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

Conditions

• Richter's Syndrome

Eligibility Criteria

Sex

ALL

Age

18 Years - N/A

Healthy Volunteers

Not accepted

Interventions

• Obinutuzumab with Ibrutinib and Venetoclax — COMBINATION_PRODUCT
  1. Obinutuzumab intravenous infusion: 2. Ibrutinib PO 560mg daily starting on cycle 1 day 1 for 12 cycles. 3. Venetoclax with an accelerated ramp-up and close inpatient Tumor Lysis Syndromes (TLS) monitoring starts on cycle 1 day 15 to the target dose of 400mg daily for a total of 12 cycles:

Study Details

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 .

Key Dates

Start date

Aug 8, 2021

Status verified

Nov 2024

Primary completion

Oct 9, 2024

Completion

Dec 4, 2024

Study Design

Enrollment

12 participants (actual)

Allocation

NA

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Arms

• Experimental: combination of Ibrutinib, Venetoclax and Obinutuzumab
  1. 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. 2. Ibrutinib PO 560mg daily starting on cycle 1 day 1 for 12 cycles. 3. 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

Primary Outcome Measure

Number of Participants With Abnormal Laboratory Values and/or Adverse Events That Are Related to Treatment parameters-Safety [ Time Frame: Up to 3 years from last patient enrollment ]