Phase 2 Evaluation of MEN1703 Monotherapy and in Combination with Glofitamab in Relapsed/Refractory Aggressive B-cell Non-Hodgkin Lymphoma
- Trial ID
- 2024-513098-31-00
- Protocol
- JASPIS-01
- Sponsor
- Ryvu Therapeutics S.A.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **safety** and **tolerability** of MEN1703, both as monotherapy and in combination with glofitamab, in patients with relapsed or refractory aggressive B-cell Non-Hodgkin Lymphoma. This evaluation is crucial for determining the potential of MEN1703 as a viable treatment option, ensuring that it can be administered safely to patients while assessing its initial therapeutic effects.
Secondary objectives include:
- Group 1: To assess the anti-lymphoma activity and clinical benefit of MEN1703 when combined with glofitamab, evaluate its safety and tolerability in later phases, characterize its pharmacokinetics, and evaluate patient-reported outcomes related to lymphoma symptoms, well-being, and general health status.
- Group 2: To evaluate the anti-lymphoma activity and clinical benefit of MEN1703 as monotherapy, assess its safety and tolerability, characterize its pharmacokinetics, and evaluate patient-reported outcomes related to lymphoma symptoms, well-being, and general health status.
Participants
The clinical trial involves a total of **44 participants** diagnosed with **relapsed or refractory aggressive B-cell Non-Hodgkin Lymphoma**. The study population includes both male and female subjects, aged 18 years and older, who have a documented histological confirmation of the disease. Participants were selected based on their medical history, having received at least two prior lines of systemic treatment for aggressive B-cell Non-Hodgkin Lymphoma. The trial excludes vulnerable populations and requires participants to have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0, 1, or 2, indicating they are ambulatory and capable of self-care. Participants must have adequate organ and hematologic function, as well as a life expectancy of at least 12 weeks. Lifestyle considerations such as diet and physical activity are not specified, but participants must agree to specific contraceptive measures during and after the trial. The selection criteria ensure that participants are in a stable health condition to undergo the trial treatments.
Plans and Procedures
The clinical trial is designed as an open-label, Phase II study to evaluate the safety, tolerability, and anti-lymphoma activity of **MEN1703** as monotherapy and in combination with **glofitamab** in patients with relapsed or refractory aggressive B-cell non-Hodgkin lymphoma. The trial is structured into two groups, each with distinct objectives. Group 1 will assess the combination therapy, while Group 2 will focus on the monotherapy. The trial is expected to commence recruitment on November 1, 2024, and conclude by December 31, 2026.
The trial will follow a sequence of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, documented histological confirmation of the disease, and adequate organ function. Participants will then proceed to the treatment phase, which includes regular follow-up visits to monitor safety and efficacy outcomes. The primary endpoints include the incidence and severity of adverse events, complete response rate for Group 1, and overall response rate for Group 2, assessed by an Independent Review Committee following the Lugano Classification. Secondary endpoints will evaluate additional response measures and changes in lymphoma symptoms and general health status.
Participants are expected to be involved in the study for the duration of the treatment period, which varies depending on the group and treatment arm. Conditions that may lead to early termination from the study include the occurrence of severe adverse events, disease progression, or withdrawal of consent. The trial will adhere to rigorous ethical standards, ensuring that all participants provide written informed consent prior to any study-related procedures. The study aims to contribute valuable data on the therapeutic potential of MEN1703, both as a standalone treatment and in combination with glofitamab, in this patient population.
Treatment
The clinical trial involves the administration of **MEN1703**, an experimental medication available in oral capsule form. MEN1703 is provided in two dosages: 100 mg and 25 mg capsules. The active substance in MEN1703 is **5,6-dibromo-4-nitro-2-piperidin-4-yl-1-propan-2-ylbenzimidazole**, a chemical compound. The maximum daily dose for MEN1703 is 150 mg, administered orally. The treatment period for MEN1703 is not explicitly limited, allowing for extended administration as required by the study protocol. Participant compliance with the dosing schedule will be monitored throughout the trial.
