CHOP Plus Mosunetuzumab as First Line in Patients With Richter´s Syndrome: a Phase II Study of the Spanish Group of CLL

Inclusion Criteria:

1. Capable of giving signed informed consent as described in Section 13.2, whichincludes compliance with the requirements and restrictions listed in the InformedConsent Form and 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 requiredhospitalizations, in the investigator's judgement.

4. Eastern Cooperative Oncology Group (ECOG) performance status (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 positivedisease as per central review (dim expression of CD20 is acceptable)

7. Adequate BM function independent of growth factor or transfusion at screening asfollows unless cytopenia is clearly due to marrow involvement of CLL:

8. Platelet count ≥75 x 109/L; in cases of thrombocytopenia clearly due to marrowinvolvement of CLL (per the discretion of the investigator), platelet countshould be ≥ 30 x 109/L.

9. ANC ≥1 x 109/L unless neutropenia is clearly due to marrow involvement of CLL (per the discretion of the investigator)

10. Total hemoglobin ≥ 9 g/dL unless anemia is due to marrow involvement of CLL (per the discretion of the investigator)

11. Measured or estimated creatinine clearance ≥ 45 mL/min by institutional standardmethod.

12. Life expectancy > 3 months

13. For women of childbearing potential (WOCBP): agreement to remain abstinent (refrainfrom heterosexual intercourse) or use contraceptive methods that result in a failurerate of < 1% per year, and agreement to refrain from donating eggs, during thetreatment period and for at least 3 months after the last dose of mosunetuzumab and 3 months after the last dose of tocilizumab (if applicable).

14. It is recommended to remain abstinent or use contraception for 12 months afterthe final dose of cyclophosphamide, doxorubicin, or vincristine.

15. A woman is considered to be of childbearing potential (WOCBP) if she ispostmenarchal, has not reached a postmenopausal state (≥ 12 continuous monthsof amenorrhea with no identified cause other than menopause), and is notpermanently infertile due to surgery (i.e., removal of ovaries, fallopiantubes, and/or uterus) or another cause as determined by the investigator (e.g.,Müllerian agenesis). The definition of childbearing potential may be adaptedfor alignment with local guidelines or regulations.

16. Examples of contraceptive methods with a failure rate of < 1% per year includebilateral tubal ligation, male sterilization, hormonal contraceptives thatinhibit ovulation, hormone-releasing intrauterine devices, and copperintrauterine devices.

17. The reliability of sexual abstinence should be evaluated in relation to theduration of the clinical trial and the preferred and usual lifestyle of theindividual. Periodic abstinence (e.g., calendar, ovulation, symptothermal, orpostovulation methods) and withdrawal are not adequate methods ofcontraception.

18. If required per local guidelines or regulations, locally recognized adequatemethods of contraception and information about the reliability of abstinencewill be described in the Informed Consent Form.

19. For men: agreement to remain abstinent (refrain from heterosexual intercourse) oruse a condom, and agreement to refrain from donating sperm, as defined below:

20. With a female partner of childbearing potential or pregnant female partner, menmust remain abstinent or use a condom during the treatment period and for 60days after the final dose of tocilizumab (if applicable) and must remainabstinent or use a condom for 12 months after the final dose ofcyclophosphamide, doxorubicin, or vincristine to avoid exposing the embryo. Menmust refrain from donating sperm during this same period.

21. The reliability of sexual abstinence should be evaluated in relation to theduration of the clinical trial and the preferred and usual lifestyle of theindividual. Periodic abstinence (e.g., calendar, ovulation, symptothermal, orpostovulation methods) and withdrawal are not adequate methods of preventingdrug exposure. If required per local guidelines or regulations, informationabout the reliability of abstinence will be described in the Informed ConsentForm.

Exclusion Criteria:

1. Pregnant or breastfeeding or intending to become pregnant during the study or within 3 months after the final dose of mosunetuzumab. a) WOCBP must have a negative serum pregnancy test result within 14 days prior toinitiation of study treatment. If a serum pregnancy test has not been performedwithin 14 days prior to receiving first study treatment, a negative urine pregnancytest 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: a) Treatment with mosunetuzumab or other CD20/CD3-directed bispecific antibodies.

3. Participants who have received any of the following treatments, whetherinvestigational or approved, given to treat RS, within the respective time periodsprior to initiation of study treatment:

4. Autologous SCT within 100 days prior to first mosunetuzumab administration.

5. Allogeneic stem cell transplant for CLL

6. CAR T-cell therapy for CLL within 100 days before first study treatment

7. Systemic corticosteroid treatment ≤ 20 mg/day prednisone or equivalent tocontrol symptoms related to disease progression for a maximum of 5 days beforestarting C1D1 and inhaled corticosteroids are permitted.

