A Phase 1/2 Dose Escalation and Cohort Expansion Study of the Safety and Efficacy of Allogeneic CRISPR-Cas9-Engineered T Cells (CTX110) in Subjects With Relapsed or Refractory B-Cell Malignancies (CARBON)
Phase: PHASE1
Conditions: B-cell Malignancy, Non-Hodgkin Lymphoma, B-cell Lymphoma, Adult B Cell ALL
Sponsor: CRISPR Therapeutics AG

Page 1 of 194
CLINICAL STUDY PROTOCOL CRSP-ONC-001
A Phase 1/2 Dose Escalation and Cohort Expansion Study of the Safety and Efficacy of 
Anti-CD19 Allogeneic CRISPR-Cas9–Engineered T Cells (CTX110) in Subjects With 
Relapsed or Refractory B Cell Malignancies
Study Drug: CTX110
Study Phase: 1/2
EudraCT: 2018-003916-38
IND: 18903
Date of Original Protocol: 06 February 2019
Date of Protocol Amendment: 12 September 2022, Amendment 6
Version: 7.0
Sponsor Emergency 
Contact
Medical Monitor
CRISPR Therapeutics 
105 West First Street
Boston, MA 02127
CRISPR Therapeutics AG
Baarerstrasse 14
CH 6300 Zug, Switzerland
Confidentiality Statement
This is a CRISPR Therapeutics document that contains confidential information. It is intended 
solely for the recipient clinical investigator(s) and must not be disclosed to any other party. 
Acceptance of this document constitutes the agreement that no unpublished information 
contained herein will be published or disclosed without prior written approval of CRISPR 
Therapeutics except that this document may be disclosed to appropriate ethics committees 
provided that they agree to keep it confidential. This material may be used only for evaluating 
or conducting clinical trials; any other proposed use requires written consent from CRISPR 
Therapeutics.
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Protocol CRSP-ONC-001
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PROTOCOL SYNOPSIS
Sponsor: CRISPR Therapeutics AG
Protocol Number: CRSP-ONC-001
Name of Investigational Product: CTX110
Phase of Development: 1/2
Protocol Title: A Phase 1/2 Dose Escalation and Cohort Expansion Study of the Safety and 
Efficacy of Anti-CD19 Allogeneic CRISPR-Cas9–Engineered T Cells (CTX110) in Subjects 
With Relapsed or Refractory B Cell Malignancies
Number of Subjects
Phase 1 Part A (dose escalation): Approximately 100
Phase 1 Part B (cohort expansion): Up to 30 
Phase 2: Approximately 97
Investigators: Multicenter
Study Type: Interventional
Investigational Product Description: CTX110 is a CD19-directed chimeric antigen receptor 
(CAR) T cell immunotherapy comprised of allogeneic T cells that are genetically modified 
ex vivo using CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats/ 
CRISPR-associated protein 9) gene editing components (single-guide RNA and Cas9 nuclease). 
The modifications include targeted disruption of the T cell receptor (TCR) alpha constant and 
beta-2 microglobulin (B2M) loci, and the insertion of an anti-CD19 CAR transgene into the 
TRAC locus via an adeno-associated virus expression cassette. The CAR is composed of an anti-
CD19 single-chain variable fragment derived from murine antibody clone FMC63, a previously 
characterized anti-CD19 monoclonal antibody, the CD8 transmembrane domain, a CD28 
costimulatory domain, and a CD3ζ signaling domain.
Study Population: 
Phase 1 (dose escalation and cohort expansion) will be performed in adult subjects with B cell 
malignancies. In Phase 1, subjects will be assigned to independent dose escalation groups based 
on disease histology. Cohorts A, B, and C will enroll adult subjects with select subtypes of 
non-Hodgkin lymphoma (NHL), including diffuse large B cell lymphoma (DLBCL) not otherwise 
specified (NOS), high-grade B cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, 
transformed follicular lymphoma (FL), grade 3b FL, and primary mediastinal B cell lymphoma 
(PMBCL). Cohort D will include adults with relapsed or refractory B cell acute lymphoblastic 
leukemia (ALL). Phase 1 (Dose escalation and cohort expansion) in the B cell ALL study 
population (Cohort D) will be conducted separately from the adult NHL study population 
(Cohorts A, B, and C).
Phase 2 will be performed in adult subjects with select subtypes of NHL.
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Duration of Subject Participation: Subjects will participate in this study for up to 5 years after 
the last CTX110 infusion. After completion of this study, all subjects will be asked to participate 
in a separate long-term follow-up study for an additional 10 years to assess safety and survival.
Study Rationale: CAR T cell therapies are adoptive T cell therapeutics used to treat human 
malignancies. Although CAR T cell therapy has led to tremendous clinical success, including 
durable remission in relapsed/refractory NHL and ALL patients, the approved products are 
autologous and require patient-specific cell collection and manufacturing. Because of this, some 
patients have experienced disease progression or death while awaiting treatment. An allogeneic 
off-the-shelf CAR T cell product could provide benefits such as immediate availability, lack of 
manufacturing failures, and chemotherapy-naïve T cells providing a more consistent product 
relative to autologous CAR T cell therapies. Numerous approaches have been described to create 
allogeneic CAR T cell therapies. With CRISPR-Cas9 editing, disruption of the endogenous TCR 
and major histocompatibility complex (MHC) class I proteins can be achieved. TCR knockout 
should significantly reduce or eliminate the risk of graft vs host disease (GvHD), whereas MHC 
knockout could increase CAR T cell persistence. This first-in-human trial in subjects with 
relapsed or refractory B cell malignancies aims to evaluate the safety as well as efficacy of this 
CRISPR-Cas9–modified allogeneic CAR T cell approach.
Objectives
Phase 1
Primary objective, Part A (dose escalation): To assess the safety of escalating doses of 
CTX110 in combination with various lymphodepletion (LD) agents in subjects with relapsed 
or refractory B cell malignancies to determine the recommended Part B or Phase 2 dose and
cohort
Primary objective, Part B (cohort expansion): To assess the preliminary efficacy of 
CTX110 in subjects with relapsed or refractory B cell malignancies, as measured by objective 
response rate (ORR)
Secondary objectives (dose escalation and cohort expansion): 
x
To further characterize the efficacy, safety, and pharmacokinetics (PK) of CTX110
x
To evaluate the changes over time in patient-reported outcomes (PROs) associated with 
CTX110
Exploratory objectives (dose escalation and cohort expansion): 
 
