A phase II open-label study evaluating valemetostat tosylate as a single agent in patients with relapse/refractory B-cell lymphoma

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Lysarc

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

10 Jun 2021 → ongoing

Decision date (initial)

2024-09-16

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2024-516181-11-00

EudraCT number

2020-005225-81

ClinicalTrials.gov

NCT04842877

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy

Evaluate efficacy of valemetostat tosylate (DS-3201b) monotherapy in relapsed/refractory B cell lymphoma patients within 5 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)
- Cohort 2: Follicular Lymphoma (grade 1, 2, 3a) EZH2 wild-type or mutant
- Cohort 3: Mantle Cell Lymphoma (MCL)
- Cohort 4: Marginal Zone Lymphoma (MZL) and others indolent lymphoma (lymphoplasmacytic lymphoma)
- Cohort 5: Hodgkin Lymphoma (HL)

Secondary objectives 5

1. Rate of complete response (CR)
2. - Progression-free survival (PFS)
3. - Duration of response (DOR)
4. - Time to response (TTR)
5. - Safety

Conditions and MedDRA coding

RELAPSE/REFRACTORY B-CELL LYMPHOMA.

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 17

1. 1. Participants with confirmed histological diagnosis 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 (lymphoplasmacytic lymphoma), or HL according to the World Health Organization (WHO) 2016 classification of hematopoietic and lymphoid tissue
2. 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. 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. 4. Participant who had previous standard therapy with at least: (note: patients having received prior CAR-T therapy can be enrolled): - For aggressive B-cell lymphoma: 2 prior lines 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 patient deemed ineligible for high-dose therapy and ASCT based on physician’s assessment or age ≥ 65 years or with a hematopoietic cell transplantation-specific comorbidity index (HCT-CI) score ≥3. In the best interest of the patient, the treating physician must ensure CAR-T have been discussed among the treament options before considering enrollment in this study. - 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 or CAR-T cells may be included. In the best interest of the patient, the treating physician must ensure CAR-T have been discussed among the treament options before considering enrollment in this study. 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; indolent (ie FL or MZL) relapse after aggressive B-cell lymphoma can be enrolled and prior treatment lines for the aggressive lymphoma are taken into account for inclusion criteria. - For MCL: 2 prior lines including at least one immunochemotherapy and one BTK inhibitor. - 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 patient deemed ineligible for high-dose therapy and ASCT based on physician’s assessment or age ≥ 65 years or with a hematopoietic cell transplantation-specific comorbidity index (HCT-CI) score ≥3
5. 5. Participant with Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2
6. 6. Adequate renal function defined as calculated creatinine clearance ≥ 40 mL/min per the Cockcroft and Gault formula
7. 7. Adequate bone marrow function: - Absolute neutrophil count (ANC) > 1000/mm3 (≥ 1 × 109/L) without growth factor support (G-CSF) for at least 7 days - Platelets ≥ 75,000/mm3 (≥ 75 × 109/L /L) evaluated after at least 7 days since last platelet transfusion - Hemoglobin > 8.0 g/dL evaluated after at least 7 days since last transfusion
8. 8. Adequate liver function: - Total bilirubin < 1.5 × the upper limit of normal (ULN) except for unconjugated hyperbilirubinemia due to Gilbert’s syndrome - Alkaline phosphatase (ALP) (in the absence of bone disease), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) < 3 × ULN (< 5 × ULN if subject has liver involvement due to lymphoma)
9. 9. Adequate tissue (surgical excision is recommended) for central pathology review and biological caracterisation
10. 10. Sufficient quantity of DNA available on the platform for EZH2 status determination (for aggressive B-cell lymphoma and FL)
11. 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. 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) during dose interruptions; and 4) for at least 3 months after discontinuation of study treatment
13. 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. 14. Male and female participant ≥18 years of age at the time of informed consent
15. 15. Patient covered by any social security system (France)
16. 16. Patient who understands and speaks one of the country official language
17. 17. Participant who has provided written consent to participate in the study

Exclusion criteria 21

1. 1. Participant with prior exposure to EZH2 inhibitor
2. 2. Participant with active lymphomatous involvement of the central nervous system (CNS) at screening
3. 3. Any prior treatment-related (ie, chemotherapy, immunotherapy, radiotherapy) clinically significant toxicities that have not resolved to ≤ Grade 1 per CTCAE version 5.0, or prior treatment-related toxicities that are clinically unstable and clinically significant at time of enrollment.
4. 4. Major surgery within 4 weeks before the first dose of study drug.
5. 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. 7. Vaccinated with live, attenuated vaccines within 6 months of enrollment (except COVID vaccine)
8. 8. Use of any standard or experimental anti-cancer drug therapy within 4 weeks or a minimum of 5 half lives of the drug, whatever the shortest prior to first administration of study drug,
9. 9. History of CAR T-cells therapy within 30 days prior to the first dose of study drug
10. 10. History of autologous or allogeneic HCT within 90 days prior to the first dose of study drug
11. 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. 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. 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. 14. Positive serology of human immunodeficiency virus (HIV)
15. 15. Participant with prolongation of corrected QT interval using Fridericia's formula (QTcF) to > 470 milliseconds (msec) (obtained on average of 3 ECGs)
16. 16. Participant with venous thrombosis or pulmonary embolism not treated
17. 17. Participant with complications of hepatic cirrhosis, interstitial pneumonia, or pulmonary fibrosis
18. 18. Knowing or suspected hypersensitivity to active substance or to any of the excipients
19. 19. Participant with active infection requiring systemic therapy
20. 20. Woman who are pregnant (positive serum pregnancy test at screening) or breastfeeding
21. Participant who were deemed as inappropriate to participate in the study by the investigator or sub-investigator

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 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.

Secondary endpoints 5

1. - Rate of complete response (CR)
2. - Progression-free survival (PFS)
3. - Duration of response (DOR)
4. - Time to response (TTR)
5. - Safety

Investigational products

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

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Lysarc

Sponsor organisation

LYSARC

Address

2d Lyon Sud Batiment

City

Pierre Benite Cedex

Postcode

69495

Country

France

Scientific contact point

Organisation

LYSARC

Contact name

Franck MORSCHHAUSER

Public contact point

Organisation

LYSARC

Contact name

Delphine Leduc

Locations

2 EU/EEA countries · 24 investigational sites

By country

Investigational sites

Country notifications

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

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 32 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

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