A Phase I Study of Glofitamab With Alternating R-CHOP/R-DHAP in Previously Untreated Mantle Cell Lymphoma
Overview
- Phase
- Phase 1
- Status
- Not yet recruiting
- Enrollment
- 16
- Primary Endpoint
- Incidence of adverse events (AEs)
Overview
Brief Summary
This phase I trial tests the safety, side effects and best dose of glofitamab given with alternating cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP)/ rituximab, dexamethasone, cytarabine, and cisplatin (R-DHAP) for the treatment of mantle cell lymphoma. Glofitamab is a monoclonal antibody that may interfere with the ability of cancer cells to grow and spread. 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). Rituximab is a monoclonal antibody. It binds to a protein called CD20, which is found on B cells (a type of white blood cell) and some types of cancer cells. This may help the immune system kill cancer cells. Cyclophosphamide is in a class of medications called alkylating agents. It works by damaging the cell's deoxyribonucleic acid (DNA) and may kill cancer cells. It may also lower the body's immune response. Doxorubicin is in a class of medications called anthracyclines. Doxorubicin damages the cell's DNA and may kill cancer cells. It also blocks a certain enzyme needed for cell division and DNA repair. Vincristine is in a class of medications called vinca alkaloids. It works by stopping cancer cells from growing and dividing and may kill them. Prednisone and dexamethasone are in a class of medications called corticosteroids. They are used to reduce inflammation and lower the body's immune response to help lessen the side effects of chemotherapy drugs. Chemotherapy drugs, such as cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Cisplatin is in a class of medications known as platinum-containing compounds. It works by killing, stopping or slowing the growth of cancer cells. Giving glofitamab may be safe, tolerable and/or effective in treating patients with mantle cell lymphoma.
Detailed Description
PRIMARY OBJECTIVES:
I. To evaluate the safety of the combination of glofitamab and alternating cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP)/ rituximab, dexamethasone, cytarabine, and cisplatin (R-DHAP) as defined by the incidence and severity of adverse events (AEs) and/or dose limiting toxicity (DLT) related to glofitamab and/or chemo-immunotherapy in patients with previously untreated mantle cell lymphoma (MCL).
II. To determine the recommended phase II dose (RP2D) for the combination of glofitamab and R-CHOP/R-DHAP.
SECONDARY OBJECTIVES:
I. To observe and record anti-tumor activity. II. To determine the tolerability of the study treatment as measured by dose interruptions, dose reductions, and treatment discontinuation due to AEs and DLTs.
III. To determine the overall response rate (ORR) after induction therapy and after maintenance therapy, complete response rate (CRR), and partial response rate (PRR) based on positron emission tomography (PET)/ computed tomography (CT) according to the 2014 Lugano Response Criteria.
IV. To assess failure-free survival and overall survival.
EXPLORATORY OBJECTIVES:
I. To evaluate minimum-residual disease (MRD)-negative CRR after completion of induction therapy, and after year(s) 1 and 2 of maintenance glofitamab therapy.
II. To determine the rates of dose delays or discontinuation of therapy, cytopenias, and occurrence of grade 3 or higher infections during glofitamab maintenance therapy.
OUTLINE: This is a dose-escalation study of glofitamab in combination with alternating doses of R-CHOP and R-DHAP followed by a dose-expansion study.
INDUCTION:
CYCLES: 1, 3 and 5: Patients receive rituximab intravenously (IV), cyclophosphamide IV, doxorubicin IV, and vincristine IV on day 1, as well as prednisone orally (PO) on days 1-5. Starting with cycle 3, patients also receive glofitamab IV, over 2-8 hours, on day 8 of each cycle. Cycles repeat every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
CYCLES 2, 4 and 6: Patients receive rituximab IV, and cisplatin IV over 24 hours on day 1, as well as cytarabine IV on day 2 and dexamethasone PO on days 1-4. Patients also receive glofitamab IV, over 2-8 hours, on days 8 and 15 of cycle 2 and on day 8 of subsequent cycles. Cycles repeat every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
MAINTENANCE: Patients receive glofitamab IV on day 1 of each cycle. Cycles repeat every 21 days for a total of 24 months of treatment, in the absence of disease progression or unacceptable toxicity.
