Phase II Study on the Safety and Efficacy of Venetoclax, Atezolizumab, and Obinutuzumab in Richter Syndrome of Chronic Lymphocytic Leukemia
- Trial ID
- 2024-516675-32-00
- Protocol
- MOLTO
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this clinical trial is to evaluate the **efficacy** of the combination of venetoclax, obinutuzumab, and atezolizumab in terms of the Overall Response Rate (ORR) in patients with **Richter syndrome of chronic lymphocytic leukemia**. This is clinically relevant as it aims to determine the potential of this combination therapy to improve treatment outcomes in a condition that is typically challenging to manage.
Secondary objectives include assessing the safety and tolerability of the combination therapy, which is crucial for understanding the risk-benefit profile of the treatment. Additionally, the trial will evaluate the efficacy in terms of several key metrics:
- Complete Response Rate (CRR)
- Duration of Response (DoR)
- Progression-Free Survival (PFS)
- Overall Survival (OS)
Participants
The clinical trial involves a total of **14 participants** diagnosed with **Richter syndrome of chronic lymphocytic leukemia**. The study population includes both male and female subjects, aged 18 years and older, with an **ECOG performance status** of 2 or less, indicating they are ambulatory and capable of all self-care but unable to carry out any work activities. Participants were selected based on their confirmed diagnosis of chronic lymphocytic leukemia or small lymphocytic lymphoma with biopsy-proven transformation to diffuse large B cell lymphoma, consistent with Richter's Syndrome. The trial includes individuals who are not considered vulnerable populations. Participants are required to have adequate coagulation, renal, and hepatic function, and meet specific hematologic criteria unless significant bone marrow involvement is confirmed. Lifestyle considerations such as diet and physical activity are not specified, but women of childbearing potential must adhere to strict contraceptive measures during the study. The trial does not specify any particular lifestyle habits or restrictions beyond the medical criteria outlined.
Plans and Procedures
The clinical trial is designed as a **Phase II**, open-label, uncontrolled study to evaluate the safety and efficacy of a combination therapy involving **venetoclax**, **atezolizumab**, and **obinutuzumab** in patients with Richter syndrome of chronic lymphocytic leukemia. The primary objective is to assess the overall response rate (ORR) of the combination therapy, with a target of achieving a minimum of 67% ORR by the end of the sixth cycle. Secondary endpoints include the incidence of adverse events, complete remission rate, duration of response, progression-free survival, and overall survival.
The trial is expected to run until December 31, 2026, with recruitment having commenced on October 8, 2019. Participants will be involved in the study for a maximum treatment period of 721 days for venetoclax, 11 days for obinutuzumab, and 18 days for atezolizumab, depending on the specific treatment regimen. The study involves multiple visits, starting with a screening visit to confirm eligibility based on criteria such as age, performance status, and hematologic parameters. Follow-up visits will be scheduled to monitor treatment response and safety, with the end-of-study visit marking the conclusion of the participant's involvement.
Participants may be withdrawn from the study early if they experience unacceptable toxicity, disease progression, or if they withdraw consent. The study will adhere to rigorous safety monitoring, with adverse events and serious adverse events being recorded and evaluated according to established criteria. The trial's design and procedures are structured to ensure the collection of robust data on the efficacy and safety of the combination therapy in this patient population.
Treatment
The clinical trial involves the administration of **venetoclax**, marketed under the names Venclexta and Venclyxto, which is provided in the form of a **film-coated tablet**. The active substance, venetoclax, is of chemical origin and is manufactured by ABBVIE, INC. The maximum daily dose of venetoclax is 400 mg, with a total maximum dose of 279,790 mg over a treatment period of up to 721 days. The tablets are administered orally, and participant compliance is monitored throughout the trial to ensure adherence to the dosing schedule.
In addition to venetoclax, the trial includes the administration of **obinutuzumab**, marketed as Gazyvaro, which is provided as a concentrate for solution for infusion. Obinutuzumab is a monoclonal antibody of protein origin, produced by ROCHE REGISTRATION GMBH. The maximum daily dose is 1,000 mg, with a total maximum dose of 10,000 mg over a treatment period of 11 days. The administration route is intravenous, and the infusion schedule is carefully monitored to ensure proper dosing and participant safety.
Another component of the trial is **atezolizumab**, marketed as Tecentriq, also provided as a concentrate for solution for infusion. Atezolizumab is a monoclonal antibody of protein origin, manufactured by ROCHE REGISTRATION GMBH. The maximum daily dose is 1,200 mg, with a total maximum dose of 21,600 mg over a treatment period of 18 days. This medication is administered intravenously, and compliance with the infusion schedule is monitored to maintain the integrity of the trial and participant safety.
The trial does not include any non-experimental treatments such as standard-of-care therapy or placebo. The focus is on evaluating the safety and efficacy of the combination of venetoclax, obinutuzumab, and atezolizumab in the treatment of Richter Transformation of Chronic Lymphocytic Leukemia (CLL). The trial is designed to assess the overall response rate (ORR) of this combination therapy.
