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Dose Optimization Trial of CD19 Redirected Autologous T Cells

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ClinicalTrials.gov Identifier: NCT01747486
Recruitment Status : Completed
First Posted : December 11, 2012
Results First Posted : February 26, 2019
Last Update Posted : August 30, 2019
Sponsor:
Information provided by (Responsible Party):
University of Pennsylvania

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: None (Open Label);   Primary Purpose: Treatment
Condition Adult Patients Who Have Relapsed or Refractory CLL (3rd Line) or SLL
Intervention Biological: CART-19
Enrollment 42
Recruitment Details First Patient Enrolled - 02-Jan-2013 Last Patient Completed - 13-Dec-2017
Pre-assignment Details Study was conducted in 2 stages. Stage 1: subjects were randomized into one of the two arms (Arm 1: Higher dose & Arm 2 : Lower dose) Stage 2: the selected dose cohort was expanded to enroll additional subjects. Based on the Stage 1 analysis performed in Nov 2014, Arm 1 was chosen for expansion in Stage 2 and enrolled additional 12 subjects.
Arm/Group Title Target Dose of 1-5x10e8 Target Dose of 1-5x10e7
Hide Arm/Group Description

Arm 1: Target dose of 1-5x10e8 CART-19 cells (calculated as range of 10-50% transduced cells in 1 x10e9 total cells)

CART-19: CART-19 cells (autologous T cells expressing CD19 chimeric antigen receptors expressing tandem TCR zeta and 4-1BB costimulatory domains)

Arm 2: Target dose of 1-5x10e7 CART-19 cells (calculated as the range of 10-50% transduced cells in 1 x10e8 total cells)

CART-19: CART-19 cells (autologous T cells expressing CD19 chimeric antigen receptors expressing tandem TCR zeta and 4-1BB costimulatory domains)

Period Title: Stage 1
Started 15 15
Completed 3 2
Not Completed 12 13
Reason Not Completed
Physician Decision             3             0
Withdrawal by Subject             4             3
Disease progression             4             9
Death             1             1
Period Title: Stage 2
Started 12 0
Completed 3 0
Not Completed 9 0
Reason Not Completed
Physician Decision             2             0
Withdrawal by Subject             1             0
New Cancer Therapy             3             0
Disease Progression             3             0
Arm/Group Title Target Dose of 1-5x10e8 Target Dose of 1-5x10e7 Total
Hide Arm/Group Description

Arm 1: Target dose of 1-5x10e8 CART-19 cells (calculated as range of 10-50% transduced cells in 1 x10e9 total cells)

CART-19: CART-19 cells (autologous T cells expressing CD19 chimeric antigen receptors expressing tandem TCR zeta and 4-1BB costimulatory domains)

Note: For baseline measures, subjects from stage 1 (15) and stage 2 (12) are combined to have total 27 subjects. In stage 2, higher dose arm (arm 1) was chosen based on the stage 1 analysis performed to expand and enrolled 12 additional subjects.

Arm 2: Target dose of 1-5x10e7 CART-19 cells (calculated as the range of 10-50% transduced cells in 1 x10e8 total cells)

CART-19: CART-19 cells (autologous T cells expressing CD19 chimeric antigen receptors expressing tandem TCR zeta and 4-1BB costimulatory domains)

Note: In stage 1, 15 subject were enrolled in this arm. Since this arm was not chosen for stage 2, no additional subjects were enrolled. total subjects in this arm were 15.

Total of all reporting groups
Overall Number of Baseline Participants 27 15 42
Hide Baseline Analysis Population Description
In high dose cohort, 15 patients were enrolled in Stage 1 and 12 were in stage 2.
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 27 participants 15 participants 42 participants
<=18 years
0
   0.0%
0
   0.0%
0
   0.0%
Between 18 and 65 years
19
  70.4%
12
  80.0%
31
  73.8%
>=65 years
8
  29.6%
3
  20.0%
11
  26.2%
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 27 participants 15 participants 42 participants
Female
6
  22.2%
4
  26.7%
10
  23.8%
Male
21
  77.8%
11
  73.3%
32
  76.2%
Ethnicity (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 27 participants 15 participants 42 participants
Hispanic or Latino
1
   3.7%
0
   0.0%
1
   2.4%
Not Hispanic or Latino
26
  96.3%
15
 100.0%
41
  97.6%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
Race (NIH/OMB)  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 27 participants 15 participants 42 participants
American Indian or Alaska Native
0
   0.0%
0
   0.0%
0
   0.0%
Asian
1
   3.7%
0
   0.0%
1
   2.4%
Native Hawaiian or Other Pacific Islander
0
   0.0%
0
   0.0%
0
   0.0%
Black or African American
0
   0.0%
0
   0.0%
0
   0.0%
White
26
  96.3%
15
 100.0%
41
  97.6%
More than one race
0
   0.0%
0
   0.0%
0
   0.0%
Unknown or Not Reported
0
   0.0%
0
   0.0%
0
   0.0%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 27 participants 15 participants 42 participants
27 15 42
1.Primary Outcome
Title Number of Patients Achieving Complete Response Within 3 Months
Hide Description Complete response (including complete response with incomplete marrow recovery) within 3 months (in evaluable patients). The eveluable set comprise of patients who have received CART19 at intended dose level and completed at least 3-month follow-up after the infusion or discontinued due to disease progression, new cancer therapy or death.
Time Frame 3 months
Hide Outcome Measure Data
Hide Analysis Population Description
The Evaluable Set comprised all patients who received high dose (1-5×10^8) or low dose (1-5×10^7) CTL019 transduced cells as randomized, and completed at least 3-month follow-up after the infusion or discontinued due to disease progression, new cancer therapy or death.
Arm/Group Title Target Dose of 1-5x10e8 Target Dose of 1-5x10e7
Hide Arm/Group Description:

Arm 1: Target dose of 1-5x10e8 CART-19 cells (calculated as range of 10-50% transduced cells in 1 x10e9 total cells)

CART-19: CART-19 cells (autologous T cells expressing CD19 chimeric antigen receptors expressing tandem TCR zeta and 4-1BB costimulatory domains)

Arm 2: Target dose of 1-5x10e7 CART-19 cells (calculated as the range of 10-50% transduced cells in 1 x10e8 total cells)

CART-19: CART-19 cells (autologous T cells expressing CD19 chimeric antigen receptors expressing tandem TCR zeta and 4-1BB costimulatory domains)

Overall Number of Participants Analyzed 18 13
Measure Type: Count of Participants
Unit of Measure: Participants
Complete Response (CR)
1
   5.6%
1
   7.7%
CR with incomplete marrow recovery (CRi)
5
  27.8%
0
   0.0%
Partial Response (PR)
4
  22.2%
2
  15.4%
PR with incomplete marrow recovery (PRi)
0
   0.0%
1
   7.7%
No Response (NR)/ Progressive Disease (PD)
8
  44.4%
9
  69.2%
Time Frame For this study, adverse events were collected until the subject is off study or until the end of study visit at 12 months before subjects were enrolled into separate long term follow up study.
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Target Dose of 1-5x10e8 Target Dose of 1-5x10e7
Hide Arm/Group Description

Arm 1: Target dose of 1-5x10e8 CART-19 cells (calculated as range of 10-50% transduced cells in 1 x10e9 total cells)

CART-19: CART-19 cells (autologous T cells expressing CD19 chimeric antigen receptors expressing tandem TCR zeta and 4-1BB costimulatory domains)

Note: For this group, subjects from stage 1 (15) and stage 2 (12) are combined to have total 27 subjects. In stage 2, higher dose arm (arm 1) was chosen based on the stage 1 analysis performed to expand and enrolled 12 additional subjects.

Arm 2: Target dose of 1-5x10e7 CART-19 cells (calculated as the range of 10-50% transduced cells in 1 x10e8 total cells)

CART-19: CART-19 cells (autologous T cells expressing CD19 chimeric antigen receptors expressing tandem TCR zeta and 4-1BB costimulatory domains)

Note: In stage 1, 15 subject were enrolled in this arm. Since this arm was not chosen for stage 2, no additional subjects were enrolled. total subjects in this arm were 15.