 
Phase 2
Primary objective: To assess the efficacy of CTX110 in subjects with select NHL subtypes, 
as measured by objective response rate (ORR)
Secondary objectives:
x
To further characterize the efficacy, safety, and pharmacokinetics (PK) of CTX110
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x
To evaluate the changes over time in patient-reported outcomes (PROs) associated with 
CTX110
Exploratory objectives:
Study Design: This is an open-label, multicenter, Phase 1/2 study evaluating the safety and 
efficacy of CTX110 in subjects with relapsed or refractory B cell malignancies. 
Phase 1
Phase 1 of the study will be divided into 2 parts: dose escalation (Part A) followed by cohort 
expansion (Part B). 
During both Part A and Part B, the study will consist of 3 main stages as follows: 
Stage 1: Screening to determine eligibility for treatment (1-2 weeks) 
Stage 2: Treatment (Stage 2A and Stage 2B); see Table S1 below for treatment by cohort 
Stage 3: Follow-up for all cohorts (up to 5 years after the last CTX110 infusion)
Phase 1 Part A (Dose Escalation)
Dose escalation (Part A) will investigate escalating doses of CTX110 and different LD regimens 
using a 3+3 design in approximately 100 subjects in 4 independent cohorts: Cohorts A, B, C, and 
D. These cohorts will allow preliminary evaluation of the safety, efficacy, and PK of CTX110 
when used with different LD regimens, with or without additional CTX110 infusions, and in 
different B cell malignancies (i.e., NHL and adult B cell ALL), and different prior autologous 
CAR T cell therapy exposure, as summarized in Table S1 below. 
After a dose level has been cleared, the sponsor, in consultation with the study safety review 
committee (SRC), may decide to enroll additional subjects at a given dose level. In any dose 
escalation cohort or subcohort, 6 additional subjects (up to 12 total subjects) may receive study 
treatment at or below the highest cleared dose level. Further, with SRC approval, 12 additional 
subjects (24 total) may receive study treatment in any one cohort or subcohort (A, B, C1, C2, D1, 
or D2) at or below the highest cleared dose level to gather additional safety information prior to 
cohort expansion.
For subjects who receive additional infusions of CTX110 based on disease response criteria and 
eligibility, as described in the protocol and in Table S1 below, the dose level for the additional 
CTX110 infusion will be at or below the highest CTX110 dose that has been cleared by the SRC 
and the sponsor with the planned LD regimen. Dose escalation rules and staggering will apply to 
all cohorts.
Table S1: Lymphodepletion Regimen and CTX110 Infusion Schedule (Part A Dose 
Cohorts)
Cohort
Disease Subtype
First Course of Treatment
A
NHL: Adult subjects with 
DLBCL NOS, high-grade B 
cell lymphoma with MYC
Stage 2A
LD chemotherapy: Co-administration of fludarabine 30 mg/m2 + 
cyclophosphamide 500 mg/m2 IV daily for 3 days; both agents 
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and BCL2 and/or BCL6
rearrangements, grade 3b FL, 
transformed FL, or PMBCL
should be started on the same day and administered for 
3 consecutive days and completed at least 48 hours (but no more 
than 7 days) prior to CTX110 infusion.
Stage 2B
x
Initial CTX110 infusion on Day 1 starting at DL1
x
A second infusion of CTX110 on Day 35 (-7 days/+21 days) 
administered with LD chemotherapy for subjects who achieve 
SD or better at Day 28 scan (based on Lugano criteria). 
B*
Same as Cohort A, with 
additional inclusion criteria 
related to prior autologous 
CAR T cell therapy
Stage 2A
LD chemotherapy: Co-administration of fludarabine 30 mg/m2 + 
cyclophosphamide 750 mg/m2 IV daily for 3 days; both agents 
should be started on the same day and administered for 
3 consecutive days and completed at least 48 hours (but no more
than 7 days) prior to CTX110 infusion.
Stage 2B
x
Initial CTX110 infusion on Day 1 starting at DL4
x
A second infusion of CTX110 on Day 35 (-7 days/+21 days) 
with LD chemotherapy (co-administration of fludarabine 
30 mg/m2 + cyclophosphamide 500 mg/m2 IV daily for 
3 days) to subjects who achieve SD or better at Day 28 scan 
(based on Lugano criteria). 
C
(Subcohorts 
C1 and C2)
Same as Cohort A
Stage 2A
LD regimen: Daratumumab + LD chemotherapy
Daratumumab administration: One dose of daratumumab1
16 mg/kg by IV infusion or 1800 mg by SC injection ≥1 day prior 
to starting LD chemotherapy and within 10 days prior to CTX110 
infusion. To facilitate administration, the first 16 mg/kg IV dose 
may be split (to 8 mg/kg) over 2 consecutive days.
LD chemotherapy: Co-administration of fludarabine 30 mg/m2 + 
cyclophosphamide 500 mg/m2 IV daily for 3 days; both agents 
should be started on the same day and administered for 
3 consecutive days and completed at least 48 hours (but no more 
than 7 days) prior to CTX110 infusion.
Stage 2B
Cohort C1
x
Initial CTX110 infusion on Day 1 starting at DL3
x
No second infusion of CTX110 on Day 35 
x
For subjects who achieve SD or better on Day 28, 
2 additional doses of daratumumab (16 mg/kg by IV infusion 
or 1800 mg by SC injection) will be administered at Day 28 
(± 4 days) and Month 2 (± 4 days) visits.
Cohort C2
x
Initial CTX110 infusion on Day 1 starting at or below the DL 
cleared in Cohort C1
x
A second infusion of CTX110 on Day 35 (-7 days/+21 days) 
administered with daratumumab2 and LD chemotherapy to 
subjects who achieve SD or better at Day 28 scan (based on 
Lugano criteria). 
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D
(Subcohorts 
D1 and D2)
Adult B cell ALL
D1: BM involvement with 
≥5% blasts. 
D2: BM <5% blasts and 
MRD-positive (>1 × 10-4
cells detected by flow 
cytometry or PCR or NGS 
including ClonoSEQ or 
positive BCR-ABL transcript 
for Ph+ disease).
Stage 2A
LD chemotherapy: Co-administration of fludarabine 30 mg/m2 + 
cyclophosphamide 500 mg/m2 IV daily for 3 days; both agents 
should be started on the same day and administered for 
3 consecutive days and completed at least 48 hours (but no more 
than 7 days) prior to CTX110 infusion.3
Stage 2B
Cohort D1 (BM involvement with ≥5% blasts)  
x
Initial CTX110 infusion on Day 1 starting at DL2 or DL3
x
A second infusion of CTX110 on Day 35 (-7 days/+21 days) 
with LD chemotherapy if subject has a decrease in BM blast 
count at Day 28 of ≥50% but blast count remains ≥5% or is 
MRD-positive.
Cohort D2 (BM involvement with <5% blasts and MRD-positive)
x
CTX110 infusion on Day 1 starting at or below the DL 
cleared in D1
x
Second infusion of CTX110 on Day 35 for subjects who have 
demonstrated a reduction in detectable MRD and remain 
MRD positive.
ALL: acute lymphoblastic leukemia; BM: bone marrow; CAR: chimeric antigen receptor;  DL: Dose Level; DLBCL: 
diffuse large B cell lymphoma; FL: follicular lymphoma; IV: intravenous(ly); LD: lymphodepleting; MRD: minimal 
residual disease; NGS: next-generation sequencing; NHL: Non-Hodgkin Lymphoma; NOS: not otherwise specified; 
PCR: polymerase chain reaction; PMBCL: primary mediastinal large B cell lymphoma;  SC: subcutaneous; SD: 
stable disease.
Note: Subjects in legacy Cohort F (discontinued in Version 6.0 of the protocol) have been merged with Cohort A. 
Note: Subjects should meet the criteria specified in the protocol prior to both the initiation of LD chemotherapy and 
infusion of CTX110 and should meet criteria specified for second or subsequent infusions prior to receiving any 
additional doses of CTX110. Criteria for LD chemotherapy should be confirmed prior to infusion of daratumumab as 
applicable. The CTX110 infusion on Day 35 (-7 days/+21 days), if applicable, may be administered without LD 
chemotherapy if subject is experiencing significant cytopenias (see protocol for details).
Subjects in all cohorts have the option to receive an additional infusion of CTX110 with LD chemotherapy 
(co-administration of fludarabine 30 mg/m2 + cyclophosphamide 500 mg/m2 IV daily for 3 days) after PD, if subjects 
had response after prior infusion. Additional infusion after PD must be within 18 months of the initial CTX110 
infusion and ≥4 weeks after last infusion.
* Cohort B will enroll subjects only at selected investigative sites, at the sponsor’s discretion.
1 Daratumumab may be administered as an SC injection (1800 mg/30,000 units of hyaluronidase-fihj) or as an IV 
infusion of 16 mg/kg, per local prescribing information.
2 For subjects in Cohort C2 who respond to treatment (i.e., achieve SD or better on Day 28), an additional dose of 
daratumumab will be administered at the Day 28 visit and an additional infusion of CTX110 will be administered on 
Day 35. A second additional daratumumab dose will be administered as part of the LD regimen for Day 35 unless 
within 14 days of the previous Day 28 dose.
3 In Cohort D, additional subjects may be enrolled to explore alternative LD dose regimen in which 
cyclophosphamide may be administered at a dose of 750 mg/m2 IV daily for 3 days, starting at a CTX110 dose level 
at or below the highest dose level that has been cleared with LD dose containing 500 mg/m2 IV daily for 3 days and if 
it has been agreed by the SRC and the sponsor. Additional subjects enrolled will follow dose escalation rules as 
described in the protocol. In that instance, for the second infusion on Day 35 (where applicable), the 
cyclophosphamide dose in LD chemotherapy will be 500 mg/m2.
Cohorts A, B, and C will comprise subjects with NHL, including DLBCL NOS, high-grade B cell 
lymphoma with MYC and BCL2 and/or BCL6 rearrangements, transformed FL, grade 3b FL, and 
PMBCL. Cohort D will consist of subjects with B cell ALL. Enrollment and allocation of subjects 
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to each cohort will be at the sponsor’s discretion. In the dose escalation part of the study, CTX110 
infusion in Cohorts B, C, and D will begin at dose levels specified in Table S1 above after 
assessment and confirmation of safety by the study SRC and sponsor. Subjects with B cell ALL 
will be exclusively assigned to Cohort D in parallel with other cohorts. 
Phase 1 Part B (Cohort Expansion)
Cohort expansion (Part B) will begin with Cohort A to further evaluate the safety and efficacy of 
CTX110 in NHL subjects. The sponsor, in agreement with the SRC and an independent data 
safety monitor board (DSMB), has selected 6 ×108 CAR+ T cells (DL4) as the recommended 
Part B dose for cohort expansion, with an initial CTX110 infusion on Day 1 at DL4 and, for 
subjects who achieve SD or better at Day 28 scan (based on Lugano criteria), a second infusion at 
DL4 on Day 35 (-7 days/+21 days), both administered with LD chemotherapy. Cohort expansion 
(Part B) can be performed for any of the NHL or adult B cell ALL cohorts that have completed 
the dose escalation part and have determined the Part B dose and regimen per the 
protocol-specified criteria.
Initially, up to 30 subjects with NHL will be enrolled in Part B. The first NHL cohort to be 
expanded may be followed by the expansion of other NHL or adult B cell ALL cohorts, as those 
complete the dose escalation part of the study, with agreement from the SRC, independent 
DSMB, and at the sponsor’s discretion. If other cohorts expand, the sample size estimation for the 
first cohort expansion will also apply to the subsequent cohort expansion, thus increasing the total 
number of enrolled subjects in Part B. Where required, regulatory approval will be obtained prior 
to enrolling any subjects from that region into any cohort expansion.
Dose escalation for other cohorts may continue in parallel to cohort expansion or Phase 2 
enrollment. Dose escalation for subjects with adult B cell ALL is anticipated to continue in 
parallel to cohort expansion and Phase 2 enrollment for NHL cohorts.
Phase 2
Following dose escalation of any Phase 1 cohort, the sponsor may begin enrollment in Phase 2 to 
evaluate efficacy and safety of CTX110 in a larger population of subjects. Enrollment to Phase 2 
will be at the sponsor’s discretion, with agreement from the SRC and DSMB.
Phase 2 will begin with subjects with NHL at the recommended Part B dose and regimen for 
Phase 1 Cohort A, to further evaluate the efficacy and safety of CTX110 in subjects with NHL. 
Approximately 97 subjects with NHL will be enrolled. Where required, regulatory approval will 
be obtained prior to enrolling any subjects from that region into Phase 2.
Phase 2 may be conducted in parallel with Phase 1 dose escalation or cohort expansion of other 
cohorts in the study. 
Considerations for Phase 1 and Phase 2
For Phase 1 Part A (dose escalation), subjects must remain within proximity of the investigative 
site (i.e., 1-hour transit time) for 28 days after each CTX110 infusion. For Phase 1 Part B (cohort 
expansion) and Phase 2, subjects must remain within proximity of the investigative site (i.e., 
1-hour transit time) for 28 days after the first CTX110 infusion and at least 14 days for subsequent 
CTX110 infusions, or longer if justified by subject’s clinical status or as required by local 
regulation or site practice. During this acute toxicity monitoring period, subjects will be routinely 
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assessed for adverse events (AEs), including cytokine release syndrome (CRS), neurotoxicity, and 
GvHD. Toxicity management guidelines are provided in the study protocol. During Phase 1 dose 
escalation, all subjects will be hospitalized for the first 7 days following each CTX110 infusion, 
or longer if required by local regulation or site practice.
After the acute toxicity monitoring period, subjects will be subsequently followed for up to 
5 years after the last CTX110 infusion with physical exams, regular laboratory and imaging 
assessments, and AE evaluations. After completion of this study, subjects will be asked to 
participate in a separate long-term follow-up study for an additional 10 years to assess long-term 
safety and survival.
For all cohorts, LD chemotherapy (or the first daratumumab dose for subjects in Phase 1 
Cohort C) will be delayed if any of the following signs or symptoms are present:
x
Significant worsening of clinical status that, according to the investigator, increases the 
potential risk of AEs associated with LD chemotherapy
x
Requirement for supplemental oxygen to maintain a saturation level of >91%
x
New uncontrolled cardiac arrhythmia 
x
Hypotension requiring vasopressor support
x
Active infection: Positive blood cultures for bacteria, fungus, or virus not responding 
to treatment, or negative culture but active infection based on investigator judgment in 
consultation with the medical monitor
x
Grade ≥2 acute neurological toxicity
x
Unresolved infusion reaction due to daratumumab treatment (Phase 1 Cohort C only)
Additional criteria for LD chemotherapy prior to subsequent CTX110 infusions after Day 1 are 
further specified in the protocol.
For all cohorts, each CTX110 infusion will be delayed if any of the following signs or symptoms 
are present:
x
New active uncontrolled infection
x
Worsening of clinical status compared to prior to start of LD chemotherapy that, in the 
opinion of the investigator, places the subject at increased risk of toxicity
x
Grade ≥2 acute neurological toxicity
Additional Day 35 infusion specific criteria are described in the respective section of the protocol.
Dose escalation will be performed using a standard 3+3 design in which 3 to 6 subjects will be 
enrolled at each dose level depending on the occurrence of dose-limiting toxicity (DLT), as 
defined in the protocol. The SRC will review available data when the DLT observation period 
ends for the last subject enrolled in each cohort. The SRC will be responsible for making dose 
escalation decisions based on review of all available safety and PK data. Throughout dose 
escalation, for cases in which a dose had been cleared in a cohort or subcohort (e.g., 
Subcohort D1) and dose escalation is permitted, the sponsor in consultation with the SRC may 
alternatively decide to enroll an additional number of subjects for a total of up to 24 at the current 
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dose level to gather additional safety data. Based on ongoing assessment of benefit and risk, the 
SRC may stop dose escalation before a maximum tolerated dose (MTD) is determined.
Dose Levels and Dose Limiting Toxicities for Phase 1 Part A (Dose Escalation)
The following doses of CTX110, based on the total number of CAR+ T cells, may be evaluated in 
this study. The starting dose for escalation will be selected separately for each cohort and will 
reflect the cumulative safety data across all cohorts for each study population (NHL, adult B cell 
ALL). Whenever escalation begins in a new cohort, the sponsor and SRC will discuss and agree 
on the starting dose level, which will not exceed the highest dose level cleared in Cohort A. There 
will be a dose limit of 
TCR+ cells/kg for all dose levels, which will determine the 
minimum weight for dosing.
Table S2: Dose Escalation of CTX110
Dose Level
Total CAR+ T Cell Dose
−1
1 × 107
1
3 × 107
2
1 × 108
3
3 × 108
3.5*
4.5 × 108
4
6 × 108
5**
9 × 108
CAR: chimeric antigen receptor; DL: Dose Level. 
* DL3.5 is an optional de-escalation dose level.
**Note: The sponsor, with approval of the safety review committee, may explore DL5 (9 × 108 CAR+ T cells) 
in parallel to cohort expansion.
The DLT evaluation period will begin with the initial CTX110 infusion and last for 28 days. 
Subjects who receive a subsequent CTX110 infusion on Day 35 and/or after disease progression, 
or who receive Day 28 and Month 2 doses of daratumumab (Cohort C1) will be monitored for 
frequency and severity of AEs and adverse events of special interest during the immediate 28-day 
period after each additional CTX110 infusion or, for Cohort C1, after additional doses of 
daratumumab in addition to the assessment of safety per the DLT criteria defined in the protocol.
For Cohort A: In Dose Level (DL) 1 (and DL-1, if required), subjects will be treated in a 
staggered manner such that the second and third subjects will only receive CTX110 after the 
previous subject has completed the DLT evaluation period. In subsequent dose levels or for 
additional subjects enrolled at the same dose level, cohorts of up to 3 subjects may be enrolled 
and dosed concurrently.
For Cohorts B, C, and D: The first 2 subjects within each cohort will be treated in a staggered 
manner at the starting dose level and at each subsequent DL, such that the second subject will 
only receive CTX110 after the previous subject has completed the DLT evaluation period. For 
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additional subjects enrolled at the same dose level, cohorts of up to 3 subjects may be enrolled 
and dosed concurrently. 
For Cohort D, the first 2 subjects at each dose level of Subcohort D1 (adult B cell ALL subjects 
with ≥5% blasts) will be treated in a staggered manner such that the second subject will only 
receive CTX110 after the previous subject has completed the DLT evaluation period. In 
Subcohort D2 (adult B cell ALL subjects with <5% blasts and MRD positive), up to 3 subjects 
may be enrolled and dosed concurrently if the dose level has been cleared by the SRC in 
Subcohort D1. The opposite will not be allowed: if 3 subjects in Subcohort D2 are cleared, then 
Subcohort D2 alone will advance to the next dose level.
Subjects must receive CTX110 to be evaluated for DLT. If a subject discontinues the study any 
time prior to the initial CTX110 infusion, the subject will not be evaluated for DLT and a 
replacement subject will be enrolled at the same dose level as the discontinued subject. If a DLT-
evaluable subject has signs or symptoms of a potential DLT, the DLT evaluation period will be 
extended according to the protocol-defined window to allow for improvement or resolution before 
a DLT is declared. 
Toxicities will be graded and documented according to National Cancer Institute Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0, except for CRS (ASTCT 
criteria), neurotoxicity (ICANS criteria and CTCAE v5.0), and GvHD (Mount Sinai Acute GVHD 
International Consortium criteria). 
A DLT will be defined as any of the following events occurring during the DLT evaluation period 
that persists beyond the specified duration (relative to the time of onset):
x
Grade ≥2 GvHD that is steroid-refractory (e.g., progression of disease [PD] after 3 
days of steroid treatment [e.g., 1 mg/kg/day], stable disease [SD] after 7 days, or 
partial response [PR] after 14 days of treatment) 
x
Death during the DLT period (except due to PD)
x
Grade 4 neurotoxicity of any duration that is related or possibly related to CTX110
x
Any CTX110-related grade 3 or 4 toxicity that is clinically significant according to the 
investigator’s judgment and does not improve within 72 hours
The following will NOT be considered as DLTs: 

