Study to Investigate the Safety and Tolerability of Odronextamab in Patients With CD20+ B-Cell Malignancies (ELM-1)

An Open-Label, Multi-Center Phase 1 Study to Investigate the Safety and Tolerability of REGN1979, an Anti-CD20 x Anti-CD3 Bispecific Monoclonal Antibody, in Patients With CD20+ B-Cell Malignancies Previously Treated With CD20-Directed Antibody Therapy (ELM-1)

This study has two parts with distinct study objectives and study design. In part A, odronextamab is studied as an intravenous (IV) administration with a dose escalation and a dose expansion phase for B-NHL and CLL. The dose escalation phase for B-NHL and the CLL study are closed at the time of protocol amendment 17. In part B, odronextamab is studied as a subcutaneous (SC) administration with a dose finding and a dose expansion phase for B-NHL.

Study Overview

• Status: Active, not recruiting
• Conditions: Chronic Lymphocytic Leukemia; Non-Hodgkin Lymphoma
• Intervention / Treatment: Drug: Odronextamab multiple dose levels; Drug: Odronextamab multiple dose levels

• Study Type: Interventional
• Enrollment (Actual): 200
• Phase: Phase 1

Expanded Access

Available outside the clinical trial. See expanded access record.

Contacts and Locations

• Study Contact: Name: Clinical Trials Administrator; Email: clinicaltrials@regeneron.com

Study Locations

• France
  • Lyon, France, 69495
    • Chu Hopital Lyon Sud
  • Haute-Normandie
    • Rouen, Haute-Normandie, France, 76038
      • Centre Henri Becquerel
  • Île-de-France
    • Villejuif, Île-de-France, France, 94800
      • Institut Gustave Roussy
• Germany
  • Bayern
    • Wurzburg, Bayern, Germany, 97080
      • Universitatsklinikum Wurzburg
• Israel
  • Haifa, Israel, 3436212
    • Lady Davis Carmel Medical Center
  • Haifa, Israel, 3109601
    • Rambam Health Care Campus - Hematology and Bone Marrow Transplantation Institute
  • HaDarom
    • Ashdod, HaDarom, Israel, 7747629
      • Assuta Ashdod University Hospital
  • HaMerkaz
    • Kfar Saba, HaMerkaz, Israel, 44281
      • Meir Medical Center
    • Tel-Hashomer, HaMerkaz, Israel, 5265601
      • The Chaim Sheba Medical Center
  • Yerushalayim
    • Jerusalem, Yerushalayim, Israel, 9112001
      • Hadassah Medical Center
• United Kingdom
  • Manchester, United Kingdom, M20 4BX
    • The Christie Nhs Foundation Trust
  • Cornwall
    • Truro, Cornwall, United Kingdom, tr1 3lq
      • Royal Cornwall Hospitals NHS Trust
• United States
  • California
    • Orange, California, United States, 92868
      • University of California, Irvine
    • Stanford, California, United States, 94305
      • Stanford University
  • Florida
    • Tampa, Florida, United States, 33612
      • H. Lee Moffitt Cancer Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
    • Boston, Massachusetts, United States, 02215
      • Dana Farber Cancer Institute (Massachusetts General Hospital and Beth Israel)
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • New Jersey
    • New Brunswick, New Jersey, United States, 08901
      • Rutgers Cancer Institute of New Jersey
  • New York
    • New York, New York, United States, 10065
      • Weill Cornell Medical College
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

1. Have documented CD20+ B-cell malignancy, with active disease not responsive to prior therapy, for whom no standard of care options exists, and for whom treatment with an anti-CD20 antibody may be appropriate:

   • Part A (IV administration) B-NHL confirmed by National Cancer Institute (NCI) working group criteria
   • Part B (SC administration): Confirmed diagnosis of B-NHL requiring therapy as defined by WHO classification 2017

2. Patients with B-NHL must have had prior treatment with an anti-CD20 antibody therapy. Patients with CLL (Part A only) are not required to have received prior treatment with an anti-CD20 antibody therapy as defined in the protocol.

   • For the inclusion in the disease-specific expansion cohort enrolling DLBCL patients after failure of CAR-T therapy, the patient must have recovered from the toxicities of the lymphodepletion therapy and CAR-T infusion.
   • For inclusion in Part B, patients must have FL grade 1-3a or DLBCL (with or without prior CAR-T) per the criteria above, and:
   • Patients with FL grade 1-3a and DLBCL must have received at least 2 prior lines of systemic therapy, including an anti-CD20 antibody and an alkylating agent
3. All patients must have at least one bi-dimensionally measurable lesion ≥1.5 cm) documented by CT or MRI scan, if CT scan is not feasible.
4. Eastern Cooperative Oncology Group (ECOG) performance status ≤1
5. Life expectancy of at least 6 months
6. Adequate bone marrow function as described in the protocol
7. Adequate organ function as described in the protocol
8. Willingness to undergo mandatory tumor biopsy pretreatment, if in the opinion of the investigator, the patient has an accessible lesion that can be biopsied without significant risk to the patient.
9. Willing and able to comply with clinic visits and study-related procedures
10. Provide signed informed consent or legally acceptable representative

Key Exclusion Criteria:

1. Primary central nervous system (CNS) lymphoma or known or suspected CNS involvement by non-primary CNS NHL

2. History of or current relevant CNS pathology such as

   • Epilepsy, seizure, paresis, aphasia, apoplexia, severe brain injuries, cerebellar disease, organic brain syndrome, psychosis, or
   • Evidence for presence of inflammatory lesions and/or vasculitis on cerebral MRI
3. Standard anti-lymphoma chemotherapy (non-biologic) or radiotherapy within 28 days prior to first administration of study drug

4. Infection with human immunodeficiency virus (HIV) or chronic infection with hepatitis B virus (HBV), hepatitis C virus (HCV), or cytomegalovirus (CMV) infection [(as noted by detectable levels on a blood polymerase chain reaction (PCR) assay)].

