Study of CAR-20/19-T Cells in Patients With Relapsed Refractory B Cell

• Sponsor: Medical College of Wisconsin (Other)
• Overall Status: Completed
• CT.gov ID: NCT03019055
• Collaborator: Children's Hospital and Health System Foundation, Wisconsin (Other)
• Enrollment: 26
• Location: 1
• Arms: 4
• Actual Duration (Months): 46.3
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

This is a phase 1/1b, interventional single arm, open label, treatment study designed to evaluate the safety and feasibility of infusion of autologous T cells engineered to contain an anti-cluster of differentiation 19 (CD19) and anti-cluster of differentiation 20 (CD20) single chain variable fragment (scFv) coupled to cluster of differentiation CD3ζ (CD3ζ) and co-stimulatory domain 4-1BB (4-1BB) signaling domains in patients with relapsed and/or refractory CD19 or CD20 positive B cell malignancies

Condition or Disease	Intervention/Treatment	Phase
Lymphoma, Non-Hodgkin; Lymphoma, B-Cell; Chronic Lymphocytic Leukemia; Small Lymphocytic Lymphoma	Biological: CAR-20/19-T cells (1.0 x10^5 CAR-20/19-T cells/kg); Biological: CAR-20/19-T cells (2.5 x10^5 CAR-20/19-T cells/kg); Biological: CAR-20/19-T cells (7.5 x10^5 CAR-20/19-T cells/kg); Biological: CAR-20/19-T cells (2.5 x10^6 CAR-20/19-T cells/kg)	Phase 1

Detailed Description

This is a single center, single arm, open label phase I/1b study to demonstrate the feasibility of manufacturing CAR-T cells expressing tandem receptors against both CD20 and CD19 (CAR-20/19-T) in a completely closed system using the CliniMACS Prodigy device and then determine the safety of this dual targeted CAR in a first-in-human study of patients with relapsed and refractory B cell malignancies. Secondary outcomes will include response rates, and observed toxicities of the treatment, specifically the development of cytokine release syndrome (CRS), an inflammatory storm that has been seen with previous CAR-T therapies.

Study Design

• Study Type: Interventional
• Actual Enrollment: 26 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Intervention Model Description: The study is divided into two phases. Phase 1 and Phase 1b. Phase 1: consists of 2 cohorts; dose escalation and dose expansion. The CAR-T cells were given over 2 days. In the phase 1 portion, there will be a dose escalation cohort to determine the safe CAR-20/19-T cell dose in patients with CLL/SLL and NHL. Once the desired dose has been identified there will be a 6 patient dose expansion phase at the specified dose level. Phase 1b: In the Phase 1b portion of the study, we will test the safety of unfractionated CAR-T cells utilizing the safe dose identified in the phase 1 portion (2.5 x 10^6 cells/kg).The study is divided into two phases. Phase 1 and Phase 1b. Phase 1: consists of 2 cohorts; dose escalation and dose expansion. The CAR-T cells were given over 2 days. In the phase 1 portion, there will be a dose escalation cohort to determine the safe CAR-20/19-T cell dose in patients with CLL/SLL and NHL. Once the desired dose has been identified there will be a 6 patient dose expansion phase at the specified dose level. Phase 1b: In the Phase 1b portion of the study, we will test the safety of unfractionated CAR-T cells utilizing the safe dose identified in the phase 1 portion (2.5 x 10^6 cells/kg).
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase 1/1b Study of Redirected Autologous T Cells Engineered to Contain an Anti CD19 and Anti CD20 scFv Coupled to CD3ζ and 4-1BB Signaling Domains in Patients With Relapsed and/or Refractory CD19 or CD20 Positive B Cell Malignancies
• Actual Study Start Date: Oct 16, 2017
• Actual Primary Completion Date: Oct 1, 2019
• Actual Study Completion Date: Aug 24, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: CAR-20/19-T cells (1.0 x10^5 CAR-20/19-T cells/kg) Dose Escalation Phase: CAR-20/19-T transduced with a lentiviral vector to express an anti CD19 and anti CD20 tandem receptor coupled to CD3ζ and 4-1BB signaling domains will be administered by IV injection. Patients will receive one of four dose levels based the study protocol. Cells will be given over 2 days, 30% of cells infused on Day 0 and 70% of cells infused on Day 1 in the Phase 1 portion and as a single infusion in the Phase 1b portion.	Biological: CAR-20/19-T cells (1.0 x10^5 CAR-20/19-T cells/kg); CAR-20/19-T cells will be administered either fresh or thawed after cryopreservation by IV injection. Phase 1 Dose Level 0: 2.5 x10^5 CAR-20/19-T cells/kg (starting dose level)
Experimental: CAR-20/19-T cells (2.5 x10^5 CAR-20/19-T cells/kg) Dose Escalation Phase: CAR-20/19-T transduced with a lentiviral vector to express an anti CD19 and anti CD20 tandem receptor coupled to CD3ζ and 4-1BB signaling domains will be administered by IV injection. Patients will receive one of four dose levels based the study protocol. Cells will be given over 2 days, 30% of cells infused on Day 0 and 70% of cells infused on Day 1 in the Phase 1 portion and as a single infusion in the Phase 1b portion.	Biological: CAR-20/19-T cells (2.5 x10^5 CAR-20/19-T cells/kg); CAR-20/19-T cells will be administered either fresh or thawed after cryopreservation by IV injection. Phase 1 Dose Level 1: 7.5 x10^5 CAR-20/19-T cells/kg
Experimental: CAR-20/19-T cells (7.5 x10^5 CAR-20/19-T cells/kg) Dose Escalation Phase: CAR-20/19-T transduced with a lentiviral vector to express an anti CD19 and anti CD20 tandem receptor coupled to CD3ζ and 4-1BB signaling domains will be administered by IV injection. Patients will receive one of four dose levels based the study protocol. Cells will be given over 2 days, 30% of cells infused on Day 0 and 70% of cells infused on Day 1 in the Phase 1 portion and as a single infusion in the Phase 1b portion.	Biological: CAR-20/19-T cells (7.5 x10^5 CAR-20/19-T cells/kg); CAR-20/19-T cells will be administered either fresh or thawed after cryopreservation by IV injection. Phase 1 Dose Level 2: 2.5 x10^6 CAR-20/19-T cells/kg (goal cell dose) Phase 1b Expansion Dose Level: 2.5 x 10^6 cells/kg (single infusion)
Experimental: CAR-20/19-T cells (2.5 x10^6 CAR-20/19-T cells/kg) Dose Escalation Phase: CAR-20/19-T transduced with a lentiviral vector to express an anti CD19 and anti CD20 tandem receptor coupled to CD3ζ and 4-1BB signaling domains will be administered by IV injection. Patients will receive one of four dose levels based the study protocol. Cells will be given over 2 days, 30% of cells infused on Day 0 and 70% of cells infused on Day 1 in the Phase 1 portion and as a single infusion in the Phase 1b portion.	Biological: CAR-20/19-T cells (2.5 x10^6 CAR-20/19-T cells/kg); CAR-20/19-T cells will be administered either fresh or thawed after cryopreservation by IV injection.