Patients undergo positron emission tomography (PET)/computed tomography (CT) scan and blood sample collection throughout the study.
After completion of study treatment, patients are followed up periodically for up to 5 years.
Study Design
- Study Type
- Interventional
- Allocation
- Na
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to 75 Years (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Patients must have histologically or cytologically confirmed previously untreated mantle cell lymphoma which is stage II bulky, stage III, or stage IV and fit for intensive chemotherapy. TP53 mutated patients are eligible
- •Patients must exhibit measurable disease by PET or CT imaging with at least one site of disease \> 1.5 cm in longest dimension or documented bone marrow involvement
- •Age ≥ 18 years to ≤ 75 years. Because no dosing or adverse event data are currently available on the use of glofitamab in combination with R-CHOP/R-DHAP in patients \< 18 years of age, children are excluded from this study
- •Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 (Karnofsky ≥ 60%)
- •Absolute neutrophil count ≥ 1,000/mcL
- •Platelets ≥ 100,000/mcL
- •Total bilirubin ≤ 2 × institutional upper limit of normal (ULN) unless total bilirubin elevation is attributable to Gilbert's syndrome or lymphomatous infiltration of the liver in whom total bilirubin must be \< 3 times ULN
- •Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase \[SGOT\])/ alanine aminotransferase (ALT) (serum glutamic pyruvic transaminase \[SGPT\]) ≤ 3 × institutional ULN
- •Creatinine clearance ≥ 30 ml/min
- •Left ventricular ejection fraction ≥ 45% by echocardiogram or Multiple-Gated Acquisition (MUGA) scan
Exclusion Criteria
- •Patients who received prior treatment for MCL, including chemotherapy, bispecific antibody therapy, or other cytotoxic or cellular therapy including autologous hematopoietic stem cell transplant (autoHCT). Since this study aims to evaluate safety and efficacy in previously untreated patients by using this regimen as a first-line therapy, prior systemic therapy would potentially bias and affect endpoints and results
- •Patients who have not recovered from AEs due to prior anti-cancer therapy (i.e., have residual toxicities \> grade 1) with the exception of alopecia
- •Patients who are receiving any other investigational agents
- •Patients with lymphoma that shows active and uncontrolled CNS involvement; uncontrolled CNS involvement may require different systemic therapy in addition to CNS directed therapy, which would interfere with the study regimen and sequence of drug administration
- •History of allergic reactions attributed to compounds of similar chemical or biologic composition to glofitamab or other agents used in study
- •Patients with active, uncontrolled infection defined as ongoing signs or symptoms of infection despite antimicrobial therapy or other infection-directed therapy
- •Patients with uncontrolled intercurrent illness or any other significant condition(s) that would make this protocol unreasonably hazardous
- •Pregnant women are excluded from this study because glofitamab is an agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with glofitamab, breastfeeding should be discontinued if the mother is treated with glofitamab. These potential risks may also apply to other agents used in this study
- •Patients with prior solid organ transplantation
- •Prior treatment with systemic immunotherapeutic agents, including but not limited to, radio-immuno-conjugates, antibody-drug conjugates, immune/cytokines and monoclonal antibodies (mAbs) (e.g., anticytotoxic T lymphocyte associated protein 4, anti-PD-1, and anti-PD-L1) within 4 weeks or five half-lives of the drug, whichever is shorter
Arms & Interventions
Treatment (glofitamab with R-CHOP/R-DHAP)
INDUCTION:
CYCLES: 1, 3 and 5: Patients receive rituximab IV, cyclophosphamide IV, doxorubicin IV, and vincristine IV on day 1, as well as prednisone PO on days 1-5. Starting with cycle 3, patients also receive glofitamab IV, over 2-8 hours, on day 8 of each cycle. Cycles repeat every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
CYCLES 2, 4 and 6: Patients receive rituximab IV, and cisplatin IV over 24 hours on day 1, as well as cytarabine IV on day 2 and dexamethasone PO on days 1-4. Patients also receive glofitamab IV, over 2-8 hours, on days 8 and 15 of cycle 2 and on day 8 of subsequent cycles. Cycles repeat every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
MAINTENANCE: Patients receive glofitamab IV on day 1 of each cycle. Cycles repeat every 21 days for a total of 24 months of treatment, in the absence of disease progression or unacceptable toxicity.
