Study of Valemetostat Tosylate as a Single Agent in Patients With Relapse/Refractory B-cell Lymphoma

Inclusion Criteria:

1 - Participants with confirmed histological diagnosis of B-cell non-Hodgkin's lymphoma of aggressive B-cell lymphoma (diffuse large B-cell lymphoma-not otherwise specified, primary mediastinal B-cell lymphoma, high grade B-cell lymphoma-not otherwise specified and high grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangement, transformed indolent lymphoma and grade 3b follicular lymphoma), FL (grade 1, 2, 3a), MCL, MZL or other indolent lymphoma (Waldenström macroglobulinemia), or HL according to the World Health Organization (WHO) 2016 classification of hematopoietic and lymphoid tissue.

2. Participant who had progressive disease (PD) or did not have a response (CR or PR)in previous systemic therapy, or relapsed or progressed after previous systemictherapy 3. Participant who has measurable disease by the Lugano criteria (ie longestdiameter of a nodal site > 1.5cm and/or longest diameter of an extranodal site > 1.0cm) 4. Participant who had previous standard therapy with at least: (note: patientshaving received prior CAR-T therapy can be enrolled):

3. For aggressive B-cell lymphoma : 1 prior line of therapy (in transformed indolentlymphoma patient must have received at least one line of treatment containing ananthracycline-based regimen before of after transformation) containing an anti-CD20antibody and an anthracycline (unless anthracycline-based therapy iscontraindicated) and if patient is considered unable to benefit from intensificationtreatment with autologous stem cell transplant (ASCT) as defined by at least one ofthe following criteria:

• Relapsed following, or refractory to, previous ASCT

• Ineligible for intensification treatment due to age or significant comorbidity

• Ineligible for intensification treatment due to failure to mobilize anacceptable number of hematopoietic stem cells

• Refused intensification treatment and/or ASCT

2. For FL, MZL and other indolent non-Hodgkin's lymphoma (NHL): 2 prior lines ofsystemic therapy with at least one anti-CD20 monoclonal antibody. Local involvedfield radiotherapy for limited stage disease is not considered as a previous line.Subjects with prior ASCT may be included. Note: for Splenic Marginal Zone Lymphoma (SMZL), splenectomy is considered as one line; for Extranodal Marginal Zone Lymphoma (ENMZL), Helicobacter pylori eradication is not considered as a previous line.

3. For MCL: 2 prior lines including at least one immunochemotherapy and one BTKinhibitor.

4. For HL: 3 prior lines including at least one line with anthracycline-basedchemotherapy (unless anthracycline-based therapy is contraindicated), one linecontaining brentuximab-vedotin and one line containing an anti-PD1 or anti-PDL1antibody and must be considered unable to benefit from intensification treatmentwith autologous stem cell transplant (ASCT) as defined by at least one of thefollowing criteria:

• Relapsed following, or refractory to, previous ASCT

• Did not achieve at least a partial response to a standard salvage regimen

• Ineligible for intensification treatment due to age or significant comorbidity

• Ineligible for intensification treatment due to failure to mobilize anacceptable number of hematopoietic stem cells

• Refused intensification treatment and/or ASCT 5. Participant with EasternCooperative Oncology Group (ECOG) performance status of 0 to 2 6. Adequaterenal function defined as calculated creatinine clearance ≥ 40 mL/min per theCockcroft and Gault formula 7. Adequate bone marrow function:

• Absolute neutrophil count (ANC) > 1000/mm3 (≥ 1 × 109/L) without growth factorsupport (G-CSF) for at least 7 days

• Platelets ≥ 75,000/mm3 (≥ 75 × 109/L) evaluated after at least 7 days sincelast platelet transfusion

• Hemoglobin > 8.0 g/dL evaluated after at least 7 days since last transfusion 8.Adequate liver function:

• Total bilirubin < 1.5 × the upper limit of normal (ULN) except for unconjugatedhyperbilirubinemia due to Gilbert's syndrome

