Obinutuzumab Containing Conditioning Regimen for Patients With Poor Risk CLL or Richter`s Transformation Requiring Allogeneic Stem Cell Transplantation

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Brief Title

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

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.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

PD-free rate

Secondary Outcome

 Minimal residual disease (MRD) negativity rate

Condition

Chronic Lymphocytic Leukemia

Intervention

Obinutuzumab

Study Arms / Comparison Groups

 Obinutuzumab
Description:  Obinutuzumab i.v.
Cycle 1: in the peri-transplant and transplantation phase
Cycle 2: if active disease and/or MRD positivity on day +60, +90, +180 or +270

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Biological

Estimated Enrollment

3

Start Date

November 13, 2017

Completion Date

June 6, 2019

Primary Completion Date

May 16, 2019

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
      

Gender

All

Ages

18 Years - 70 Years

Accepts Healthy Volunteers

No

Contacts

Michael von Bergwelt-Baildon, Prof. Dr. med. Dr. rer. nat., , 

Location Countries

Germany

Location Countries

Germany

Administrative Informations


NCT ID

NCT03153514

Organization ID

CLLTX1

Secondary IDs

2015-000568-32

Responsible Party

Sponsor

Study Sponsor

German CLL Study Group

Collaborators

 Hoffmann-La Roche

Study Sponsor

Michael von Bergwelt-Baildon, Prof. Dr. med. Dr. rer. nat., Principal Investigator, University Hospital of Cologne


Verification Date

October 2019