Efficacy
The efficacy of the combination therapy involving **venetoclax**, **atezolizumab**, and **obinutuzumab** in the treatment of Richter Transformation of Chronic Lymphocytic Leukemia (CLL) will be assessed primarily through the Overall Response Rate (ORR). The primary endpoint is defined as achieving a minimum of 67% ORR at the end of the sixth cycle of treatment. Patients will be evaluated according to the Lugano Criteria for aggressive lymphomas, which allows for the persistence of residual underlying CLL in nodes and/or marrow while still qualifying as a complete response (CR) for Richter's Transformation (RT) to treatment.
Secondary endpoints include the incidence of adverse events (AE) and serious adverse events (SAE) as measured per NCI CTCAE v4.0, significant laboratory abnormalities, and dose tolerability, including dose modifications and discontinuations. Additionally, the efficacy of the combination will be further assessed in terms of Complete Remission Rate (CRR), Duration of Response (DoR), Progression-Free Survival (PFS), and Overall Survival (OS). These parameters will provide a comprehensive evaluation of the treatment's impact on disease progression and patient outcomes.
Inclusion and Exclusion Criteria
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;
- Subjects with Gilbert's Syndrome or resolving autoimmunehemolytic anemia may have a bilirubin up to 3.0 × ULN and are still eligible
- Negative pregnancy tests as verified by the investigator prior to starting any treatment
- Contraception/ breastfeeding: For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use a contraceptive method with a failure rate of < 1% per year during the treatment period and for at least 30 days after the last dose of venetoclax, 5 months after the last dose of atezolizumab or 18 months after the last dose of obinutuzumab, whichever is longer A woman is considered to be of childbearing potential if she is post-menarchal, has not reached a postmenopausal state (>12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus).
Exclusion Criteria
- Prior treatment for Richter transformation.
- Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug.
- Known bleeding disorders (eg, von Willebrand's disease) or hemophilia.
- History of human immunodeficiency virus (HIV) or active hepatitis C virus (HCV) or active hepatitis B virus (HBV).
- Any life-threatening illness, medical condition, or organ system dysfunction that, inthe 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.
- 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.
- Evidence of significant, uncontrolled concomitant diseases that could affect compliance with the protocol or interpretation of results or that could increase risk to the patient, including renal disease that would preclude chemotherapy administration or pulmonary disease (including obstructive pulmonary disease and history of bronchospasm).
- 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: a) Patients with curatively treated basal or squamous cell carcinoma or stage 1 melanoma of the skin or in situ carcinoma of the cervix b) 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. c) 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 Cycle 1, Day 1
- Major surgery within 4 weeks of first dose of study drug.
- Requires anticoagulation with vitamin K antagonists (e.g. phenprocoumon, warfarin)
- Currently active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia or Class 2 or higher congestive heart failure as defined by the New York Heart Association Functional Classification; or a history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to randomization.
- Unable to swallow capsules or malabsorption syndrome, symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction at time of screening.
- Breastfeeding or pregnant
- Clinically significant history of liver disease, including autoimmune hepatitis, current alcohol abuse, or cirrhosis.
- Presence of positive PCR for hepatitis B, hepatitis C or positive hepatitis B surface antigen (HbsAg). Patients who are positive for HCV antibody must be negative for HCV by polymerase chain reaction (PCR) to be eligible for study participation. Patients with occult or prior HBV infection (defined as positive total hepatitis B core antibody [HBcAb] and negative HBsAg) may be included if HBV DNA is undetectable. These patients must be willing to receive prophylactic lamivudine or entecavir and undergo monthly DNA testing during treatment and up to 6 months’ post treatment..
- Patients with uncontrolled autoimmune hemolytic anemia or immune thrombocytopenia.
- History of active autoimmune disease.
- 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.
- Male subject who is considering fathering a child or donating sperm during the study or for approximately 6 months after the last dose of study drugs.
- Unwilling or unable to participate in all required study evaluations and procedures. Unable to understand the purpose and risks of the study and to provide a signed and dated informed consent form (ICF)
- Patients receiving any other study agents
- Patients with known CNS involvement
- Concurrent administration of medications or foods that are strong inhibitors or inducers of CYP3A Concurrent administration of medications or foods that are strong inhibitors or inducers of CYP3A see Appendix 9.
- Strong and moderate CYP3A inhibitors within 7 days prior to the first dose of study drug administration
- History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibodies, known sensitivity or allergy to murine products.
- Unable to receive prophylactic treatment for pneumocystis, herpes simplex virus (HSV), and herpes zoster (VZV) at start of treatment
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Italy | Not Recruiting | 08 Oct 2019 | 14 |
Sites & Investigators
Research sites
Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Venclexta, Venclyxto | Test | FILM-COATED TABLET | ORAL | 400 | 721 | PRD9859718 |
Tecentriq 1 200 mg concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS | 1200 | 18 | PRD5434939 |
Venclexta, Venclyxto | Test | FILM-COATED TABLET | ORAL USE | 400 | 721 | PRD9859717 |
Venclexta, Venclyxto | Test | FILM-COATED TABLET | ORAL USE | 400 | 721 | PRD9859716 |
Gazyvaro 1,000 mg concentrate for solution for infusion. | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 1000 | 11 | PRD1753415 |