A Study to Evaluate the Efficacy and Safety of Obinutuzumab, Ibrutinib, and Venetoclax in Patients With Richter’s Syndrome;

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Brief Title

A Study to Evaluate the Efficacy and Safety of Obinutuzumab, Ibrutinib, and Venetoclax in Patients With Richter's Syndrome;

Official Title

A Prospective, Phase-II Study to Evaluate the Efficacy and Safety of Obinutuzumab, Ibrutinib, and Venetoclax in Patients With Richter's Syndrome. GIVeRS Protocol: On Behalf of the Israeli CLL Study Group

Brief Summary

      Richter's syndrome (RS) is a life-threatening complication of chronic lymphocytic leukemia
      (CLL). It is associated with a switch in histopathology and biology, generally with a
      transformation of the original CLL clone to diffuse large B-cell lymphoma (DLBCL). The
      development of RS is accompanied by the onset of B symptoms, rapid growth of lymphadenopathy,
      extra-nodal disease, significant elevations of lactate dehydrogenase (LDH), and associated
      multi-organ dysfunction from invasive or obstructive processes RS occurs in 2-10% of CLL
      patients with an incidence rate of 0.5% per year. The molecular pathogenesis of RS involves
      inactivation of the tumor protein p53 (TP53) tumor suppressor gene in 50-60% of cases and
      activating aberrations of NOTCH1 and myelocytomatosis oncogene (MYC) in about 30% of cases. .

      These distinct molecular footprints of RS are chemoresistance leading to an aggressive
      clinical course with low response rates and poor outcomes.Taking into consideration that in
      addition to the underlying aggressive disease, most RS patients are often at an advanced age
      and suffer from numerous other comorbidities. Additionally, intensive chemotherapy regimens
      are highly toxic to this population group and lead to excessive treatment-related morbidity.
      Enrolling DLBCL-RS patients in clinical trials is therefore justifiable, particularly those
      with RS that is clonally related to the predisposed underlining CLL disease. Due to the poor
      activity of immunochemotherapy, the possibility of using novel agents in the treatment of RS
      is of great interest.

      The toxicity and the efficacy of the combination of cluster of anti differentiation antigen
      20 (anti-CD20) antibody (e.g. Obinutuzumab or Rituximab) with Ibrutinib and/or Venetoclax
      have been already reported in both relapsed and naïve patients with CLL. The use of these
      three agents in combination is highly active in CLL and has manageable side effects. In
      addition, recent reports showed that treatment with Ibrutinib or Venetoclax as a single drug
      are active in RS.

      Herein the investigators propose a phase 2, open-label, non-randomized, single arm,
      multi-center study aiming to assess the safety and efficacy with the combination of
      Ibrutinib, Venetoclax and Obinutuzumab in patients with RS

      .
    

Detailed Description

      Richter's syndrome (RS) is a life-threatening complication of chronic lymphocytic leukemia
      (CLL). It is associated with a switch in histopathology and biology, generally with a
      transformation of the original CLL clone to diffuse large B-cell lymphoma (DLBCL). The
      development of RS is accompanied by the onset of B symptoms, rapid growth of lymphadenopathy,
      extra-nodal disease, significant elevations of LDH, and associated multi-organ dysfunction
      from invasive or obstructive processes.

      Previous research has increased general knowledge on the distinct evolutionary patterns of RS
      and provided a deeper understanding of the risk factors and molecular events predisposing to
      transformation. However, currently there're main few targetable aberrations and treatment is
      largely ineffective with a dismal prognosis leaving these patients with a high unmet medical
      need for better treatment strategies.

      RS occurs in 2-10% of CLL patients with an incidence rate of 0.5% per year. The molecular
      pathogenesis of RS involves inactivation of the TP53 tumor suppressor gene in 50-60% of cases
      and activating aberrations of NOTCH1 and MYC in about 30% of cases.

      These distinct molecular footprints of RS are chemoresistance leading to an aggressive
      clinical course with low response rates and poor outcomes. Patients with RS are usually
      excluded from clinical trials and there is no established standard of care in the treatment
      of RS today.