**Glofitamab** is another investigational treatment used in this trial, provided as a concentrate for solution for infusion. It is available in two concentrations: 2.5 mg and 10 mg. Glofitamab is a protein-based therapeutic, specifically an anti-CD20/CD3 bispecific monoclonal antibody. The maximum daily dose of glofitamab is 30 mg, administered via intravenous infusion. The maximum treatment period for glofitamab is 252 days. The administration of glofitamab will be closely monitored to ensure adherence to the dosing schedule and to evaluate participant response.
Additionally, **Gazyvaro** (obinutuzumab) is used as a comparator treatment in the study. It is provided as a 1,000 mg concentrate for solution for infusion. Obinutuzumab is a protein-based therapeutic, administered via intravenous infusion. The maximum daily and total dose for Gazyvaro is 1,000 mg, with a treatment period limited to a single day. The administration of Gazyvaro will be conducted under controlled conditions to ensure participant safety and compliance with the study protocol.
Efficacy
The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. For Group 1, the primary endpoint is the **Complete Response (CR) rate**, which will be evaluated by an Independent Review Committee (IRC) following the Lugano Classification. For Group 2, the primary endpoint is the **Overall Response Rate (ORR)**, also assessed by the IRC using the same classification. Secondary endpoints for both groups include the incidence and severity of adverse events (AEs), pharmacokinetics (PK) of MEN1703, and changes in lymphoma symptoms, well-being, and general health status measured by FACT–Lym and EORTC QLQ C30.
Additional secondary endpoints for Group 1 include the ORR, Duration of Response (DoR), Duration of Complete Response (DoCR), Progression-free survival (PFS), Overall survival (OS), Time to response, and Time to next treatment, all assessed by IRC and locally following the Lugano Classification. Similarly, Group 2 will have secondary endpoints including CR Rate, DoR, DoCR, PFS, OS, Time to response, and Time to next treatment, also assessed by IRC and locally. The schedule for measuring these endpoints will be aligned with the trial protocol, ensuring consistent and accurate data collection throughout the study duration.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Age ≥18 years old at time of written informed consent, provided prior to Screening.
- Life expectancy of ≥12 weeks.
- Eastern Cooperative Oncology Group (ECOG) Performance Status 0, 1 or 2.
- 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.
- 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.
- Capable of providing written informed consent
- Coagulation parameters as follows: prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin time (PTT) <1.5X ULN.
- 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).
- 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).
- 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.
- 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.
- 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.
- 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
- Primary central nervous system (CNS) lymphoma or CNS involvement by lymphoma at screening
- 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.
- Concurrent participation in another therapeutic clinical study.
- 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
- Prior treatment with a PIM inhibitor.
- Group 1 only: Any prior therapy with a bispecific antibody targeting CD3 and CD20.
- 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.
- Contraindication to all uric acid lowering agents.
- Major surgery within 1 month prior to first dose of study drug.
- Hematopoietic stem cell transplant within 4 months prior to first dose of study drug.
- Requires systemic immune-modulating therapy (regardless of dose) or has confirmed history or current autoimmune disease or other diseases resulting in permanent immunosuppression.
- Exposed to live or live attenuated vaccine(s) within 4 weeks prior to signing the informed consent form (ICF).
- 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.
- 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.
- 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.
- Ongoing drug-induced pneumonitis.
- Ongoing inflammatory bowel disease.
- 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.
- 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.
- 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.
- 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.
- 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.
- Any disease, syndrome or condition which may significantly affect drug intake via oral route.
- 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.
- 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.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Recruiting | 01 Nov 2024 | 28 |
 Poland | Recruiting | 01 Nov 2024 | 46 |
 Spain | Recruiting | 01 Nov 2024 | 44 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Columvi 10 mg concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENIOUS INFUSION | 30 | 252 | PRD10561235 |
MEN1703 oral capsule 100 mg | Test | CAPSULE | ORAL | 150 | 9999999 | PRD7071327 |
MEN1703 oral capsule 25 mg | Test | CAPSULE | ORAL | 150 | 9999999 | PRD7071326 |
Gazyvaro 1,000 mg concentrate for solution for infusion. | Other | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENIOUS INFUSION | 1000 | 1 | PRD2159925 |
Columvi 2.5 mg concentrate for solution for infusion | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENIOUS INFUSION | 30 | 252 | PRD10561231 |