Grade 3 or 4 CRS that improves to grade ≤2 within 72 hours

Grade 3 neurotoxicity (e.g., encephalopathy, confusion) that improves to grade ≤2 
within 14 days

Grade 3 or 4 fever

Bleeding in the setting of thrombocytopenia (platelet count <50 ×109/L); 
documented bacterial infections or fever in the setting of neutropenia (absolute 
neutrophil count <1000/mm3)

Hypogammaglobulinemia
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
Grade 3 or 4 pulmonary toxicity that resolves to grade ≤2 within 7 days. For 
subjects intubated due to fluid overload from supportive care, this may be extended 
to 14 days.

Grade 3 or 4 liver function studies that improve to grade ≤2 within 14 days

Grade 3 or 4 renal insufficiency that improves to grade ≤2 within 21 days

Grade 3 or 4 thrombocytopenia, neutropenia, anemia, or lymphopenia will be 
assessed retrospectively. After at least 6 subjects are infused, if ≥50% of subjects 
have prolonged cytopenias (i.e., lasting more than 28 days post infusion), dose 
escalation will be suspended pending SRC assessment. For Cohort D: grade ≥3 
cytopenias that were present at the start of LD chemotherapy may not be 
considered a DLT pending SRC review and identification of another etiology.
AEs that have no plausible causal relationship with CTX110 will not be considered DLTs.
Study Oversight
A study SRC consisting of investigators and sponsor representatives will review all available 
safety data and make decisions regarding dose escalation (or de-escalation), additional CTX110 
infusion, LD chemotherapy dose regimen, and daratumumab (Darzalex®, Janssen) dose regimen 
to determine the recommended Phase 1 Part B dose and regimen for cohort expansion or the 
recommended Phase 2 dose and regimen. The SRC may also propose revisions to the DLT 
definitions and dosing schema during dose escalation. The SRC will continue to meet regularly 
during the expansion parts of the trial to discuss toxicity management algorithms and review of 
individual subject cases. 
An independent DSMB consisting of at least 2 physicians and 1 statistician with appropriate 
scientific and medical expertise will review expedited reports of any serious adverse events 
(SAEs), including expedited SAEs, SAEs resulting in death, and aggregate safety data twice a 
year. The DSMB will also review the interim analysis in Phase 2.
Study Eligibility
Inclusion Criteria
For all cohorts, unless otherwise specified.
1. Age ≥18 years (Phase 1 Cohorts A, B, and C and Phase 2), or ≥18 to ≤70 years (Phase 1 
Cohort D)
2. Able to understand and comply with protocol-required study procedures and voluntarily 
sign a written informed consent document
3. Diagnosed with 1 of the following B cell malignancies:
Phase 1 Cohorts A, B, and C (C1 and C2) and Phase 2: Histologically confirmed B cell 
NHLs: DLBCL NOS, high-grade B cell lymphoma with MYC and BCL2 and/or BCL6
rearrangements, transformed FL, grade 3b FL, or PMBCL 
x
Confirmation of tumor histology from local pathology lab (archival tissue from last 
relapse/progression [within 3 months of enrollment] or biopsy during screening [or 
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CTX110 for B Cell Malignancies
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within 28 days prior to CTX110 infusion, if a recent sample was collected as part of 
standard of care])
x
At least 1 measurable lesion that is fluorodeoxyglucose positron emission tomography 
(PET)–positive, as defined by Lugano criteria (Deauville score of 4 or 5 on Lugano 
criteria 5-point scale). Note: Previously irradiated lesions will be considered 
measurable only if progression is documented following completion of radiation 
therapy.
Phase 1 Cohort D: Histologically confirmed B cell ALL
x
Subcohort D1: Bone marrow involvement with ≥5% blasts (see investigational plan in 
the protocol body)
x
Subcohort D2: Bone marrow minimal residual disease (MRD)–positive (defined as 
>1 × 10-4 cells detected by flow cytometry or polymerase chain reaction [PCR] or 
next-generation sequencing [NGS] including ClonoSeq or positive BCR-ABL 
transcript for Ph+ disease) in subjects with bone marrow with ≤5% blasts. Subjects in 
Subcohort D2 may be enrolled with local baseline MRD results pending, as long as 
qualifying results within 3 months of enrollment are available.
4. Refractory or relapsed disease, as evidenced by the following cohort-specific criteria:
Phase 1 Cohorts A, B, and C (NHL) and Phase 2 (NHL): 2 or more prior therapies, 
including an anti-CD20 monoclonal antibody and an anthracycline-containing regimen. 
Subjects who have received
must have recovered from HSCT-related 
toxicities.
x
Refractory disease is defined as subjects with PD on last therapy, or SD following at 
least 2 cycles of therapy.
x
For subjects with transformed FL, subjects must have received at least 1 line of 
chemotherapy for disease after transformation to DLBCL.
x
For Phase 1 Cohort B, subjects must meet the following criteria:

Received prior treatment with an approved autologous CD19-directed CAR T cell 
therapy (e.g., axicabtagene ciloleucel, tisagenlecleucel, lisocabtagene maraleucel) 
≥12 months prior to enrollment

Achieved a CR for ≥4 months duration from prior treatment with autologous 
CD19-directed CAR T cell therapy

No grade ≥ 2 ICANS from prior CAR T cell therapy

No history of grade 4 CRS

No other prior or residual toxicity from prior CAR T cell therapy that, in the 
investigator’s judgement, would place subject at increased risk of toxicity from a 
subsequent CAR T cell therapy

