Study of MEN1703 in Patients with Relapsed or Refractory Aggressive B-cell Non-Hodgkin Lymphoma

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Ryvu Therapeutics S.A.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

14 Nov 2024 → ongoing

Decision date (initial)

2025-01-23

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2024-513098-31-00

WHO UTN

U1111-1309-7407

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Pharmacokinetic, Efficacy, Others

• Group 1: Part 1 (Safety Run-in): To evaluate safety and tolerability of MEN1703 given in combination with glofitamab
• Group 1: Part 2 and Part 3: To evaluate anti-lymphoma activity of MEN1703 given in combination with glofitamab
• Group 2: Part 1 (Safety Run-in): To evaluate safety and tolerability of MEN1703 monotherapy
• Group 2: Part 2: To evaluate anti-lymphoma activity of MEN1703 monotherapy

Secondary objectives 1

1. • Group 1: To evaluate anti-lymphoma activity and/or clinical benefit of MEN1703 when given in combination with glofitamab; To evaluate safety and tolerability of MEN1703 when given in combination with glofitamab (Part 2 and Part 3); To characterize single and multiple dose pharmacokinetics (PK) of MEN1703 when given in combination with glofitamab; To evaluate patient reported outcomes (PRO) related to lymphoma symptoms, well-being, and general health status in participants receiving MEN1703 given in combination with glofitamab • Group 2: To evaluate anti-lymphoma activity and/or clinical benefit of MEN1703 monotherapy; To evaluate safety and tolerability of MEN1703 monotherapy (Part 2); To characterize single and multiple dose pharmacokinetics (PK) of MEN1703 monotherapy; To evaluate patient reported outcomes (PRO) related to lymphoma symptoms, well-being, and general health status in participants receiving MEN1703 monotherapy

Conditions and MedDRA coding

Relapsed or Refractory Aggressive B-cell Non-Hodgkin Lymphoma

Study design 5 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. Age ≥18 years old at time of written informed consent, provided prior to Screening.
2. Life expectancy of ≥12 weeks.
3. Eastern Cooperative Oncology Group (ECOG) Performance Status 0, 1 or 2.
4. Adequate organ function at Screening, including: a) Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≤2.5X the upper limit of normal (ULN); b) Total bilirubin ≤1.5X ULN Note: Total bilirubin ≤3.0X ULN is acceptable in patients with documented history of Gilbert’s syndrome. c) Adequate renal function: serum creatinine ≤1.5X ULN or a creatinine clearance (CrCl) calculated by Cockroft-Gault formula of ≥50 mL/min for patients in whom, in the investigator’s judgment, serum creatinine levels do not adequately reflect renal function; d) Left ventricular ejection fraction (LVEF) ≥40% as per local assessment practice.
5. Adequate hematologic function defined as the following: a) Lymphocyte count <5.0 ×109/L b) Platelet count ≥75 ×109/L (or, in the presence of bone marrow involvement or splenomegaly, ≥50 ×109/L), and platelet transfusion free within 14 days prior to first dose of study drug c) Hemoglobin ≥10.0 g/dL (6.2 mmol/L) and transfusion free within 21 days prior to first dose of study drug d) Absolute neutrophil count (ANC) ≥1.0 ×109/L, with growth factor support permitted per local, institutional standards.
6. Capable of providing written informed consent
7. Coagulation parameters as follows: prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin time (PTT) <1.5X ULN.
8. Negative serum pregnancy test at Screening and within 3 days of first dose of drug (applies to women of child-bearing potential [WOCBP] only; menopausal status is defined as serum follicle stimulating hormone level ≥30 IU/L in the absence of hormone replacement therapy, or complete absence of menses for at least 12 consecutive months which is not due to medication; or successful surgical sterilization).
9. Women of child-bearing potential must agree to use highly effective contraceptive methods during treatment and for 1 month after the last dose of MEN1703, 2 months after the last dose of glofitamab, or 18 months after the last dose of obinutuzumab, whichever is longer. or Male participants who are sexually active must use condoms during treatment with MEN1703 and for 1 month after the last dose of MEN1703. Sexually active male participants are asked to advise their female partners of childbearing potential to also use highly effective contraception for the same time period. Contraception guidance for male participants taking glofitamab and obinutuzumab should be according to the current EU SmPC (Columvi Summary of Product Characteristics) or the USPI (COLUMVI™ [glofitamab-gxbm] Prescribing Information).
10. Agree not to donate blood or eggs (ova) during treatment and for 1 month after the last dose of MEN1703, 2 months after the last dose of glofitamab, or 18 months after last dose of obinutuzumab, whichever is longer; or not to donate sperm during treatment with MEN1703 and for 1 month after the last dose of MEN1703.
11. Documented histological confirmation of aggressive B-cell non-Hodgkin lymphoma including DLBCL NOS and transformed indolent B-cell lymphoma, according to the 5th edition of the WHO classification of lymphoid neoplasms.
12. R/R disease having received at least 2 prior lines of systemic treatment for aggressive B-cell non-Hodgkin lymphoma, and: • Additional for Group 1: anti-CD3xCD20 bispecific antibody treatment naïve • Additional for Group 2: exhausted all standard, available treatment options.
13. At least 1 measurable site of disease based on computed tomography (CT) or positron emission tomography (PET)-CT scan with involvement of 2 or more clearly demarcated lesions and or nodes.

