B-cell Lymphomas, Large B-cell Lymphoma, Lymphoma, Relapsed/Refractory Large B-cell Lymphoma
Conditions
Keywords
GLORY, lymphoma, liso-cel, glofit-gemox, leukapheresis, CAR T-cell, bridging therapy
Brief summary
The goal of this clinical trial is to assess the clinical efficacy of bridging therapy with glofitamab/gemcitabine/oxaliplatin (Glofit-GemOx) followed by lisocabtagene maraleucel (liso-cel) in relapsed/refractory large B-cell lymphomas. This clinical trial also aims to investigate other efficacy parameters of the combination of Glofit-GemOx plus liso-cel and assess the safety of the combination of Glofit-GemOx bridging plus liso-cel. The main questions it aims to answer are: * How effective Glofit-GemOx bridged to liso-cel therapy is compared to liso-cel alone? * How will Glofit-GemOx bridged to liso-cel therapy affect other factors such as how long treatment effects last, how long patients survive after treatment, re-hospitalization rates, and more? * How many patients receiving Glofit-GemOx bridging to liso-cel will experience side effects of differing severities? Participants will receive an obinutuzumab intravenous infusion 3 days prior to undergoing a leukapheresis procedure. 2 days after leukapheresis, participants will receive 1-2 cycles of Glofit-GemOx therapy via intravenous infusion. After completing Glofit-GemOx therapy, participants will receive lymphodepleting chemotherapy via intravenous infusion for 3 consecutive days, 3-5 days prior to then receiving an intravenous infusion of liso-cel.
Detailed description
This is a multi-center, phase II single-arm study to assess the efficacy and safety of glofitamab/gemcitabine/oxaliplatin (Glofit-GemOx) as bridging therapy followed by lisocabtagene maraleucel (liso-cel) in patients with relapsed/refractory large B-cell lymphomas. Participants will also receive obinutuzumab pre-treatment and undergo apheresis. The U.S. Food and Drug Administration (FDA) has approved obinutuzumab as a treatment option for relapsed/refractory large B-cell lymphomas. Obinutuzumab is a targeted cancer drug called a monoclonal antibody. Obinutuzumab works by attaching to a specific marker on certain white blood cells (including cancerous ones), flagging them so the body's immune system knows which cells to destroy. The U.S. Food and Drug Administration (FDA) has approved glofitamab as a treatment option for relapsed/refractory large B-cell lymphomas. Glofitamab is a T-cell-bispecific antibody that works by bringing the body's immune cells directly to cancer cells. Specifically, glofitamab attaches to cancerous B cells on one side and to T cells (the immune system's "killer" cells) on the other side, helping the T cells recognize and attack the cancer. This process activates the immune system so it can amplify its response and destroy tumor cells. Gemcitabine/oxaliplatin (GemOx) is a standard, widely used chemotherapy treatment for diffuse large B-cell lymphoma that has returned or gotten worse. Gemcitabine is a nucleoside analog chemotherapy agent that stops cancer cells from making new DNA. Cells need DNA to grow and divide so, by blocking this process, gemcitabine slows down or kills the cancer cells. Oxaliplatin is a platinum-based chemotherapy drug that damages the DNA inside cancer cells, preventing them from growing and dividing. This damage causes the cancer cells to stop working properly and, eventually, die. The U.S. Food and Drug Administration (FDA) has approved lisocabtagene maraleucel (liso-cel) as a treatment option for relapsed/refractory large B-cell lymphomas. Lisocabtagene maraleucel is a CAR-T cell therapy made from an individual's own immune (T) cells. A patient's T cells are extracted though a process called leukapheresis and engineered into CAR-T cells that recognize and attack cancer cells. These CAR-T cells are then returned into the body so they can find and kill the cancer. The resulting re-engineered cell product is called lisocabtagene maraleucel. The U.S. Food and Drug Administration (FDA) has not approved glofitamab with gemcitabine and oxaliplatin (Glofit-GemOx) as a treatment for any disease, but has been incorporated into the National Cancer Center Network (NCCN) guidelines as a recommended treatment in the United States for diffuse large B-cell lymphoma that has returned or gotten worse. Participants will receive treatment until completion or until their disease progresses, they experience another disease or illness that prevents further administration of study treatment, they experience unacceptable side effects, they demonstrate an inability or unwillingness to receive the medication regimen, or they withdraw from the study. Participants will be followed for up to 24 months after the last participant is enrolled. It is expected that about 52 people will take part in this research study. Bristol Myers Squibb Company is supporting this research study by providing funding for the clinical trial activities.