8. Central nervous system (CNS) involvement as documented by spinal fluid cytology orimaging.

9. Transformation of CLL to prolymphocytic leukemia.

10. History of prior malignancy, except for conditions as listed below if patients haverecovered from the acute side effects incurred as a result of previous therapy:

11. Malignancies treated with curative intent and with no known active diseasepresent for ≥ 2 years before enrollment.

12. Adequately treated non-melanoma skin cancer or lentigo maligna without evidenceof disease.

13. Adequately treated cervical carcinoma in situ without evidence of disease.

14. Surgically/adequately treated low grade, early stage, localized prostate cancerwithout evidence of disease.

15. Any of the following laboratory abnormalities:

16. Calculated creatinine Clearance < 45 mL/min (by institutional standardmethod.).

17. Absolute neutrophil count (ANC) < 1.0 x 109/L, unless secondary to bone marrowinvolvement by CLL.

18. Platelet count <75 x 109/L except if thrombocytopenia is clearly due to marrowinvolvement of CLL (per the discretion of the investigator) for which exclusioncriteria would be platelet count < 30 x 109/L.

19. 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).

20. Serum total bilirubin > 1.5 x ULN, except in cases of Gilbert's syndrome.

21. History of severe allergic or anaphylactic reactions to humanized or murinemonoclonal antibody therapy (or recombinant antibody-related fusion proteins)

22. Contraindication to tocilizumab.

23. Presence of any autoimmune disorder including autoimmune hemolytic anemia orautoimmune thrombocytopenia active at the moment of first dose of therapy. a) Participants with a history of disease-related immune thrombocytopenic purpura orautoimmune hemolytic anemia may be eligible.

24. 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 antiphospholipidsyndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome,multiple sclerosis, vasculitis, or glomerulonephritis. Exceptions include thefollowing:

25. Participants with a history of autoimmune-related hypothyroidism on a stabledose of thyroid replacement hormone may be eligible.

26. Participants with controlled Type 1 diabetes mellitus who are on an insulinregimen are eligible for the study.

27. Participants with a remote history of, or well-controlled autoimmune disease,with a treatment-free interval from immunosuppressive therapy for 12 months maybe eligible after review and discussion with the Coordinators.

28. History of solid organ transplantation

29. Participants with infections requiring IV treatment with antibiotics orhospitalization (Grade 3 or 4) within the last 4 weeks prior to enrollment or knownactive bacterial, viral (including SARS-CoV-2), fungal, mycobacterial, parasitic, orother infection (excluding fungal infections of nail beds) at study enrollment.

30. History of confirmed progressive multifocal leukoencephalopathy (PML)

31. Positive serologic HIV test at screening

32. Positive test results for chronic hepatitis B infection (defined as positivehepatitis B surface antigen [HBsAg] serology). Participants with occult or priorhepatitis B infection (defined as positive total hepatitis B core antibody andnegative HBsAg) may be included if hepatitis B virus (HBV) DNA is undetectable atthe time of screening. These participants must be willing to undergo monthly DNAtesting and appropriate prophylactic antiviral therapy as indicated.

33. Acute or chronic hepatitis C virus (HCV) infection. Participants who are positivefor HCV antibody must be negative for HCV by polymerase chain reaction (PCR) to beeligible for study participation.

34. Known or suspected chronic active Epstein Barr Virus infection (CAEBV).

35. Patients with history of macrophage activation syndrome (MAS)/hemophagocyticlymphohistiocytosis (HLH)

36. Received a live, attenuated vaccine within 4 weeks before first dose of studytreatment, or in whom it is anticipated that such a live attenuated vaccine will berequired during the study period or within 5 months after the final dose of studytreatment.

37. Left ventricular ejection fraction (LVEF) <50% by multiple-gated acquisition (MUGA)scan or echocardiogram.

38. Evidence of any significant, concomitant disease that could affect compliance withthe protocol or interpretation of results, including, but not limited to:

39. significant cardiovascular disease (e.g., New York Heart Association Class IIIor IV cardiac disease, myocardial infarction within the previous 3 months,unstable arrhythmia, or unstable angina)

40. significant pulmonary disease (such as obstructive pulmonary disease or historyof bronchospasm)

41. clinically significant history of liver disease, including viral or otherhepatitis, or cirrhosis.

42. current or past history of CNS disease, such as stroke, epilepsy, CNSvasculitis, or neurodegenerative disease.

43. Participants with a history of stroke who have not experienced a stroke ortransient ischemic attack in the past year and have no residual neurologicdeficits as judged by the investigator are allowed.

44. Participants with a history of epilepsy who have had no seizures in the past 2years with or without anti-epileptic medications can be eligible.

45. Recent major surgery within 4 weeks prior to first study treatment administration,with the exception of protocol-mandated procedures (e.g., tumor biopsies and bonemarrow biopsies)

46. Participants who are in dependence to the Sponsor or an investigator.

47. Any serious medical condition or abnormality in clinical laboratory tests that, inthe investigator's judgment, precludes an individual's safe participation in andcompletion of the study.