Exclusion criteria 25

1. Primary central nervous system (CNS) lymphoma or CNS involvement by lymphoma at screening
2. Received anti-cancer treatments, including cytotoxic chemotherapy, radiotherapy, hormonal therapy, biologic, immunotherapy, or investigational drugs within 14 days or 5 half-lives (whichever is shorter) before the first dose of study drug. Prior treatment with CAR-T cell or an anti-CD3xCD20 bispecific antibody therapy (permitted for Group 2 only), requires a wash out period of ≥4 weeks.
3. Concurrent participation in another therapeutic clinical study.
4. Ongoing clinically significant toxicity (for example, alopecia is not clinically significant) from any prior anti-cancer therapy that has not resolved to Grade 1 or less prior to the first dose of study drug
5. Prior treatment with a PIM inhibitor.
6. Group 1 only: Any prior therapy with a bispecific antibody targeting CD3 and CD20.
7. Known risk of allergy to: • Group 1 and Group 2: MEN1703 or its excipients •Group 1 only: obinutuzumab or its excipients, or glofitamab or its excipients.
8. Contraindication to all uric acid lowering agents.
9. Major surgery within 1 month prior to first dose of study drug.
10. Hematopoietic stem cell transplant within 4 months prior to first dose of study drug.
11. Requires systemic immune-modulating therapy (regardless of dose) or has confirmed history or current autoimmune disease or other diseases resulting in permanent immunosuppression.
12. Exposed to live or live attenuated vaccine(s) within 4 weeks prior to signing the informed consent form (ICF).
13. Evidence of ongoing and uncontrolled systemic bacterial, fungal, or viral infection, except for documented Grade Common Terminology Criteria for Adverse Events (CTCAE) ≤2 infections with evidence of improvement or without evidence of worsening infection.
14. Known human immunodeficiency virus (HIV) infection defined as any of the following: a) CD4+ T-cell count of less than 350 cells/μL at Screening b) AIDS defining opportunistic infection within the past 12 months c) On established antiretroviral therapy (ART) for less than 4 weeks or presenting with a viral load of more than 400 copies/mL prior to Screening d) On ART or prophylactic antimicrobials that are expected to cause significant drug-drug interactions or overlapping toxicities with study treatment. Note: HIV testing is not required unless mandated locally.
15. Current active liver disease from any cause including hepatitis A (hepatitis A virus IgM positive), hepatitis B (hepatitis B virus [HBV] surface antigen positive), or hepatitis C (hepatitis C virus [HCV] antibody positive, confirmed by HCV RNA). Subjects with HCV with undetectable virus after treatment are eligible. Subjects with a prior history of HBV are eligible if quantitative PCR for HBV DNA is negative.
16. Ongoing drug-induced pneumonitis.
17. Ongoing inflammatory bowel disease.
18. Active known second malignancy, except for any of the following: a) Adequately treated basal cell carcinoma, squamous cell carcinoma of the skin, or in situ cervical cancer b) Adequately treated Stage 1 cancer from which the participant is currently in remission and has been in remission for ≥2 years c) Low-risk prostate cancer with a Gleason score <7 and a prostate-specific antigen (PSA) level <10 ng/mL d) Any other cancer from which the participant has been disease-free for ≥3 years.
19. Received an agent known to be a sensitive CYP2D6 substrate or a CYP2D6 substrate with a narrow therapeutic range, a strong or moderate CYP2D6 inhibitor, or a BCRP inhibitor within 14 days or 5 half-lives (whichever is shorter), prior to the first dose of study drug.
20. Cardiac dysfunction is defined as myocardial infarction within 6 months of study entry, New York Heart Association (NYHA) Class III or IV heart failure, uncontrolled dysrhythmias, or poorly controlled angina.
21. Receiving treatment for active, ongoing thromboembolic event. Note: Does not apply to prophylactic treatment to prevent or avoid reoccurrence of a prior resolved event. To review with Medical Monitor where further risk assessment is needed.
22. History of serious ventricular arrhythmia (e.g., VT or VF, ≥3 beats in a row), or QT interval corrected for heart rate (QTc) ≥480 ms. Note: QTc values up to 500 ms will be acceptable where patient’s medical history e.g., bundle branch block, is known to cause mild QTc prolongation and the condition is well controlled.
23. Any disease, syndrome or condition which may significantly affect drug intake via oral route.
24. Currently pregnant or breast-feeding or planning to become pregnant or breastfeed during treatment and for 1 month after the last dose of study drug.
25. Any other prior or current medical condition, intercurrent illness, surgical history, physical or 12-lead electrocardiogram (ECG) findings, laboratory abnormalities, or extenuating circumstance (e.g., alcohol or drug addiction) that, in the investigator’s opinion, could jeopardize patient safety or interfere with the objectives of the study.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. • Group 1 and 2: Incidence and severity of adverse events (AE)
2. • Group 1: Complete Response (CR) rate, assessed by Independent Review Committee (IRC) following the Lugano Classification (see Section 16)
3. • Group 2: Over all response rate (ORR), assessed by Independent Review Committee (IRC) following the Lugano Classification (see Section 16 of the protocol)