      A number of chemotherapy regimens have been evaluated in the treatment of DLBCL-RS resulting
      in overall responses ranging between 40%-60% which are short lived with disappointing
      Progression Free Survival (PFS) and Overall Survival (OS) ranging between 3 - 10 and 6 - 21
      months, respectively.

      In Israel the current treatment strategy used for newly diagnosed DLBCL-RS is an
      anthracycline-based regimen, rituximab, cyclophosphamide, doxorubicin, vincristine, and
      prednisone (R-CHOP). This treatment regimen has shown poor efficacy in a cohort study of 15
      DLBCL-RS patients prospectively evaluated by a German CLL study group trial. The ORR was 67%
      with only 7% Complete Response (CR). The median PFS and median OS were 10 and 21 months,
      respectively in these patients. In terms of the safety profile of R-CHOP for patients with
      DLBCL-RS or CLL patients, 15 of the 60 (25%) patients enrolled in this study had therapy
      discontinued earlier than planned because of the treatment-related toxicity.

      Taking into consideration that in addition to the underlying aggressive disease, most RS
      patients are often at an advanced age and suffer from numerous other comorbidities, therefore
      only 10%-15% of patient scan undergo the potentially curative allogeneic Hematopoietic Stem
      Cell Transplantation (HSCT). Additionally, intensive chemotherapy regimens are highly toxic
      to this population group and lead to excessive treatment-related morbidity. Enrolling
      DLBCL-RS patients in clinical trials is therefore justifiable, particularly those with RS
      that is clonally related to the predisposed underlining CLL disease. Due to the poor activity
      of immunochemotherapy, the possibility of using novel agents in the treatment of RS is of
      great interest.

      The toxicity and the efficacy of the combination of anti-CD20 antibody (e.g. Obinutuzumab or
      Rituximab) with Ibrutinib and/or Venetoclax have been already reported in both relapsed and
      naïve patients with CLL. The use of these three agents in combination is highly active in CLL
      and has manageable side effects. In addition, recent reports showed that treatment with
      Ibrutinib or Venetoclax as a single drug are active in RS.

      Herein the investigators propose a phase 2, open-label, non-randomized, single arm,
      multi-center study aiming to assess the safety and efficacy with the combination of
      Ibrutinib, Venetoclax and Obinutuzumab in patients with RS.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Number of Participants With Abnormal Laboratory Values and/or Adverse Events That Are Related to Treatment parameters-Safety

Secondary Outcome

 Progression-free survival -PFS

Condition

Richter's Syndrome

Intervention

Obinutuzumab with Ibrutinib and Venetoclax

Study Arms / Comparison Groups

 combination of Ibrutinib, Venetoclax and Obinutuzumab
Description:  Obinutuzumab intravenous infusion:
Cycles 1: Day 1: Obinutuzumab 100 mg Day 1 (or 2): Obinutuzumab 900 mg Day 8: Obinutuzumab 1000 mg Day 15: Obinutuzumab 1000 mg Cycles 2-6: Day 1: Obinutuzumab 1000 mg The first infusion of Obinutuzumab may be administered at the full dose (1000 mg) on day 1 of cycle 1, if the infusion of a test-dosage of 100 mg is well tolerated by the patient. Alternatively, if the first 100 mg infusion on day 1 is not well tolerated, the remaining 900 mg of the first dose should be administered on day 2.
Ibrutinib PO 560mg daily starting on cycle 1 day 1 for 12 cycles.
Venetoclax with an accelerated ramp-up and close inpatient TLS monitoring starts on cycle 1 day 15 to the target dose of 400mg daily for a total of 12 cycles:
Cycle 1: Day 15: Venetoclax 20 mg Days 16-17: Venetoclax 50 mg Days 18-21: Venetoclax 100 mg Days: 22-28: Venetoclax 200 mg Cycles 2-12: Days 1-28: Venetoclax 400 mg

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

Combination Product

Estimated Enrollment

15

Start Date

August 8, 2021

Completion Date

September 10, 2024

Primary Completion Date

March 10, 2024

Eligibility Criteria

        Inclusion Criteria:

          1. Subject must be 18 years of age or older.

          2. Patients with histopathological confirmation of Richter's transformation into diffuse
             large B-cell lymphoma (DLBCL).

