Epcoritamab, Zanubrutinib, and Rituximab (EZR) for R/R FL Relapsed or Refractory Follicular Lymphoma

Recruitment & Eligibility

Status: Not yet recruiting

Sex: All

Target Recruitment: 24

Inclusion Criteria

Inclusion Criteria: - Histologically confirmed diagnosis of CD20+ FL (grade 1-3A) (at time of trial entry) with review of the diagnostic pathology specimen at one of the participating institutions. Patients with current histologic transformation are excluded. - Receipt of at least one prior line of therapy for FL (with prior treatment including both a CD20 monoclonal antibody and an alkylating agent). - Measurable disease, defined as =1 measurable nodal lesion (long axis >1.5 cm or short axis >1.0 cm) or =1 measurable extra-nodal lesion (long axis >1.0 cm) on PET, CT, or magnetic resonance imaging (MRI). Disease should be FDG-avid based on PET. - Meets at least one criterion to begin treatment based on the modified GELF (Groupe d'Etude des Lymphomes Folliculaires) criteria: - Symptomatic adenopathy - Organ function impairment due to disease involvement, including cytopenias due to marrow involvement (WBC <1.5x109/L; absolute neutrophil count [ANC] <1.0x109/L, Hgb <10g/dL; or platelets <100x109/L) - Constitutional symptoms (defined as persistent fevers >100.4 F, shaking chills, drenching night sweats, or loss of >10% of body weight within a 6 month period) - Any nodal or extranodal tumor mass >7 cm in maximum diameter -->3 nodal sites of involvement >3 cm - Local compressive symptoms or imminent risk thereof - Splenomegaly (craniocaudal diameter > 16cm on CT imaging) - Clinically significant pleural or peritoneal effusion - Leukemic phase (>5x109/L circulating malignant cells) - Rapid generalized disease progression - Renal infiltration - Bone lesions - Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. (Appendix A) - Age =18 years. - Adequate hematologic and organ function: - Absolute neutrophil count > 1.0x109/L unless due to marrow involvement by lymphoma in which case ANC must be >0.5x109/L - Platelets > 75 x109/L, unless due to marrow involvement by lymphoma, in which case platelets must be >50 x109/L - Estimated CrCl (based on Cockcroft Gault or MDRD) = 45ml/min or =45ml/min/1.73m2 - Total bilirubin < 1.5 X ULN, unless Gilbert syndrome, in which case direct bilirubin must be < 1.5 x ULN - AST/ALT < 2.5 X ULN, unless documented liver involvement by lymphoma, in which case AST/ALT must be <5 x ULN - Ability to understand and the willingness to sign a written informed consent document. - Willingness to provide a pre-treatment tumor sample by core needle or excisional surgical biopsy. A fresh biopsy is strongly encouraged, but an archival sample is acceptable if it is collected within 90 days and without intervening treatment and the following provisions are met: 1) availability of a tumor-containing formalin-fixed, paraffin-embedded (FFPE) tissue block, 2) if the tumor containing FFPE tissue block cannot be provided in total, sections from this block should be provided that are freshly cut and mounted on positively-charged glass slides. Preferably, 25 slides should be provided; if not possible, a minimum of 15 slides is required. Exceptions to this criterion may be made with approval of the Sponsor-Investigator. - Willingness to remain abstinent1 or to use two effective contraceptive methods that result in a failure rate of <1% per year from screening until: (a) at least 3 months after pre- treatment with rituximab, 12 months after the last dose of epcoritamab, or 3 months after the last dose of zanubrutinib, whichever is longer, if the patient is a male or (b) until at least 18 months after pre-treatment with rituximab, 12 months after the last dose of epcoritamab, or 3 months after the last dose of zanubrutinib, whichever is longer, if patient is a female. Examples of contraceptive methods with a failure rate of <1% per year include: - Tubal ligation, male sterilization, hormonal implants, established proper use of hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices. - Alternatively, two methods (e.g., two barrier methods such as a condom and a cervical cap) may be combined to achieve a failure rate of <1% per year. Barrier methods must always be supplemented with the use of a spermicide. - True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject. In contrast, periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception. Exclusion Criteria: - Patients who require systemic immunosuppressive therapy for an ongoing medical condition will be excluded. For corticosteroids, patients receiving a prednisone dose of >10 mg daily (or equivalent) will not be eligible. A short course of steroids (up to 14 days) for lymphoma-related symptom palliation or for prophylaxis (i.e., IV contrast allergy) is allowed, in which case patients should be off steroids prior to treatment start. - Patients with bulky cervical adenopathy that is compressing the upper airway or could result in significant airway compression during a tumor flare event. - Patients, who have had a major surgery or significant traumatic injury within 4 weeks of start of study drug, patients who have not recovered from the side effects of any major surgery (defined as requiring general anesthesia). - Presence of HCV antibody. Patients with presence of HCV antibody are eligible if HCV RNA is undetectable (NOTE: the limit of detection for HCV RNA must have a sensitivity of < 15 IU/mL). Subjects who received treatment for HCV that was intended to eradicate the virus and who have an undetectable HCV RNA may participate without serial HCV RNA screening. Other patients may participate if they are willing to undergo every 3- month monitoring for HCV reactivation. - Presence of hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb). Patients with positive hepatitis B serologies with undetectable HBV DNA (NOTE: the limit of detection for HBV DNA must have a sensitivity of < 20 IU/mL) are permitted in the trial but should receive prophylactic antiviral therapy (i.e. entecavir) and undergo every 3 month HBV DNA monitoring. - Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) requiring antimicrobial therapy at trial enrolment or significant infections within 2 weeks prior to the first dose of epcoritamab. - Subject has a known active severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2) infection. If a subject has signs/symptoms suggestive of SARS-CoV-2 infection or has had recent known exposure to someone with SARS-CoV-2 infection, the subject must have a negative molecular (e.g., PCR) test, or 2 negative antigen test results at least 24 hours apart, to rule out SARS-CoV-2 infection. Subjects who do not meet SARS- CoV-2

Exclusion Criteria

Not provided

Study & Design

Study Type: Interventional

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Complete Metabolic Response (CMR) Rate

Secondary Outcome Measures

Name	Time	Method
Objective Response Rate (ORR);Partial Response Rate (PRR);End-of-treatment Objective Response Rate (EOT ORR);End-of-treatment Partial Response Rate (EOT PRR);End-of-treatment Complete Response Rate (EOT CRR);Duration of Response (DOR);Duration of Complete Response (DOCR);2-Year Progression Free Survival (PFS2);Median Progression Free Survival;Median Time-to-next treatment (TTNT);Median Overall Survival (OS);Incidence of Histological Transformation;Cytokine Release Syndrome (CRS) Rate;Immune Effector Cell-associated Neurotoxicity Syndrome (ICANS) Rate;Rate of Grade 3 or Higher Toxicity Regardless of Attribution;Rate of Grade 2 or Higher Toxicity at Least Possibly Related to Study Treatment

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