Age <70 years old

No elevated lactate dehydrogenase (LDH) (per institutional normal range)
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Note: Subjects with relapse after autologous CAR T cell therapy <6 months and/or 6 to 
12 months prior to enrollment, those with elevated LDH, and those >70 years old may 
be considered after SRC review of safety and efficacy data from at least 6 subjects in 
Cohort B.
Phase 1 Cohort D (adult B cell ALL):
x
2 or more prior therapies, or
x
Any bone marrow relapse after allogeneic HSCT; or
x
Philadelphia chromosome–positive if subjects are intolerant to or ineligible for 
tyrosine kinase inhibitor (TKI) therapy or have progressed after at least 1 line of TKI 
therapy.
5. Eastern Cooperative Oncology Group performance status 0 or 1
6. Meets criteria to undergo LD chemotherapy (all Phase 1 cohorts and Phase 2), CAR T cell 
infusion (all Phase 1 cohorts and Phase 2), and daratumumab administration (Phase 1 
Cohort C only)
7. Adequate organ function:
x
Renal: Estimated glomerular filtration rate >50 mL/min/1.73 m2
x
Liver: Aspartate transaminase or alanine transaminase <3 × upper limit of normal 
(ULN); total bilirubin <1.5 × ULN (for subjects with Gilbert’s syndrome, total 
bilirubin <2 mg/dL)
x
Cardiac: Hemodynamically stable and left ventricular ejection fraction ≥45% by 
echocardiogram
x
Pulmonary: Oxygen saturation level on room air >91% per pulse oximetry
8. Female subjects of childbearing potential (postmenarcheal with an intact uterus and at 
least 1 ovary, who are less than 1 year postmenopausal) must agree to use acceptable 
method(s) of contraception from enrollment through at least 12 months after the most 
recent CTX110 infusion.
9. Male subjects must agree to use effective acceptable method(s) of contraception as 
specified in the protocol from enrollment through at least 12 months after the most recent 
CTX110 infusion.
Phase 1 Exclusion Criteria
For all cohorts, unless otherwise specified.
1. Treatment with the following therapies as described below:
x
Prior treatment with any gene therapy or genetically modified cell therapy, including 
CAR T cells. Exception: Phase 1 Cohort B will enroll subjects who received prior 
treatment with an approved autologous CD19-directed CAR T cell therapy. 
x
Prior treatment with a CD19-directed therapy (e.g., CD19-directed antibody, bispecific 
T cell engager, or antibody-drug conjugate), unless there is confirmed CD19 
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expression (by immunohistochemistry or flow cytometry) after progression or relapse 
following most recent CD19-directed treatment. The requirement to confirm CD19 
expression is optional in Phase 1 Subcohort D2. Subjects in Phase 1 Cohort B should 
demonstrate confirmed CD19 expression.
2. Prior allogeneic HSCT. Exception: For subjects with B cell ALL (Phase 1 Cohort D), prior 
allogeneic HSCT is permissible if it has been more than 6 months from HSCT at the time 
of enrollment; there is no evidence of acute or chronic GvHD; and the subject has 
recovered from HSCT-related toxicities, has been off immunosuppressive therapies for at 
least 3 months prior to enrollment, and has not received donor lymphocyte infusion for at 
least 2 months prior to enrollment. 
3. Diagnosis of Burkitt’s lymphoma/leukemia
4. Known contraindication to daratumumab (Phase 1 Cohort C only), cyclophosphamide, 
fludarabine, or any of the excipients of CTX110 product 
5. Prior CNS disease
x
For NHL subjects: Detectable malignant cells from cerebrospinal fluid (CSF) or 
magnetic resonance imaging (MRI) indicating brain metastases during screening, or a 
history of central nervous system (CNS) involvement by malignancy (CSF or 
imaging).  
x
For B cell ALL subjects: a prior history of CNS involvement with no evidence of 
current CNS disease during screening and/or those with CNS-2 disease, which is 
defined as the presence of blast cells in CSF containing <5 white blood cells/μL per 
National Comprehensive Cancer Network (NCCN) guidelines V2.2021 (NCCN, 
2021), without neurological symptoms are eligible for the study. The SRC will review 
the first 2 subjects with CNS-2 ALL to allow additional subjects with CNS disease to 
be enrolled.
6. History of a seizure disorder, major cerebrovascular ischemia/hemorrhage, dementia, 
cerebellar disease, or any autoimmune disease with CNS involvement 
7. Unstable angina, clinically significant arrhythmia, or myocardial infarction within 6 
months of enrollment, or grade 3 or higher pericardial effusion at the time of enrollment.
8. Presence of active bacterial, viral, or fungal infection that is uncontrolled, based on 
investigator judgment in consultation with the medical monitor
9. Positive for presence of human immunodeficiency virus (HIV) type 1 or 2, or active 
hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. Subjects with prior history 
of HBV or HCV infection who have documented undetectable viral load (by quantitative 
PCR or nucleic acid testing) are permitted. Infectious disease testing (HIV-1, HIV-2, HCV 
antibody and PCR, HBV surface antigen, HBV surface antibody, HBV core antibody) 
performed within 45 days of enrollment may be considered for subject eligibility
10. Previous or concurrent malignancy, except basal cell or squamous cell skin carcinoma, 
adequately resected and in situ carcinoma of cervix, or a previous malignancy that was 
completely resected and has been in remission for ≥5 years of enrollment
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11. Radiation therapy within 14 days of enrollment
12. For Phase 1 Cohorts A, B, and C (NHL) and Phase 2 (NHL): Use of systemic antitumor 
therapy or investigational agent within 14 days or 5 half-lives, whichever is longer, of 
CTX110 infusion. Exceptions: 1) prior inhibitory/stimulatory immune checkpoint 
molecule therapy, which is prohibited within 3 half-lives of CTX110 infusion; and 2) 
rituximab, other anti-CD20 monoclonal antibodies, or polatuzumab vedotin use within 
30 days prior to CTX110 infusion is prohibited (however PET/computed tomography scan 
needs to occur at least 2 weeks after last dose).
For Phase 1 Cohort D (adult B cell ALL): Use of systemic antitumor therapy within 7 days 
of CTX110 infusion. Exceptions: 1) immunotherapy agents (i.e., rituximab, inotuzumab) 
must be stopped at least 14 days prior to CTX110 infusion; 2) long-acting chemotherapy 
agents (e.g., pegylated asparaginase, methotrexate >25 mg/m2) must be stopped at least 
14 days prior to CTX110 infusion; 3) Hydroxyurea must be stopped ≥72 hours before 
CTX110 infusion; and 4) investigational agent(s) must be stopped after 5 half-lives have 
passed before CTX110 infusion. Subjects must have recovered to grade 1 CTCAE from 
acute toxicity (except hematological) of all previous therapy prior to CTX110 infusion. 
5) Steroids are permitted until the day before starting LD chemotherapy for maintenance 
or to allow for control of peripheral blood blasts.
13. Primary immunodeficiency disorder or active autoimmune disease requiring steroids 
and/or other immunosuppressive therapy
14. Diagnosis of significant psychiatric disorder or other medical condition that, in the opinion 
of the investigator, could impede the subject’s ability to participate in the study
15. Women who are pregnant or breastfeeding
16. Life expectancy of less than 6 weeks
17. For Phase 1 Subcohort D2 only: Exclusion of isolated extramedullary disease (defined as 
any subject with ≤5% blasts in the bone marrow and confirmation of the presence of 
clonal blasts in any tissue other than the medullary compartments)
Statistical Methods
Sample Size
The sample size in Phase 1 Part A (dose escalation) of the study will be approximately 100, i.e., 
approximately 70 subjects with NHL and approximately 30 subjects with B cell ALL, depending 
on the number of dose levels and cohorts evaluated, and the occurrence of DLTs.
In Phase 1 Part B (cohort expansion), the sample size will be up to 30 subjects.
To test for efficacy, group sequential design with error-spending function will be employed. One 
interim analysis for futility and efficacy will be performed at an information level of 0.5
(proportion of total subjects), and boundaries based on error-spending function will be used for 
the interim analysis. 
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Endpoints
Primary Endpoints
x
Phase 1 Part A (dose escalation) for all cohorts: The incidence of AEs, defined as 
DLTs for each of the cohorts (A, B, C, and D)
x
Phase 1 Part B (cohort expansion) and Phase 2: The objective response rate (CR + 
PR) per the Lugano Response Criteria for Malignant Lymphoma, as determined by 
independent central review 
Secondary Endpoints (Phase 1 Dose Escalation and Cohort Expansion and Phase 2)
Efficacy
x
Duration of response/remission (central read/assessment)
x
Duration of clinical benefit (central read/assessment)
x
Treatment-failure–free survival
x
Progression-free survival 
x
Overall survival
x
For adult B cell ALL (Phase 1 Cohort D): ORR (CR + complete remission with 
incomplete blood count recovery [CRi])
Safety
x
Frequency and severity of AEs and clinically significant laboratory abnormalities
Pharmacokinetic
x
Levels of CTX110 in blood over time
Patient-reported Outcomes
x
Change over time in PROs 
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TABLE OF CONTENTS
CLINICAL STUDY PROTOCOL CRSP-ONC-001.......................................................................1
PROTOCOL SYNOPSIS ................................................................................................................2
LIST OF ABBREVIATIONS........................................................................................................25
STUDY SCHEMA PHASE 1........................................................................................................29
STUDY SCHEMA PHASE 2........................................................................................................31
1.
INTRODUCTION ......................................................................................................32
1.1.
CD19+ B Cell Malignancies .......................................................................................32
1.2.
Non-Hodgkin Lymphoma...........................................................................................32
1.2.1.
Diffuse Large B Cell Lymphoma ...............................................................................32
1.2.2.
Follicular Lymphoma Grade 3b and Transformed Follicular Lymphoma .................33
1.2.3.
High Grade Lymphoma ..............................................................................................34
1.2.4.
Primary Mediastinal Large B Cell Lymphoma ..........................................................34
1.3.
Adult Acute Lymphoblastic Leukemia.......................................................................35
1.4.
CAR T Cell Therapy...................................................................................................37
1.5.
Clinical Experience With CAR T Cell Therapy.........................................................37
1.5.1.
Autologous CAR T Cells............................................................................................37
1.5.2.
Allogeneic CAR T Cells.............................................................................................39
1.6.
CRISPR Technology ..................................................................................................42
1.7.
CTX110 ......................................................................................................................44
1.8.
Study Rationale...........................................................................................................46
2.
STUDY OBJECTIVES ..............................................................................................47
3.
SUBJECT ELIGIBILITY...........................................................................................49
3.1.
Inclusion Criteria ........................................................................................................49
3.2.
Exclusion Criteria.......................................................................................................51
4.
STUDY DESIGN .......................................................................................................54
4.1.
Phase 1 Investigational Plan .......................................................................................54
4.1.1.
Phase 1 Study Design .................................................................................................58
4.1.2.
Phase 1 Study Subjects ...............................................................................................58
4.1.3.
Phase 1 Study Duration ..............................................................................................59
4.1.4.
Phase 1 Part A Dose Escalation..................................................................................59
4.1.4.1.
CTX110 Dose Rationale: Part A ................................................................................61
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4.1.4.2.
DLT Definitions..........................................................................................................62
4.1.4.3.
Rationale for DLT Definitions....................................................................................63
4.1.5.
Phase 1 Part B Cohort Expansion and Recommended Dose......................................64
4.2.
Phase 2 Investigational Plan .......................................................................................65
4.2.1.
Phase 2 Study Design .................................................................................................65
4.2.2.
Phase 2 Study Subjects ...............................................................................................66
4.2.3.
Phase 2 Study Duration ..............................................................................................66
4.2.4.
Phase 2 Dose Rationale ..............................................................................................66
5.
STUDY TREATMENT..............................................................................................67
5.1.
Daratumumab Administration in Phase 1...................................................................67
5.1.1.
Daratumumab Infusion Reactions ..............................................................................67
5.1.2.
Additional Considerations ..........................................................................................68
5.1.3.
Daratumumab Dose Rationale....................................................................................68
5.2.
Lymphodepleting Chemotherapy ...............................................................................70
5.2.1.
Lymphodepleting Chemotherapy Dose Rationale......................................................72
5.3.
Administration of CTX110.........................................................................................72
5.3.1.
Additional CTX110 Infusion(s)..................................................................................73
5.3.1.1.
Rationale for CTX110 Additional Infusions ..............................................................73
5.3.1.2.
Administration Schedule for Subsequent Infusions of CTX110 ................................74
5.3.1.3.
Criteria for Day 35 CTX110 Infusions Within the First Course of Treatment ..........75
5.3.1.4.
Second Course of Treatment After Progressive Disease for All Cohorts ..................77
5.3.2.
CTX110 Postinfusion Monitoring..............................................................................78
