Safety and Efficacy of Epcoritamab With Gemcitabine, Dexamethasone, and Cisplatin (GDP) Salvage Chemotherapy in Relapsed Refractory Large B-cell Lymphoma

Study Overview
=================
Brief Summary
-----------------
Subjects with relapsed large cell lymphoma will receive 3 cycles of combination therapy consisting of GDP and epcoritamab. Each cycle will last 21 days. GDP consists of gemcitabine 1000 mg/m2 IV on Days 1 and 8, cisplatin 75 mg/m2 IV on Day 1, and dexamethasone 40 mg orally on Days 1 through 4. Epcoritamab will be administered subcutaneously (SC) on Days 1, 8, and 15. Patients will receive granulocyte colony stimulating factor (G-CSF) on Day 9 or 10 of each cycle of combination therapy. Patients will then undergo radiology imaging for disease assessment. Patients can proceed to autoSCT or CAR T-cell therapy or epcoritamab monotherapy upon completion of Cycle 3 per investigator discretion. The rationale for subjects not proceeding to autoSCT or CAR T-cell therapy will be captured in the eCRFs. Hematopoietic stem cell mobilization and collection will be performed according to institutional standards. Patients who do not undergo autoSCT or CAR T-cell therapy may remain on study treatment and continue epcoritamab monotherapy following completion of Cycle 3. Epcoritamab monotherapy may continue from Cycle 4 to Cycle 9, or until unacceptable toxicity, or disease progression per the Lugano Criteria.

Official Title
-----------------
A Phase II Trial Evaluating Safety and Efficacy of Epcoritamab With Gemcitabine, Dexamethasone, and Cisplatin (GDP) Salvage Chemotherapy in Relapsed Refractory Large B-cell Lymphoma

Conditions
-----------------
Large Cell Lymphoma, Diffuse, Relapsed Cancer, Refractory Cancer