Outcome Measures

Primary Outcome Measures

1. Number of Adverse Events After CAR 20/19-T Cell Infusion [28 days after infusion]

   This measure is the number of adverse events with grade 3 to 5 severity per Common Terminology Criteria for Adverse Events (ver. 4.03) occurring within the first 28 days following infusion.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria

1. Diagnosis of B-cell non-Hodgkin lymphoma (NHL) or chronic lymphocytic leukemia (CLL) / small lymphocytic leukemia (SLL): Patients must be aged≥18 years with relapsed, refractory disease and no available curative options that meet clinical criteria to initiate treatment.

2. Patients with B-cell NHL or CLL/SLL must have either CD19 or CD20 positive disease on most recent biopsy performed (a repeat biopsy is not mandatory for this study except as noted below). A minimum of 5% CD19 or CD20 positivity by immunohistochemistry or flow cytometry on prior or repeat biopsy is required.

3. Absolute CD3+ T cell count ≥50/mm^3.

4. MRI brain and Lumbar Puncture with cerebral spinal fluid (CSF) analysis by cytology and flow cytometry without evidence of central nervous system (CNS) involvement only in patients with history of CNS involvement.

5. Measurable disease must have been documented within 4 weeks of the time of consent defined as the following by disease specific subtype:

6. B-cell NHL: Active disease defined as nodal lesions greater than 20 mm in the long axis or extranodal lesions >10 mm in long and short axis or bone marrow involvement that is biopsy proven.

7. CLL/SLL: Active disease by either bone marrow, peripheral flow cytometry, or CT and/or positron emission tomography (PET) imaging with nodal disease.

8. Patients should have failed at least two lines of a standard treatment and meet disease specific criteria detailed below:

9. CLL/SLL: measurable disease as defined above that has relapsed after at least one line of chemo-immunotherapy and progressed or intolerant to ibrutinib monotherapy.

10. CD19 or CD20 positive B cell NHL limited to the following histologies: Advanced Stage III or IV Follicular Lymphoma, Diffuse Large B cell Lymphoma and associated subtypes (e.g. aggressive B-cell lymphoma, T-cell/histocyte rich B-cell lymphoma, primary mediastinal B-cell lymphoma, Epstein Barr virus positive diffuse large B-cell lymphoma, transformed lymphoma such as transformed follicular or marginal zone lymphoma, and Richter's transformation) and Mantle cell lymphoma. Specific criteria include:

• Patients must have active, measurable disease after two lines of cytotoxic chemotherapy of which one must be anthracycline containing.

• Must have received Rituximab or another CD20 antibody and at minimum two chemotherapy regimens appropriate for their disease.

• Either failed autologous transplant or ineligible to receive autologous transplant

1. Karnofsky performance score ≥70. See Appendix A for scales.

2. Normal Baseline Neurological Evaluation: Mini-Mental Status Exam Score 24-30.

3. Adequate hepatic function, defined as aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <5 x upper limit of normal (ULN); serum bilirubin and alkaline phosphatase <5 x ULN, or considered not clinically significant as per the clinical PIs discretion (e.g. Gilbert's or indirect hyperbilirubinemia) or felt to be due to underlying disease.

4. Adequate renal function, defined as creatinine clearance>60 ml/min

5. Able to provide written informed consent.

6. Agree to practice birth control during the study.

7. Adequate cardiac function as indicated by New York Heart Association (NYHA) classification I or II AND left ventricular ejection fraction of ≥35% (by echocardiogram or MUGA) and adequate pulmonary function as indicated by room air oxygen saturation of ≥92%.

8. Expected survival >12 weeks.

9. Negative urine or serum pregnancy test in females of child bearing potential at study entry and again within 48 hours' prior lymphodepleting chemotherapy.

10. Patients with prior blinatumomab treatment require repeat biopsy post-blinatumomab treatment that demonstrates CD19 or CD20 positive disease.

11. Meet criteria for regarding fertility and contraception.

12. Central line access will be required for CAR-20/19-T cell infusion.

Exclusion Criteria

1. Positive beta-human chorionic gonadotropin in females of child-bearing potential.

2. Patients with known systemic allergy to bovine or murine products.

3. Known prior positive serology for human anti-mouse antibody (HAMA).

4. Confirmed active human immunodeficiency virus (HIV), Hepatitis B or C infection.

5. History of significant autoimmune disease OR active, uncontrolled autoimmune phenomenon: such as systemic lupus erythematous, Wegner's glomerulonephritis, autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura (AIHA, ITP) requiring steroid therapy defined as >20 mg of prednisone or equivalent daily.

6. Presence of ≥grade 3 non-hematologic toxicities as per CTCAE version 5.0 from any previous treatment unless it is felt to be due to underlying disease.

7. Concurrent use of investigational therapeutic agents or enrollment on another therapeutic clinical trial at any institution. Minimum of ≥4 weeks required from administration of any other investigational agents on other clinical trials prior to enrollment on this CAR-T protocol.

8. Refusal to participate in the long-term follow-up protocol.

9. Patients with active CNS involvement by malignancy on MRI or by lumbar puncture.

1. Patients with prior CNS disease that has been effectively treated will be eligible providing treatment was >4 weeks before enrollment and a remission documented within 8 weeks of planned CAR-T cell infusion by MRI brain and CSF analysis.

1. Previous recipients of allogeneic hematopoietic stem cell transplantation (AHCT) are excluded if they are <100 days' post-transplant, have evidence of active graft-versus-host-disease (GVHD) of any grade, or are currently on immunosuppression.

2. Previous CAR-T cell therapy directed at either CD19 or CD20 within 100 days of planned CAR-20/19-T cell infusion (does not include re-enrollment)

1. Patients with prior CAR-T treatment against CD19 or CD20 must have repeat biopsy confirming a minimum of 5% CD19 or CD20 positivity by immunohistochemistry or flow cytometry.

1. Anti-CD20 antibody treatment within 4 weeks of cell infusion.

2. Anti-CD19 antibody treatment within 4 weeks of cell infusion.

3. Cytotoxic chemotherapy other than lymphodepletion within 14 days of CAR-T cell infusion.

4. Cytotoxic chemotherapy treatment within 14 days or steroid treatment (other than replacement dose steroids) within 7 days prior to apheresis collection for CAR-T cells.