Interventions
DRUGObinutuzumab
Intravenous infusion received once, 5 days prior to receiving the first doses of glotfitamab, gemcitabine, and oxaliplatin.
DRUGGlofitamab
Intravenous infusion received on days 1, 3, 8, and 15 of cycle 1 and on day 15 of the optional cycle 2 (each cycle is 21 days).
Intravenous infusions received on day 1 of cycle 1 and an optional cycle 2 (each cycle is 21 days).
PROCEDURELeukapheresis
Procedure to collect stem cells for modification that will occur 2 days prior to administration of the first doses of glofitamab, gemcitabine, and oxaliplatin.
Intravenous infusions of cyclophosphamide and fludarabine administered for 3 consecutive days 3-5 days prior to receive lisocabtagene maraleucel.
Intravenous infusion of participant's re-manufactured stem cells administered one 3-5 days after completing lymphodepleting chemotherapy.
Sponsors
Massachusetts General Hospital
Bristol-Myers Squibb
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
* Histologically confirmed large B-cell NHL including diffuse large B-cell lymphoma (DLBCL), either de novo or transformed from any indolent B-cell lymphoma, DLBCL NOS, primary mediastinal \[thymic\] large B-cell lymphoma (PMBCL), high grade B-cell lymphoma NOS, or high grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements \[double/triple-hit lymphoma (DHL/THL)\]; and grade 3B follicular lymphoma. * Relapsed or refractory to 1 prior line of systemic lymphoma therapy if relapse/refractory within 12 months of initial treatment. Previous therapy must have included a CD20-targeted agent and an anthracycline or alkylating agent. Patients may have received steroids and/or polatuzumab-rituximab (without bendamustine), and/or radiation therapy for disease control and/or palliation "holding therapy" between frontline therapy and protocol registration and this will not be considered an additional line of systemic therapy. OR Relapsed or refractory to 1 prior line of systemic lymphoma therapy at any time after initial treatment if patient is ineligible for a stem cell transplant. Previous therapy must have included a CD20-targeted agent and an anthracycline or alkylating agent. Patients may have received steroids and/or polatuzumab-rituximab (without bendamustine), and/or radiation therapy for disease control and/or palliation "holding therapy" between frontline therapy and protocol registration and this will not be considered an additional line of systemic therapy. * Intent and eligibility to proceed to therapy with lisocabtagene maraleucel * Adult patients ≥ 18 years * PET-positive measurable disease per Lugano criteria * ECOG performance status 0-2 * Estimated creatinine clearance of ≥30 mL/min, calculated using the Cockcroft and Gault equation (if male: \[140 - Age\] x Mass \[kg\] / \[72 x creatinine g/dL\]; multiply by 0.85 if female) * Serum Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) ≤ 3 times the ULN * Total Bilirubin ≤1.5 x ULN, unless directly attributable to Gilbert-Meulengracht syndrome and ≤3.0 mg/dL * Absolute neutrophil count (ANC) ≥ 1000/mm3 (G-CSF support allowed if ≥ 24 hours prior to screening lab draw) * Hemoglobin ≥8g/dL * Platelets ≥ 50,000/mm3 without transfusion within 7 days * Patients with primary CNS lymphoma are not eligible. Patients with secondary CNS involvement by lymphoma are eligible if they otherwise meet all eligibility criteria. * The effects of glofitamab, gemcitabine, and oxaliplatin on the developing human fetus are unknown. For this reason and because immunotherapy/chemotherapy agents are known to be teratogenic, women of child-bearing potential and men must agree to use adequate double-method (each partner) contraception (acceptable means of birth control: condoms (male), condoms (female), intrauterine devices, contraceptive implants, combined hormonal contraceptives (pills, patches, vaginal rings), progestin-only pills, depot medroxyprogesterone acetate (DMPA) injections; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men and women treated or enrolled on this protocol must also agree to use adequate contraception for the duration of study participation, and 12 months after completion of lisocabtagene maraleucel administration. * Willing and able to participate in all required evaluations and procedures in this study protocol. * Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information. * Ability to understand and agree to forgo donation of blood, organs, sperm, semen, or egg cells after treatment with liso-cel for 12 months.