Intervention / Treatment
-----------------
* Procedure: AutoSCT OR CAR T-cell Therapy
* Drug: GDP
* Drug: Epcoritamab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Written informed consent and HIPAA authorization for release of personal health information prior to registration. NOTE: HIPAA authorization may be included in the informed consent or obtained separately. Age ≥ 18 years at the time of consent. ECOG Performance Status of 0-2 within 28 days prior to registration. Histological confirmed CD20+ relapsed large cell lymphoma according to the 5th edition of the WHO classification of the hematolymphoid tumors and the 2022 international consensus classification of mature lymphoid neoplasms including de-novo and transformed from prior indolent B-cell NHL such as follicular lymphoma, or marginal zone lymphoma (33, 34). NOTE: Subjects with high-grade B-cell lymphoma (HGBCL), NOS subtype, and high-grade B-cell lymphoma with c-MYC, Bcl2 and/or Bcl6 rearrangements (double or triple hit lymphoma) are eligible. Patients with primary mediastinal B-cell lymphoma, and T-cell histiocyte-rich B-cell lymphoma, primary cutaneous diffuse large B-cell lymphoma, leg type, Intravascular large B-cell lymphoma, Epstein-Barr virus-positive diffuse large B-cell lymphoma, NOS, Diffuse large B-cell lymphoma associated with chronic inflammation, and ALK-positive large B-cell lymphoma are eligible. Patients with Burkitt lymphoma or lymphoplasmacytic lymphoma are not eligible. Positron emission tomography (PET) positive measurable disease with at least 1 node having the longest diameter (LDi) greater than (>) 1.5 centimeter (cm) or 1 extranodal lesion with LDi >1 cm (per the Lugano Criteria 2014). Have received at least 1 prior line of systemic therapy for the treatment of large cell lymphoma. NOTE: Prior radiation therapy or systemic corticosteroids will not be considered a line of therapy. Must have had relapsed or refractory disease following standard frontline chemotherapy. Refractory disease is defined as large cell lymphoma not achieving complete remission, progressing or relapsing within 6 months after first-line chemotherapy based on PET/CT per the Lugano criteria. Relapsed disease is defined as disease that recurs beyond 6 months after completion of initial chemotherapy based on PET/CT per the Lugano criteria. Patients must be deemed eligible to proceed with high dose chemotherapy and stem cell transplantation or CAR T-cell therapy per treating physician discretion. Archival tissue obtained within 6 months is required if available and will be identified at screening and shipped prior to Cycle 1 Day 1. If archival tissue is not available, tissue from a fresh tissue from a standard of care biopsy is required. If a subject does not have archival tissue or is not undergoing a standard of care biopsy, they are not eligible for the trial. NOTE: A pre-treatment fresh tissue core or excisional biopsy at screening is preferred which should be considered standard of care. Demonstrate adequate organ function. All screening labs to be obtained within 21 days prior to registration. *Patients with bone marrow involvement will be eligible to participate in the study but must meet hematologic parameters. Life expectancy of ≥ 6 months, as determined by the enrolling physician or protocol designee. Females subjects of childbearing potential must have a negative serum pregnancy test within 24 hours prior to study treatment. Female subjects of childbearing potential and male subjects must be willing to abstain from heterosexual intercourse or to use an effective method(s) of contraception. HIV-infected subjects on effective anti-retroviral therapy with undetectable viral load and CD4 count of > 200 are eligible for this trial. Testing for HIV viral load and antibody at screening is mandatory. Subjects with a history of chronic hepatitis B virus (HBV) infection, must have an undetectable HBV viral load on suppressive therapy, if indicated. Subjects with evidence of prior HBV but who are PCR-negative are permitted in the trial but should receive prophylactic antiviral therapy. Subjects with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, the HCV viral load must be undetectable to be eligible for this trial. Subjects who received treatment for HCV that was intended to eradicate the virus may participate if hepatitis C RNA levels are undetectable. Testing for HBV and HCV is mandatory at screening. As determined by the enrolling physician or protocol designee, ability of the subject to understand and comply with study procedures for the entire length of the study. Exclusion Criteria: Previous treatment with gemcitabine, cisplatin, and epcoritamab or other bispecific T-cell engager antibody (BiTE) such aas glofitamab, mosunetuzumab, or odronextamab. Known active central nervous system or meningeal involvement by large cell lymphoma at time of screening. Patients diagnosed with CNS disease who achieved and maintained CNS CR at the time of relapse are eligible. Lumbar puncture must be done in this case prior to study entry to demonstrate CNS CR status. Tests to investigate CNS involvement are required otherwise only if clinically indicated (i.e. disease suspected on basis of symptoms or other findings). Contraindication to any drug contained in the combination therapy regimen (GDP). Known hypersensitivity or allergic reaction to epcoritamab or its' excipients. Any AE related to the previous large cell lymphoma therapy which has not recovered to Grade ≤ 1 (CTCAE v.5.0) or baseline by C1D1, except alopecia. Use of any standard or experimental anti-large cell lymphoma therapy (including nonpalliative radiation, chemotherapy, immunotherapy, radio-immunotherapy, or any other anticancer therapy) < 14 days prior to C1D1 (prednisone up to 50 mg or equivalent for 5 days is permitted; palliative radiation is permitted only if on non-target lesions). Major surgery < 14 days of Cycle 1 Day 1. Neuropathy Grade ≥ 2 (CTCAE v.5.0). Patients with a history of other malignancies, except adequately treated non-melanoma skin cancer, non-invasive superficial bladder cancer, curatively treated in-situ cancer of the cervix, DCIS of the breast, localized low grade prostate cancer (up to Gleason score 6), or other solid tumours curatively treated with no evidence of disease for at least 3 years. Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) at trial enrolment or significant infections within 2 weeks prior to the first dose of epcoritamab. Confirmed history or current autoimmune disease or other diseases requiring permanent immunosuppressive therapy. Low-dose (10 mg/day) prednisolone (or equivalent) for rheumatoid arthritis or similar conditions is allowed. Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the mother is being treated on study). Treatment with an investigational drug within 4 weeks or 5 half-lives, whichever is longer, prior to the first dose of epcoritamab. Any life-threatening illness, medical condition, or organ system dysfunction which, in the Investigator's opinion, could compromise the subject's safety, or being compliant with the study procedures.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GDP + Epcoritamab + AutoSCT or CAR T-cell therapy<br>Cycles 1-3 (Cycle = 21 days) Epcoritamab will be administered by subcutaneous injection Days 1, 8, and 15. Epcoritamab Day 1: 0.16mg, Day 8: 0.8mg, Day 15: 48mg except Cycle 2-Epcoritamab will administered at 48mg on Days 1, 8 and 15 Gemcitabine will be administered by IV infusion on Days 1 and 8. Gemcitabine Days 1,8: 1,000mg/m^2 Cisplatin will be administered by IV infusion on Day 1. Cisplatin Day 1: 75mg/m^2 Dexamethasone will be given by mouth on Days 1-4. Dexamethasone Days 1-4: 40mg After completion of Cycle 3 Autologous stem cell transplant (AutoSCT) OR CAR T-cell therapy | Procedure: AutoSCT OR CAR T-cell Therapy<br>* Autologous stem cell transplant (AutoSCT) or CAR T-cell therapy will be performed after Cycle 3 of receiving epcoritamab and GDP<br>* Other names: chimeric antigen receptor (CAR) T-cell;Drug: GDP<br>* Gemcitabine Cisplatin Dexamethasone<br>Drug: Epcoritamab<br>* Epcoritamab<br>|
| Experimental: GDP + Epcoritamab + Epcoritamab Maintenance<br>Cycles 1-3 (Cycle = 21 days) Epcoritamab will be administered by subcutaneous injection Days 1, 8, and 15 of each Cycle. Epcoritamab Day 1: 0.16mg, Day 8: 0.8mg, Day 15: 48mg except Cycle 2-Epcoritabab will administered at 48mg on Days 1, 8 and 15 Gemcitabine will be administered by IV infusion on Days 1 and 8 of each Cycle. Gemcitabine Days 1,8: 1,000mg/m^2 Cisplatin will be administered by IV infusion on Day 1 of each Cycle. Cisplatin Day 1: 75mg/m^2 Dexamethasone will be given by mouth on Days 1-4 of Cycle 1 ONLY. Dexamethasone Days 1-4: 40mg Cycles 4-9 (Cycle =28 Days) Epcoritamab will be administered by subcutaneous injection on Days 1, 8, and 15 of Cycles 4-9. | Drug: GDP<br>* Gemcitabine Cisplatin Dexamethasone<br>Drug: Epcoritamab<br>* Epcoritamab<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete Response (CR) | CR rate is defined as proportion of subjects with a CR based on the Lugano Criteria 2022 following 3 cycles of combination treatment. | 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate (ORR) | ORR is defined as the proportion of subjects with a CR + PR based on Lugano Criteria 2022 | 4 years | 
| Duration of Response (DOR) | DOR is defined as time from first observed response (CR or PR) to date of progression (PD) based on the Lugano Criteria 2022 or death, whichever occurs first. | 4 years | 
| Progression-free Survival (PFS) | PFS is defined as the time from treatment initiation until disease progression based on the Lugano Criteria 2022 or death from any cause. | 4 years | 
| Overall Survival (OS) | OS is defined as the time from treatment initiation until death from any cause. | 4 years | 
| Feasibility of AutoSCT or CAR T-cell | Feasibility of stem cell mobilization or CAR T-cell therapy will be assessed based on the number of subjects that undergo autologous transplant or CAR T-cell therapy. | 6 months |