Intervention: Biospecimen Collection (Procedure)
Treatment (glofitamab with R-CHOP/R-DHAP)
INDUCTION:
CYCLES: 1, 3 and 5: Patients receive rituximab IV, cyclophosphamide IV, doxorubicin IV, and vincristine IV on day 1, as well as prednisone PO on days 1-5. Starting with cycle 3, patients also receive glofitamab IV, over 2-8 hours, on day 8 of each cycle. Cycles repeat every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
CYCLES 2, 4 and 6: Patients receive rituximab IV, and cisplatin IV over 24 hours on day 1, as well as cytarabine IV on day 2 and dexamethasone PO on days 1-4. Patients also receive glofitamab IV, over 2-8 hours, on days 8 and 15 of cycle 2 and on day 8 of subsequent cycles. Cycles repeat every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
MAINTENANCE: Patients receive glofitamab IV on day 1 of each cycle. Cycles repeat every 21 days for a total of 24 months of treatment, in the absence of disease progression or unacceptable toxicity.
Intervention: Computed Tomography (Procedure)
Treatment (glofitamab with R-CHOP/R-DHAP)
INDUCTION:
CYCLES: 1, 3 and 5: Patients receive rituximab IV, cyclophosphamide IV, doxorubicin IV, and vincristine IV on day 1, as well as prednisone PO on days 1-5. Starting with cycle 3, patients also receive glofitamab IV, over 2-8 hours, on day 8 of each cycle. Cycles repeat every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
CYCLES 2, 4 and 6: Patients receive rituximab IV, and cisplatin IV over 24 hours on day 1, as well as cytarabine IV on day 2 and dexamethasone PO on days 1-4. Patients also receive glofitamab IV, over 2-8 hours, on days 8 and 15 of cycle 2 and on day 8 of subsequent cycles. Cycles repeat every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
MAINTENANCE: Patients receive glofitamab IV on day 1 of each cycle. Cycles repeat every 21 days for a total of 24 months of treatment, in the absence of disease progression or unacceptable toxicity.
Intervention: Positron Emission Tomography (Procedure)
Treatment (glofitamab with R-CHOP/R-DHAP)
INDUCTION:
CYCLES: 1, 3 and 5: Patients receive rituximab IV, cyclophosphamide IV, doxorubicin IV, and vincristine IV on day 1, as well as prednisone PO on days 1-5. Starting with cycle 3, patients also receive glofitamab IV, over 2-8 hours, on day 8 of each cycle. Cycles repeat every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
CYCLES 2, 4 and 6: Patients receive rituximab IV, and cisplatin IV over 24 hours on day 1, as well as cytarabine IV on day 2 and dexamethasone PO on days 1-4. Patients also receive glofitamab IV, over 2-8 hours, on days 8 and 15 of cycle 2 and on day 8 of subsequent cycles. Cycles repeat every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
MAINTENANCE: Patients receive glofitamab IV on day 1 of each cycle. Cycles repeat every 21 days for a total of 24 months of treatment, in the absence of disease progression or unacceptable toxicity.
Intervention: Prednisone (Drug)
Treatment (glofitamab with R-CHOP/R-DHAP)
INDUCTION:
CYCLES: 1, 3 and 5: Patients receive rituximab IV, cyclophosphamide IV, doxorubicin IV, and vincristine IV on day 1, as well as prednisone PO on days 1-5. Starting with cycle 3, patients also receive glofitamab IV, over 2-8 hours, on day 8 of each cycle. Cycles repeat every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
CYCLES 2, 4 and 6: Patients receive rituximab IV, and cisplatin IV over 24 hours on day 1, as well as cytarabine IV on day 2 and dexamethasone PO on days 1-4. Patients also receive glofitamab IV, over 2-8 hours, on days 8 and 15 of cycle 2 and on day 8 of subsequent cycles. Cycles repeat every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
MAINTENANCE: Patients receive glofitamab IV on day 1 of each cycle. Cycles repeat every 21 days for a total of 24 months of treatment, in the absence of disease progression or unacceptable toxicity.
