Integrated Glofit and Ibrutinib as Novel Immune Therapy Evaluation in Treatment-Naive Mantle Cell Lymphoma (IGNITE MCL): A Phase Ib/II Study of Glofitamab Plus Ibrutinib With Obinutuzumab Pretreatment in MCL Patients ≥ 65 or Ages 18-64 With High-Risk Features
This phase IB/II trial tests the safety, side effects and effectiveness of glofitamab plus ibrutinib with obinutuzumab for the treatment of patients with mantle cell lymphoma (MCL). Glofitamab is in a class of medications called bispecific monoclonal antibodies. It works by killing cancer cells. A monoclonal antibody is a type of protein that can bind to certain targets in the body, such as molecules that cause the body to make an immune response (antigens). In the body, glofitamab binds to a receptor called CD3 on T-cells (a type of immune cells) and a receptor called CD20 on B-cells, a receptor that is often over-expressed on the surface of cancerous B-cells. When glofitamab binds to CD3 and CD20 receptors, it causes an immune response against the CD20-expressing cancerous B-cells. Ibrutinib is in a class of medications called kinase inhibitors. It works by blocking the action of the abnormal protein that signals cancer cells to multiply. This helps stop the spread of cancer cells. Obinutuzumab is a monoclonal antibody that may interfere with the ability of cancer cells to grow and spread. Glofitamab plus ibrutinib with obinutuzumab may be safe tolerable and/or effective in treating patients with MCL.
• Ability to understand the purpose and risks of the study and to provide signed informed consent
• Pathologically confirmed MCL, with documentation of chromosome translocation t(11;14)(q13;q32) and/or overexpression of cyclin D1 in association with other relevant markers (e.g., CD5, CD19, CD20, PAX5). Cyclin D1 negative or t(11,14) negative/SOX 11 positive MCL patients can be enrolled if eligibility criteria are otherwise satisfied
• Age 18-64 with one or more of the following poor risk features defined as:
‣ High risk mutational variants including p53 aberrations (mutation\[s\] by next generation sequencing \[NGS\] and/or 17p deletion), KMT2D, NSD2, NOTCH1,CDKN2A, NOTCH2, SMARCA4, and CCND1;
⁃ Blastoid or pleomorphic phenotype;
⁃ Complex karyotype with ≥ 3 abnormalities (in addition to t(11,14)) on routine karyotyping;
⁃ Ki67 \> 30%;
⁃ High risk Mantle Cell Lymphoma International Prognostic Index (MIPI) score ≥ 6.2; and/or
⁃ p53 expression on immunohistochemistry (IHC), defined as ≥ 50%
• Age ≥ 65. For this population, no poor risk features are required to be eligible
• No prior systemic anticancer therapies for MCL
• Presence of radiologically measurable lymphadenopathy and/or extranodal lymphoid malignancy
• Able to provide biosamples for MRD testing and pathology. If fresh tissue is not available, archival samples can be used for some assessments at the discretion of the investigator
• Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2
• Absolute neutrophil count (ANC) ≥ 1.0 × 10\^9/L independent of growth factor support
• Platelets ≥ 100 × 10\^9/L (≥ 50 × 10\^9/L if bone marrow \[BM\] involvement), independent of transfusion support in either situation
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 × upper limit of normal (ULN)
• Total bilirubin ≤ 1.5 × ULN (unless due to Gilbert's syndrome or of non hepatic origin)
• Estimated creatinine clearance ≥ 50 mL/min by Cockcroft Gault method
• Undetectable hepatitis B virus (HBV) surface antigen (sAg) serology. Confirmed by polymerase chain reaction (PCR) for HBV deoxyribonucleic acid (DNA) if results are disputable
• Undetectable hepatitis C virus (HCV) antigen serology. Confirmed by PCR for HCV ribonucleic acid (RNA) if results are disputable
• Undetectable HIV based on serology. Enrollment will be considered if HIV is controlled with treatment (i.e., undetectable viral load for 6 months prior and the CD4 counts is ≥ 200/µL). Such patients must be willing to modify HIV therapy while on-treatment and during applicable wash-out periods, as needed, to address drug-drug interactions
• Willing and able to participate in all required evaluations and procedures in this protocol including swallowing capsules without difficulty
• Persons of childbearing potential (PCBP): Persons of childbearing potential must have a negative serum (beta-human chorionic gonadotropin \[b-hCG\]) or urine pregnancy test at Screening and be willing to use approved contraception while on treatment and for the longest following, applicable time period: 18 months after the last dose of obinutuzumab, 2 months after the last dose of glofitamab, 3 months for tocilizumab, or 1 month after the last dose of ibrutinib. Women who are pregnant or breastfeeding are ineligible for this study
• Persons that produce viable sperm: Willingness to use approved contraception while on-treatment and for the longest applicable time period following: 6 months after the last dose of obinutuzumab or 2 months after the last dose of glofitamab, tocilizumab, or ibrutinib
• Willingness to not breastfeed or donate ova or sperm: If obinutuzumab was the last study drug received, the participant must wait for 6 months. Otherwise, patients must agree to wait 3 months for sperm and 1 month for ova donations (and to breastfeed) after the last dose other study drugs
• The effects of GLIB on the developing human fetus are unknown. Should a participant or participant's sexual partner become pregnant or suspect a pregnancy while participating in this study, the individual should inform their treating physician immediately