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

Prior treatment

• Hematopoietic stem cell transplant within 4 months prior to first dose of study drug.
• Exposed to live or live attenuated vaccine(s) within 4 weeks prior to signing the informed consent form (ICF).
• 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). Participants with HCV with undetectable virus after treatment are eligible. Participants with a prior history of HBV are eligible if quantitative PCR for HBV DNA is negative.
• 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.

Other illness

• Requires systemic immune-modulating therapy (regardless of dose) or has confirmed history or current autoimmune disease or other diseases resulting in permanent immunosuppression.
• 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.
• Ongoing drug-induced pneumonitis.
• Ongoing inflammatory bowel disease.
• Prior history of malignancies other than DLBCL NOS or DLBCL arising from transformation of an indolent B-cell lymphoma, unless the participant has been free of the disease for at least 3 years before Screening. Malignancies that are not expected to interfere with the study objectives are allowed, including: • Basal cell carcinomaof the skin • Non-metastatic squamous cell carcinoma of the skin, • Carcinoma in situ of the cervix • Carcinoma in situ of the breast • Carcinoma in situ of the bladder • Incidental histological finding of prostate cancer (Tumor/Node/Metastasis stage of T1a or T1b). Note: Eligibility of participants with history of malignancies other than DLBCL must be discussed with the Medical Monitor

Lab values

• 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.
• 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. Note Radiation therapy received within 14 days prior to the start of trial treatment may not be considered exclusionary if administered for symptom management or for palliative treatment purposes. Note Radiation therapy received within 14 days prior to the start of trial treatment may not be considered exclusionary if administered for symptom management or for palliative treatment purposes.
  • 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 (QTcF) ≥480 ms. Note: QTc values up to 500 ms will be acceptable where participant’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 or Sponsor’s opinion, could jeopardize participant safety or interfere with the objectives of the study.
  • 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.

Other

• Primary central nervous system (CNS) lymphoma or CNS involvement by lymphoma at screening

• Age ≥18 years old at time of written informed consent, provided prior to Screening.
• 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, diagnosed according to the 5th edition of the World Health Organization (WHO) (Alaggio 2022), including, but not limited to, diffuse large B-cell lymphoma (DLBCL) not otherwise specified (NOS) and DLBCL arising from transformation of an indolent B-cell lymphoma (e.g. follicular lymphoma).
• 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 or ineligible for all standard, available treatment options.
• At least one FDG-avid, measurable target lesion at Screening, assessed by PET-CT according to Lugano Classification (Cheson 2014), that is measurable in 2 perpendicular dimensions on the CT component of PET-CT and is metabolically active with FDG uptake consistent with lymphoma, defined as: • nodal lesion: longest diameter > 1.5 cm; or • extranodal lesion: longest diameter > 1.0 cm. The lesion should be suitable for serial measurement. Previously irradiated lesions should not be selected as target lesions if irradiated within 4 weeks before study treatment, unless there is unequivocal progression after radiotherapy.
• 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 participants with documented history of Gilbert’s syndrome. c) Adequate renal function defined as either: serum creatinine ≤1.5X ULN or a creatinine clearance (CrCl) ≥40 mL/min calculated by Cockroft-Gault formula for participants 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 ≥9.0 g/dL Note: RBC transfusion and/or erythropoiesis-stimulating agents (e.g., EPO) are permitted during the Screening period as clinically indicated. Eligibility must be confirmed using the most recent hemoglobin value 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).