Secondary endpoints 5

1. • Group 1: Complete Response (CR) rate, assessed locally following the Lugano classification (see Section 16)
2. • Group 2: Overall Response Rate (ORR), assessed locally following the Lugano classification (see Section 16 of the protocol)
3. • Group 1: The following endpoint measures are assessed by IRC and locally following the Lugano Classification (see Section 16): Overall Response Rate (ORR); Duration of Response (DoR); Duration of Complete Response (DoCR); Progression-free survival (PFS); Overall survival (OS); Time to response; Time to next treatment)
4. • Group 2: The following endpoint measures are assessed by IRC and locally following the Lugano Classification (see Section 16 of the protocol): Complete Response (CR) Rate; Duration of Response (DoR); Duration of Complete Response (DoCR); Progression-free survival (PFS); Overall survival (OS); Time to response; Time to next treatment)
5. • Group 1 and 2: Incidence and severity of AEs; PK of MEN1703 including Cmax, tmax, AUCtau, AUCinf, and t½; Changes in lymphoma symptoms, well-being, and general health status measured by FACT–Lym and EORTC QLQ C30

Investigational products

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

Test 4

Auxiliary 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Ryvu Therapeutics S.A.

Sponsor organisation

Ryvu Therapeutics S.A.

Address

Ul. Leona Henryka Sternbacha 2

City

Cracow

Postcode

30-394

Country

Poland

Scientific contact point

Organisation

Ryvu Therapeutics S.A.

Contact name

Chadi Saba

Public contact point

Organisation

Ryvu Therapeutics S.A.

Contact name

Ryvu ClinicalTrials

Third parties 9

Locations

3 EU/EEA countries · 31 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 29 files

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

Application history

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