Intervention: Rituximab (Biological)
Treatment (glofitamab with R-CHOP/R-DHAP)
INDUCTION:
CYCLES: 1, 3 and 5: Patients receive rituximab IV, cyclophosphamide IV, doxorubicin IV, and vincristine IV on day 1, as well as prednisone PO on days 1-5. Starting with cycle 3, patients also receive glofitamab IV, over 2-8 hours, on day 8 of each cycle. Cycles repeat every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
CYCLES 2, 4 and 6: Patients receive rituximab IV, and cisplatin IV over 24 hours on day 1, as well as cytarabine IV on day 2 and dexamethasone PO on days 1-4. Patients also receive glofitamab IV, over 2-8 hours, on days 8 and 15 of cycle 2 and on day 8 of subsequent cycles. Cycles repeat every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
MAINTENANCE: Patients receive glofitamab IV on day 1 of each cycle. Cycles repeat every 21 days for a total of 24 months of treatment, in the absence of disease progression or unacceptable toxicity.
Intervention: Dexamethasone (Drug)
Treatment (glofitamab with R-CHOP/R-DHAP)
INDUCTION:
CYCLES: 1, 3 and 5: Patients receive rituximab IV, cyclophosphamide IV, doxorubicin IV, and vincristine IV on day 1, as well as prednisone PO on days 1-5. Starting with cycle 3, patients also receive glofitamab IV, over 2-8 hours, on day 8 of each cycle. Cycles repeat every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
CYCLES 2, 4 and 6: Patients receive rituximab IV, and cisplatin IV over 24 hours on day 1, as well as cytarabine IV on day 2 and dexamethasone PO on days 1-4. Patients also receive glofitamab IV, over 2-8 hours, on days 8 and 15 of cycle 2 and on day 8 of subsequent cycles. Cycles repeat every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
MAINTENANCE: Patients receive glofitamab IV on day 1 of each cycle. Cycles repeat every 21 days for a total of 24 months of treatment, in the absence of disease progression or unacceptable toxicity.
Intervention: Cisplatin (Drug)
Treatment (glofitamab with R-CHOP/R-DHAP)
INDUCTION:
CYCLES: 1, 3 and 5: Patients receive rituximab IV, cyclophosphamide IV, doxorubicin IV, and vincristine IV on day 1, as well as prednisone PO on days 1-5. Starting with cycle 3, patients also receive glofitamab IV, over 2-8 hours, on day 8 of each cycle. Cycles repeat every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
CYCLES 2, 4 and 6: Patients receive rituximab IV, and cisplatin IV over 24 hours on day 1, as well as cytarabine IV on day 2 and dexamethasone PO on days 1-4. Patients also receive glofitamab IV, over 2-8 hours, on days 8 and 15 of cycle 2 and on day 8 of subsequent cycles. Cycles repeat every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
MAINTENANCE: Patients receive glofitamab IV on day 1 of each cycle. Cycles repeat every 21 days for a total of 24 months of treatment, in the absence of disease progression or unacceptable toxicity.
Intervention: Cytarabine (Drug)
Treatment (glofitamab with R-CHOP/R-DHAP)
INDUCTION:
CYCLES: 1, 3 and 5: Patients receive rituximab IV, cyclophosphamide IV, doxorubicin IV, and vincristine IV on day 1, as well as prednisone PO on days 1-5. Starting with cycle 3, patients also receive glofitamab IV, over 2-8 hours, on day 8 of each cycle. Cycles repeat every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
CYCLES 2, 4 and 6: Patients receive rituximab IV, and cisplatin IV over 24 hours on day 1, as well as cytarabine IV on day 2 and dexamethasone PO on days 1-4. Patients also receive glofitamab IV, over 2-8 hours, on days 8 and 15 of cycle 2 and on day 8 of subsequent cycles. Cycles repeat every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
MAINTENANCE: Patients receive glofitamab IV on day 1 of each cycle. Cycles repeat every 21 days for a total of 24 months of treatment, in the absence of disease progression or unacceptable toxicity.