5.3.3.
Investigational Product Accountability ......................................................................79
5.4.
Prior and Concomitant Medications ...........................................................................79
5.4.1.
Allowed Medications..................................................................................................79
5.4.2.
Prohibited Medications...............................................................................................79
6.
TOXICITY MANAGEMENT....................................................................................80
6.1.
General Guidance .......................................................................................................80
6.2.
Toxicity-Specific Guidance........................................................................................81
6.2.1.
Infusion Reactions ......................................................................................................81
6.2.2.
Febrile Reaction and Infection Prophylaxis ...............................................................81
6.2.3.
Tumor Lysis Syndrome ..............................................................................................81
6.2.4.
Cytokine Release Syndrome.......................................................................................81
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6.2.5.
Neurotoxicity..............................................................................................................84
6.2.5.1.
ICANS ........................................................................................................................85
6.2.5.2.
Viral Encephalitis .......................................................................................................86
6.2.6.
B Cell Aplasia.............................................................................................................88
6.2.7.
Hemophagocytic Lymphohistiocytosis ......................................................................88
6.2.8.
Cytopenias ..................................................................................................................90
6.2.9.
Graft vs Host Disease .................................................................................................90
6.2.10.
Hypotension and Renal Insufficiency.........................................................................92
6.2.11.
Special Consideration During COVID-19 Pandemic.................................................92
7.
STUDY PROCEDURES............................................................................................94
7.1.
Subject Screening, Enrollment, and Withdrawal......................................................107
7.1.1.
Subject Screening and Enrollment............................................................................107
7.1.2.
Subject Identification................................................................................................107
7.1.3.
Assignment of Subjects to Treatment Cohorts .........................................................107
7.1.4.
Replacement of Subjects...........................................................................................108
7.1.5.
Subject Withdrawal or Removal...............................................................................108
7.2.
Study Assessments....................................................................................................108
7.2.1.
Informed Consent .....................................................................................................109
7.2.2.
Medical History ........................................................................................................109
7.2.3.
Physical Exam ..........................................................................................................109
7.2.4.
Vital Signs, Including Height and Weight................................................................109
7.2.5.
Pregnancy Test..........................................................................................................109
7.2.6.
ECOG Performance Status .......................................................................................110
7.2.7.
Echocardiogram........................................................................................................110
7.2.8.
Electrocardiogram.....................................................................................................110
7.2.9.
NHL Tumor Pathology.............................................................................................110
7.2.10.
Brain MRI.................................................................................................................111
7.2.11.
Lumbar Puncture ......................................................................................................111
7.2.12.
Immune Effector Cell–associated Encephalopathy (ICE) Assessment....................111
7.2.13.
Patient-reported Outcomes .......................................................................................111
7.2.14.
Hospitalizations and Health Care Resource Utilization ...........................................112
7.2.15.
PET/CT and Radiologic Disease Response Assessments for NHL..........................112
7.2.15.1.
Imaging of Extramedullary Disease in B cell ALL..................................................113
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7.2.16.
Bone Marrow Biopsy and Aspirate for NHL ...........................................................113
7.2.17.
Optional Tumor Biopsy for NHL .............................................................................113
7.2.18.
Bone Marrow Biopsy and Aspirate for B Cell ALL.................................................114
7.2.19.
Laboratory Tests .......................................................................................................114
7.3.1.
CTX110 Pharmacokinetic Analysis .........................................................................115
7.3.4.
Daratumumab Pharmacokinetic Analysis (Phase 1 Cohort C).................................116
8.
SAFETY, ADVERSE EVENTS, AND STUDY OVERSIGHT..............................117
8.1.
Adverse Events .........................................................................................................117
8.2.
Serious Adverse Event..............................................................................................118
8.3.
Adverse Events of Special Interest...........................................................................119
8.4.
Adverse Event Severity ............................................................................................119
8.5.
Adverse Event Causality...........................................................................................120
8.6.
Outcome....................................................................................................................120
8.7.
Adverse Event Collection Period..............................................................................121
8.8.
Adverse Event Reporting..........................................................................................121
8.9.
Pregnancy .................................................................................................................122
8.10.
Disease Progression..................................................................................................122
8.11.
Reporting Deaths ......................................................................................................123
8.12.
Study Oversight ........................................................................................................123
8.12.1.
Safety Review Committee ........................................................................................123
8.12.2.
Independent Data Safety Monitoring Board.............................................................123
9.
STOPPING RULES AND STUDY TERMINATION.............................................124
9.1.
Stopping Rules..........................................................................................................124
9.2.
Stopping Rules for Individual Subjects ....................................................................125
9.3.
End of Study Definition............................................................................................125
9.4.
Study Termination ....................................................................................................125
9.5.
Long-Term Follow-up Study....................................................................................125
10.
STATISTICAL ANALYSES ...................................................................................126
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10.1.
Study Objectives and Hypotheses ............................................................................126
10.2.
Study Endpoints........................................................................................................126
10.2.1.
Primary Endpoints ....................................................................................................126
10.2.2.
Secondary Efficacy Endpoints (Phase 1 and Phase 2)..............................................126
10.2.3.
Secondary Safety Endpoints (Phase 1 and Phase 2).................................................127
10.2.4.
Pharmacokinetics (Phase 1 and Phase 2)..................................................................127
10.2.5.
Secondary Patient-reported Outcome Endpoint (Phase 1 and Phase 2) ...................127
10.3.
Analysis Sets.............................................................................................................128
10.4.
Sample Size ..............................................................................................................128
10.5.
Interim Analyses.......................................................................................................129
10.5.1.
Efficacy Interim Analysis.........................................................................................129
10.5.2.
Safety Interim Analyses............................................................................................129
10.6.
Planned Method of Analyses....................................................................................129
10.6.1.
Efficacy Analysis......................................................................................................130
10.6.2.
Safety Analysis .........................................................................................................130
10.6.3.
Pharmacokinetic and Pharmacodynamic Analyses ..................................................130
10.6.5.
Patient-reported Outcomes .......................................................................................131
11.
DATA MANAGEMENT .........................................................................................132
11.1.
Data Recording and eCRF Processing......................................................................132
12.
ADMINISTRATIVE ................................................................................................133
12.1.
Institutional Review Board/Ethics Committee.........................................................133
12.2.
Study Conduct ..........................................................................................................133
12.3.
Subject Privacy.........................................................................................................133
12.4.
Written Informed Consent........................................................................................133
12.5.
Delegation of Investigator Responsibilities..............................................................134
12.6.
Study Files ................................................................................................................134
12.7.
Retention of Study Documents.................................................................................134
12.8.
Protocol Compliance ................................................................................................134
12.9.
Monitoring Functions and Responsibility ................................................................135
12.10.
Quality Control and Quality Assurance....................................................................135
12.11.
Disclosure of Data ....................................................................................................136
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12.12.
Confidentiality and Publication ................................................................................136
12.13.
Clinical Study Report ...............................................................................................137
13.
REFERENCES .........................................................................................................138
14.
APPENDICES ..........................................................................................................150
14.1.
Appendix A: Lugano Response Evaluation Criteria in Lymphoma.........................150
14.2.
Appendix B: Eastern Cooperative Oncology Group Performance Status 
Scale..........................................................................................................................153
14.3.
Appendix C: Contraception Requirements...............................................................154
14.4.
Appendix D: Postinfusion Hospitalization...............................................................156
14.5.
Appendix E: National Cancer Institute Common Terminology Criteria for 
Adverse Events Version 5.0 .....................................................................................157
14.6.
Appendix F: B Cell Acute Lymphoblastic Leukemia Response Evaluation............158
14.7.
Appendix G: Protocol History and Summary of Changes to Protocol 
CRSPONC001..........................................................................................................160
14.7.1.
Summary of Changes to the Current Protocol Version 7.0, Amendment 6 
(Global or Rest of World).........................................................................................160
14.7.2.
Summary of Changes to Protocol Version 6.0, Amendment 5 (Global or Rest 
of World) ..................................................................................................................168
14.7.3.
Summary of Changes to Protocol Version 5.0, Amendment 4 (Global or Rest 
of World) ..................................................................................................................177
14.7.4.
Summary of Changes to Protocol CRSP-ONC-001 V4.0, Amendment 3 
(Global or Rest of the World)...................................................................................188
14.7.5.
Protocol History........................................................................................................192
14.8.
Appendix H: Signature Pages...................................................................................193
LIST OF FIGURES
Figure 1:
Schematic of the CRISPR-Cas9 Complex..................................................................43
Figure 2:
CRISPR-Cas9–Mediated Genome Editing Strategies................................................43
Figure 3:
Schematic of CTX110 Production..............................................................................45
Figure 4:
Estimated Daratumumab Plasma Concentration After a Single Dose or 
3 Consecutive Intravenous Doses...............................................................................69
LIST OF TABLES
Table 1:
CAR T Cell Clinical Trial Results in ALL.................................................................36
Table 2:
Overview of Key Allogeneic CAR T Programs by Other Sponsors ..........................40
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Table 3:
Lymphodepletion Regimen and CTX110 Infusion Schedule (Part A Dose 
Cohorts) ......................................................................................................................56
Table 4:
Dose Escalation of CTX110 .......................................................................................59
Table 5:
CAR+ T Cell Doses.....................................................................................................61
Table 6:
Frequency of Severe AEs Reported With Tisagenlecleucel and Axicabtagene 
Ciloleucel in Subjects With NHL...............................................................................63
Table 7:
Grading of CRS According to ASTCT Consensus Criteria .......................................82
Table 8:
CRS Management Guidance.......................................................................................83
Table 9:
ICANS Grading ..........................................................................................................85
Table 10:
ICE Assessment..........................................................................................................86
Table 11:
ICANS Management Guidance ..................................................................................86
Table 12:
Differentiating Between ICANS and HHV-6 Encephalitis After CAR T Cell 
Therapy.......................................................................................................................87
Table 13:
Criteria for Diagnosis of HLH....................................................................................89
Table 14:
Criteria for Grading Acute GvHD ..............................................................................91
Table 15:
Acute GvHD Management .........................................................................................92
Table 16:
Phase 1 Schedule of Assessments (Screening to Month 24) ......................................95
Table 17:
Phase 2 Schedule of Assessments (Screening to Month 24) ....................................100
Table 18:
Phase 1 and Phase 2 Schedule of Assessments (Months 30-60) ..............................105
Table 19:
Local Laboratory Tests.............................................................................................114
Table 20:
Adverse Event Severity ............................................................................................119
Table 21:
Adverse Event Collection by Study Time Period.....................................................121
Table 22:
Summary of Futility and Efficacy Boundaries in the Group Sequential 
Design to Test Efficacy in the NHL during Phase 2 ................................................129
Table 23:
Lugano Classification Assessment Components......................................................150
Table 24:
Lugano Criteria for Response Assessment...............................................................151
Table 25:
B Cell ALL Disease Response .................................................................................158
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LIST OF ABBREVIATIONS
Abbreviation
Term
AAV
adeno-associated virus
ADL
Activities of Daily Living
AE
adverse event
AESI
adverse event of special interest
ALL
acute lymphoblastic leukemia
ALT
alanine aminotransferase
ANC
absolute neutrophil count
AST
aspartate aminotransferase
ASTCT
American Society for Transplantation and Cellular Therapy
E2M/B2M
beta-2 microglobulin 
BiPAP
bilevel positive airway pressure
BM
Bone marrow
CAR
chimeric antigen receptor
CARTOX
CAR T cell-therapy-associated TOXicity 
Cas9
CRISPR-associated protein 9
CBC
complete blood count
CFR
Code of Federal Regulations
CI
confidence interval
CIHHV-6
chromosomally integrated human herpesvirus 6
CLL
chronic lymphocytic leukemia
CMV
cytomegalovirus
CNS
central nervous system
CPAP
continuous positive airway pressure
CR
complete response or complete remission
CRF
case report form
CRi
complete remission with incomplete blood count recovery
CRISPR
clustered regularly interspaced short palindromic repeats
CRP
C-reactive protein
crRNA
crispr RNA
CRS
cytokine release syndrome
CSF
cerebrospinal fluid
CT
computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
DES
DLT evaluable set
DL
dose level
DLBCL
diffuse large B cell lymphoma
DLT
dose-limiting toxicity
DOCB 
duration of clinical benefit
DOR
duration of response
DSB
double-stranded break
DSMB
data safety monitoring board
EC
ethics committee
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Abbreviation
Term
EC90
90% effective concentration
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EEG
electroencephalogram
EFS
event-free survival
EQ-5D-5L
EuroQoL Group 5-Dimension 
FACIT
Functional Assessment of Chronic Illness Therapy
FACT/-G/-Lym/Leu
Functional Assessment of Cancer Therapy/-general/-subscale for lymphoma/leukemia
FAS
full analysis set
FDG or F18 FDG
fluorodeoxyglucose or fluorodeoxyglucose F18
FL
follicular lymphoma
G-CSF
granulocyte colony-stimulating factor
GCP
Good Clinical Practice
GI
gastrointestinal
GM-CSF
granulocyte-macrophage colony-stimulating factor
GTD
greatest traverse diameter
GvHD
graft vs host disease
HBV
hepatitis B virus
HCV
hepatitis C virus
HDR
homology-directed repair
HHV-6
human herpesvirus 6
HIV
human immunodeficiency virus
HLA
human leukocyte antigen
HLH
hemophagocytic lymphohistiocytosis
HSCT
hematopoietic stem cell transplant
HSV
herpes simplex virus
ICANS
immune effector cell–associated neurotoxicity syndrome
ICE
immune effector cell–associated encephalopathy
ICF
informed consent form
ICH
International Conference on Harmonisation
ICP
intracranial pressure
Ig
immunoglobulin
IL
interleukin
IPI
International Prognostic Index
IRB
institutional review board
IV
intravenous(ly)
KO
knockout
LBCL
large B cell lymphoma
LD
lymphodepleting
LP
lumbar puncture
MAGIC
Mount Sinai Acute GVHD International Consortium
MCL
mantle cell lymphoma
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Abbreviation
Term
MedDRA
Medical Dictionary for Regulatory Activities
MHC
major histocompatibility complex
MM
multiple myeloma
MRD
minimal residual disease
MRI
magnetic resonance imaging
mRNA
messenger ribonucleic acid
MSKCC
Memorial Sloan Kettering Cancer Center
MTD
maximum tolerated dose
NCCN
National Comprehensive Cancer Network
NGS
next-generation sequencing
NHEJ
nonhomologous end-joining
NHL
Non-Hodgkin lymphoma
NK
natural killer
NOS
not otherwise specified
NR
not reached
ORR
objective response rate
OS
overall survival
PAM
protospacer-adjacent motif
PBMC
peripheral blood mononuclear cell
PCR
polymerase chain reaction
PD
progressive disease/progression of disease
PET
positron emission tomography
PFS
progression-free survival
Ph+
Philadelphia chromosome-positive
PK
pharmacokinetic(s)
PMBCL
primary mediastinal large B cell lymphoma
PO
per os (orally)
PPD
product of the perpendicular diameters
PR
partial response
PRO
patient-reported outcome
R-CHOP
chemoimmunotherapy consisting of rituximab, cyclophosphamide, doxorubicin, 
vincristine, and prednisone
R/R
relapsed or refractory
SAE
serious adverse event
SAS
safety analysis set
SC
subcutaneous
scFv
single-chain variable fragment
SD
stable disease
SF-36
Short Form Survey Instrument
SGOT
serum glutamic oxaloacetic transaminase
SGPT
serum glutamic pyruvic transaminase
sgRNA
single-guide RNA
SPD
sum of product diameters
SRC
safety review committee
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Abbreviation
Term
TAA
tumor-associated antigen
TBNK
T-, B-, natural killer (cells)
TCR
T cell receptor
TEAE
treatment-emergent adverse event
TFFS
treatment-failure–free survival
TKI
tyrosine kinase inhibitor
TLS
tumor lysis syndrome
TRAC
T cell receptor alpha constant
tracrRNA
trans-activating crRNA
ULN
upper limit of normal
VAS
visual analogue scale
VZV
varicella zoster virus
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STUDY SCHEMA PHASE 1
Phase 1 Cohorts A, B, and D: Day 1 and Day 35 CTX110 Infusions Within the First Course of Treatment
ALL: acute lymphoblastic leukemia; BM: bone marrow; D: day; DLBCL: diffuse large B cell lymphoma; DLT: dose-limiting toxicity; FL: follicular lymphoma; IV: 
intravenously; LD: lymphodepleting; M: month; MRD: minimal residual disease; NHL: non-Hodgkin lymphoma; NOS: not otherwise specified; SD: stable disease.
Cohorts A and B will enroll subjects with NHL subtypes: DLBCL NOS, high-grade B cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, grade 3b 
FL, transformed FL, or primary mediastinal large B cell lymphoma. Cohort D (Subcohorts D1 and D2) will enroll subjects with B cell ALL.
For Cohorts A and D, LD chemotherapy comprises co-administration of fludarabine 30 mg/m2 and cyclophosphamide 500 mg/m2 IV daily for 3 days. For Cohort B, 
LD chemotherapy comprises co-administration of fludarabine 30 mg/m2 and cyclophosphamide 750 mg/m2 IV daily for 3 days.
* Subjects in Cohorts A, B, and D who achieve a clinical response on Day 28 (SD or better for NHL subjects and a decrease in BM blast count of ≥50% but blast 
count remains >5% or MRD positivity for adult B cell ALL subjects) will receive a second infusion of CTX110 on Day 35 (-7 days/+21 days) with LD 
chemotherapy (or without LD chemotherapy if the subject is experiencing significant cytopenia) if they meet the protocol-specified criteria (Section 5.3.1). 
For Cohort B, LD chemotherapy prior to the second infusion will be co-administration of fludarabine 30 mg/m2 and cyclophosphamide 500 mg/m2 IV daily for 3 days.
Note: The first course of treatment will comprise the first (Day 1) and the second (Day 35) CTX110 infusions and associated LD regimen, as applicable.
Note: For all cohorts, subjects may receive a second course of treatment with a single CTX110 infusion with LD chemotherapy upon disease progression if a subject 
has had prior clinical response after the first infusion and meets the criteria for an additional infusion (Section 5.3.1.4).
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Phase 1 Cohort C: Day 1 and Day 35 CTX110 Infusions Within the First Course of Treatment
ALL: acute lymphoblastic leukemia; BM: bone marrow; CR: complete response; D: day; Dara: daratumumab; DLBCL: diffuse large B cell lymphoma; DLT: dose-
limiting toxicity; FL: follicular lymphoma; IV: intravenous; LD: lymphodepleting; M: month; MRD: minimal residual disease; NHL: non-Hodgkin lymphoma; NOS: 
not otherwise specified; SC: subcutaneous; SD: stable disease; SRC: safety review committee.
Cohort C (Subcohorts C1 and C2) will enroll subjects with NHL subtypes: DLBCL NOS, high-grade B cell lymphoma with MYC and BCL2 and/or BCL6
rearrangements, grade 3b FL, transformed FL, or primary mediastinal large B cell lymphoma. 
Subjects will receive an IV infusion (16 mg/kg) or SC injection (1800 mg) of daratumumab followed by LD chemotherapy (co-administration of fludarabine 30 
mg/m2 and cyclophosphamide 500 mg/m2 IV daily for 3 days). Daratumumab will be administered at least 1 day prior to starting LD chemotherapy and within 
10 days prior to CTX110 infusion. CTX110 will be administered 48 hours to 7 days after LD chemotherapy. For subjects in Subcohorts C1 who achieve SD or better 
(on Day 28, 2 additional doses of daratumumab (16 mg/kg IV or 1800 mg SC) will be administered at the Day 28 (± 4 days) and Month 2 (± 4 days) visits. Subcohort 
C1 will not receive any additional CTX110 infusion on Day 35 (-7 days/+21 days).
* Subjects in Subcohort C2 who achieve a clinical response on Day 28 (SD or better for NHL subjects and a decrease in BM blast count of ≥50% or MRD positivity 
for adult B cell ALL subjects) will receive a second infusion of CTX110 on Day 35 (-7 days/+21 days) with daratumumab and LD chemotherapy (or without LD 
chemotherapy if the subject is experiencing significant cytopenia) if they meet the protocol-specified criteria (Section 5.3.1). For subjects who are eligible for an 
additional infusion of CTX110 on Day 35, the Day 28 daratumumab administration will be repeated as part of LD regimen unless received within 14 days prior to 
the additional CTX110 infusion.
Note: The first course of treatment will comprise the first (Day 1) and the second (Day 35) CTX110 infusions and associated LD regimen, as applicable.
Note: For all cohorts, subjects may receive a second course of treatment with a single CTX110 infusion with LD chemotherapy after disease progression if a subject 
has had prior objective response within 18 months of the initial CTX110 infusion and ≥4 weeks from the prior CTX110 infusion and meets the criteria for an 
additional infusion (Section 5.3.1.4). The second course of treatment will be administered with standard lymphodepletion (i.e., without daratumumab). 
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STUDY SCHEMA PHASE 2
Phase 2 for Subjects with NHL: Day 1 and Day 35 CTX110 Infusions Within the First Course of Treatment
D: day; DLBCL: diffuse large B cell lymphoma; FL: follicular lymphoma; LD: lymphodepleting; M: month; NHL: non-Hodgkin lymphoma; NOS: not otherwise specified; SD: stable 
disease.
Phase 2 will enroll subjects with NHL subtypes: DLBCL NOS, high-grade B cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, grade 3b FL, transformed FL, or 
primary mediastinal large B cell lymphoma. 
LD chemotherapy comprises co-administration of fludarabine 30 mg/m2 and cyclophosphamide 500 mg/m2 IV daily for 3 days. The dose level for each CTX110 infusion will be 
6 × 108 CAR+ T cells.
* Subjects who achieve a clinical response on Day 28 (SD or better) will receive a second infusion of CTX110 on Day 35 (-7 days/+21 days) with LD chemotherapy 
(or without LD chemotherapy if the subject is experiencing significant cytopenia) if they meet the protocol-specified criteria (Section 5.3.1). 
Note: The first course of treatment will comprise the first (Day 1) and the second (Day 35) CTX110 infusions and associated LD regimen, as applicable.
Note: Subjects may receive a second course of treatment with a single CTX110 infusion with LD chemotherapy upon disease progression if a subject has had prior clinical response 
after the first infusion and meets the criteria for an additional infusion (Section 5.3.1.4).
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1.
INTRODUCTION
This study will evaluate the safety, efficacy, pharmacokinetics (PK), and pharmacodynamic 
effects of CTX110, an allogeneic chimeric antigen receptor (CAR) T cell therapy, in subjects 
with relapsed or refractory B cell malignancies.
1.1.
CD19+ B Cell Malignancies
CD19 is a type I transmembrane protein and belongs to the immunoglobulin (Ig) superfamily. 
CD19 is typically found in a complex with CD81 and CD21 and plays important roles in B cell 
activation and signaling. CD19 is expressed in B cells and follicular dendritic cells. Genetic 
perturbations of CD19 in mice or humans lead to defects in B cell function and impaired immune 
responses (Wang et al., 2012). CD19 is expressed by most B cell leukemia and lymphoma cells 
and has been the target of several therapeutic modalities, including antibodies such as 
blinatumomab and CD19-directed CAR T cells. 
1.2.
Non-Hodgkin Lymphoma
Non-Hodgkin lymphomas (NHLs) are a heterogeneous group of malignancies originating from 
B lymphocytes, T lymphocytes, or natural killer (NK) cells. The World Health Organization 
defines more than 60 different subcategories of NHL based on cell type in which the cancer 
originates, histology, mutational profiling, and protein markers on the cellular surface, and NHL 
