Safety and Efficacy of ALLO-715 BCMA Allogenic CAR T Cells in in Adults With Relapsed or Refractory Multiple Myeloma (UNIVERSAL) (UNIVERSAL)

A Single-Arm, Open-Label, Phase 1 Study of the Safety, Efficacy, and Cellular Kinetics/Pharmacodynamics of ALLO-715 to Evaluate an Anti-BCMA Allogeneic CAR T Cell Therapy With or Without Nirogacestat in Subjects With Relapsed/Refractory Multiple Myeloma

The purpose of the UNIVERSAL study is to assess the safety, efficacy, cell kinetics, and immunogenicity of ALLO-715 with or without Nirogacestat in adults with relapsed or refractory multiple myeloma after a lymphodepletion regimen of ALLO-647 in combination with fludarabine and/or cyclophosphamide, or ALLO-647 alone.

Study Overview

• Status: Active, not recruiting
• Conditions: Relapsed/Refractory Multiple Myeloma
• Intervention / Treatment: Biological: ALLO-647; Drug: Fludarabine; Drug: Cyclophosphamide; Genetic: ALLO-715; Drug: Nirogacestat

• Study Type: Interventional
• Enrollment (Estimated): 132
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Gilbert, Arizona, United States, 85234
      • Banner MD Anderson Cancer Center
  • California
    • Duarte, California, United States, 91010
      • City of Hope
    • Palo Alto, California, United States, 94305
      • Stanford Cancer Institute
  • Colorado
    • Denver, Colorado, United States, 80218
      • Sarah Cannon/Colorado Blood Cancer Institute
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Taussig Cancer Center
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Vanderbilt-Ingram Cancer Center
  • Texas
    • Austin, Texas, United States, 78704
      • St. David's South Austin Medical Center
    • San Antonio, Texas, United States, 78229
      • Texas Transplant Institute
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Documented diagnosis of relapsed/refractory multiple myeloma (MM) with measurable disease (serum, urine, or free light chain [FLC]) per International Myeloma Working Group (IMWG) criteria
• At least 3 prior lines of MM therapy, including a proteasome inhibitor, immunomodulatory agent, and anti-CD38 antibody (unless contraindicated), and refractory to the last treatment line.
• Eastern Cooperative Oncology Group (ECOG) 0 or 1
• Absence of donor (product)-specific anti-HLA antibodies
• Adequate hematologic, renal, hepatic, pulmonary, and cardiac function

Exclusion Criteria:

• Current or history of Central Nervous System (CNS) involvement of myeloma or plasma cell leukemia
• Clinically significant CNS disorder
• Current or history of thyroid disorder
• Autologous stem cell transplant within the last 6 weeks, or any allogeneic stem cell transplant
• Prior treatment with anti-BCMA therapy, any gene therapy, any genetically modified cell therapy, or adoptive T cell therapy
• History of HIV infection or acute or chronic active hepatitis B or C infection
• Patients unwilling to participate in an extended safety monitoring period

Additional Exclusion Criteria for Nirogacestat plus ALLO-715 Cohorts

• Inability to swallow tablets
• Subject has known malabsorption syndrome or preexisting gastrointestinal conditions that may impair absorption of nirogacestat
• Use of strong/moderate CYP3A4 inhibitors, and strong CYP3A4 inducers within 14 days before starting nirogacestat.
• Use of concomitant medications that are known to prolong the QT/QTcF interval

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: ALLO-647, ALLO-715, Nirogacestat

Biological: ALLO-647; ALLO-647 is a monoclonal antibody that recognizes a CD52 antigen; Drug: Fludarabine; Chemotherapy for lymphodepletion; Drug: Cyclophosphamide; Chemotherapy for lymphodepletion; Genetic: ALLO-715; ALLO-715 is an allogeneic CAR T cell therapy targeting BCMA; Drug: Nirogacestat; a small molecule, selective, reversible, noncompetitive inhibitor of γsecretase (GSI) that increases BCMA target density on the surface of multiple myeloma cells.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of subjects experiencing Dose Limiting Toxicities at increasing doses of ALLO-715	Dose limiting toxicities are defined as ALLO-715-related adverse events with onset within 28 days following infusion of ALLO-715.	28 Days
To assess the overall safety profile and tolerability of ALLO-647 in combination with Fludarabine and/or cyclophosphamide or ALLO-647 alone, prior to ALLO-715 to confirm the dose of ALLO-647.	The proportion of subjects in a dose cohort with DLTs of ALLO-647	33 days
To assess the overall safety profile and tolerability of nirogacestat given concomitantly with ALLO-715 following lymphodepletion with Flu/ Cy/ ALLO-647.	Dose limiting toxicities are defined as ALLO-715-related adverse events with onset within 28 days following infusion of ALLO-715.	28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cellular kinetics of ALLO-715	Levels of anti-BCMA CAR T cells in blood	up to 60 months
antitumor activity of ALLO-715 in combination with nirogacestat	overall -response rate (ORR)	up to 60 months
Cellular kinetics of ALLO-715 in combination with nirogacestat	Levels of anti-BCMA CAR T cells in blood	up to 60 months
Pharmacokinetics of ALLO-647	Serum concentration levels of ALLO-647	up to 60 months
Pharmacokinetics of nirogacestat	Serum concentration levels of nirogacestat	up to 60 months
Incidence of immunogenicity against ALLO-715 and ALLO-647	detection and levels of anti-drug antibodies	up to 60 months
Immune monitoring after lymphodepletion regimen	Detection of the following circulating cells: T cell subset, B lymphocytes, and NK cells	up to 60 months
Anti-tumor activity of ALLO-715	overall response rate	up to 60 months
Anti-tumor activity of ALLO-715	duration of response	up to 60 months
Anti-tumor activity of ALLO-715	overall survival	up to 60 months
Anti-tumor activity of ALLO-715	minimal residual disease	up to 60 months
To evaluate the expression of BCMA in bone marrow plasma cells with and without nirogacestat	Overall response rate of ALLO-715 with and without Nirogacestat	up to 60 months

Collaborators and Investigators

• Sponsor: Allogene Therapeutics

Publications and helpful links

General Publications

• Mailankody S, Matous JV, Chhabra S, Liedtke M, Sidana S, Oluwole OO, Malik S, Nath R, Anwer F, Cruz JC, Htut M, Karski EE, Lovelace W, Dillon M, Butz E, Ying W, Balakumaran A, Kumar SK. Allogeneic BCMA-targeting CAR T cells in relapsed/refractory multiple myeloma: phase 1 UNIVERSAL trial interim results. Nat Med. 2023 Feb;29(2):422-429. doi: 10.1038/s41591-022-02182-7. Epub 2023 Jan 23. Erratum In: Nat Med. 2023 Mar 17;:

Study record dates

Study Major Dates

• Study Start (Actual): September 23, 2019
• Primary Completion (Estimated): September 1, 2027
• Study Completion (Estimated): September 1, 2027

Study Registration Dates

• First Submitted: September 16, 2019
• First Submitted That Met QC Criteria: September 16, 2019
• First Posted (Actual): September 18, 2019

Study Record Updates

• Last Update Posted (Actual): August 14, 2023
• Last Update Submitted That Met QC Criteria: August 9, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Immunoproliferative Disorders; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Multiple Myeloma; Neoplasms, Plasma Cell; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Gamma Secretase Inhibitors and Modulators; Cyclophosphamide; Fludarabine; Nirogacestat
• Other Study ID Numbers: ALLO-715-101

Drug and device information, study documents

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