Phase II Evaluation of Mosunetuzumab Combined with CHOP Regimen in Treatment-Naïve Patients with Richter's Syndrome
- Trial ID
- 2023-505621-13-00
- Protocol
- GELLC-9-RICHTER
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **efficacy** of mosunetuzumab combined with CHOP (M-CHOP) after the end of induction (EoI) in patients with therapy-naïve Diffuse Large B-Cell Lymphoma associated with **Richter's Syndrome** (DLBCL-RS). This is clinically relevant as it aims to establish a first-line treatment option for this aggressive transformation of chronic lymphocytic leukemia, potentially improving patient outcomes.
Secondary objectives include:
- Evaluating the efficacy of M-CHOP after the end of induction and maintenance (EoM) in patients with therapy-naïve Richter's Syndrome.
- Determining the incidence and severity of adverse events associated with the treatment.
- Evaluating the study treatment exposure.
- Assessing the relationship between various screening prognostic markers (clinical and biological) and clinical outcomes.
- Assessing minimal residual disease (MRD) using several technologies, including circulating tumor DNA (ctDNA).
Participants
The clinical trial involves participants diagnosed with **Richter's syndrome**, specifically the diffuse large B cell variant, who have not previously received therapy. The study population includes both male and female subjects aged between 18 and 79 years. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) performance score of 2 or less, indicating they are ambulatory and capable of all self-care but unable to carry out any work activities. The trial does not include a vulnerable population. Participants must demonstrate adequate bone marrow function, with specific thresholds for platelet count, absolute neutrophil count, and hemoglobin levels, unless cytopenia is attributed to marrow involvement of chronic lymphocytic leukemia (CLL). Additionally, a creatinine clearance of at least 45 mL/min is required. The sponsor has not provided information regarding the total number of participants. The selection criteria ensure that participants can comply with the study protocol and procedures, including required hospitalizations, as judged by the investigator. Lifestyle considerations such as diet and physical activity are not specified in the available data.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy of **mosunetuzumab** combined with CHOP (M-CHOP) in patients with **Richter's syndrome** who have not previously received therapy. This is a Phase II, randomized, double-blind, controlled study. The trial is expected to commence recruitment on March 1, 2024, and conclude by September 30, 2028. The study involves multiple visits, starting with an inclusion (screening) visit to assess eligibility based on criteria such as age, performance status, and adequate bone marrow function. Participants will be required to attend regular follow-up visits to monitor treatment response and adverse events, with the primary endpoint being complete remission evaluated by an independent review committee using PET/CT scans. The end-of-study visit will occur 8-12 weeks after the end of induction (EoI) to assess the primary endpoint.
Participants will be involved in the study for a maximum treatment period of 54 weeks, with the possibility of early termination if they experience unacceptable toxicity, disease progression, or withdrawal of consent. The study will include the administration of **vincristine sulfate**, **doxorubicin hydrochloride**, **cyclophosphamide monohydrate**, and **prednisone**, with **mosunetuzumab** being the investigational product. The administration routes include intravenous for most drugs and oral for prednisone. The trial will also assess secondary endpoints such as objective response rate, progression-free survival, and overall survival, alongside the incidence and severity of adverse events. The study aims to provide valuable insights into the treatment of **Richter's syndrome** and improve therapeutic outcomes for patients with this condition.
Treatment
The clinical trial involves the administration of several **experimental medications**. The first medication is **Vincristine Sulfate**, marketed as Vincristina Pfizer 1 mg/ml solución inyectable EFG. This medication is provided in the form of a **solution for injection** and is administered **intravenously**. The dosage is calculated based on body surface area, with a maximum daily and total dose of 1.4 mg/m². The treatment period for this medication is up to 21 days.
Another medication used in the trial is **Doxorubicin Hydrochloride**, available as Doxorrubicina Accord 2 mg/ml Concentrado para solução para perfusão. This is a **solution for infusion** administered **intravenously**. The maximum daily and total dose is 50 mg/m², with a treatment period of up to 21 days.