Exclusion criteria
* History of prior malignancy that could affect compliance with the protocol or interpretation of results, except for the following: Non-melanoma skin cancers, in situ malignancies, prostate cancer followed with watchful waiting, indolent lymphoma, any previously treated malignancy felt at low risk for recurrence. * Evidence of disease (such as severe or uncontrolled systemic diseases) that, in the investigator's opinion, make it undesirable for the patient to participate in the study or that would jeopardize compliance with the protocol * Treatment with prior CAR T-cell therapy. * Treatment with prior CD20:CD3 bispecific antibody therapy. * History of or ongoing confirmed progressive multifocal leukoencephalopathy (PML) * Received any investigational drug within 30 days or 5 half-lives (whichever is shorter) before first dose of study drug. * Received a live virus vaccination within 28 days of first dose of study drug. * Concurrent participation in another therapeutic clinical trial. * Current life-threatening illness, medical condition, or organ system dysfunction which, in the Investigator's opinion, could compromise the subject's safety or put the study at risk * Previous treatment with gene therapy product or adoptive T cell therapy * Allogeneic stem cell transplant within 90 days of leukapheresis * Active acute or chronic GVHD requiring immunosuppressive therapy within 6 weeks prior to enrollment * Grade 2 or higher peripheral neuropathy * HIV infection with positive viral titer by PCR. HIV with negative viral titer by PCR is not an exclusion as long as CD4 count is ≥200 and patient is taking combination antiretroviral therapy. * Serologic status reflecting active hepatitis B or C infection 1. Subjects who are hepatitis B core antibody (HBcAb) positive and who are hepatitis B surface antigen (HBsAg) negative will need to have a negative PCR result before enrollment and must be willing to undergo DNA PCR testing during the study and take anti-HBV therapy with entecavir or equivalent. Those who are HBsAg-positive or hepatitis B PCR positive will be excluded. 2. Subjects who are hepatitis C antibody positive will need to have a negative PCR result before enrollment. Those who are hepatitis C PCR positive will be excluded. * Any active significant infection (e.g., bacterial, viral, or fungal, including subjects with positive cytomegalovirus \[CMV\] DNA polymerase chain reaction \[PCR\]) * Clinically relevant CNS pathology * Autoimmune disease requiring chronic systemic corticosteroids at a dose of greater than 10 mg of prednisone daily or an equivalent dose of another corticosteroid * Treatment with alemtuzumab, fludarabine, and/or bendamustine within 6 months leukapheresis or cladribine within 3 months of leukapheresis * Known history of hypersensitivity or anaphylaxis to study drug(s) including active product or excipient components. * Breastfeeding or pregnant: Pregnant women are excluded from this study because glofitamab, gemcitabine, oxaliplatin, fludarabine, and cyclophosphamide are agents with the potential for teratogenic or abortifacient effects. Breastfeeding should be discontinued for at least 12 months after last exposure if the mother is treated with these agents.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Complete Response Rate (CRR) to lisocabtagene maraleucel | Screening to start of another non-study anticancer therapy or for up to 2 years from the day the last participant is enrolled, whichever occurs first. | The complete response rate (CRR) is defined as the proportion of subjects achieving an objective response of complete response prior to start of another non-study anticancer therapy. CRR is based on the best overall response post-lisocabtagene maraleucel infusion. CRR will be defined according to the Lugano Classification. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate to Glofit-GemOx bridging | Screening to start of another non-study anticancer therapy or for up to 2 years from the day the last participant is enrolled, whichever occurs first. | Overall response rate is the proportion of participants achieving partial response (PR) or complete response (CR) according to the Lugano Classification. Overall response rate is based on the PR or CR to glofitamab, gemcitabine, and oxaliplatin (Glofit-GemOx) bridging therapy. |
| Progression-Free Survival (PFS) after lisocabtagene maraleucel | Registration to death or up to 2 years after the day of the lisocabtagene maraleucel infusion. | Progression-free survival (PFS) is defined as the time from registration to the earlier of progression or death due to any cause. Participants alive without disease progression are censored at date of last disease evaluation. PFS is based on the lisocabtagene maraleucel infusion. PFS will be summarized using Kaplan-Meier estimates. |
| Overall Survival (OS) after lisocabtagene maraleucel | Registration to death or up to 2 years after the day of the lisocabtagene maraleucel infusion. | Overall survival (OS) is defined as the time from registration to death due to any cause or censored at date last known alive. OS is based on the lisocabtagene maraleucel infusion. OS will be summarized using Kaplan-Meier estimates. |
| Overall Response Rate (ORR) to lisocabtagene maraleucel | Screening to start of another non-study anticancer therapy or for up to 2 years from the day the last participant is enrolled, whichever occurs first. | Overall response rate is the proportion of participants achieving partial response (PR) or complete response (CR) according to the Lugano Classification. Overall response rate is based on the PR or CR to lisocabtagene maraleucel infusion. |