          3. Subjects must have at least 1 measurable site of disease according to Revised Response
             Criteria for Malignant Lymphoma. The site of disease must be greater than 1.5 cm in
             the long axis regardless of short axis measurement or greater than 1.0 cm in the short
             axis regardless of long axis measurement, and clearly measurable in 2 perpendicular
             dimensions.

          4. Eastern Cooperative Oncology Group (ECOG) status 0 to 2; ECOG 3 is only permitted if
             related to RS.

          5. Adequate renal function, as indicated by an estimated creatinine clearance higher than
             30 ml/min, adequate platelet count > 25 x 109/L, adequate liver function as indicated
             by total bilirubin < x 2 and Alanine transaminase (ALT) < x 2.5 of the institutional
             upper normal levels, unless directly attributable to the RS or to Gilbert's Syndrome.

          6. Negative serological testing for hepatitis B (anti-hepatitis Bc negative, patients
             positive for anti-hepatitis Bc may be included if Polymerase chain reaction (PCR) for
             HBV DNA is negative) and negative HIV test performed within 6 weeks prior to
             enrollment.

          7. Ability and agreement to provide written informed consent and to adhere to the study
             visit schedule and other protocol requirements.

        Exclusion Criteria:

          1. Diagnosed or treated for malignancy other than DLBCL-RS or CLL/Small Lymphocytic
             Lymphoma (SLL) , except:

               1. Malignancy treated with curative intent and with no known active disease present
                  at enrollment.

               2. Adequately treated non-melanoma skin cancer or lentigo maligna melanoma without
                  evidence of disease.

               3. Adequately treated carcinoma in situ without evidence of disease.

          2. Clinically significant cardiovascular disease such as uncontrolled or symptomatic
             arrhythmias, congestive heart failure, or myocardial infarction within 6 months of
             enrollment, or any Class 3 (moderate) or Class 4 (severe) cardiac disease as defined
             by the New York Heart Association Functional Classification.

          3. Requires anticoagulation with coumadin or equivalent vitamin K antagonists (e.g.,
             phenprocoumon).

          4. Requirement of therapy with strong CYP3A4 and CYP3A5 inhibitors/inducers.

          5. Documented resistance to Ibrutinib and/or Venetoclax.

          6. Pregnant women and nursing mothers (a negative pregnancy test is required for all
             women of childbearing potential within 7 days before start of treatment; further
             pregnancy testing will be performed regularly).

          7. Fertile men or women of childbearing potential unless:

               1. surgically sterile or ≥ 2 years after the onset of menopause

               2. Willing to use two methods of reliable contraception including one highly
                  effective contraceptive method (Pearl Index <1) and one additional effective
                  (barrier) method during study treatment and for 18 months after the end of study
                  treatment.

          8. Positive serological test for human immunodeficiency virus (HIV) or active Hepatitis C
             Virus (HCV; RNA polymerase chain reaction [PCR]-positive) or active Hepatitis B Virus
             (HBV; DNA PCR-positive) infection or any uncontrolled active systemic infection.
             Subjects with PCR-negative HBV and HCV are permitted in the study.

          9. Legal incapacity.

         10. Any life-threatening illness, medical condition, or organ system dysfunction which, in
             the investigator's opinion, could compromise the subject's safety, interfere with the
             absorption or metabolism of Ibrutinib capsules, or put the study outcomes at undue
             risk.

         11. Participation in other clinical trials, including those with other investigational
             agents not included in this trial, within 30 days of the start of this trial and
             throughout the duration of this trial.
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

Yair Herishanu, Prof, 04-8359218, [email protected]

Location Countries

Israel

Location Countries

Israel

Administrative Informations


NCT ID

NCT04939363

Organization ID

SA-002804


Responsible Party

Sponsor

Study Sponsor

Bnai Zion Medical Center

Collaborators

 Tel-Aviv Sourasky Medical Center

Study Sponsor

Yair Herishanu, Prof, Principal Investigator, TASMC


Verification Date

May 2021