Intervention: Cyclophosphamide (Drug)
Treatment (glofitamab with R-CHOP/R-DHAP)
INDUCTION:
CYCLES: 1, 3 and 5: Patients receive rituximab IV, cyclophosphamide IV, doxorubicin IV, and vincristine IV on day 1, as well as prednisone PO on days 1-5. Starting with cycle 3, patients also receive glofitamab IV, over 2-8 hours, on day 8 of each cycle. Cycles repeat every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
CYCLES 2, 4 and 6: Patients receive rituximab IV, and cisplatin IV over 24 hours on day 1, as well as cytarabine IV on day 2 and dexamethasone PO on days 1-4. Patients also receive glofitamab IV, over 2-8 hours, on days 8 and 15 of cycle 2 and on day 8 of subsequent cycles. Cycles repeat every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
MAINTENANCE: Patients receive glofitamab IV on day 1 of each cycle. Cycles repeat every 21 days for a total of 24 months of treatment, in the absence of disease progression or unacceptable toxicity.
Intervention: Doxorubicin (Drug)
Treatment (glofitamab with R-CHOP/R-DHAP)
INDUCTION:
CYCLES: 1, 3 and 5: Patients receive rituximab IV, cyclophosphamide IV, doxorubicin IV, and vincristine IV on day 1, as well as prednisone PO on days 1-5. Starting with cycle 3, patients also receive glofitamab IV, over 2-8 hours, on day 8 of each cycle. Cycles repeat every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
CYCLES 2, 4 and 6: Patients receive rituximab IV, and cisplatin IV over 24 hours on day 1, as well as cytarabine IV on day 2 and dexamethasone PO on days 1-4. Patients also receive glofitamab IV, over 2-8 hours, on days 8 and 15 of cycle 2 and on day 8 of subsequent cycles. Cycles repeat every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
MAINTENANCE: Patients receive glofitamab IV on day 1 of each cycle. Cycles repeat every 21 days for a total of 24 months of treatment, in the absence of disease progression or unacceptable toxicity.
Intervention: Glofitamab (Biological)
Treatment (glofitamab with R-CHOP/R-DHAP)
INDUCTION:
CYCLES: 1, 3 and 5: Patients receive rituximab IV, cyclophosphamide IV, doxorubicin IV, and vincristine IV on day 1, as well as prednisone PO on days 1-5. Starting with cycle 3, patients also receive glofitamab IV, over 2-8 hours, on day 8 of each cycle. Cycles repeat every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
CYCLES 2, 4 and 6: Patients receive rituximab IV, and cisplatin IV over 24 hours on day 1, as well as cytarabine IV on day 2 and dexamethasone PO on days 1-4. Patients also receive glofitamab IV, over 2-8 hours, on days 8 and 15 of cycle 2 and on day 8 of subsequent cycles. Cycles repeat every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
MAINTENANCE: Patients receive glofitamab IV on day 1 of each cycle. Cycles repeat every 21 days for a total of 24 months of treatment, in the absence of disease progression or unacceptable toxicity.
Intervention: Vincristine (Drug)
Outcomes
Primary Outcomes
Incidence of adverse events (AEs)
Time Frame: Up to 5 years
Will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5 for all AEs other than cytokine release syndrome (CRS), immune effector cell associated neurotoxicity syndrome (ICANS), and hemophagocytic lymphohistiocytosis (HLH). CRS, ICANS, and HLH will be graded according to American Society for Transplantation and Cellular Therapy criteria.
Dose limiting toxicity (DLT)
Time Frame: From cycle 2, day 8 to cycle 5 day 1 (cycle length = 21 days)
DLT is defined as any grade 4 or higher CRS event, any grade CRS event that does not improve to \< grade 2 within 72 hours, any grade 3 or higher neurologic toxicity event including ICANS events, any grade 3 or higher non-hematologic toxicity, grade 3 aspartate aminotransferase (AST) or alanine aminotransferase (ALT) elevation that does not resolve to grade 2 or less within 14 days, grade 4 AST or ALT is a DLT regardless of duration, grade 4 thrombocytopenia lasting more than 7 days, grade 3 thrombocytopenia with hemorrhage, grade 3 thrombocytopenia lasting ≥ 28 days or grade 4 neutropenia lasting ≥ 14 days despite the use of growth factors.
Secondary Outcomes
- Complete response rate(Up to 5 years)
- Overall response rate(From completion of induction therapy, up to 5 years)
- Partial response rate(Up to 5 years)
- Failure free survival(From enrollment to stable disease at the end of induction therapy, progressive disease, or death from any cause, up to 5 years)
- Overall survival(From enrollment to death from any cause, up to 5 years)