• Alkaline phosphatase (ALP) (in the absence of bone disease), alanineaminotransferase (ALT), and aspartate aminotransferase (AST) < 3 × ULN (< 5 ×ULN if subject has liver involvement due to lymphoma) 9. Adequate tissue (surgical excision is recommended) for central pathology review and biologicalcharacterisation 10. Patient being successfully tested for EZH2 mutation statusat study specific laboratories (for cohort 1, 2 and 2bis) 11. Subjects with ahistory of hepatitis B or C are eligible on the condition that subjects haveadequate liver function and are hepatitis B surface antigen negative and haveundetectable serum hepatitis B virus (HBV) DNA and hepatitis C virus (HCV) RNA,respectively.

12. Females of childbearing potential must agree to use an highly effectivebirth control methods (defined in §13.6.1) during the following timeperiods related to this study: 1) for at least 28 days before startingstudy drug; 2) while participating in the study; 3) dose interruptions;and 4) for at least 3 months after discontinuation of study treatment 13.Males with partners of childbearing potential must agree to use highlyeffective birth control methods during the study and 3 months after lasttreatment administration 14. Male and female participant ≥18 years of ageat the time of informed consent 15. Patient covered by any social securitysystem (France) 16. Patient who understands and speaks one of the countryofficial language 17. Participant who has provided written consent toparticipate in the study

Exclusion Criteria:

1. Participant with prior exposure to EZH2 inhibitor

2. Participant with active lymphomatous involvement of the central nervous system (CNS)at screening

3. Any prior treatment-related (ie, chemotherapy, immunotherapy, radiotherapy),clinically significant toxicities have not resolved to ≤ Grade 1 per CTCAE version 5.0, or prior treatment-related toxicities are clinically unstable and clinicallysignificant at time of enrollment.

4. Major surgery within 4 weeks before the first dose of study drug.

5. Inability to take oral medication, or malabsorption syndrome or any otheruncontrolled gastrointestinal condition (eg, nausea, diarrhea, or vomiting) thatmight impair the bioavailability of the drug

6. Subjects currently taking medications that are known moderate or strong CYP3Ainducers

• If currently used, these medications need to be discontinued at least 14 daysprior to study drug administration; replacement by alternative medications thatare not moderate or strong CYP3A inducers can be considered according tomedical need

7. Vaccinated with live, attenuated vaccines within 6 months of enrollment (exceptCOVID vaccine)

8. Use of any standard or experimental anti-cancer drug therapy within 4 weeks or aminimum of 3 half lives of the drug, whatever the shortest prior to firstadministration of study drug,

9. History of CAR T-cells therapy within 30 days prior to the first dose of study drug

10. History of autologous or allogeneic hematopoietic cell transplantation (HCT) within 90 days prior to the first dose of study drug

11. Patients taking corticosteroids within 2 weeks prior to first administration ofstudy drug, unless administered at a cumulated dose equivalent of prednisone to ≤ 10mg /day (within these 2 weeks).

12. Participant with significant cardiovascular impairment: history of congestive heartfailure greater than New York Heart Association (NYHA) Class II, uncontrolledarterial hypertension, unstable angina, myocardial infarction, or stroke within 6months of the first dose of study drug; or cardiac ventricular arrhythmia

13. Subjects with malignancies other than B cell lymphomas except subjects who have beendisease-free for 2 years (subjects with a history of a completely resectednon-melanoma skin cancer or successfully treated in situ carcinoma are eligible).

14. Positive serology of human immunodeficiency virus (HIV)

15. Participant with prolongation of corrected QT interval using Fridericia's formula (QTcF) to > 470 milliseconds (msec) (obtained on average of 3 ECGs)

16. Participant with venous thrombosis or pulmonary embolism not treated

17. Participant with complications of hepatic cirrhosis, interstitial pneumonia, orpulmonary fibrosis

18. Participant with active infection requiring systemic therapy

19. Woman who are pregnant (positive serum pregnancy test at screening) or breastfeeding

20. Participant who were deemed as inappropriate to participate in the study by theinvestigator or coinvestigator