Mantle Cell Lymphoma
Conditions
Brief summary
This phase II trial tests the safety and effectiveness of glofitamab given in combination with pirtobrutinib in treating patients with mantle cell lymphoma that has come back after a period of improvement (relapsed) or that has not responded to previous treatment (refractory). Glofitamab and obinutuzumab are monoclonal antibodies that may interfere with the ability of cancer cells to grow and spread. Obinutuzumab may also reduce the risk of immune-related conditions from treatment. Pirtobrutinib is in a class of medications called kinase inhibitors. It works by blocking the action of the protein that signals cancer cells to multiply. Giving glofitamab in combination with pirtobrutinib may be safe, tolerable and/or effective in treating patients with relapsed or refractory mantle cell lymphoma.
Detailed description
PRIMARY OBJECTIVES: I. To characterize the safety and tolerability of the combination of glofitamab and pirtobrutinib in the first six participants enrolled. II. To evaluate the preliminary efficacy of glofitamab and pirtobrutinib in participants with relapsed or refractory mantle cell lymphoma (MCL) as measured by complete response rate. SECONDARY OBJECTIVES: I. To evaluate the preliminary efficacy of glofitamab and pirtobrutinib in participants with relapsed or refractory MCL as measured by progression-free survival and overall survival. II. To characterize the magnitude and duration of anti-tumor activity by objective response rate and duration of response. III. To characterize the safety and tolerability of the combination of glofitamab and pirtobrutinib. IV. To evaluate the preliminary efficacy of glofitamab and pirtobrutinib in participants with relapsed or refractory MCL as measured by complete response without measurable disease (CRMRD-) rate. V. To evaluate the time-to-complete response without measurable residual disease (CRMRD-). VI. To evaluate the treatment-free interval among participants who discontinue treatment following CRMRD- status. EXPLORATORY OBJECTIVES: I. To explore associations between baseline tumor characteristics including genetic (e.g. mutations in BTK) and immune profiles (e.g. expression of co-inhibitory receptors and T cell phenotypes) and outcomes in participants administered the combination of glofitamab and pirtobrutinib. II. To explore the effects of the combination of glofitamab and pirtobrutinib on pharmacodynamic markers relating to drug mechanism (e.g. emergence of clones with mutations conferring resistance to the study combination). III. To estimate the quality of life of participants during therapy with glofitamab and pirtobrutinib. IV. To explore time-to-CRMRD- during therapy with glofitamab and pirtobrutinib. OUTLINE: Participants receive study treatments until the absence of disease progression or unacceptable toxicity. Participants may also have a bone marrow biopsy and aspiration at cycle 13 and plasma and blood samples collected throughout study for correlative research. Additionally, participants may undergo a tissue biopsy at relapse or progression. Participants are followed for 30 days after treatment discontinuation for safety. Participants who discontinue treatment due to complete response (CR) with undetectable MRD will complete in-person visits through the end of study visit, 94 weeks from start of treatment. Participants who discontinue treatment for any reason other than CR will be followed every 3 months for up to 94 weeks from start of treatment, until death, loss to follow up, study termination, or participant withdrawal.
Interventions
BIOLOGICALObinutuzumab
Given intravenously (IV)
BIOLOGICALGlofitamab
Given IV
DRUGPirtobrutinib
Given Orally (PO)
PROCEDURETumor Imaging
Undergo regular care imaging/scans
PROCEDUREBiospecimen Collection
Blood and tissue samples
DEVICEClonoSeq Assay
ClonoSEQ is an FDA-cleared, Clinical Laboratory Improvement Amendments of 1988 (CLIA)-validated measure used to determine minimal residual disease (MRD). This helps uncover how much, if any, cancer remains in your body during and after treatment.
PROCEDUREBone Marrow Biopsy
Undergo bone marrow biopsy and aspiration.
Sponsors
Eli Lilly and Company
Genentech, Inc.