All-Cause Mortality
Target Dose of 1-5x10e8 Target Dose of 1-5x10e7
Affected / at Risk (%) Affected / at Risk (%)
Total   6/27 (22.22%)   6/15 (40.00%) 
Hide Serious Adverse Events
Target Dose of 1-5x10e8 Target Dose of 1-5x10e7
Affected / at Risk (%) Affected / at Risk (%)
Total   23/27 (85.19%)   9/15 (60.00%) 
Blood and lymphatic system disorders     
Febrile Neutropenia  1  4/27 (14.81%)  4/15 (26.67%) 
Gastrointestinal disorders     
Abdominal Pain  1  1/27 (3.70%)  0/15 (0.00%) 
Diarrhoea  1  0/27 (0.00%)  1/15 (6.67%) 
General disorders     
Pyrexia  1  5/27 (18.52%)  5/15 (33.33%) 
Fatigue  1  0/27 (0.00%)  1/15 (6.67%) 
Immune system disorders     
Cytokine Release Syndrome  1  12/27 (44.44%)  6/15 (40.00%) 
Infections and infestations     
Pneumonia  1  1/27 (3.70%)  1/15 (6.67%) 
Sinusitis  1  1/27 (3.70%)  1/15 (6.67%) 
Upper respiratory tract infection  1  1/27 (3.70%)  1/15 (6.67%) 
Streptococcal sepsis  1  1/27 (3.70%)  0/15 (0.00%) 
Sepsis  1  1/27 (3.70%)  0/15 (0.00%) 
Otitis externa  1  1/27 (3.70%)  0/15 (0.00%) 
Influenza  1  0/27 (0.00%)  2/15 (13.33%) 
Post procedural infection  1  0/27 (0.00%)  1/15 (6.67%) 
Metabolism and nutrition disorders     
Hypercalcaemia  1  1/27 (3.70%)  0/15 (0.00%) 
Musculoskeletal and connective tissue disorders     
Myalgia  1  1/27 (3.70%)  0/15 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Lung adenocarcinoma  1  1/27 (3.70%)  0/15 (0.00%) 
Neuroendocrine carcinoma  1  1/27 (3.70%)  0/15 (0.00%) 
Nervous system disorders     
Encephalopathy  1  1/27 (3.70%)  0/15 (0.00%) 
Syncope  1  0/27 (0.00%)  1/15 (6.67%) 
Renal and urinary disorders     
Acute kideny injury  1  1/27 (3.70%)  1/15 (6.67%) 
Respiratory, thoracic and mediastinal disorders     
Hypoxia  1  1/27 (3.70%)  0/15 (0.00%) 
Pleural effusion  1  1/27 (3.70%)  0/15 (0.00%) 
Pneumonitis  1  1/27 (3.70%)  0/15 (0.00%) 
Pulmonary oedema  1  1/27 (3.70%)  0/15 (0.00%) 
1
Term from vocabulary, CTCAE (4.0)
Indicates events were collected by systematic assessment
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Target Dose of 1-5x10e8 Target Dose of 1-5x10e7
Affected / at Risk (%) Affected / at Risk (%)
Total   24/27 (88.89%)   11/15 (73.33%) 
Blood and lymphatic system disorders     
Anaemia  1  12/27 (44.44%)  7/15 (46.67%) 
Febrile neutropenia  1  3/27 (11.11%)  5/15 (33.33%) 
Neutropenia  1  5/27 (18.52%)  4/15 (26.67%) 
Gastrointestinal disorders     
Nausea  1  3/27 (11.11%)  7/15 (46.67%) 
Constipation  1  5/27 (18.52%)  3/15 (20.00%) 
Diarrhoea  1  3/27 (11.11%)  7/15 (46.67%) 
Vomiting  1  2/27 (7.41%)  0/15 (0.00%) 
General disorders     
Fatigue  1  10/27 (37.04%)  6/15 (40.00%) 
Pyrexia  1  4/27 (14.81%)  8/15 (53.33%) 
Chills  1  3/27 (11.11%)  4/15 (26.67%) 
Oedema peripheral  1  2/27 (7.41%)  4/15 (26.67%) 
Immune system disorders     
Cytokine release syndrome  1  12/27 (44.44%)  6/15 (40.00%) 
Infections and infestations     
Post procedural infection  1  0/27 (0.00%)  1/15 (6.67%) 
Clostridium difficile infection  1  2/27 (7.41%)  0/15 (0.00%) 
Upper respiratory tract infection  1  2/27 (7.41%)  0/15 (0.00%) 
Investigations     
White blood cell count decreased  1  8/27 (29.63%)  9/15 (60.00%) 
CD4 lymphocytes decreased  1  10/27 (37.04%)  11/15 (73.33%) 
Lymphocyte count decreased  1  8/27 (29.63%)  4/15 (26.67%) 
Neutrophil count decreased  1  6/27 (22.22%)  6/15 (40.00%) 
Platelet count decreased  1  5/27 (18.52%)  4/15 (26.67%) 
Aspratate aminotransferase increased  1  3/27 (11.11%)  0/15 (0.00%) 
Blood bilirubin increased  1  2/27 (7.41%)  0/15 (0.00%) 
Metabolism and nutrition disorders     
Hypocalcemia  1  8/27 (29.63%)  4/15 (26.67%) 
Hypokalemia  1  5/27 (18.52%)  0/15 (0.00%) 
Hypomagnesaemia  1  4/27 (14.81%)  0/15 (0.00%) 
Hyponatremia  1  4/27 (14.81%)  0/15 (0.00%) 
Hypophosphataemia  1  3/27 (11.11%)  0/15 (0.00%) 
Nervous system disorders     
Headche  1  3/27 (11.11%)  0/15 (0.00%) 
Psychiatric disorders     
Insomnia  1  3/27 (11.11%)  3/15 (20.00%) 
Renal and urinary disorders     
Acute kidney injury  1  2/27 (7.41%)  0/15 (0.00%) 
Respiratory, thoracic and mediastinal disorders     
Cough  1  3/27 (11.11%)  5/15 (33.33%) 
Hypoxia  1  2/27 (7.41%)  1/15 (6.67%) 
Skin and subcutaneous tissue disorders     
Rash  1  2/27 (7.41%)  0/15 (0.00%) 
Vascular disorders     
Hypotension  1  2/27 (7.41%)  4/15 (26.67%) 
1
Term from vocabulary, CTCAE (4.0)
Indicates events were collected by systematic assessment
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Noelle Frey, MD
Organization: Abramson Cancer Center of the University of Pennsylvania
Phone: 215-662-6901
EMail: noelle.frey@uphs.upenn.edu
Layout table for additonal information
Responsible Party: University of Pennsylvania
ClinicalTrials.gov Identifier: NCT01747486    
Other Study ID Numbers: UPCC 03712, 816556
First Submitted: December 10, 2012
First Posted: December 11, 2012
Results First Submitted: December 11, 2018
Results First Posted: February 26, 2019
Last Update Posted: August 30, 2019