   1. Patients with hepatitis B (HepBsAg+) who have controlled infection (serum hepatitis B virus deoxyribonucleic acid (DNA) that is below the limit of detection AND receiving anti-viral therapy for hepatitis B) are permitted upon consultation with the physician managing the infection.
   2. Patients who show detectable levels of CMV at screening will need to be treated with appropriate antiviral therapy and demonstrate at least 2 undetectable levels of CMV by PCR assay (at least 7 days apart) before being re-considered for eligibility.
5. Patients who have received a live vaccination within 28 days of first dose of study treatment

Note: Other protocol Inclusion/Exclusion criteria apply

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part A; DLBCL post CAR-T	Drug: Odronextamab multiple dose levels; Administered by intravenous (IV) infusion; Other Names: REGN1979; Drug: Odronextamab multiple dose levels; Administered by subcutaneous (SC) injection; Other Names: REGN1979
Experimental: 1N Part B; FL	Drug: Odronextamab multiple dose levels; Administered by intravenous (IV) infusion; Other Names: REGN1979; Drug: Odronextamab multiple dose levels; Administered by subcutaneous (SC) injection; Other Names: REGN1979
Experimental: 2N Part B; DLBCL	Drug: Odronextamab multiple dose levels; Administered by intravenous (IV) infusion; Other Names: REGN1979; Drug: Odronextamab multiple dose levels; Administered by subcutaneous (SC) injection; Other Names: REGN1979

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety/overall frequency of adverse events (AEs)	Part A and B	Up to 24 months
Safety/dose limiting toxicities (DLTs)	Part A and B	Up to 28 days
Antitumor activity as measured by the objective response rate (ORR)	Expansion Cohorts: • Diffuse large B-cell lymphoma (DLBCL) after failure of CAR-T therapy Part A	Through study completion, an average of 24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetics (Concentration of odronextamab)	Peak plasma concentration (Cmax) of odronextamab Part A and B	Up to 10 months
Incidence of anti-drug antibodies (ADA) to odronextamab	Part A and B	Over time; up to approximately 15 months
Titer of ADA to odronextamab	Part A and B	Over time; up to approximately 15 months
Incidence of neutralizing antibodies (NAb) to odronextamab over time	Part A and B	Over time; Up to approximately 15 months
Objective response rate (ORR)	For dose escalation portion and expansion cohorts: Aggressive lymphoma expansion cohort 2; FL grade 1-3a expansion cohorts 1 and 2 (Part A) For dose escalation and dose expansion cohorts: FL grade 1-3a; DLBCL; DLBCL post CAR T failure (Part B)	Through study completion, an average of 24 months
Progression-free survival	Part A and B	Up to 48 months
Overall Survival	Part A and B	Until death or lost to follow-up/ withdrawal, approximately up to 48 months
Duration of response (DOR)	Part A and B	Until progression, approximately up to 48 months
Minimal residual disease (MRD) for patients with CLL	Part A	Up to 24 months
Duration of Complete Response (DOCR)	Part B	Until progression, approximately up to 48 months

Collaborators and Investigators

• Sponsor: Regeneron Pharmaceuticals
• Investigators: Study Director: Clinical Trial Management, Regeneron Pharmaceuticals

Publications and helpful links

General Publications

• Bannerji R, Arnason JE, Advani RH, Brown JR, Allan JN, Ansell SM, Barnes JA, O'Brien SM, Chavez JC, Duell J, Rosenwald A, Crombie JL, Ufkin M, Li J, Zhu M, Ambati SR, Chaudhry A, Lowy I, Topp MS. Odronextamab, a human CD20xCD3 bispecific antibody in patients with CD20-positive B-cell malignancies (ELM-1): results from the relapsed or refractory non-Hodgkin lymphoma cohort in a single-arm, multicentre, phase 1 trial. Lancet Haematol. 2022 May;9(5):e327-e339. doi: 10.1016/S2352-3026(22)00072-2. Epub 2022 Apr 1.
• Zhu M, Olson K, Kirshner JR, Khaksar Toroghi M, Yan H, Haber L, Meagher C, Flink DM, Ambati SR, Davis JD, DiCioccio AT, Smith EJ, Retter MW. Translational findings for odronextamab: From preclinical research to a first-in-human study in patients with CD20+ B-cell malignancies. Clin Transl Sci. 2022 Apr;15(4):954-966. doi: 10.1111/cts.13212. Epub 2022 Jan 7.

Study record dates

Study Major Dates

• Study Start (Actual): January 9, 2015
• Primary Completion (Estimated): December 2, 2025
• Study Completion (Estimated): December 2, 2025

Study Registration Dates

• First Submitted: November 7, 2014
• First Submitted That Met QC Criteria: November 11, 2014
• First Posted (Estimated): November 14, 2014

Study Record Updates

• Last Update Posted (Actual): September 7, 2023
• Last Update Submitted That Met QC Criteria: September 6, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: Follicular lymphoma (FL); Aggressive lymphoma; Diffuse large B-cell lymphoma (DLBCL)
• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Disease Attributes; Leukemia, Lymphoid; Leukemia; Leukemia, B-Cell; Chronic Disease; Lymphoma; Leukemia, Lymphocytic, Chronic, B-Cell
• Other Study ID Numbers: R1979-HM-1333; 2015-004491-30 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No