Adaptive Biotechnologies
University of California, San Francisco
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age ≥ 18 years at the time of signing the informed consent form. * Have a life expectancy (in the opinion of the investigator) of at least 12 weeks. * Eastern Cooperative Oncology Group (ECOG) performance status \< 2 (Karnofsky \> 60%). * History of previously treated MCL meeting the following criteria: Relapsed after or failed to respond to at least one prior line of systemic therapy including anti-CD20 monoclonal antibody and alkylator-containing chemotherapy. * At least one bi-dimensionally measurable nodal lesion ( \> 1.5 cm in its largest dimension by PET/CT scan), or at least one bi-dimensionally measurable extranodal lesion ( \> 1.0 cm in its largest dimension by PET/CT scan) and FDG-avid. * Availability of leftover tissue from the time of progression for pathology confirmation and correlative studies. Note: Formalin fixed paraffin embedded blocks are preferred. If blocks are not available, 12-15 slides containing unstained, serial sections are acceptable. * Hemoglobin ≥ 9 g/dL (Independent of transfusions and within 7 days prior to screening assessment). * Absolute neutrophil count \>= 1.0 x 10\^9/L (Independent of growth factor support and within 7 days prior to screening assessment). * Platelets ≥ 75 x 10\^9/L or \>= 50 x 10\^9/L if due to bone marrow involvement (Independent of transfusions and within 7 days prior to screening assessment, and independent of growth factor support and within 7 days prior to screening assessment). If the patient is cytopenic there should be no evidence of myelodysplasia orhypoplastic bone marrow. * Total bilirubin ≤ 1.5 x upper limit of normal (ULN) (or ≤ 3 x ULN for participants with Gilbert syndrome, or \<= 3 x ULN if due to underlying lymphoma). * Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase (SGOT)) \<= 2.5 X institutional upper limit of normal. * Alanine aminotransferase (ALT)(serum glutamic pyruvic transaminase (SGPT)) \<= 2.5 X institutional upper limit of normal. * Creatinine clearance \>= 50 mL/min (by Cockcroft-Gault formula). * Activated partial thromboplastin time (aPTT) or partial thromboplastin time (PTT) \<= 1.5 x ULN. * Prothrombin (PT) or (international normalized ratio (INR) \<= 1.5 x ULN. * In women of childbearing potential, negative serum pregnancy test within 7 days prior to study treatment and either abstinence or use of highly effective contraception methods from the time of screening for at least 18 months after pre-treatment with obinutuzumab, 2 months after the final dose of glofitamab, 1 month after last dose of pirtobrutinib, 3 months after the final dose of tocilizumab (if applicable), whichever is longer. Women of childbearing potential should not donate oocytes for 1 month after last dose of pirtobrutinib. * For men: agreement to remain abstinent or use contraceptive measures and agreement to refrain from donating sperm, with female partners of childbearing potential or pregnant female partners, men must remain abstinent or use a condom during the treatment period and for at least 3 months after pre-treatment with obinutuzumab, 2 months after the final dose of glofitamab, 28 days after last dose of pirtobrutinib, 3 months after the final dose of tocilizumab (if applicable), whichever is longer. * Willing and capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in the protocol. * Participants with prior treatment-related adverse events (AEs) must have recovered to grade \<= 1 with the exception of alopecia and grade 2 peripheral neuropathy. * Participants must be able to swallow oral medications. * Participants with positive hepatitis B core antibody (anti-HBc) and negative hepatitis B surface antigen (HBsAg) require a negative hepatitis B polymerase chain reaction (PCR) evaluation before initiating study treatment on cycle 1 day 1. Participants with positive anti-HBc antibody are required to receive prophylactic antiviral therapy with lamivudine, tenofovir, or entecavir for the duration of treatment and for at least 6 months following the end of study treatment. Hepatitis B PCR should be repeated as clinically indicated. * Individuals with a history of hepatitis C virus (HCV) infection must have been treated and cured. For individuals with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load.
