Phase 2 Study of Glofitamab and Gemcitabine and Oxaliplatin (Glofit-GemOx) Bridging to Lisocabtagene Maraleucel in Relapsed/Refractory Aggressive B-cell Lymphomas
试验速览
- 阶段
- 2 期
- 状态
- 尚未招募
- 入组人数
- 56
- 试验地点
- 2
- 主要终点
- Complete Response Rate (CRR) to lisocabtagene maraleucel
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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
- •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.
- •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.
结局指标
主要结局
Complete Response Rate (CRR) to lisocabtagene maraleucel
时间窗: 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.
次要结局
- 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.)
- Progression-Free Survival (PFS) after lisocabtagene maraleucel(Registration to death or up to 2 years after the day of the lisocabtagene maraleucel infusion.)
- Overall Survival (OS) after lisocabtagene maraleucel(Registration to death or up to 2 years after the day of the lisocabtagene maraleucel infusion.)
- 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.)
- 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.)
- 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.)
- 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.)
- 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 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 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 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 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 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 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.)
研究者
Jeremy Abramson, MD
Principal Investigator
Massachusetts General Hospital