| Duration of Response (DOR) after lisocabtagene maraleucel | Day of first measurement meeting CR or PR criteria to the day of first documentation of recurrent or progressive disease or for up to 2 years after the day of the lisocabtagene maraleucel infusion. | The duration of response is measured from the time measurement criteria are met for complete response (CR) or partial response (PR) (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started, or death due to any cause. Duration of response is based on the CR or PR of the lisocabtagene maraleucel infusion. Participants without events reported are censored at the last disease evaluation). DOR will be summarized using Kaplan-Meiser estimates. |
| Incidence of Treatment-Emergent Adverse Events from Glofit-GemOx to 90 days post-lisocabtagene maraleucel | Day of initiation of Glofit-GemOx therapy to 90 days post-lisocabtagene maraleucel infusion. | Incidence of treatment-emergent adverse events (AEs) is defined as the percentage of participants that experience an AE requiring emergent treatment. Incidence of treatment-emergent AEs is based on the time from initiation of gemcitabine, glofitamab, and oxaliplatin (Glofit-GemOx) to 90 days after receiving the lisocabtagene maraleucel infusion. AEs other than CRS and ICANS will be coded using CTCAE v6 criteria. Frequency and percentage of treatment-emergent AEs will be calculated. |
| Proportion of Participants Receiving Interventions for CRS or Neurotoxicity | Screening to start of another non-study anticancer therapy or for up to 2 years from the day the last participant is enrolled, whichever occurs first. | Proportion of participants receiving interventions for Cytokine Release Syndrome (CRS) or neurotoxicity is defined as the number of participants that receive treatment for CRS or neurotoxicity divided by the total number of participants. Median, mean, and range of participants receiving interventions for CRS or neurotoxicity will be calculated. |
| Incidence of Cytokine Release Syndrome (CRS) | Screening to start of another non-study anticancer therapy or for up to 2 years from the day the last participant is enrolled, whichever occurs first. | Incidence of Cytokine Release Syndrome (CRS) is defined as the percentage of participants who experience CRS of any grade as graded by the ASTCT consensus grading criteria. Frequency and percentage of CRS occurrences will be calculated. |
| Incidence of Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) | Screening to start of another non-study anticancer therapy or for up to 2 years from the day the last participant is enrolled, whichever occurs first. | Incidence of Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) is defined as the percentage of participants who experience ICANS of any grade as graded by the ASTCT consensus grading criteria. Frequency and percentage of ICANS occurrences will be calculated. |
| Incidence of Grade ≥3 Cytokine Release Syndrome (CRS) | Screening to start of another non-study anticancer therapy or for up to 2 years from the day the last participant is enrolled, whichever occurs first. | Incidence of grade ≥3 Cytokine Release Syndrome (CRS) is defined as the percentage of participants who experience CRS of grade 3 or higher as graded by the ASTCT consensus grading criteria. Frequency and percentage of CRS occurrences will be calculated. |
| Incidence of Grade ≥3 Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) | Screening to start of another non-study anticancer therapy or for up to 2 years from the day the last participant is enrolled, whichever occurs first. | Incidence of grade ≥3 Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) is defined as the percentage of participants who experience ICANS of grade 3 or higher as graded by the ASTCT consensus grading criteria. Frequency and percentage of ICANS occurrences will be calculated. |
| Incidence and Grading of Infection | Screening to start of another non-study anticancer therapy or for up to 2 years from the day the last participant is enrolled, whichever occurs first. | Incidence of infection is defined as the percentage of participants experiencing any grade of infection. The grading of each occurrence according to CTCAE v6 criteria will be reported. Frequency and percentage of infections will be calculated. |
| Incidence and Grading of Cytopenias | Screening to start of another non-study anticancer therapy or for up to 2 years from the day the last participant is enrolled, whichever occurs first. | Incidence of cytopenias is defined as the percentage of participants experiencing any grade of neutropenia, lymphopenia, thrombocytopenia, and/or anemia. The grading of each occurrence according to CTCAE v6 criteria will be reported. Frequency and percentage of cytopenias will be calculated. |
| Incidence and Number of Transfusions | Screening to start of another non-study anticancer therapy or for up to 2 years from the day the last participant is enrolled, whichever occurs first. | Incidence of transfusions is defined as the percentage of participants who receive a transfusion of either red blood cells or platelets. The total number of transfusions will be reported. Frequency and percentage of transfusions received will be calculated. |
Countries
United States
Contacts
CONTACTJeremy Abramson, MD, MMSc
PRINCIPAL_INVESTIGATORJeremy Abramson, MD, MMSc
Massachusetts General Hospital
Outcome results
None listed