is the tenth most common malignancy worldwide (Chihara et al., 2015; Trask et al., 2012). NHL 
accounts for 4.3% of all new cancer cases reported and is the eighth leading cause of cancer 
deaths in the United States. In 2018, it is estimated that 74,680 NHL cases will be reported, with 
approximately 19,910 NHL-associated deaths (National Cancer Institute, 2018). In Europe, the 
crude incidence of NHL is approximately 3.8/100,000/year (Tilly et al., 2015). The major 
subtypes of NHL include diffuse large B cell lymphoma (DLBCL), chronic lymphocytic 
leukemia (CLL), and follicular lymphoma (FL; (Teras et al., 2016; Trask et al., 2012). CD19 
expression is ubiquitous on B cell malignancies and maintained among indolent and aggressive 
subtypes of NHL (Scheuermann and Racila, 1995), which has contributed to the increase of 
development of CD19-directed therapies in these indications
1.2.1.
Diffuse Large B Cell Lymphoma
DLBCL is the most common type of NHL, accounting for 30-40% of diagnosed cases (Sehn and 
Gascoyne, 2015). Approximately 30-50% achieve cure with first-line chemoimmunotherapy 
consisting of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP; 
(Coiffier et al., 2010; Maurer et al., 2016). However, approximately 20% are refractory to 
R-CHOP and 30% relapse following complete response (CR) (Maurer et al., 2016).
In patients who relapse after R-CHOP, the best long-term clinical outcomes are achieved through 
 hematopoietic stem cell transplant (HSCT). For patients who are healthy enough to 
undergo this procedure and have chemosensitive disease, commonly used induction 
chemotherapy consists of either R-ICE (rituximab, ifosfamide, carboplatin, and etoposide) or 
R-DHAP (rituximab, dexamethasone, cytarabine, and cisplatin). In a large randomized trial of 
R-ICE vs R-DHAP in transplant-eligible subjects with DLBCL (the CORAL study), 63% of 
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subjects achieved an objective response to either regimen, with a 26% CR rate (Gisselbrecht et 
al., 2010). For patients who are not eligible for
treatment options are limited 
and focused on palliation (Friedberg, 2011; Maurer et al., 2016; Raut and Chakrabarti, 2014).
For patients with progressive disease (PD) after 2 or more lines of therapy, prognosis continues 
to be poor, with an estimated median survival of 3 months for patients who relapse following 
(Friedberg, 2011). In those cases, allogeneic HSCT is an option but only for 
the limited number of patients who qualify based on performance status and presence of 
chemosensitive disease (Raut and Chakrabarti, 2014; Sarkozy et al., 2015).
The poor outcomes in the relapsed/refractory population were further highlighted in the recent 
SCHOLAR study, which retrospectively analyzed survival and response rates in more than 
600 subjects with relapsed/refractory DLBCL, transformed FL, and primary mediastinal large 
B cell lymphoma (PMBCL). The outcomes demonstrated an overall response rate of 26% (CR 
rate of 7%) and median overall survival of 6.3 months, further emphasizing the need for curative 
treatment options in this setting (Crump et al., 2017). Although the advent of cellular 
immunotherapy and autologous CAR T cells has presented potential options to 
relapsed/refractory patients with DLBCL, the duration of follow-up has been short. Furthermore, 
there have been challenges surrounding manufacturing of autologous cellular products, the 
duration of manufacturing, and the need for bridging chemotherapy, all of which may be 
addressed by an allogeneic off-the-shelf CAR T cell product.
1.2.2.
Follicular Lymphoma Grade 3b and Transformed Follicular Lymphoma
FL is a heterogeneous disease, usually indolent, and accounts for about 20% of reported NHL. 
The course is characterized by initial response to therapies followed by relapse and, at times, 
transformation to a more aggressive form of lymphoma. It is generally considered incurable at 
more advanced stages, although the 10-year survival rate is 71% for subjects with early-stage 
disease and 0 to 1 risk factors based on Follicular Lymphoma International Prognostic Index 
score (Solal-Céligny et al., 2004). FL is divided into grades 1-3 based on histologic assessment 
and proportion of centrocytes to centroblasts, and grade 3 is subdivided into 3a and 3b. FL 
grade 3b is now considered a biologically distinct entity, with frequent absence of t(14;18) and 
CD10 expression, and increased p53 and MUM1/IRF4 expression (Horn et al., 2011). A large 
retrospective analysis of more than 500 FL cases further confirmed that the clinical course of FL 
grade 3a is similar to FL grade 1-2, whereas FL grade 3b has a clinical course more similar to 
that of DLBCL (Kahl and Yang, 2016; Wahlin et al., 2012). Because of this, FL grade 3b is 
typically managed similarly to DLBCL (Kahl and Yang, 2016). 
FL patients are at risk of transformation to an aggressive form of lymphoma at a rate of 9-17% at 
5 years and 15-30% at 10 years, as observed in retrospective studies (Bains et al., 2013; Giné et 
al., 2006). Initial treatment approaches are driven by prior therapies; however, even in the 
rituximab era, the outcomes are poor (Fischer et al., 2018). A study comparing outcomes of 
subjects with DLBCL and FL found that FL subjects relapsing with transformed disease had 
worse outcomes compared with subjects diagnosed with de novo DLBCL (median survival 
2 years vs 6 years, P < .0003; (Jack et al., 2013). Treatment options for relapsed/refractory 
transformed FL remain similar to DLBCL, with comparably poor outcomes, further underlining 
the unmet medical need in this patient population.
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1.2.3.
High Grade Lymphoma
High grade B cell lymphoma refers to cases of lymphoma that morphologically resemble 
DLBCL but also contain MYC and BCL2 and/or BCL6 rearrangements (also referred to as 
“double hit” / “triple-hit” lymphoma). This diagnosis was established in the 2016 revision of the 
World Health Organization (WHO) classification of lymphoid neoplasms (Swerdlow et al., 
2016).
Incidence of high grade B cell lymphoma is variable across studies, affecting approximately 8% 
(Green et al., 2012; Scott et al., 2018) of patients with DLBCL morphology. Some studies 
observed a hit rate of up to 21% (Johnson et al., 2012).
MYC, BCL2, and BCL6 rearrangements are diagnosed by fluorescence in situ hybridization or 
cytogenetics. The MYC transcription factor regulates the expression of genes involved in the cell 
cycle, DNA damage repair, metabolism, protein synthesis, and response to stress (Dang et al., 
2006). MYC translocations are predominantly observed in the germinal B cell–like cell-of-origin 
subtype (Scott et al., 2018). B cell lymphoma-2 (BCL2) is an anti-apoptotic protein (Opferman 
and Kothari, 2018). In the event of a translocation of chromosomes 14 and 18, t(14; 18), the 
BCL2 transcription is constitutively dysregulated resulting in a survival advantage for affected 
B cells. Most BCL2 translocations occur in the germinal B cell–like subtype. B cell lymphoma-6 
(BCL6) is expressed in normal mature germinal center B cells and acts as a transcription 
repressor. However, when BCL6 is overexpressed, it acts as a proto-oncogene by suppressing 
p53 and preventing apoptosis in response to DNA damage in germinal center B cells.
High grade B cell lymphoma is associated with an aggressive clinical course with overall inferior 
prognosis compared to DLBCL when treated with standard of care combination of rituximab, 
cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone (R-CHOP) 
chemotherapy (Green et al., 2012; Horn et al., 2013; Hu et al., 2013; Johnson et al., 2012). Until 
the recently available data from an ongoing trial (POLARIX; NCT03274492), intensified 
induction regimens were not shown to improve outcomes in the past 20 years (D¨uhrsen, 2018). 
The median overall survival for high grade lymphoma ranges from 4.5 to 34 months (Akyurek et 
al., 2012; Bertrand et al., 2007; Johnson et al., 2009; Kanungo et al., 2006; Le Gouill et al., 2007; 
Lin and Medeiros, 2007; Niitsu et al., 2009; Oki et al., 2014; Petrich et al., 2014; Ye et al., 
2015). This poor prognosis results from the increased risk of central nervous system 
involvement, the higher risk of chemoimmunotherapy refractoriness, and the increased rate of 
relapse (Kesavan et al., 2019). Additionally, autologous stem cell transplantation in the relapse 
setting is associated with poor outcomes (Cuccuini et al., 2012).
1.2.4.
Primary Mediastinal Large B Cell Lymphoma
Primary mediastinal large B-cell lymphoma (PMBCL) is a rare type of NHL that accounts for 
2% to 3% of NHL cases and tends to impact adolescents and young adults, predominantly white 
women age 30 to 39 (Yu et al., 2021). First-line treatments include dose-adjusted etoposide, 
prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab with or without 
radiotherapy and R-CHOP combined with radiotherapy. For relapsed or refractory patients 
(10%-30% of total cases), the PD-1 inhibitor pembrolizumab was shown in a Phase 2 study to 
have an ORR of 45%, with 13% of 53 subjects achieving CR and 32% partial response (PR). 
PD-1 monoclonal antibodies have been shown to further improve efficacy in patients with 
relapsed/refractory PMBCL when combined with chemotherapy; camrelizumab combined with 
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gemcitabine, vinorelbine, and pegylated liposomal doxorubicin (GVD) produced an ORR of 
74%, with 56% of 27 subjects achieving CR, and nivolumab combined with brentuxiumab 
vedotin produced an ORR of 73%; however, more AEs were observed than from pembrolizumab 
alone. Of note, PD-1/PD-L1 inhibitors combined with platinum-based chemotherapies have also 
shown efficacy.
Autologous CAR T cell therapies have been evaluated in patients with R/R PMBCL and, 
although patient numbers are small, therapeutic potential has been observed in the ZUMA-1 
study (ORR = 82% for 101 total patients, including 8 patients with relapsed/refractory PMBCL) 
and in the transcend NHL-001 study (CR = 53% for the 15 patients with R/R PMBCL).
1.3.
Adult Acute Lymphoblastic Leukemia
Acute lymphoblastic leukemia (ALL) is a hematologic malignancy characterized by highly 
proliferative immature lymphoid cells in the bone marrow and peripheral blood. In adults, ALL 
accounts for approximately 20% of all leukemias, the second most common, with an incidence of 
more than 6,500 cases per year in the United States alone (Terwilliger and Abdul-Hay, 2017). 
ALL carries a poor prognosis in adults, with a 5-year overall survival of 24% in patients ages 40 
to 59 years, and 18% in patients ages 60 to 69 years (Terwilliger and Abdul-Hay, 2017; Wang et 
al., 2015). 
The hallmark of ALL is chromosomal abnormalities and genetic alterations involved in 
differentiation and proliferation of lymphoid precursor cells. The main goal of treatment is to 
allow the patient to achieve complete remission (CR) and to consolidate this remission with 
either a maintenance regimen or an allogeneic stem cell transplant. 
The backbone of front-line therapy remains multi-agent chemotherapy (e.g., vincristine, 
corticosteroids, and an anthracycline) followed by an allogeneic stem cell transplantation for 
eligible candidates. Elderly patients are often unable to tolerate the intense chemotherapy 
regimen and have a particularly poor prognosis. Despite a high rate of response to induction 
chemotherapy, only 30-40% of adult patients with ALL will achieve long-term remission 
(Terwilliger and Abdul-Hay, 2017). 
Adult patients with relapsed or refractory ALL have poor outcomes, with survival of less than 
6 months. Treatment options in the salvage setting are limited to conventional cytotoxic 
chemotherapy, which have minimal activity, necessitating the development of novel therapies to 
improve outcomes (Paul et al., 2019). Advances in the development of novel targeted therapies 
include: antibody-based therapies such as blinatumomab (bispecific T cell–engaging antibody 
engineered to form a synapse between CD3 T cells and CD19 B cells) and inotuzumab 
ozogamicin (CD22-directed antibody linked to calicheamicin that causes double-stranded DNA 
breaks that lead to apoptosis once released in the target cell); and CAR T cell therapy in relapsed 
or refractory ALL, which has made possible an approach to treatment that is more effective and 
patient-centered than the historical standard chemotherapies. These new advances have provided 
patients with additional options in relapsed setting, although outcomes remain poor. For 
example, subjects with relapsed or refractory ALL who received inotuzomab achieved a CR/ 
complete remission with incomplete blood count recovery (CRi) rate of 88%, with a median 
duration of response (DOR) of 5.4 months (Kantarjian et al., 2016). Blinatumomab was 
approved in subjects with relapsed/refractory ALL based on a CR rate of 34% and median DOR 
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of 7.3 months. However, the need for continuous administration of the product and associated 
adverse events have made it challenging (Kantarjian et al., 2017).
CAR T cell therapy is revolutionizing the treatment of both pediatric and adult relapsed or 
refractory B cell ALL (Table 1). The promising efficacy of the CD19-directed CAR T cell 
tisagenlecleucel (Kymriah®, Novartis) in a Phase 1/2a clinical trial led to a Phase 2 clinical trial 
in pediatric and young adult patients with relapsed or refractory ALL, and its US approval in 
2017. Another CD19-directed CAR T cell product, brexucabtagene autoleucel (Tecartus®, Kite 
Pharma), is approved in the US for treatment of relapsed or refractory B cell precursor ALL 
supported by the Phase 1/2 ZUMA-3 clinical trial (Shah et al., 2021; Wierda et al., 2018). 
Table 1:
CAR T Cell Clinical Trial Results in ALL
Clinical Trial
Pedi CART19
ELIANA
MSKCC*
ZUMA-3
Costimulatory 
Domain
4-1BB 
(Maude 2014) 1
4-1BB 
(Maude 2018, Grupp 
2018) 2
CD28
(Park 2018) 3
CD28 
(Shah 2021) 4
Number of subjects 5
30
79
53
55
Treatment setting
R/R pediatric 
and adult ALL
R/R pediatric 
and young adult ALL
R/R adult ALL
R/R adult ALL
CR rate
90%
82%
83%
71% 6,7
Estimated EFS
6 months
12 months
18 months
67%
NR
NR
73%
50%
66%
Median 6.1 months
Median 11.6 months8
Estimated OS
6 months
12 months
18 months
78%
NR
NR
90%
76%
70%
Median 12.9 months
Median 18.2 months 6
ALL: acute lymphocytic leukemia; CAR: chimeric antigen receptor; CR: complete remission; EFS: event-free 
survival; MSKCC: Memorial Sloan Kettering Cancer Center; N/A: not available; NR: not reached; OS: overall 
survival; R/R: relapsed or refractory
1 Maude et al. (2014b); NCT01626495
2 Maude et al. (2018) and (Grupp et al., 2018); NCT02435849
3 Park et al. (2018); NCT01044069
4 Shah et al. (2021); NCT02614066
5 Subjects who received infusion 
6 Subjects treated with 1 × 106 CAR+ T cells/kg
7 CR or CR with incomplete hematological recovery 
8 Reflects relapse-free survival
*The clinical trial was conducted by MSKCC.
Despite toxicities associated with CAR T cell therapies, clinicians remain interested because of 
the responses seen with this approach. To overcome the logistic challenges associated with 
autologous CAR T cell therapies, allogeneic ‘off-the-shelf’ CAR T cells are currently being 
investigated in clinical trials (Paul et al., 2019). The CALM and PALL studies evaluated the 
safety and activity of the allogeneic CD19 CAR T cell (UCART19) in adult and pediatric 
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subjects with relapsed or refractory ALL. A total of 21 subjects received at least 1 UCART19 
infusion of whom 14 (67%) achieved CR or CRi, and 10 of the 14 (71%) subjects achieved 
 
