M-CHOP in Richter´s Syndrome

The purpose of the study is to assess the efficacy, safety and tolerability of mosunetuzumab combined with CHOP in patients with untreated DLBCL-RS syndrome, identifying biological factors to address the probability of response.

In addition, efficacy and tolerability of maintenance with mosunetuzumab in patients not receiving an allo-SCT will be ascertained.

The primary study objective and associated endpoint is to evaluate the efficacy of mosunetuzumab combined with CHOP (M-CHOP) after the end of induction (EoI) in patients with RS who have never received therapy.

Primary endpoint will be complete remission (CR) evaluated by an independent review committee according to modified Lugano classification using PET/CT scan after the 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 in patients with at least one dose of mosunetuzumab will be included in the efficacy population.

The secondary study objectives and associated endpoints are:

* To evaluate the efficacy of mosunetuzumab combined with CHOP (M-CHOP) after the end of induction (EoI) and maintenance (EoM) in patients with therapy naive RS.
* Overall response rate (ORR), defined as the proportion of participants with a complete response (CR) or partial response (PR) at the end of induction (EoI) and maintenance (EoM), as determined by local and independent review committee according to modified Lugano classification using PET/CT scan and IWCLL criteria (Hallek 2018).
* Complete remission (CR) at the EoM will be defined as a score of 1, 2 or 3 (no uptake above background) for lymph nodes and extralymphatic sites at PET without new lesions and no evidence of fluorodeoxyglucose (FDG)-avid disease in bone marrow. In addition, patients need to have a normal blood count with normal/immunohistochemistry (IHC)-negative bone marrow morphology as per iwCLL criteria (Hallek 2018). All PET evaluable patients with at least one dose of mosunetuzumab will be included in the efficacy population.
* Best overall response: the best response is defined as the achievement of a PET score of 1-3 associated with a normal blood count with normal/immunohistochemistry (IHC)-negative bone marrow morphology as per iwCLL criteria, or a PET score of 1-3 associated with incomplete recovery in blood and normal/immunohistochemistry (IHC)-negative bone marrow morphology evaluated at any time during the treatment induction or maintenance, whichever occurs first.
* Minimal residual disease (MRD) response rate determined by the proportion of patients with MRD-negativity (defined as \< 1 CLL cell in 10,000 leukocytes), assessed by flow cytometry in responders (CR/PR) in peripheral blood (PB) and/or bone marrow (BM) after the EoI and EoM.
* Progression free survival (PFS), defined as the time from the first study treatment to the first occurrence of disease progression or death from any cause, whichever occurs first. PFS will be assessed by the investigator, using the Lugano criteria.
* Overall survival (OS), defined as the time from first dose to death from any cause.
* Duration of response (DoR), defined as the time from best overall response (the first occurrence of a documented objective response) to disease progression by Lugano criteria or death from any cause, whichever occurs first.

To determine the incidence and severity of adverse events

* Incidence of adverse events (AEs): number and percentage of patients with 1 or more AE.
* Severity of AEs according to NCI CTCAE v5.0. For events of CSR, severity will be determined by ASTCT CSR consensus grading criteria. For events of TLS, the presence of laboratory and/or clinical TLS will be determined according to Howard criteria.

To evaluate the study treatment exposure:

* Treatment duration
* Total dose received
* Number of cycles and dose modifications
* Treatment interruptions and discontinuations

Eligibility Criteria:
Inclusion Criteria:

* Patients meeting all the following inclusion criteria will be eligible for participation in the study:

  1. Capable of giving signed informed consent as described in Section 13.2, which includes compliance with the requirements and restrictions listed in the Informed Consent 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 required hospitalizations, 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 positive disease as per central review (dim expression of CD20 is acceptable)
  7. Adequate BM function independent of growth factor or transfusion at screening as follows unless cytopenia is clearly due to marrow involvement of CLL:

     1. Platelet count ≥75 x 109/L; in cases of thrombocytopenia clearly due to marrow involvement of CLL (per the discretion of the investigator), platelet count should be ≥ 30 x 109/L.
     2. ANC ≥1 x 109/L unless neutropenia is clearly due to marrow involvement of CLL (per the discretion of the investigator)
     3. 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 (WOCBP): 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).

      1. It is recommended to remain abstinent or use contraception for 12 months after the final dose of cyclophosphamide, doxorubicin, or vincristine.
      2. A woman is considered to be of childbearing potential (WOCBP) 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.

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 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:

   a) 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:

   1. Autologous SCT within 100 days prior to first mosunetuzumab administration.
   2. Allogeneic stem cell transplant for CLL
   3. CAR T-cell therapy for CLL within 100 days before first study treatment
   4. 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:

   1. Malignancies treated with curative intent and with no known active disease present for ≥ 2 years before enrollment.
   2. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease.
   3. Adequately treated cervical carcinoma in situ without evidence of disease.
   4. Surgically/adequately treated low grade, early stage, localized prostate cancer without evidence of disease.
7. Any of the following laboratory abnormalities:

   1. Calculated creatinine Clearance \< 45 mL/min (by institutional standard method.).
   2. Absolute neutrophil count (ANC) \< 1.0 x 109/L, unless secondary to bone marrow involvement by CLL.
   3. Platelet count \<75 x 109/L except if thrombocytopenia is clearly due to marrow involvement of CLL (per the discretion of the investigator) for which exclusion criteria would be platelet count \< 30 x 109/L.
   4. 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).
   5. 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 hemolytic anemia or autoimmune thrombocytopenia active at the moment of first dose of therapy.

    a) 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. Exceptions include the following:

    1. Participants with a history of autoimmune-related hypothyroidism on a stable dose of thyroid replacement hormone may be eligible.
    2. Participants with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study.
    3. 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:

    1. 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)
    2. significant pulmonary disease (such as obstructive pulmonary disease or history of bronchospasm)
    3. clinically significant history of liver disease, including viral or other hepatitis, or cirrhosis.
    4. current or past history of CNS disease, such as stroke, epilepsy, CNS vasculitis, or neurodegenerative disease.
    5. Participants with a history of stroke who have not experienced a stroke or transient ischemic attack in the past year and have no residual neurologic deficits as judged by the investigator are allowed.
    6. 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.
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.