5. Patients post solid organ transplant who develop high grade lymphomas or leukemias.

6. Concurrent active malignancy other than basal or squamous cell carcinomas of the skin.

Special Criteria for regarding Fertility and Contraception

Female subjects of reproductive potential (women who have reached menarche or women who have not been post-menopausal for at least 24 consecutive months, i.e., who have had menses within the preceding 24 months, or have not undergone a sterilization procedure [hysterectomy or bilateral oophorectomy]) must have a negative serum or urine pregnancy test performed as part of eligibility criteria and again within 48 hours of initiation of lymphodepleting chemotherapy.

Due to the high-risk level of this study, while enrolled, all subjects must agree not to participate in a conception process (e.g., active attempt to become pregnant or to impregnate, sperm donation, in vitro fertilization). Additionally, if participating in sexual activity that could lead to pregnancy, the study subject must agree to use reliable and double barrier methods of contraception during the follow-up period of the protocol.

Acceptable birth control includes a combination of two of the following methods:

• Condoms* (male or female) with or without a spermicidal agent.

• Diaphragm or cervical cap with spermicide

• Intrauterine device (IUD)

• Hormonal-based contraception Subjects who are not of reproductive potential (women who are premenarche or have been post-menopausal for at least 24 consecutive months or have undergone hysterectomy tubal ligation, salpingectomy, and/or bilateral oophorectomy or men who have documented azoospermia) are eligible without requiring the use of contraception.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Froedtert Hospital & Medical College of Wisconsin	Milwaukee	Wisconsin	United States	53226

Sponsors and Collaborators

• Medical College of Wisconsin
• Children's Hospital and Health System Foundation, Wisconsin

Investigators

• Principal Investigator: Nirav Shah, MD, Medical College of Wisconsin

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jun 18, 2019
• Informed Consent Form - Jul 9, 2019

More Information

Publications

None provided.

• Responsible Party: Nirav Shah, Associate Professor, Medical College of Wisconsin
• ClinicalTrials.gov Identifier: NCT03019055
• Other Study ID Numbers: PRO00028724
• First Posted: Jan 12, 2017
• Last Update Posted: Jul 14, 2022
• Last Verified: Jun 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Nirav Shah, Associate Professor, Medical College of Wisconsin: CAR-T; Chimeric antigen receptor T-cell therapy; CAR Therapy
• Additional relevant MeSH terms: Lymphoma; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Non-Hodgkin; Lymphoma, B-Cell

Study Results

Participant Flow

Recruitment Details	Of 31 enrolled subjects who signed the informed consent form, 26 met all eligibility criteria.

Arm/Group Title	CAR-20/19-T Cells (1.0 x10^5 CAR-20/19-T Cells/kg)	CAR-20/19-T Cells (2.5 x10^5 CAR-20/19-T Cells/kg)	CAR-20/19-T Cells (7.5 x10^5 CAR-20/19-T Cells/kg)	CAR-20/19-T Cells (2.5 x10^6 CAR-20/19-T Cells/kg)
Arm/Group Description	Dose Escalation Phase: CAR-20/19-T transduced with a lentiviral vector to express an anti CD19 and anti CD20 tandem receptor coupled to CD3ζ and 4-1BB signaling domains will be administered by IV injection. Patients will receive one of four dose levels based the study protocol. Cells will be given over 2 days, 30% of cells infused on Day 0 and 70% of cells infused on Day 1 in the Phase 1 portion and as a single infusion in the Phase 1b portion. CAR-20/19-T cells (1.0 x10^5 CAR-20/19-T cells/kg): CAR-20/19-T cells will be administered either fresh or thawed after cryopreservation by IV injection. Phase 1 Dose Level 0: 2.5 x10^5 CAR-20/19-T cells/kg (starting dose level)	Dose Escalation Phase: CAR-20/19-T transduced with a lentiviral vector to express an anti CD19 and anti CD20 tandem receptor coupled to CD3ζ and 4-1BB signaling domains will be administered by IV injection. Patients will receive one of four dose levels based the study protocol. Cells will be given over 2 days, 30% of cells infused on Day 0 and 70% of cells infused on Day 1 in the Phase 1 portion and as a single infusion in the Phase 1b portion. CAR-20/19-T cells (2.5 x10^5 CAR-20/19-T cells/kg): CAR-20/19-T cells will be administered either fresh or thawed after cryopreservation by IV injection. Phase 1 Dose Level 1: 7.5 x10^5 CAR-20/19-T cells/kg	Dose Escalation Phase: CAR-20/19-T transduced with a lentiviral vector to express an anti CD19 and anti CD20 tandem receptor coupled to CD3ζ and 4-1BB signaling domains will be administered by IV injection. Patients will receive one of four dose levels based the study protocol. Cells will be given over 2 days, 30% of cells infused on Day 0 and 70% of cells infused on Day 1 in the Phase 1 portion and as a single infusion in the Phase 1b portion. CAR-20/19-T cells (7.5 x10^5 CAR-20/19-T cells/kg): CAR-20/19-T cells will be administered either fresh or thawed after cryopreservation by IV injection. Phase 1 Dose Level 2: 2.5 x10^6 CAR-20/19-T cells/kg (goal cell dose) Phase 1b Expansion Dose Level: 2.5 x 10^6 cells/kg (single infusion)	Dose Escalation Phase: CAR-20/19-T transduced with a lentiviral vector to express an anti CD19 and anti CD20 tandem receptor coupled to CD3ζ and 4-1BB signaling domains will be administered by IV injection. Patients will receive one of four dose levels based the study protocol. Cells will be given over 2 days, 30% of cells infused on Day 0 and 70% of cells infused on Day 1 in the Phase 1 portion and as a single infusion in the Phase 1b portion. CAR-20/19-T cells (2.5 x10^6 CAR-20/19-T cells/kg): CAR-20/19-T cells will be administered either fresh or thawed after cryopreservation by IV injection.
Period Title: Overall Study
STARTED	0	3	3	20
COMPLETED	0	3	3	20
NOT COMPLETED	0	0	0	0

Baseline Characteristics

Arm/Group Title	CAR-20/19-T Cells (1.0 x10^5 CAR-20/19-T Cells/kg)	CAR-20/19-T Cells (2.5 x10^5 CAR-20/19-T Cells/kg)	CAR-20/19-T Cells (7.5 x10^5 CAR-20/19-T Cells/kg)	CAR-20/19-T Cells (2.5 x10^6 CAR-20/19-T Cells/kg)	Total
Arm/Group Description	Dose Escalation Phase: CAR-20/19-T transduced with a lentiviral vector to express an anti CD19 and anti CD20 tandem receptor coupled to CD3ζ and 4-1BB signaling domains will be administered by IV injection. Patients will receive one of four dose levels based the study protocol. Cells will be given over 2 days, 30% of cells infused on Day 0 and 70% of cells infused on Day 1 in the Phase 1 portion and as a single infusion in the Phase 1b portion. CAR-20/19-T cells (1.0 x10^5 CAR-20/19-T cells/kg): CAR-20/19-T cells will be administered either fresh or thawed after cryopreservation by IV injection. Phase 1 Dose Level 0: 2.5 x10^5 CAR-20/19-T cells/kg (starting dose level)	Dose Escalation Phase: CAR-20/19-T transduced with a lentiviral vector to express an anti CD19 and anti CD20 tandem receptor coupled to CD3ζ and 4-1BB signaling domains will be administered by IV injection. Patients will receive one of four dose levels based the study protocol. Cells will be given over 2 days, 30% of cells infused on Day 0 and 70% of cells infused on Day 1 in the Phase 1 portion and as a single infusion in the Phase 1b portion. CAR-20/19-T cells (2.5 x10^5 CAR-20/19-T cells/kg): CAR-20/19-T cells will be administered either fresh or thawed after cryopreservation by IV injection. Phase 1 Dose Level 1: 7.5 x10^5 CAR-20/19-T cells/kg	Dose Escalation Phase: CAR-20/19-T transduced with a lentiviral vector to express an anti CD19 and anti CD20 tandem receptor coupled to CD3ζ and 4-1BB signaling domains will be administered by IV injection. Patients will receive one of four dose levels based the study protocol. Cells will be given over 2 days, 30% of cells infused on Day 0 and 70% of cells infused on Day 1 in the Phase 1 portion and as a single infusion in the Phase 1b portion. CAR-20/19-T cells (7.5 x10^5 CAR-20/19-T cells/kg): CAR-20/19-T cells will be administered either fresh or thawed after cryopreservation by IV injection. Phase 1 Dose Level 2: 2.5 x10^6 CAR-20/19-T cells/kg (goal cell dose) Phase 1b Expansion Dose Level: 2.5 x 10^6 cells/kg (single infusion)	Dose Escalation Phase: CAR-20/19-T transduced with a lentiviral vector to express an anti CD19 and anti CD20 tandem receptor coupled to CD3ζ and 4-1BB signaling domains will be administered by IV injection. Patients will receive one of four dose levels based the study protocol. Cells will be given over 2 days, 30% of cells infused on Day 0 and 70% of cells infused on Day 1 in the Phase 1 portion and as a single infusion in the Phase 1b portion. CAR-20/19-T cells (2.5 x10^6 CAR-20/19-T cells/kg): CAR-20/19-T cells will be administered either fresh or thawed after cryopreservation by IV injection.	Total of all reporting groups
Overall Participants	0	3	3	20	26
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	52.33 (2.31)	55.00 (8.19)	55.85 (14.44)	55.35 (12.87)
Sex: Female, Male (Count of Participants)
Female	1 Infinity	0 0%	3 100%	4 20%
Male	2 Infinity	3 100%	17 566.7%	22 110%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 NaN	0 0%	0 0%	0 0%
Not Hispanic or Latino	3 Infinity	3 100%	20 666.7%	26 130%
Unknown or Not Reported	0 NaN	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 NaN	0 0%	1 33.3%	1 5%
Asian	1 Infinity	0 0%	1 33.3%	2 10%
Native Hawaiian or Other Pacific Islander	0 NaN	0 0%	0 0%	0 0%
Black or African American	0 NaN	0 0%	2 66.7%	2 10%
White	2 Infinity	3 100%	16 533.3%	21 105%
More than one race	0 NaN	0 0%	0 0%	0 0%
Unknown or Not Reported	0 NaN	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	3 Infinity	3 100%	20 666.7%	26 130%

Outcome Measures

1. Primary Outcome

Title	Number of Adverse Events After CAR 20/19-T Cell Infusion
Description	This measure is the number of adverse events with grade 3 to 5 severity per Common Terminology Criteria for Adverse Events (ver. 4.03) occurring within the first 28 days following infusion.
Time Frame	28 days after infusion

Outcome Measure Data

Analysis Population Description

Of the eligible subjects, CAR cell product did not reach the required cell concentration for infusion for 4 subjects in the highest dosage level. These subjects were withdrawn by the investigator. Overall, 22 subjects received the investigational product in this study. The initial concentration for the study was 2.5x10^5 cells/kg. No dose limiting toxicities were experienced at this concentration and the reduced dose of 1.0x10^5 cells/kg was not used.

Arm/Group Title	CAR-20/19-T Cells (1.0 x10^5 CAR-20/19-T Cells/kg)	CAR-20/19-T Cells (2.5 x10^5 CAR-20/19-T Cells/kg)	CAR-20/19-T Cells (7.5 x10^5 CAR-20/19-T Cells/kg)	CAR-20/19-T Cells (2.5 x10^6 CAR-20/19-T Cells/kg)
Arm/Group Description	Dose Escalation Phase: CAR-20/19-T transduced with a lentiviral vector to express an anti CD19 and anti CD20 tandem receptor coupled to CD3ζ and 4-1BB signaling domains will be administered by IV injection. Patients will receive one of four dose levels based the study protocol. Cells will be given over 2 days, 30% of cells infused on Day 0 and 70% of cells infused on Day 1 in the Phase 1 portion and as a single infusion in the Phase 1b portion. CAR-20/19-T cells (1.0 x10^5 CAR-20/19-T cells/kg): CAR-20/19-T cells will be administered either fresh or thawed after cryopreservation by IV injection. Phase 1 Dose Level 0: 2.5 x10^5 CAR-20/19-T cells/kg (starting dose level)	Dose Escalation Phase: CAR-20/19-T transduced with a lentiviral vector to express an anti CD19 and anti CD20 tandem receptor coupled to CD3ζ and 4-1BB signaling domains will be administered by IV injection. Patients will receive one of four dose levels based the study protocol. Cells will be given over 2 days, 30% of cells infused on Day 0 and 70% of cells infused on Day 1 in the Phase 1 portion and as a single infusion in the Phase 1b portion. CAR-20/19-T cells (2.5 x10^5 CAR-20/19-T cells/kg): CAR-20/19-T cells will be administered either fresh or thawed after cryopreservation by IV injection. Phase 1 Dose Level 1: 7.5 x10^5 CAR-20/19-T cells/kg	Dose Escalation Phase: CAR-20/19-T transduced with a lentiviral vector to express an anti CD19 and anti CD20 tandem receptor coupled to CD3ζ and 4-1BB signaling domains will be administered by IV injection. Patients will receive one of four dose levels based the study protocol. Cells will be given over 2 days, 30% of cells infused on Day 0 and 70% of cells infused on Day 1 in the Phase 1 portion and as a single infusion in the Phase 1b portion. CAR-20/19-T cells (7.5 x10^5 CAR-20/19-T cells/kg): CAR-20/19-T cells will be administered either fresh or thawed after cryopreservation by IV injection. Phase 1 Dose Level 2: 2.5 x10^6 CAR-20/19-T cells/kg (goal cell dose) Phase 1b Expansion Dose Level: 2.5 x 10^6 cells/kg (single infusion)	Dose Escalation Phase: CAR-20/19-T transduced with a lentiviral vector to express an anti CD19 and anti CD20 tandem receptor coupled to CD3ζ and 4-1BB signaling domains will be administered by IV injection. Patients will receive one of four dose levels based the study protocol. Cells will be given over 2 days, 30% of cells infused on Day 0 and 70% of cells infused on Day 1 in the Phase 1 portion and as a single infusion in the Phase 1b portion. CAR-20/19-T cells (2.5 x10^6 CAR-20/19-T cells/kg): CAR-20/19-T cells will be administered either fresh or thawed after cryopreservation by IV injection.
Measure Participants	0	3	3	16
Number [Serious Adverse Events]	7	4	22

Adverse Events

Time Frame	28 days
Adverse Event Reporting Description	No subjects were enrolled in the 1.0x10^5 cells/kg dosage group.
Arm/Group Title	CAR-20/19-T Cells (1.0 x10^5 CAR-20/19-T Cells/kg)		CAR-20/19-T Cells (2.5 x10^5 CAR-20/19-T Cells/kg)		CAR-20/19-T Cells (7.5 x10^5 CAR-20/19-T Cells/kg)		CAR-20/19-T Cells (2.5 x10^6 CAR-20/19-T Cells/kg)
Arm/Group Description	Dose Escalation Phase: CAR-20/19-T transduced with a lentiviral vector to express an anti CD19 and anti CD20 tandem receptor coupled to CD3ζ and 4-1BB signaling domains will be administered by IV injection. Patients will receive one of four dose levels based the study protocol. Cells will be given over 2 days, 30% of cells infused on Day 0 and 70% of cells infused on Day 1 in the Phase 1 portion and as a single infusion in the Phase 1b portion. CAR-20/19-T cells (1.0 x10^5 CAR-20/19-T cells/kg): CAR-20/19-T cells will be administered either fresh or thawed after cryopreservation by IV injection. Phase 1 Dose Level 0: 2.5 x10^5 CAR-20/19-T cells/kg (starting dose level)		Dose Escalation Phase: CAR-20/19-T transduced with a lentiviral vector to express an anti CD19 and anti CD20 tandem receptor coupled to CD3ζ and 4-1BB signaling domains will be administered by IV injection. Patients will receive one of four dose levels based the study protocol. Cells will be given over 2 days, 30% of cells infused on Day 0 and 70% of cells infused on Day 1 in the Phase 1 portion and as a single infusion in the Phase 1b portion. CAR-20/19-T cells (2.5 x10^5 CAR-20/19-T cells/kg): CAR-20/19-T cells will be administered either fresh or thawed after cryopreservation by IV injection. Phase 1 Dose Level 1: 7.5 x10^5 CAR-20/19-T cells/kg		Dose Escalation Phase: CAR-20/19-T transduced with a lentiviral vector to express an anti CD19 and anti CD20 tandem receptor coupled to CD3ζ and 4-1BB signaling domains will be administered by IV injection. Patients will receive one of four dose levels based the study protocol. Cells will be given over 2 days, 30% of cells infused on Day 0 and 70% of cells infused on Day 1 in the Phase 1 portion and as a single infusion in the Phase 1b portion. CAR-20/19-T cells (7.5 x10^5 CAR-20/19-T cells/kg): CAR-20/19-T cells will be administered either fresh or thawed after cryopreservation by IV injection. Phase 1 Dose Level 2: 2.5 x10^6 CAR-20/19-T cells/kg (goal cell dose) Phase 1b Expansion Dose Level: 2.5 x 10^6 cells/kg (single infusion)		Dose Escalation Phase: CAR-20/19-T transduced with a lentiviral vector to express an anti CD19 and anti CD20 tandem receptor coupled to CD3ζ and 4-1BB signaling domains will be administered by IV injection. Patients will receive one of four dose levels based the study protocol. Cells will be given over 2 days, 30% of cells infused on Day 0 and 70% of cells infused on Day 1 in the Phase 1 portion and as a single infusion in the Phase 1b portion. CAR-20/19-T cells (2.5 x10^6 CAR-20/19-T cells/kg): CAR-20/19-T cells will be administered either fresh or thawed after cryopreservation by IV injection.
All Cause Mortality
	CAR-20/19-T Cells (1.0 x10^5 CAR-20/19-T Cells/kg)		CAR-20/19-T Cells (2.5 x10^5 CAR-20/19-T Cells/kg)		CAR-20/19-T Cells (7.5 x10^5 CAR-20/19-T Cells/kg)		CAR-20/19-T Cells (2.5 x10^6 CAR-20/19-T Cells/kg)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		0/3 (0%)		0/3 (0%)		0/16 (0%)
Serious Adverse Events
	CAR-20/19-T Cells (1.0 x10^5 CAR-20/19-T Cells/kg)		CAR-20/19-T Cells (2.5 x10^5 CAR-20/19-T Cells/kg)		CAR-20/19-T Cells (7.5 x10^5 CAR-20/19-T Cells/kg)		CAR-20/19-T Cells (2.5 x10^6 CAR-20/19-T Cells/kg)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		3/3 (100%)		3/3 (100%)		16/16 (100%)
Blood and lymphatic system disorders
Blood and lymphatic system disorders - Other, specify	0/0 (NaN)	0	1/3 (33.3%)	1	1/3 (33.3%)	1	2/16 (12.5%)	2
Febrile neutropenia	0/0 (NaN)	0	0/3 (0%)	0	0/3 (0%)	0	1/16 (6.3%)	1
Gastrointestinal disorders
Diarrhea	0/0 (NaN)	0	0/3 (0%)	0	0/3 (0%)	0	1/16 (6.3%)	1
General disorders
Fever	0/0 (NaN)	0	0/3 (0%)	0	0/3 (0%)	0	1/16 (6.3%)	1
Multi-organ failure	0/0 (NaN)	0	0/3 (0%)	0	0/3 (0%)	0	1/16 (6.3%)	1
Immune system disorders
Cytokine release syndrome	0/0 (NaN)	0	3/3 (100%)	3	0/3 (0%)	0	2/16 (12.5%)	2
Infections and infestations
Infections and infestations - Other, specify	0/0 (NaN)	0	0/3 (0%)	0	0/3 (0%)	0	1/16 (6.3%)	1
Upper respiratory infection	0/0 (NaN)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/16 (0%)	0
Investigations
Lymphocyte count increased	0/0 (NaN)	0	0/3 (0%)	0	0/3 (0%)	0	1/16 (6.3%)	1
Metabolism and nutrition disorders
Anorexia	0/0 (NaN)	0	0/3 (0%)	0	0/3 (0%)	0	1/16 (6.3%)	2
Dehydration	0/0 (NaN)	0	0/3 (0%)	0	0/3 (0%)	0	1/16 (6.3%)	2
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify	0/0 (NaN)	0	1/3 (33.3%)	1	0/3 (0%)	0	3/16 (18.8%)	3
Nervous system disorders
Nervous system disorders - Other, specify	0/0 (NaN)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/16 (0%)	0
Psychiatric disorders
Psychiatric disorders - Other, specify	0/0 (NaN)	0	1/3 (33.3%)	1	0/3 (0%)	0	2/16 (12.5%)	3
Renal and urinary disorders
Hematuria	0/0 (NaN)	0	0/3 (0%)	0	0/3 (0%)	0	1/16 (6.3%)	3
Respiratory, thoracic and mediastinal disorders
Pleural effusion	0/0 (NaN)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/16 (0%)	0
Pneumonitis	0/0 (NaN)	0	0/3 (0%)	0	1/3 (33.3%)	1	0/16 (0%)	0
Other (Not Including Serious) Adverse Events
	CAR-20/19-T Cells (1.0 x10^5 CAR-20/19-T Cells/kg)		CAR-20/19-T Cells (2.5 x10^5 CAR-20/19-T Cells/kg)		CAR-20/19-T Cells (7.5 x10^5 CAR-20/19-T Cells/kg)		CAR-20/19-T Cells (2.5 x10^6 CAR-20/19-T Cells/kg)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		3/3 (100%)		3/3 (100%)		16/16 (100%)
Blood and lymphatic system disorders
Anemia	0/0 (NaN)	0	3/3 (100%)	13	2/3 (66.7%)	12	14/16 (87.5%)	37
Blood and lymphatic system disorders - Other, specify	0/0 (NaN)	0	0/3 (0%)	0	0/3 (0%)	0	1/16 (6.3%)	1
Disseminated intravascular coagulation	0/0 (NaN)	0	0/3 (0%)	0	1/3 (33.3%)	2	2/16 (12.5%)	2
Febrile neutropenia	0/0 (NaN)	0	0/3 (0%)	0	0/3 (0%)	0	1/16 (6.3%)	1
Leukocytosis	0/0 (NaN)	0	0/3 (0%)	0	0/3 (0%)	0	1/16 (6.3%)	3
Cardiac disorders
Atrial fibrillation	0/0 (NaN)	0	0/3 (0%)	0	0/3 (0%)	0	2/16 (12.5%)	2
Sinus bradycardia	0/0 (NaN)	0	1/3 (33.3%)	1	0/3 (0%)	0	3/16 (18.8%)	3
Sinus tachycardia	0/0 (NaN)	0	0/3 (0%)	0	2/3 (66.7%)	3	10/16 (62.5%)	15
Ear and labyrinth disorders
Ear pain	0/0 (NaN)	0	0/3 (0%)	0	0/3 (0%)	0	1/16 (6.3%)	1
Tinnitus	0/0 (NaN)	0	0/3 (0%)	0	0/3 (0%)	0	1/16 (6.3%)	2
Eye disorders
Blurred vision	0/0 (NaN)	0	0/3 (0%)	0	0/3 (0%)	0	1/16 (6.3%)	1
Dry eye	0/0 (NaN)	0	0/3 (0%)	0	0/3 (0%)	0	1/16 (6.3%)	1
Eye pain	0/0 (NaN)	0	0/3 (0%)	0	0/3 (0%)	0	1/16 (6.3%)	1
Floaters	0/0 (NaN)	0	0/3 (0%)	0	1/3 (33.3%)	2	1/16 (6.3%)	1
Watering eyes	0/0 (NaN)	0	0/3 (0%)	0	0/3 (0%)	0	1/16 (6.3%)	2
Gastrointestinal disorders
Abdominal distension	0/0 (NaN)	0	1/3 (33.3%)	2	0/3 (0%)	0	2/16 (12.5%)	2
Abdominal pain	0/0 (NaN)	0	1/3 (33.3%)	1	0/3 (0%)	0	2/16 (12.5%)	2
Bloating	0/0 (NaN)	0	0/3 (0%)	0	0/3 (0%)	0	2/16 (12.5%)	3
Constipation	0/0 (NaN)	0	0/3 (0%)	0	1/3 (33.3%)	8	6/16 (37.5%)	9
Diarrhea	0/0 (NaN)	0	2/3 (66.7%)	4	0/3 (0%)	0	11/16 (68.8%)	18
Dyspepsia	0/0 (NaN)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/16 (0%)	0
Dysphagia	0/0 (NaN)	0	1/3 (33.3%)	1	0/3 (0%)	0	2/16 (12.5%)	3
Fecal incontinence	0/0 (NaN)	0	0/3 (0%)	0	0/3 (0%)	0	2/16 (12.5%)	2
Gingival pain	0/0 (NaN)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/16 (0%)	0
Nausea	0/0 (NaN)	0	1/3 (33.3%)	2	1/3 (33.3%)	6	11/16 (68.8%)	17
Stomach pain	0/0 (NaN)	0	0/3 (0%)	0	0/3 (0%)	0	3/16 (18.8%)	5
Toothache	0/0 (NaN)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/16 (0%)	0
Vomiting	0/0 (NaN)	0	0/3 (0%)	0	1/3 (33.3%)	4	3/16 (18.8%)	4
Gastroesophageal reflux disease	0/0 (NaN)	0	1/3 (33.3%)	1	0/3 (0%)	0	1/16 (6.3%)	1