**Cyclophosphamide Monohydrate** is also included in the trial, marketed as Genoxal 200 mg polvo para solución inyectable y para perfusión. This medication is available as a **solution for injection/infusion** and is administered **intravenously**. The maximum daily and total dose is 750 mg/m², with a treatment period of up to 21 days.
The trial also involves the use of **Mosunetuzumab**, marketed as Lunsumio 30 mg concentrate for solution for infusion. This medication is provided as a **solution for infusion** and is administered **intravenously**. The maximum daily and total dose is 30 mg, with a treatment period of up to 54 days.
Lastly, **Prednisone** is used in the trial, available as prednisona cinfa 2.5 mg comprimidos EFG. This medication is in **tablet** form and is administered **orally**. The maximum daily and total dose is 60 mg/m², with a treatment period of up to 21 days.
All medications are administered according to the specified dosing schedules, and participant compliance is monitored throughout the trial. The trial aims to evaluate the efficacy of these medications in combination, specifically targeting patients with **Richter's Syndrome**. The medications are provided by their respective manufacturers, ensuring adherence to regulatory standards and quality control measures.
Efficacy
The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is the complete remission (CR) rate, evaluated by an independent review committee according to the modified Lugano classification using PET/CT scans. This assessment will occur 8-12 weeks after the end of induction (EoI) visit. CR is defined as a score of 1, 2, or 3 for lymph nodes and extra-lymphatic sites at PET without new lesions and no evidence of fluorodeoxyglucose (FDG)-avid disease in bone marrow. All PET evaluable patients who have received at least one dose of **Mosunetuzumab** will be included in the efficacy population.
Secondary endpoints include the objective response rate (ORR), complete remission rate (CR), best overall response, minimal residual disease (MRD), progression-free survival (PFS), overall survival (OS), and duration of response (DOR). Additionally, the incidence and severity of adverse events will be monitored, including cytokine release syndrome (CRS) and tumor lysis syndrome (TLS), with severity determined according to ASTCT CRS consensus grading criteria and Howard criteria, respectively. The study will also evaluate treatment exposure, such as treatment duration, total dose received, and number of cycles and dose modifications. Furthermore, the relationship between molecular and genetic prognostic factors, clonality, and efficacy endpoints, as well as the relationship between MRD response and efficacy endpoints such as PFS and OS, will be analyzed.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Capable of giving signed informed consent as described in Appendix 1, which includes compliance with the requirements and restrictions listed in the Informed Consent Form and in this protocol
- Aged between 18 and 79 years at the time of signing the Informed Consent Form
- Ability to comply with the study protocol and procedures and required hospitalizations, in the investigator’s judgement
- Eastern Cooperative Oncology Group (ECOG) performance score (PS) of ≤2.
- Adult patients with previously untreated, histologically proven Richter's syndrome, diffuse large B cell variants, following WHO 2008 criteria (Swerdlow SH, 2008)
- Screening flow cytometry or immunohistochemistry (IHC) evidence of CD20 positive disease as per central review (dim expression of CD20 is acceptable)
- Adequate BM function independent of growth factor or transfusion support, within 2 weeks of screening, at screening as follows unless cytopenia is clearly due to marrow involvement of CLL: − Platelet count ≥75,000/mm3; in cases of thrombocytopenia clearly due to marrow involvement of CLL (per the discretion of the investigator), platelet count should be ≥ 30,000/mm3 − ANC ≥1000/mm3 unless neutropenia is clearly due to marrow involvement of CLL (per the discretion of the investigator) − Total hemoglobin ≥ 9 g/dL unless anemia is due to marrow involvement of CLL (per the discretion of the investigator)
- Measured or estimated creatinine clearance ≥ 45 mL/min by institutional standard method
- Life expectancy > 3 months
- For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of < 1% per year, and agreement to refrain from donating eggs, during the treatment period and for at least 3 months after the last dose of mosunetuzumab and 3 months after the last dose of tocilizumab (if applicable). − It is recommended to remain abstinent or use contraception for 12 months after the final dose of cyclophosphamide, doxorubicin, or vincristine. − A woman is considered to be of childbearing potential if she is postmenarchal, has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause other than menopause), and is not permanently infertile due to surgery (i.e., removal of ovaries, fallopian tubes, and/or uterus) or another cause as determined by the investigator (e.g., Müllerian agenesis). The definition of childbearing potential may be adapted for alignment with local guidelines or regulations. − Examples of contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices. − The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the individual. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not adequate methods of contraception. − If required per local guidelines or regulations, locally recognized adequate methods of contraception and information about the reliability of abstinence will be described in the local Informed Consent Form.
