A Multi-Center, Open Label, Uncontrolled, Phase II Clinical Trial Evaluating the Safety and Efficacy of Venetoclax in Combination With Atezolizumab and Obinutuzumab in Richter Transformation of CLL (MOLTO)

  • STATUS
    Recruiting
  • End date
    Dec 19, 2026
  • participants needed
    28
  • sponsor
    Niguarda Hospital
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Updated on 19 October 2022
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Summary

This study is a multicenter, open-label, uncontrolled, phase II trial aimed to establish the safety and tolerability of venetoclax, atezolizumab and obinutuzumab combination in Richter Transformation of CLL.

Description

This study is a multicenter, open-label, uncontrolled, phase II trial. Initial safety run phase is designed to establish the safety and tolerability of venetoclax, atezolizumab and obinutuzumab combination.

There is no dose-finding step. The doses of obinutuzumab and atezolizumab in lymphomas were previously clearly established in combination (Till BG et al. Blood 2015).

It has also been shown that in a balance between efficacy and toxicity, the recommended dose of venetoclax single-agent in Follicular Lymphoma (FL) and DLBCL was 800 mg daily (Davids MS et al. JCO 2017 ). The investigators chose the lower dose level (400 mg) for this study, also corresponding to the registered one for patients with CLL, in association with two other drugs. Nine patients having achieved 9 weeks (=3 cycles) of treatment (6 doses of obinutuzumab, 3 doses of atezolizumab, 7 weeks of venetoclax) or having discontinued treatment within the first 9 weeks of treatment will be enrolled in this cohort for safety profile. If one of these 9 patients prematurely discontinue at least one of study drugs for a reason other than safety (e.g. for disease progression), he/she will be replaced.

All AEs occurring during the course of the study will be captured, regardless of their intensity / grading. Grading of AEs will be completed according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTC-AE), version 4.0. Based on known safety profile of the 3 drugs, some adverse events of special interest will be assessed. During the initial safety run phase, all haematological toxicities and immune-related toxicities whatever the grade, and grade ≥ 2 for other toxicities will be monitored and, in this case, safety review meeting will be organized with Independent Data Monitoring Committee (IDMC) members. In case of more than 3 non-infective and non-hematologic grade ≥4 adverse events in the initial safety run cohort that according to the experience of the investigators are considered related to the combination treatment, inclusions will be stopped and IDMC members will evaluate the possibility of an early enrollment termination.

The treatment schedule applied to the initial safety run cohort will be employed for the remaining patients.

The 9 patients from the safety run will be included in the efficacy analysis. A response evaluation according with Lugano criteria for aggressive lymphomas (Cheson et al. JCO 2014) will be performed at the end of the sixth cycle to define treatment efficacy and, in case of achievement of 16 responses, treatment will be considered successful.

The planned enrollment for this study is 28 patients.

Patients will receive 35 cycles of treatment:

  • From cycle 1 to cycle 8 patients will receive a combination of obinutuzumab, atezolizumab and venetoclax
  • From cycle 9 to cycle 18 patients will receive atezolizumab and venetoclax
  • From cycle 19 to cycle 35 patients will receive venetoclax monotherapy.

Details
Condition CLL Transformation
Treatment Obinutuzumab 25 MG/ML [Gazyva], Atezolizumab 60 MG/ML [Tecentriq], Venetoclax Oral Tablet
Clinical Study IdentifierNCT04082897
SponsorNiguarda Hospital
Last Modified on19 October 2022

Eligibility

 Yes No Not Sure

Inclusion Criteria

Ability to understand and the willingness to sign a written informed consent document
Signed Informed Consent
Confirmed diagnosis of chronic lymphocytic leukemia or small lymphocytic lymphoma as IW-CLL 2008 criteria (Hallek et al, 2008) with biopsy proven transformation to diffuse large B cell lymphoma (DLBCL), consistent with Richter's Syndrome
Age greater than or equal to 18 years
ECOG performance status <= 2
Patients must meet the following hematologic criteria at screening, unless they have significant bone marrow involvement of their malignancy confirmed on biopsy
Absolute neutrophil count >=1000 cells/mm3 (1.0 x 10^9/L)
Platelet count >= 50,000 cells/mm3 (50 x 10^9/L) within 7 days of screening
Total hemoglobin > 9 g/dL (without transfusion support, unless anemia is due to marrow involvement of CLL)
Subject must have adequate coagulation, renal, and hepatic function, per laboratory
reference range at screening as follows
Activated partial thromboplastin time (aPTT) and International normalized ratio (INR) > 1.5 x ULN for patients not receiving therapeutic anticoagulation
Creatinine <= 1.5 x ULN or creatinine clearance >= 50 mL/min based on Cockcroft-Gault formula
Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <= 2.5 × ULN
Bilirubin <= 1.5 × ULN
Negative pregnancy tests as verified by the investigator prior to starting any treatment
Subjects with Gilbert's Syndrome or resolving autoimmunohemolytic anemia may have a
bilirubin up to 3.0 × ULN and are still eligible

Exclusion Criteria

Prior treatment for Richter transformation
Prior treatment with obinutuzumab anti PD-1 or PDL-1 antibodies
Prior treatment with venetoclax
Hypersensitivity to obinutuzumab, venetoclax or atezolizumab or their formulation excipients
Patients with the Hodgkin variant transformation of CLL
Prolymphocytic transformation
Patients with a previous history of indolent B cell malignancies other than CLL
History of other malignancy other than CLL and Richter syndrome that could affect compliance with the protocol or interpretation of results with the exception of
Patients with curatively treated basal or squamous cell carcinoma or stage 1 melanoma of the skin or in situ carcinoma of the cervix
Patients with a malignancy that has been treated with surgery alone with curative intent. Individuals in documented remission without treatment for > 2 years prior to enrollment may be included at the discretion of the Sponsor-Investigator
Low-risk prostate cancer on active surveillance
Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) at study enrollment, or any major episode of infection requiring treatment with IV antibiotics or hospitalization (relating to the completion of the course of antibiotics) within 4 weeks prior to Cycle1, Day1
Evidence of significant, uncontrolled concomitant diseases that could affect
Clinically significant history of liver disease, including autoimmune hepatitis, current alcohol abuse, or cirrhosis
compliance with the protocol or interpretation of results or that could
Presence of positive PCR for hepatitis B, hepatitis C or positive hepatitis B surface antigen
increase risk to the patient, including renal disease that would preclude
Patients with uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia
chemotherapy administration or pulmonary disease (including obstructive
History of active autoimmune disease
pulmonary disease and history of bronchospasm)
History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis per chest CT scan at screening. History of radiation pneumonitis in the radiation field (fibrosis) is allowed
Concurrent systemic immunosuppressant therapy within 28 days of the first dose of study drug
Corticosteroids are allowed, but must be dosed at prednisone 30 mg (or equivalent) or lower prior to the start of chemotherapy
Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug
Known bleeding disorders (eg, von Willebrand's disease) or hemophilia
Requires anticoagulation with vitamin K antagonists (e.g. phenprocoumon, warfarin)
History of human immunodeficiency virus (HIV) or active hepatitis C virus (HCV) or active hepatitis B virus (HBV)
Major surgery within 4 weeks of first dose of study drug
Any life-threatening illness, medical condition, or organ system dysfunction that, in the investigator's opinion, could compromise the subject's safety or put the study outcomes at undue risk
Patients with infections requiring IV treatment (Grade 3 or 4) within the last 2 months prior to enrolment
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