Clinical trial NCT02776813: Study of ACTR087 in Subjects With Relapsed or Refractory B-cell Lymphoma
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Lymphoma
Keywords: CD20+
B-cell
ACTR087
Relapsed
Refractory
Lead sponsor: Cogent Biosciences, Inc.
Sponsor class: INDUSTRY
First posted: 2016-05-18
Enrollment: 34
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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

Primary outcomes:
measure: Safety as assessed by dose limiting toxicities (DLTs)
timeFrame: 28 days
measure: Safety as assessed by determination of the maximum tolerated dose (MTD)
timeFrame: 24 months
measure: Safety as assessed by determination of the recommended phase 2 dose (RP2D)
timeFrame: 24 months
measure: Safety as assessed by and adverse events, laboratory assessments and physical examinations
timeFrame: 24 months
measure: Safety as assessed by mini-mental state examination (MMSE)
timeFrame: 24 months
Secondary outcomes:
measure: Overall response rate
timeFrame: 24 months
measure: Duration of response
timeFrame: 24 months
measure: Progression free survival
timeFrame: 24 months
measure: Overall survival
timeFrame: 60 months
Other outcomes:
measure: ACRT087 persistence
timeFrame: 60 months
measure: Serum inflammatory markers
timeFrame: 169 days
measure: Serum cytokine levels
timeFrame: 169 days
measure: Rituximab serum concentrations
timeFrame: 147 days
Locations:
city: Gilbert
country: United States
facility: Banner MD Anderson Cancer Center
state: Arizona
city: New Haven
country: United States
facility: Yale University
state: Connecticut
city: Maywood
country: United States
facility: Loyola University Chicago
state: Illinois
city: Indianapolis
country: United States
facility: Indiana Bone and Marrow Transplantation
state: Indiana
city: Boston
country: United States
facility: Massachusetts General Hospital
state: Massachusetts
city: Durham
country: United States
facility: Duke University Medical Center
state: North Carolina
city: Columbus
country: United States
facility: Ohio State University
state: Ohio
Study officials:
affiliation: Cogent Biosciences, Inc.
name: Jessica Sachs, MD
role: STUDY_DIRECTOR
References:
citation: 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.