Exclusion criteria
* Pregnant, or intention of becoming pregnant during the study or within 18 months after treatment with obinutuzumab or 2 months after the last dose of glofitamab, or 3 months after treatment with tocilizumab, whichever is longer; and 1 month after the last dose of pirtobrutinib. * Participants should avoid chest-feeding until at least 1 week after discontinuing pirtobrutinib. * Have received the following treatments/procedures prior to study entry: * Participants who experienced a major bleeding event or grade ≥ 3 arrhythmia on prior treatment with a BTK inhibitor. NOTE: Major bleeding is defined as bleeding having one or more of the following features: potentially life-threatening bleeding with signs or symptoms of hemodynamic compromise; bleeding associated with a decrease in the hemoglobin level of at least 2g per deciliter; or bleeding in a critical area or organ (e.g., retroperitoneal, intraarticular, pericardial, epidural, or intracranial bleeding or intramuscular bleeding with compartment syndrome) * Participants who discontinued a covalent BTK inhibitor due to disease progression or relapse. NOTE: Participants who discontinued covalent BTK inhibitor therapy due to intolerance will not be excluded. Covalent BTK inhibitor intolerance is defined as: * Any grade 3 or higher non-hematologic toxicity, except a major bleeding event or grade \>= 3 arrhythmia which are
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of participants with high grade, treatment-emergent adverse events (AEs) | Approximately 2 weeks | The severity of the toxicities will be graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0. AEs and clinically significant laboratory abnormalities meeting grade 3 4 or 5 will be summarized by maximum intensity and relationship to study drug for the first 6 participants from the initiation of the study drug combination (Cycle 2 Day 8 (C2D8)) through the end of cycle 2 (Cycle 2 Day 21 (C2D21)), approximately 14 days. |
| Proportion of participants with Complete Response (CR) | Up to 94 weeks | CR will be defined as the proportion of treated participants who experience a CR per Lugano criteria among evaluable participants. The Lugano classification recommends the Deauville five-point scale for reporting response by Fluorodeoxyglucose (FDG) Positron Emission Tomography (PET)/Computerized tomography (CT): (1) no uptake or no residual uptake (when used interim) (2) slight uptake, but below blood pool (mediastinum) (3) uptake above mediastinal, but below or equal to uptake in the liver (4) uptake slightly to moderately higher than liver (5) markedly increased uptake or any new lesion (on response evaluation) from cycle 5 Day 1 through the follow-up period up to 94 weeks. |
| Proportion of participants with reported Cytokine-release syndrome (CRS) | Approximately 2 weeks | The proportion of participants with a diagnosed incident of CRS for the first 6 participants from the initiation of the study drug combination (Cycle 2 Day 8 (C2D8)) through the end of cycle 2 (Cycle 2 Day 21 (C2D21)), approximately 14 days, and graded according to the American Society of Transplantation and Cellular Therapy (ASTCT) criteria will be reported. |
| Proportion of participants with immune effector cell-associated neurotoxicity syndrome (ICANS) | Approximately 2 weeks | The proportion of participants with a diagnosed incident of ICANS for the first 6 participants from the initiation of the study drug combination (Cycle 2 Day 8 (C2D8)) through the end of cycle 2 (Cycle 2 Day 21 (C2D21)), approximately 14 days, and graded according to the American Society of Transplantation and Cellular Therapy (ASTCT) criteria will be reported. |
| Proportion of participants with reported Hemophagocytic lymphohistiocytosis (HLH) | Approximately 2 weeks | The proportion of participants with a diagnosed incident of HLH for the first 6 participants from the initiation of the study drug combination (Cycle 2 Day 8 (C2D8)) through the end of cycle 2 (Cycle 2 Day 21 (C2D21)), approximately 14 days, and graded according to the American Society of Transplantation and Cellular Therapy (ASTCT) criteria will be reported. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Median Time to CRMRD | Up to 94 weeks | Time to CRMRD will calculate the time that elapses between the initiation of trial therapy and the day of first documented CRMRD and summarized using Kaplan-Meier method. |
| Median Progression-free survival (PFS) | Up to 94 weeks | PFS will be defined as the time that elapses between initiation of trial therapy and the earlier of the day of first documented disease progression or death from any cause. Progression is defined by Lugano criteria of (1) new or increased adenopathy; an individual node must be abnormal with: (a) longest transverse diameter (LDi) \>1.5 cm AND (2) splenic volume increase (3) new or larger non-measured lesions (4) recurrent previously resolved lesions (5) new extranodal lesion \>1 cm in any axis (new lesions \<1 cm in any axis are included if these are unequivocally attributable to lymphoma) (6) a new node \>1.5 cm in any axis . PFS will be summarized using Kaplan-Meier method. |
| Median Treatment-free interval | Up to 94 weeks | Treatment-free interval will be defined as the time that elapses from CRMRD status to the time of recurrence and summarized using Kaplan-Meier method. |
| Median Overall Survival (OS) | Up to 94 weeks | OS will be defined as the time that elapses between the initiation of trial therapy and the date of death from any cause for all evaluable participants. OS will be summarized using Kaplan-Meier method. |
| Objective Response Rate (ORR) | Up to 94 weeks | OR will be defined as the proportion of treated participants who experience an objective response (CR or partial response (PR) per Lugano criteria) among evaluable participants. |
| Duration of response (DOR) | Up to 94 weeks | DOR will be defined as the time that elapses between the day of first documented response to trial therapy (CR or PR, whichever is first recorded) and subsequent disease progression. |
| Proportion of participants with complete response without measurable disease (CRMRD) | At cycle 13, day 1 (a cycle is 21 days) | CRMRD will be defined as the achievement of =\< 1 x 10-6 malignant cells in peripheral blood, as assessed by ClonoSEQ assay in a participant who meets all other criteria for CR. |
Countries
United States
Contacts
Primary ContactUCSF Hematopoietic Malignancies Clinical Trial Recruitment
Outcome results
None listed