Chop Plus Mosunetuzumab as First Line in Patients with Richter´s Syndrome: a Phase Ii Study of the Spanish Group of CLL (GELLC-9-RICHTER)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Grupo Espanol De Leucemia Linfocitica Cronica

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

14 May 2024 → ongoing

Decision date (initial)

2024-04-26

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy

To evaluate the efficacy of mosunetuzumab combined with CHOP (M-CHOP) after the end of induction (EoI) in patients with DLBCL-RS who have never received therapy.

Secondary objectives 5

1. To evaluate the efficacy of mosunetuzumab combined with CHOP (M-CHOP) after the end of induction (EoI) and maintenance (EoM) in patients with therapy naïve RS.
2. To determine the incidence and severity of adverse events.
3. To evaluate the study treatment exposure.
4. To evaluate the relationship between various screening prognostic markers (clinical and biological) and clinical outcome.
5. To assess MRD using several technologies, including ctDNA.

Conditions and MedDRA coding

Richter´syndrome

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. 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
2. Aged between 18 and 79 years at the time of signing the Informed Consent Form
3. Ability to comply with the study protocol and procedures and required hospitalizations, in the investigator’s judgement
4. Eastern Cooperative Oncology Group (ECOG) performance score (PS) of ≤2.
5. Adult patients with previously untreated, histologically proven Richter's syndrome, diffuse large B cell variants, following WHO 2008 criteria (Swerdlow SH, 2008)
6. Screening flow cytometry or immunohistochemistry (IHC) evidence of CD20 positive disease as per central review (dim expression of CD20 is acceptable)
7. 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)
8. Measured or estimated creatinine clearance ≥ 45 mL/min by institutional standard method
9. Life expectancy > 3 months
10. 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.
11. 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 25

1. 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.
2. Participants who have received any of the following treatments prior to study entry: − Treatment with mosunetuzumab or other CD20/CD3-directed bispecific antibodies
3. 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.
4. Central nervous system (CNS) involvement as documented by spinal fluid cytology or imaging.
5. Transformation of CLL to prolymphocytic leukemia
6. 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
7. 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
8. History of severe allergic or anaphylactic reactions to humanized or murine monoclonal antibody therapy (or recombinant antibody-related fusion proteins)
9. Contraindication to tocilizumab
10. 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
11. 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.
12. History of solid organ transplantation
13. 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
14. History of confirmed progressive multifocal leukoencephalopathy (PML)
15. Positive serologic HIV test at screening
16. 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.
17. 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.
18. Known or suspected chronic active Epstein Barr Virus infection (CAEBV)
19. Patients with history of macrophage activation syndrome (MAS)/hemophagocytic lymphohistiocytosis (HLH)
20. 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
21. Left ventricular ejection fraction (LVEF) <50% by multiple-gated acquisition (MUGA) scan or echocardiogram
22. 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
23. 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)
24. Participants who are in dependence to the Sponsor or an investigator
25. 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

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Primary end point will be CR evaluated by an independent review committee according to modified Lugano classification using PET/CT scan (Cheson et al. 2014) at 8-12 weeks after the EoI visit. CR will be 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 with at least one dose of Mosunetuzumab will be included in the efficacy population.

Secondary endpoints 5

1. Objective response rate (ORR),Complete remission rate (CR), Best overall response, Minimal residual disease (MRD), Progression free survival (PFS),Overall survival (OS), Duration of response (DOR),
2. Incidence and severity of adverse events, including for CRS, severity determined according to ASTCT CRS consensus grading criteria (Lee et al 2019); for TLS, presence of laboratory and/or clinical TLS determined according to Howard criteria (Howard et al 2011).
3. Study treatment exposure (such as treatment duration, total dose received, and number of cycles and dose modifications)
4. Relationship between molecular and genetic prognostic factors as well as clonality and efficacy endpoints
5. Relationship between MRD response and efficacy endpoints such as PFS and OS.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 5

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Grupo Espanol De Leucemia Linfocitica Cronica

Sponsor organisation

Grupo Espanol De Leucemia Linfocitica Cronica

Address

Calle De Panama 10 1 D

City

Madrid

Postcode

28036

Country

Spain

Scientific contact point

Organisation

Grupo Espanol De Leucemia Linfocitica Cronica

Contact name

Ana Mendez

Public contact point

Organisation

Grupo Espanol De Leucemia Linfocitica Cronica

Contact name

Ana Mendez

Third parties 12

Locations

1 EU/EEA country · 16 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Application history

1 submissions — initial application plus substantial / non-substantial modifications