- For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom, and agreement to refrain from donating sperm, as defined below: − With a female partner of childbearing potential or pregnant female partner, men must remain abstinent or use a condom during the treatment period and for 60 days after the final dose of tocilizumab (if applicable) and must remain abstinent or use a condom for 12 months after the final dose of cyclophosphamide, doxorubicin, or vincristine to avoid exposing the embryo. Men must refrain from donating sperm during this same period. − The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the individual. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not adequate methods of preventing drug exposure. If required per local guidelines or regulations, information about the reliability of abstinence will be described in the local Informed Consent Form.
Exclusion Criteria
- Pregnant or breastfeeding, or intending to become pregnant during the study or within 3 months after the final dose of mosunetuzumab. − Women of childbearing potential must have a negative serum pregnancy test result within 14 days prior to initiation of study treatment. If a serum pregnancy test has not been performed within 14 days prior to receiving first study treatment, a negative urine pregnancy test result (performed within 7 days prior to study treatment) must be available.
- Participants who have received any of the following treatments prior to study entry: − Treatment with mosunetuzumab or other CD20/CD3-directed bispecific antibodies
- Participants who have received any of the following treatments, whether investigational or approved, given to treat RS, within the respective time periods prior to initiation of study treatment: - Autologous SCT within 100 days prior to first mosunetuzumab administration − Allogeneic stem cell transplant for CLL. CAR T-cell therapy for CLL within 100 days prior to first mosunetuzumab administration − Systemic corticosteroid treatment ≤ 20 mg/day prednisone or equivalent to control symptoms related to disease progression for a maximum of 5 days before starting C1D1 and inhaled corticosteroids are permitted.
- Central nervous system (CNS) involvement as documented by spinal fluid cytology or imaging.
- Transformation of CLL to prolymphocytic leukemia
- History of prior malignancy, except for conditions as listed below if patients have recovered from the acute side effects incurred as a result of previous therapy: − Malignancies treated with curative intent and with no known active disease present for ≥ 2 years before enrollment − Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease − Adequately treated cervical carcinoma in situ without evidence of disease − Surgically/adequately treated low grade, early stage, localized prostate cancer without evidence of disease
- Any of the following laboratory abnormalities: − Calculated creatinine Clearance < 45 mL/min (method of Cockroft-Gault). − Absolute neutrophil count (ANC) < 1.0 X 109/L, unless secondary to bone marrow involvement by CLL. − Platelet count < 30 X 109/L. − Serum aspartate aminotransferase (AST)/serum glutamic-oxaloacetictransaminase (SGOT) or alanine transaminase (ALT)/serum glutamate pyruvate transaminase (SGPT) >2.5 x upper limit of normal (ULN). − Serum total bilirubin > 1.5 x ULN, except in cases of Gilbert’s syndrome
- History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibody therapy (or recombinant antibody-related fusion proteins)
- Contraindication to tocilizumab
- Presence of any autoimmune disorder including autoimmune haemolytic anemia or autoimmune thrombocytopenia active at the moment of first dose of therapy. − Participants with a history of disease-related immune thrombocytopenic purpura or autoimmune hemolytic anemia may be eligible
- History of autoimmune disease, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis (see Appendix 6) − Participants with a history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone may be eligible. − Participants with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study. Participants with a remote history of, or well-controlled autoimmune disease, with a treatment-free interval from immunosuppressive therapy for 12 months may be eligible after review and discussion with the Coordinators.
- History of solid organ transplantation
- Participants with infections requiring IV treatment with antibiotics or hospitalization (Grade 3 or 4) within the last 4 weeks prior to enrollment or known active bacterial, viral (including SARS-CoV-2), fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) at study enrollment
- History of confirmed progressive multifocal leukoencephalopathy (PML)
- Positive serologic HIV test at screening
- Positive test results for chronic hepatitis B infection (defined as positive hepatitis B surface antigen [HBsAg] serology). Participants with occult or prior hepatitis B infection (defined as positive total hepatitis B core antibody and negative HBsAg) may be included if hepatitis B virus (HBV) DNA is undetectable at the time of screening. These participants must be willing to undergo monthly DNA testing and appropriate prophylactic antiviral therapy as indicated.
- Acute or chronic hepatitis C virus (HCV) infection. Participants who are positive for HCV antibody must be negative for HCV by polymerase chain reaction (PCR) to be eligible for study participation.
- Known or suspected chronic active Epstein Barr Virus infection (CAEBV)
- Patients with history of macrophage activation syndrome (MAS)/hemophagocytic lymphohistiocytosis (HLH)
- Received a live, attenuated vaccine within 4 weeks before first dose of study treatment, or in whom it is anticipated that such a live attenuated vaccine will be required during the study period or within 5 months after the final dose of study treatment
- Left ventricular ejection fraction (LVEF) <50% by multiple-gated acquisition (MUGA) scan or echocardiogram
- Evidence of any significant, concomitant disease that could affect compliance with the protocol or interpretation of results, including, but not limited to: − significant cardiovascular disease (e.g., New York Heart Association Class III or IV cardiac disease, myocardial infarction within the previous 3 months, unstable arrhythmia, or unstable angina) − significant pulmonary disease (such as obstructive pulmonary disease or history of bronchospasm) − clinically significant history of liver disease, including viral or other hepatitis, or cirrhosis current or past history of CNS disease, such as stroke, epilepsy, CNS vasculitis, or neurodegenerative disease Participants with a history of stroke who have not experienced a stroke or transient ischemic attack in the past 1 year and have no residual neurologic deficits as judged by the investigator are allowed. Participants with a history of epilepsy who have had no seizures in the past 2 years with or without anti-epileptic medications can be eligible only for the expansion cohort − Known or suspected history of HLH
- Recent major surgery within 4 weeks prior to first study treatment administration, with the exception of protocol-mandated procedures (e.g., tumor biopsies and bone marrow biopsies)
- Participants who are in dependence to the Sponsor or an investigator
- Any serious medical condition or abnormality in clinical laboratory tests that, in the investigator's judgment, precludes an individual's safe participation in and completion of the study
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Spain | Not Recruiting | 01 Mar 2024 | 34 |
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 |
|---|---|---|---|---|---|---|
Vincristina Pfizer 1 mg/ml solución inyectable EFG | Test | SOLUCIÓN INYECTABLE | INTRAVENOUS | 1.4 | 21 | PRD4403595 |
Doxorrubicina Accord 2 mg/ml Concentrado para solução para perfusão | Test | CONCENTRADO PARA SOLUÇÃO PARA PERFUSÃO | INTRAVENOUS | 50 | 21 | PRD379844 |
Genoxal 200 mg polvo para solución inyectable y para perfusión | Test | POLVO PARA SOLUCIÓN INYECTABLE Y PARA PERFUSIÓN | INTRAVENOUS | 750 | 21 | PRD347452 |
Lunsumio 30 mg concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS | 30 | 54 | PRD9721620 |
prednisona cinfa 2,5 mg comprimidos EFG | Test | COMPRIMIDOS | ORAL | 60 | 21 | PRD2934231 |