General disorders
Chills	0/0 (NaN)	0	0/3 (0%)	0	0/3 (0%)	0	2/16 (12.5%)	2
Facial pain	0/0 (NaN)	0	0/3 (0%)	0	0/3 (0%)	0	1/16 (6.3%)	1
Fatigue	0/0 (NaN)	0	2/3 (66.7%)	3	3/3 (100%)	7	12/16 (75%)	20
Fever	0/0 (NaN)	0	0/3 (0%)	0	0/3 (0%)	0	4/16 (25%)	6
Flu like symptoms	0/0 (NaN)	0	0/3 (0%)	0	0/3 (0%)	0	1/16 (6.3%)	1
Malaise	0/0 (NaN)	0	0/3 (0%)	0	0/3 (0%)	0	1/16 (6.3%)	1
Multi-organ failure	0/0 (NaN)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/16 (0%)	0
Pain	0/0 (NaN)	0	0/3 (0%)	0	0/3 (0%)	0	1/16 (6.3%)	1
Edema limbs	0/0 (NaN)	0	0/3 (0%)	0	0/3 (0%)	0	4/16 (25%)	4
Infusion related reaction	0/0 (NaN)	0	0/3 (0%)	0	0/3 (0%)	0	2/16 (12.5%)	2
Non-cardiac chest pain	0/0 (NaN)	0	0/3 (0%)	0	0/3 (0%)	0	1/16 (6.3%)	2
Infusion site extravasation	0/0 (NaN)	0	0/3 (0%)	0	0/3 (0%)	0	1/16 (6.3%)	1
Immune system disorders
Cytokine release syndrome	0/0 (NaN)	0	1/3 (33.3%)	1	1/3 (33.3%)	4	13/16 (81.3%)	18
Infections and infestations
Infections and infestations - Other, specify	0/0 (NaN)	0	0/3 (0%)	0	1/3 (33.3%)	1	3/16 (18.8%)	4
Sepsis	0/0 (NaN)	0	0/3 (0%)	0	0/3 (0%)	0	1/16 (6.3%)	1
Upper respiratory infection	0/0 (NaN)	0	0/3 (0%)	0	0/3 (0%)	0	1/16 (6.3%)	1
Urinary tract infection	0/0 (NaN)	0	0/3 (0%)	0	0/3 (0%)	0	3/16 (18.8%)	3
Enterocolitis infectious	0/0 (NaN)	0	0/3 (0%)	0	0/3 (0%)	0	1/16 (6.3%)	1
Lung infection	0/0 (NaN)	0	1/3 (33.3%)	2	0/3 (0%)	0	3/16 (18.8%)	3
Injury, poisoning and procedural complications
Fracture	0/0 (NaN)	0	0/3 (0%)	0	0/3 (0%)	0	1/16 (6.3%)	1
Vascular access complication	0/0 (NaN)	0	0/3 (0%)	0	0/3 (0%)	0	3/16 (18.8%)	4
Investigations
Activated partial thromboplastin time prolonged	0/0 (NaN)	0	1/3 (33.3%)	1	1/3 (33.3%)	1	6/16 (37.5%)	7
Alanine aminotransferase increased	0/0 (NaN)	0	2/3 (66.7%)	2	0/3 (0%)	0	7/16 (43.8%)	10
Alkaline phosphatase increased	0/0 (NaN)	0	0/3 (0%)	0	0/3 (0%)	0	6/16 (37.5%)	10
Aspartate aminotransferase increased	0/0 (NaN)	0	1/3 (33.3%)	1	0/3 (0%)	0	9/16 (56.3%)	17
Blood bilirubin increased	0/0 (NaN)	0	1/3 (33.3%)	3	1/3 (33.3%)	2	3/16 (18.8%)	6
Creatinine increased	0/0 (NaN)	0	2/3 (66.7%)	7	0/3 (0%)	0	8/16 (50%)	14
Fibrinogen decreased	0/0 (NaN)	0	0/3 (0%)	0	0/3 (0%)	0	2/16 (12.5%)	2
Lymphocyte count decreased	0/0 (NaN)	0	2/3 (66.7%)	8	3/3 (100%)	15	16/16 (100%)	49
Lymphocyte count increased	0/0 (NaN)	0	1/3 (33.3%)	4	0/3 (0%)	0	1/16 (6.3%)	1
Neutrophil count decreased	0/0 (NaN)	0	3/3 (100%)	12	3/3 (100%)	21	16/16 (100%)	59
Platelet count decreased	0/0 (NaN)	0	2/3 (66.7%)	12	2/3 (66.7%)	11	13/16 (81.3%)	32
Weight loss	0/0 (NaN)	0	0/3 (0%)	0	0/3 (0%)	0	1/16 (6.3%)	1
White blood cell decreased	0/0 (NaN)	0	3/3 (100%)	9	3/3 (100%)	13	16/16 (100%)	68
Metabolism and nutrition disorders
Anorexia	0/0 (NaN)	0	1/3 (33.3%)	1	0/3 (0%)	0	4/16 (25%)	5
Hypercalcemia	0/0 (NaN)	0	2/3 (66.7%)	8	0/3 (0%)	0	2/16 (12.5%)	3
Hyperglycemia	0/0 (NaN)	0	0/3 (0%)	0	1/3 (33.3%)	6	9/16 (56.3%)	14
Hyperkalemia	0/0 (NaN)	0	0/3 (0%)	0	1/3 (33.3%)	2	2/16 (12.5%)	2
Hypermagnesemia	0/0 (NaN)	0	1/3 (33.3%)	1	1/3 (33.3%)	2	1/16 (6.3%)	1
Hypernatremia	0/0 (NaN)	0	1/3 (33.3%)	2	0/3 (0%)	0	3/16 (18.8%)	7
Hypertriglyceridemia	0/0 (NaN)	0	0/3 (0%)	0	0/3 (0%)	0	2/16 (12.5%)	2
Hyperuricemia	0/0 (NaN)	0	0/3 (0%)	0	0/3 (0%)	0	1/16 (6.3%)	3
Hypoalbuminemia	0/0 (NaN)	0	3/3 (100%)	11	1/3 (33.3%)	1	10/16 (62.5%)	27
Hypocalcemia	0/0 (NaN)	0	2/3 (66.7%)	6	1/3 (33.3%)	6	13/16 (81.3%)	27
Hypoglycemia	0/0 (NaN)	0	0/3 (0%)	0	0/3 (0%)	0	1/16 (6.3%)	1
Hypokalemia	0/0 (NaN)	0	2/3 (66.7%)	5	0/3 (0%)	0	7/16 (43.8%)	16
Hypomagnesemia	0/0 (NaN)	0	1/3 (33.3%)	2	0/3 (0%)	0	2/16 (12.5%)	7
Hyponatremia	0/0 (NaN)	0	1/3 (33.3%)	8	1/3 (33.3%)	2	9/16 (56.3%)	21
Hypophosphatemia	0/0 (NaN)	0	1/3 (33.3%)	4	1/3 (33.3%)	2	4/16 (25%)	6
Tumor lysis syndrome	0/0 (NaN)	0	0/3 (0%)	0	1/3 (33.3%)	2	0/16 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia	0/0 (NaN)	0	0/3 (0%)	0	1/3 (33.3%)	1	3/16 (18.8%)	3
Back pain	0/0 (NaN)	0	0/3 (0%)	0	1/3 (33.3%)	2	1/16 (6.3%)	1
Flank pain	0/0 (NaN)	0	1/3 (33.3%)	1	0/3 (0%)	0	2/16 (12.5%)	2
Myalgia	0/0 (NaN)	0	0/3 (0%)	0	0/3 (0%)	0	1/16 (6.3%)	2
Neck pain	0/0 (NaN)	0	0/3 (0%)	0	0/3 (0%)	0	2/16 (12.5%)	2
Pain in extremity	0/0 (NaN)	0	0/3 (0%)	0	0/3 (0%)	0	1/16 (6.3%)	1
Generalized muscle weakness	0/0 (NaN)	0	0/3 (0%)	0	0/3 (0%)	0	2/16 (12.5%)	2
Nervous system disorders
Dizziness	0/0 (NaN)	0	1/3 (33.3%)	1	1/3 (33.3%)	1	6/16 (37.5%)	10
Dysphasia	0/0 (NaN)	0	0/3 (0%)	0	0/3 (0%)	0	1/16 (6.3%)	1
Headache	0/0 (NaN)	0	2/3 (66.7%)	3	1/3 (33.3%)	1	8/16 (50%)	11
Lethargy	0/0 (NaN)	0	0/3 (0%)	0	0/3 (0%)	0	1/16 (6.3%)	1
Movements involuntary	0/0 (NaN)	0	0/3 (0%)	0	0/3 (0%)	0	1/16 (6.3%)	1
Paresthesia	0/0 (NaN)	0	0/3 (0%)	0	1/3 (33.3%)	2	0/16 (0%)	0
Peripheral sensory neuropathy	0/0 (NaN)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/16 (0%)	0
Presyncope	0/0 (NaN)	0	0/3 (0%)	0	0/3 (0%)	0	1/16 (6.3%)	1
Somnolence	0/0 (NaN)	0	0/3 (0%)	0	0/3 (0%)	0	1/16 (6.3%)	1
Syncope	0/0 (NaN)	0	0/3 (0%)	0	0/3 (0%)	0	2/16 (12.5%)	2
Tremor	0/0 (NaN)	0	0/3 (0%)	0	0/3 (0%)	0	1/16 (6.3%)	1
Vasovagal reaction	0/0 (NaN)	0	0/3 (0%)	0	0/3 (0%)	0	1/16 (6.3%)	1
Facial muscle weakness	0/0 (NaN)	0	0/3 (0%)	0	0/3 (0%)	0	1/16 (6.3%)	1
Psychiatric disorders
Agitation	0/0 (NaN)	0	0/3 (0%)	0	1/3 (33.3%)	2	1/16 (6.3%)	1
Anxiety	0/0 (NaN)	0	1/3 (33.3%)	1	0/3 (0%)	0	2/16 (12.5%)	2
Confusion	0/0 (NaN)	0	1/3 (33.3%)	1	0/3 (0%)	0	3/16 (18.8%)	4
Delirium	0/0 (NaN)	0	1/3 (33.3%)	1	0/3 (0%)	0	3/16 (18.8%)	4
Hallucinations	0/0 (NaN)	0	0/3 (0%)	0	0/3 (0%)	0	1/16 (6.3%)	1
Insomnia	0/0 (NaN)	0	0/3 (0%)	0	1/3 (33.3%)	2	0/16 (0%)	0
Psychiatric disorders - Other, specify	0/0 (NaN)	0	1/3 (33.3%)	1	0/3 (0%)	0	4/16 (25%)	5
Renal and urinary disorders
Hematuria	0/0 (NaN)	0	1/3 (33.3%)	1	0/3 (0%)	0	3/16 (18.8%)	4
Proteinuria	0/0 (NaN)	0	0/3 (0%)	0	0/3 (0%)	0	2/16 (12.5%)	2
Urinary frequency	0/0 (NaN)	0	0/3 (0%)	0	0/3 (0%)	0	1/16 (6.3%)	1
Urinary incontinence	0/0 (NaN)	0	0/3 (0%)	0	0/3 (0%)	0	3/16 (18.8%)	3
Urinary retention	0/0 (NaN)	0	0/3 (0%)	0	0/3 (0%)	0	1/16 (6.3%)	1
Urinary tract pain	0/0 (NaN)	0	0/3 (0%)	0	0/3 (0%)	0	1/16 (6.3%)	1
Acute kidney injury	0/0 (NaN)	0	1/3 (33.3%)	1	0/3 (0%)	0	3/16 (18.8%)	3
Reproductive system and breast disorders
Genital edema	0/0 (NaN)	0	0/3 (0%)	0	0/3 (0%)	0	1/16 (6.3%)	1
Respiratory, thoracic and mediastinal disorders
Allergic rhinitis	0/0 (NaN)	0	0/3 (0%)	0	1/3 (33.3%)	1	1/16 (6.3%)	1
Apnea	0/0 (NaN)	0	0/3 (0%)	0	0/3 (0%)	0	1/16 (6.3%)	1
Aspiration	0/0 (NaN)	0	0/3 (0%)	0	0/3 (0%)	0	1/16 (6.3%)	1
Atelectasis	0/0 (NaN)	0	0/3 (0%)	0	0/3 (0%)	0	1/16 (6.3%)	1
Cough	0/0 (NaN)	0	1/3 (33.3%)	2	1/3 (33.3%)	1	5/16 (31.3%)	7
Dyspnea	0/0 (NaN)	0	1/3 (33.3%)	2	0/3 (0%)	0	2/16 (12.5%)	2
Hypoxia	0/0 (NaN)	0	2/3 (66.7%)	3	0/3 (0%)	0	4/16 (25%)	6
Pleural effusion	0/0 (NaN)	0	1/3 (33.3%)	1	1/3 (33.3%)	1	0/16 (0%)	0
Productive cough	0/0 (NaN)	0	0/3 (0%)	0	1/3 (33.3%)	2	1/16 (6.3%)	1
Respiratory failure	0/0 (NaN)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/16 (0%)	0
Respiratory, thoracic and mediastinal disorders - Other, specify	0/0 (NaN)	0	0/3 (0%)	0	0/3 (0%)	0	2/16 (12.5%)	2
Sore throat	0/0 (NaN)	0	0/3 (0%)	0	0/3 (0%)	0	4/16 (25%)	5
Wheezing	0/0 (NaN)	0	0/3 (0%)	0	0/3 (0%)	0	1/16 (6.3%)	1
Skin and subcutaneous tissue disorders
Hyperhidrosis	0/0 (NaN)	0	0/3 (0%)	0	0/3 (0%)	0	2/16 (12.5%)	2
Pruritus	0/0 (NaN)	0	0/3 (0%)	0	0/3 (0%)	0	1/16 (6.3%)	2
Rash maculo-papular	0/0 (NaN)	0	0/3 (0%)	0	1/3 (33.3%)	2	2/16 (12.5%)	2
Skin and subcutaneous tissue disorders - Other, specify	0/0 (NaN)	0	0/3 (0%)	0	0/3 (0%)	0	1/16 (6.3%)	1
Surgical and medical procedures
Surgical and medical procedures - Other, specify	0/0 (NaN)	0	1/3 (33.3%)	1	0/3 (0%)	0	0/16 (0%)	0
Vascular disorders
Hypertension	0/0 (NaN)	0	2/3 (66.7%)	8	3/3 (100%)	9	8/16 (50%)	13
Hypotension	0/0 (NaN)	0	0/3 (0%)	0	2/3 (66.7%)	3	7/16 (43.8%)	15
Thromboembolic event	0/0 (NaN)	0	0/3 (0%)	0	0/3 (0%)	0	1/16 (6.3%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.