transformation of CLL to aggressive NHL (Richter's transformation) The CLL patients should have at least one therapy with the newer targeted agents such as BCL-2 inhibitors or BCR targeting agents. Both poor risk CLL patients and patients with Richter's transformation should achieve the best possible response defined as disease sensitivity measured as CR, PR or SD prior to transplant with an available salvage therapy
3. Availability of a suitable fully matched (10/10) sibling or unrelated donor
4. Must have an Eastern Cooperative Oncology Group (ECOG) performance status score of ≤ 1.
5. Hematology values within the following limits unless cytopenia is caused by the underlying disease, i.e., no evidence of additional bone marrow dysfunction (e.g. myelodysplastic syndrome 2, hypoplastic bone marrow):

   * Absolute neutrophil count ≥ 1.0 x 109/L
   * Platelets ≥ 50 x 109/L and more than 7 days since last transfusion
6. Adequate liver function as indicated by a total bilirubin AST, and ALT ≤1.5 the institutional ULN value, unless directly attributable to the patient's CLL
7. Negative serological testing for hepatitis B (HBsAg negative and anti-HBc negative, patients positive for anti-HBc may be included if PCR for HBV DNA is negative and HBV-DNA PCR is performed every month until 1 year after last dosage of obinutuzumab), negative testing for hepatitis-C RNA and negative HIV test within 6 weeks prior to registration
8. 18 years of age or older but not older then 70 years
9. Able and willing to provide written informed consent and to comply with the study protocol procedures
10. Patient agrees to inform other physicians about study participation

Exclusion Criteria:

1. Previous allogeneic stem cell transplant
2. Known central nervous system (CNS) involvement
3. Patients with a history of confirmed PML
4. Clinically significant cardiac disease including unstable angina, acute myocardial infarction within six months prior to randomization, congestive heart failure (left ventricular ejection fraction \< 50%).
5. Organ dysfunction DLCO \< 50%, TLC \< 70%, FEV1 \< 70% and or receiving supplementary oxygen, Inadequate renal function: Creatinine clearance \< 50ml/min
6. Patients with active non-controlled infectious disease under treatment (no decrease of CRP or PCT) including active viral infection and active fungal infections with radiological progression despite treatment with Ambisome or active Triazole for more than a month
7. History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies. Known sensitivity or allergy to murine products
8. Hypersensitivity to obinutuzumab or to any of the excipients such as for example Mannitol
9. Hypersensitivity to Fludarabine or hypersensitivity to both Treosulphan and Busulphan or any of the excipients of the used products
10. Hypersensitivity to both Ciclosporin A and calcineurin inhibitors or hypersensitivity to Mycophenolat-Mofetil or any of the excipients of the used products
11. Uncontrolled haemolytic anemia
12. Participation in another experimental drug trial (including chemotherapy, antibody treatment, kinase inhibitors, BCL2-antagonists or immunmodulatory agents) with start of the conditioning regimen/first obinutuzumab application.
13. Pregnant women and nursing mothers (a negative pregnancy test is required for all women of childbearing potential within 14 days before start of treatment)
14. Fertile men or women of childbearing potential unless:

    * Surgically sterile or ≥ 2 years after the onset of menopause
    * Willing to use two methods of reliable contraception including one highly effective (Pearl Index \< 1) such as oral hormonal contraceptives, intrauterine device, sexual abstinence and one additional effective (barrier) while on study and maintained for up to 3 years after allogeneic transplantation or 18 months after the last dose of obinutuzumab therapy, whichever is longer
15. Vaccination with a live vaccine a minimum of 28 days prior to randomization
16. Prisoners or patients who are institutionalized by regulatory or court order or persons who are in dependence to the sponsor or an investigator

Primary outcomes:
measure: PD-free rate
timeFrame: 12 months post-transplant
Secondary outcomes:
measure: Minimal residual disease (MRD) negativity rate
timeFrame: days +60, +90, +180, +270 and months 12, 18 and 24 post-transplant
measure: Overall response rate (ORR)
timeFrame: 6 months post-transplant
measure: Progression-free survival (PFS)
timeFrame: up to month 24 post-transplant
measure: Event-free survival (EFS)
timeFrame: up to month 24 post-transplant
measure: Overall survival (OS)
timeFrame: up to month 24 post-transplant
Other outcomes:
Locations:
city: Bonn
country: Germany
facility: Universitätsklinikum Bonn
city: Essen
country: Germany
facility: Universitätsklinikum Essen
city: Heidelberg
country: Germany
facility: Universitätsklinikum Heidelberg
city: Köln
country: Germany
facility: Universitätsklinikum Köln
city: Leipzig
country: Germany
facility: Universitätsklinikum Leipzig
city: Magdeburg
country: Germany
facility: Universitätsklinikum Magdeburg
city: München
country: Germany
facility: Universitätsklinikum München
Study officials:
affiliation: University Hospital of Cologne
name: Michael von Bergwelt-Baildon, Prof. Dr. med. Dr. rer. nat.
role: PRINCIPAL_INVESTIGATOR
References: