Study of ACTR087 in Subjects With Relapsed or Refractory B-cell Lymphoma

Phase 1 Study of ACTR087, Autologous T Lymphocytes Expressing Antibody Coupled T-cell Receptors (CD16V-41BB-CD3ζ), in Combination With Rituximab, in Subjects With Relapsed or Refractory CD20-Positive B-Cell Lymphoma

This is a phase 1, multi-center, single-arm, open-label study evaluating the safety and efficacy of an autologous T-cell product expressing ACTR in combination with rituximab in subjects with refractory or relapsed CD20+ B-cell lymphoma.

Study Overview

• Status: Completed
• Conditions: Lymphoma
• Intervention / Treatment: Biological: rituximab; Biological: ACTR087

• Study Type: Interventional
• Enrollment (Actual): 34
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Gilbert, Arizona, United States, 85234
      • Banner MD Anderson Cancer Center
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • Yale University
  • Illinois
    • Maywood, Illinois, United States, 60153
      • Loyola University Chicago
  • Indiana
    • Indianapolis, Indiana, United States, 46237
      • Indiana Bone and Marrow Transplantation
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Massachusetts General Hospital
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Ohio State University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Signed written informed consent obtained prior to study procedures

• Histologically-confirmed relapsed or refractory CD20+ B-cell lymphoma of one of the following types, with documented disease progression or recurrence following the immediate prior therapy:

  • DLBCL, regardless of cell of origin or underlying molecular genetics
  • MCL
  • PMBCL
  • Gr3b-FL
  • TH-FL
• Biopsy-confirmed CD20+ expression of the underlying malignancy by immunohistochemical staining or flow cytometry between the most recent dose of an anti-CD20 monoclonal antibody (mAb) and study enrollment
• At least 1 measurable lesion on imaging. Lesions that have been previously irradiated will be considered measurable only if progression has been documented following completion of radiation therapy

• Must have received adequate prior therapy for the underlying CD20+ B-cell lymphoma, defined as an anti-CD20 mAb in combination with an anthracycline-containing chemotherapy regimen (i.e. chemo-immunotherapy) and at least one of the following:

  • biopsy-proven refractory disease after frontline chemo-immunotherapy
  • relapse within 1 year from frontline chemo-immunotherapy and ineligible for autologous hematopoietic stem cell transplant (auto-HSCT)
  • For subjects with DLBCL, PMBCL, and Gr3b-FL: relapsed or refractory disease following at least 2 prior regimens or following an auto-HSCT
  • For subjects with TH-FL: relapsed or refractory disease following at least 2 prior regimens or following an auto-HSCT. At least 1 prior regimen with an anti-CD20 mAb in combination with chemotherapy is required following documented transformation
  • For subjects with MCL (confirmed with cyclin D1 expression or evidence of t(11;14) by cytogenetics, fluorescent in situ hybridization (FISH) or PCR): relapsed or refractory disease after at least 1 prior regimen with chemo-immunotherapy (prior auto-HSCT is allowable)
• Karnofsky performance scale ≥ 60%
• Life expectancy of at least 6 months
• ANC > 1000/µL
• Platelet count > 50,000/µL
• For women of childbearing potential (defined as physiologically capable of becoming pregnant), agreement to use of highly effective contraception for at least 1 year following ACTR087 infusion. For men with partners of childbearing potential, agreement to use effective barrier contraception for at least 1 year following ACTR087 infusion

Exclusion Criteria:

• Known active central nervous system (CNS) involvement by malignancy. Subjects with prior CNS involvement with their lymphoma must have completed effective treatment of their CNS disease at least 3 months prior to enrollment with no evidence of disease clinically and at least stable findings on relevant CNS imaging

• Prior treatment as follows:

  • alemtuzumab within 6 months of enrollment
  • fludarabine, cladribine, or clofarabine within 3 months of enrollment
  • external beam radiation within 2 weeks of enrollment
  • mAb (including rituximab) within 2 weeks of enrollment
  • other lymphotoxic chemotherapy (including steroids except as below) within 2 weeks of enrollment
  • experimental agents within 3 half-lives prior to enrollment, unless progression is documented on therapy
• Serum creatinine ≥ 1.5 X age-adjusted upper limits of normal (ULN)
• Pulse oximetry < 92% on room air
• Direct bilirubin ≥ 3.0 mg/dL (50 mmol/L)
• Alanine transaminase (ALT) ≥ 3 times the ULN, unless determined to be directly due to lymphoma.
• Aspartate transaminase (AST) ≥ 3 times the ULN, unless determined to be directly due to lymphoma
• Class III or IV heart failure as defined by the New York Heart Association (NYHA), history of cardiac angioplasty or stenting, documented myocardial infarction or unstable angina within 6 months prior to enrollment, cardiac ejection fraction of < 45%, or other clinically significant cardiac disease
• Clinical history of, prior diagnosis of, or overt evidence of autoimmune disease, regardless of severity
• Clinically significant active infection, in the judgment of the investigator
• Pregnancy (negative serum pregnancy test to be obtained within 6 days prior to enrollment for subjects of childbearing potential)
• Breastfeeding
• Primary immunodeficiency
• Seropositive for Human Immunodeficiency Virus (HIV) 1 or HIV 2, or positive hepatitis B surface antigen (HBsAg) or hepatitis C antibody
• Will need or has needed active treatment of a second malignancy within the prior 3 years before enrollment, other than FL, non-melanoma skin cancers, localized prostate cancer treated with curative intent, or cervical carcinoma in situ
• Is unable to receive any of the agents used in this study due a history of severe immediate hypersensitivity reaction (e.g. hypersensitivity to dimethyl sulfoxide (DMSO))
• History of prior allogeneic HSCT
• History of Richter's transformation from CLL
• Prior infusion of a genetically modified therapy

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: ACTR087, in combination with rituximab	Biological: rituximab; Biological: ACTR087

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Safety as assessed by dose limiting toxicities (DLTs)	28 days
Safety as assessed by determination of the maximum tolerated dose (MTD)	24 months
Safety as assessed by determination of the recommended phase 2 dose (RP2D)	24 months
Safety as assessed by and adverse events, laboratory assessments and physical examinations	24 months
Safety as assessed by mini-mental state examination (MMSE)	24 months

Secondary Outcome Measures

Outcome Measure	Time Frame
Duration of response	24 months
Overall survival	60 months
Progression free survival	24 months
Overall response rate	24 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
ACRT087 persistence	Blood samples will be collected and analyzed for the presence of T-cells which express antibody coupled T-cell receptors, using flow cytometry and qPCR	60 months
Serum inflammatory markers		169 days
Serum cytokine levels		169 days
Rituximab serum concentrations		147 days

Collaborators and Investigators

• Sponsor: Cogent Biosciences, Inc.

Publications and helpful links

General Publications

• Ernst M, Oeser A, Besiroglu B, Caro-Valenzuela J, Abd El Aziz M, Monsef I, Borchmann P, Estcourt LJ, Skoetz N, Goldkuhle M. Chimeric antigen receptor (CAR) T-cell therapy for people with relapsed or refractory diffuse large B-cell lymphoma. Cochrane Database Syst Rev. 2021 Sep 13;9(9):CD013365. doi: 10.1002/14651858.CD013365.pub2.

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2016
• Primary Completion (Actual): February 12, 2020
• Study Completion (Actual): February 12, 2020

Study Registration Dates

• First Submitted: May 4, 2016
• First Submitted That Met QC Criteria: May 16, 2016
• First Posted (Estimate): May 18, 2016

Study Record Updates

• Last Update Posted (Actual): March 31, 2020
• Last Update Submitted That Met QC Criteria: March 27, 2020
• Last Verified: March 1, 2020

More Information

Terms related to this study

• Keywords: Relapsed; Refractory; B-cell; CD20+; ACTR087
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents; Immunologic Factors; Antineoplastic Agents, Immunological; Rituximab
• Other Study ID Numbers: UT-201501; ATTCK-20-2 (Other Identifier: Unum Therapeutics)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO