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

Phase

Condition

N/A

Treatment

Obinutuzumab with Ibrutinib and Venetoclax

Clinical Study ID

NCT04939363

SA-002804

Ages > 18
All Genders

Study 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

Eligibility Criteria

Inclusion

Inclusion Criteria:

Subject must be 18 years of age or older.
Patients with histopathological confirmation of Richter's transformation intodiffuse large B-cell lymphoma (DLBCL).
Subjects must have at least 1 measurable site of disease according to RevisedResponse 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 cmin the short axis regardless of long axis measurement, and clearly measurable in 2perpendicular dimensions.
Eastern Cooperative Oncology Group (ECOG) status 0 to 2; ECOG 3 is only permitted ifrelated to RS.
Adequate renal function, as indicated by an estimated creatinine clearance higherthan 30 ml/min, adequate platelet count > 25 x 109/L, adequate liver function asindicated by total bilirubin < x 2 and Alanine transaminase (ALT) < x 2.5 of theinstitutional upper normal levels, unless directly attributable to the RS or toGilbert's Syndrome.
Negative serological testing for hepatitis B (anti-hepatitis Bc negative, patientspositive 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 toenrollment.
Ability and agreement to provide written informed consent and to adhere to the studyvisit schedule and other protocol requirements.

Exclusion

Exclusion Criteria:

Diagnosed or treated for malignancy other than DLBCL-RS or CLL/Small LymphocyticLymphoma (SLL) , except:
Malignancy treated with curative intent and with no known active diseasepresent at enrollment.
Adequately treated non-melanoma skin cancer or lentigo maligna melanoma withoutevidence of disease.
Adequately treated carcinoma in situ without evidence of disease.
Clinically significant cardiovascular disease such as uncontrolled or symptomaticarrhythmias, congestive heart failure, or myocardial infarction within 6 months ofenrollment, or any Class 3 (moderate) or Class 4 (severe) cardiac disease as definedby the New York Heart Association Functional Classification.
Requires anticoagulation with coumadin or equivalent vitamin K antagonists (e.g.,phenprocoumon).
Requirement of therapy with strong CYP3A4 and CYP3A5 inhibitors/inducers.
Documented resistance to Ibrutinib and/or Venetoclax.
Pregnant women and nursing mothers (a negative pregnancy test is required for allwomen of childbearing potential within 7 days before start of treatment; furtherpregnancy testing will be performed regularly).
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 highlyeffective contraceptive method (Pearl Index <1) and one additional effective (barrier) method during study treatment and for 18 months after the end ofstudy treatment.
Positive serological test for human immunodeficiency virus (HIV) or active HepatitisC Virus (HCV; RNA polymerase chain reaction [PCR]-positive) or active Hepatitis BVirus (HBV; DNA PCR-positive) infection or any uncontrolled active systemicinfection. Subjects with PCR-negative HBV and HCV are permitted in the study.
Legal incapacity.
Any life-threatening illness, medical condition, or organ system dysfunction which,in the investigator's opinion, could compromise the subject's safety, interfere withthe absorption or metabolism of Ibrutinib capsules, or put the study outcomes atundue risk.
Participation in other clinical trials, including those with other investigationalagents not included in this trial, within 30 days of the start of this trial andthroughout the duration of this trial.

Study Design

Obinutuzumab with Ibrutinib and Venetoclax

August 08, 2021

December 04, 2024

Study Description

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.

Connect with a study center

Bnai Zion Medical Center
Haifa,
Israel
Site Not Available
Hadassah Medical Center
Jerusalem,
Israel
Site Not Available
TASMC
Tel Aviv,
Israel
Site Not Available
Sheba Medical Center
Tel HaShomer,
Israel
Site Not Available

Not the study for you?

Let us help you find the best match. Sign up as a volunteer and receive email notifications when clinical trials are posted in the medical category of interest to you.