| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| RELAPSE/REFRACTORY B-CELL LYMPHOMA |
|
| E.1.1.1 | Medical condition in easily understood language |
| RELAPSE/REFRACTORY B-CELL LYMPHOMA |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10003902 |
| E.1.2 | Term | B-cell lymphoma recurrent |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10003903 |
| E.1.2 | Term | B-cell lymphoma refractory |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Evaluate efficacy of valemetostat tosylate (DS-3201b) monotherapy in relapsed/refractory B cell lymphoma patients within 6 distinct cohorts:
- Cohort 1: 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 rerrangement, transformed indolent lymphoma and grade 3b follicular lymphoma) (with at least 8 EZH2 mutant)
- Cohort 2: Follicular Lymphoma (grade 1, 2, 3a) EZH2 wild-type
- Cohort 2bis: Follicular Lymphoma (grade 1, 2, 3a) EZH2 mutant (gain of function mutations)
- Cohort 3: Mantle Cell Lymphoma (MCL)
- Cohort 4: Marginal Zone Lymphoma (MZL) and others indolent lymphoma (Waldenström macroglobulinemia)
- Cohort 5: Hodgkin Lymphoma (HL) |
|
| E.2.2 | Secondary objectives of the trial |
- Rate of complete response (CR)
- Progression-free survival (PFS)
- Duration of response (DOR)
- Time to response (TTR)
- Safety
- To evaluate the plasma pharmacokinetics of valemetostat tosylate (DS-3201b) and major metabolite (CALZ-1809a). |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 rerrangement, 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 systemic therapy
3. Participant who has measurable disease by the Lugano criteria (ie longest diameter of a nodal site > 1.5cm and/or longest diameter of an extranodal site > 1.0 cm)
4. Participant who had previous standard therapy with at least:
(note: patients having received prior CAR-T therapy can be enrolled):
4a. For aggressive B-cell lymphoma: 1 prior line of therapy (in transformed indolent lymphoma patient must have received at least one line of treatment containing an anthracycline-based regimen before or after transformation) containing an anti-CD20 antibody and an anthracycline (unless anthracycline-based therapy is contraindicated) and if patient is considered unable to benefit from intensification treatment with autologous stem cell transplant (ASCT) as defined by at least one of the 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 an acceptable number of hematopoietic stem cells
- Refused intensification treatment and/or ASCT
4b. For FL, MZL and other indolent NHL: 2 prior lines of systemic therapy with at least one anti-CD20 monoclonal antibody. Local involved field 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.
4c. For MCL: 2 prior lines including at least one immunochemotherapy and one BTK inhibitor.
4d. For HL: 3 prior lines including at least one line with anthracycline-based chemotherapy (unless anthracycline-based therapy is contraindicated), one line containing brentuximab-vedotin and one line containing an anti-PD1 or anti-PDL1 antibody and must be considered unable to benefit from intensification treatment with autologous stem cell transplant (ASCT) as defined by at least one of the following 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 an acceptable number of hematopoietic stem cells
- Refused intensification treatment and/or ASCT
5. Participant with Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2
6. Adequate renal function defined as calculated creatinine clearance ≥ 40 mL/min per the Cockcroft and Gault formula
7. Adequate bone marrow function
8. Adequate liver function:
9. Adequate tissue (surgical excision is recommended) for central pathology review and biological caracterisation
10. Patient being successfully tested for EZH2 mutation status at study specific laboratories (for cohort 1, 2 and 2bis)
11. Subjects with a history of hepatitis B or C are eligible on the condition that subjects have adequate liver function and are hepatitis B surface antigen negative and have undetectable serum HBV DNA and HCV RNA, respectively.
12. Females of childbearing potential must agree to use an highly effective birth control methods (defined in §13.6.1) during the following time periods related to this study: 1) for at least 28 days before starting study 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 highly effective birth control methods during the study and 3 months after last treatment administration
14. Male and female participant ≥18 years of age at the time of informed consent
15. Patient covered by any social security system (France)
16. Patient who understands and speaks one of the country official language
17. Participant who has provided written consent to participate in the study |
|
| E.4 | Principal 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 clinically significant 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 other uncontrolled gastrointestinal condition (eg, nausea, diarrhea, or vomiting) that might impair the bioavailability of the drug
6. Subjects currently taking medications that are known moderate or strong CYP3A inducers (refer to Appendix 7 for a list of example drugs)
o If currently used, these medications need to be discontinued at least 14 days prior to study drug administration; replacement by alternative medications that are not moderate or strong CYP3A inducers can be considered according to medical need
7. Vaccinated with live, attenuated vaccines within 6 months of enrollment (except COVID vaccine)
8. Use of any standard or experimental anti-cancer drug therapy within 4 weeks or a minimum of 3 half lives of the drug, whatever the shortest prior to first administration 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 HCT within 90 days prior to the first dose of study drug
11. Patients taking corticosteroids within 2 weeks prior to first administration of study 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 heart failure greater than New York Heart Association (NYHA) Class II, uncontrolled arterial hypertension, unstable angina, myocardial infarction, or stroke within 6 months of the first dose of study drug; or cardiac ventricular arrhythmia
13. Subjects with malignancies other than B cell lymphomas except subjects who have been disease-free for 2 years (subjects with a history of a completely resected non-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, or pulmonary 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 the investigator or sub-investigator |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Primary endpoint will be the overall response rate (ORR) defined as the proportion of subjects achieving best overall response of partial response (PR) or complete response (CR) at any time, according to the Lugano 2014 classification (PET-CT–Based Response for FDG-avid lymphomas or CT-Based Response if not) and determined by investigator. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| For each cohort, the primary endpoint analysis will be performed when the number of evaluable patients requested has received at least 12 cycles of study treatment, have died, have withdrawn their consent, have stopped treatment or are lost to follow up (whatever the event that occurs first). |
|
| E.5.2 | Secondary end point(s) |
- Rate of complete response (CR)
- Progression-free survival (PFS)
- Duration of response (DOR)
- Time to response (TTR)
- Safety
- To evaluate the plasma pharmacokinetics of valemetostat tosylate (DS-3201b) and major metabolite (CALZ-1809a). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| The final analysis (secondary endpoints) will be performed when all patients received at least 12 cycles of study treatment, have died, have withdrawn their consent, or are lost to follow up (whatever the event that occurs first). |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 18 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 22 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
Print