 CRS was observed in 19 subjects (91%; grade 1-2, n = 16; grade >3, n = 3) 
(Benjamin et al., 2020). A Phase 1 clinical trial of another allogeneic CAR T cell therapy, 
PBCAR019, which uses homing endonuclease technology to insert a CD19 CAR, reported 
positive initial data for 9 treated subjects with NHL or B cell ALL (Jacobson et al., 2019); see 
also Section 1.5.2). This further underlines a continued interest in allogeneic CAR T cell 
therapies for B cell ALL indication and the unmet medical need for relapsed/refractory patients. 
1.4.
CAR T Cell Therapy
CAR T cell therapies are a form of adoptive T cell therapeutics used to treat human malignancies 
(Rosenberg and Restifo, 2015). These treatments consist of T cells, usually from the cancer 
patient (autologous), that are genetically manipulated ex vivo to target tumor-associated antigens 
(TAAs) before infusion back into the patient. 
CARs are synthetic modular proteins that consist of an extracellular target-binding domain with 
the ability to recognize and bind to a tumor cell–specific ligand, a hinge region, a transmembrane 
domain that anchors the CAR to the cell membrane, and an intracellular signaling domain that 
results in T cell activation upon antigen binding (Gill and June, 2015). The target-binding 
domain consists of a single-chain variable fragment (scFv) derived from an antibody that confers 
major histocompatibility complex (MHC)–independent TAA specificity and is expressed on the 
surface of the CAR T cell. The scFv is linked to a transmembrane domain that is linked to T cell 
signaling domains. These T cell signaling domains can include a signaling region of the CD3ζ 
molecule or the FcRγ chain as well as a costimulatory domain to provide additional signaling 
output downstream of ligand engagement. The most common costimulatory domains in current 
clinical use are derived from the CD28 or CD137 (4-1BB) proteins (Gill and June, 2015).
1.5.
Clinical Experience With CAR T Cell Therapy
The past decade has seen intensive nonclinical and clinical research in the field of CAR T cell 
therapies for both hematological malignancies and solid tumors. A variety of approaches are 
currently under investigation and include CAR T cells engineered with different (1) extracellular 
target domains, (2) intracellular signaling domains, (3) sources of T cells (e.g., autologous vs 
allogeneic), and (4) genetic approaches to encode and deliver the CAR and induce other 
cell-specific modifications, such as knocking out cell surface proteins. 
1.5.1.
Autologous CAR T Cells
The most advanced clinical data on CAR T cells come from studies involving autologous 
CD19-directed CAR T cells (Maude et al., 2015; Neelapu et al., 2017; Schuster et al., 2019). 
Autologous CAR T cell products are manufactured using a patient’s own T cells, which are 
collected via apheresis. For commercial CD19-directed CAR T cell therapies, isolated T cells are 
either selected or expanded ex vivo, then transduced with a retroviral or lentiviral vector for the 
stable integration and expression of the anti-CD19 CAR construct. The CAR T cell product is 
infused into the patient after lymphodepleting (LD) chemotherapy, approximately 2 to 8 weeks 
after initial T cell collection. During this time, some patients may receive bridging chemotherapy 
to keep their disease in control while awaiting the final product. 
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Following infusion, CAR T cells undergo significant expansion of up to 100,000-fold in vivo, 
with later redistribution and persistence, in some cases reported for years following infusion. 
CAR T cells have also been documented to traffic into the cerebrospinal fluid (CSF), bone 
marrow, and tumor tissue (June et al., 2018). During the expansion of CAR T cells, many 
patients experience some degree of cytokine release syndrome. Patients may also develop 
neurotoxicity, the pathophysiology of which is not fully understood, with suspected contributing 
factors including
CAR T cells trafficking in CSF, and/or increased permeability of the 
blood brain barrier. Some patients may also experience prolonged neutropenia and 
thrombocytopenia, likely due to a combination of underlying disease, CRS with resulting 
immunosuppression, and LD chemotherapy. Other toxicities experienced by patients receiving 
CAR T cell therapies include infections, hemophagocytic lymphohistiocytosis (HLH), and 
hypogammaglobulinemia. The latter is a direct result of persistent CD19-directed CAR T cells, 
which do not differentiate between CD19 expressed on tumor cells and on normal B cells. The 
majority of these toxicities have been successfully managed, and many patients have achieved 
durable complete responses with autologous CAR T cell therapy. Several completed clinical 
trials have led to the US Food and Drug Administration and European Medicines Agency 
approvals of tisagenlecleucel for pediatric and young adult relapsed/refractory ALL and adult 
relapsed/refractory DLBCL; axicabtagene ciloleucel for adult relapsed/refractory DLBCL, 
PMBCL, and transformed FL; and lisocabtagene maraleucel (BREYANZI®, Juno/Bristol-Myers 
Squibb) for adult patients with relapsed or refractory large B cell lymphoma after 2 or more lines 
of systemic therapy, including DLBCL NOS (including DLBCL arising from indolent 
lymphoma), high-grade B cell lymphoma, PMBCL, and FL grade 3B (Maude et al., 2015; 
Neelapu et al., 2017; Schuster et al., 2017). 
In the pivotal trial of axicabtagene ciloleucel involving 101 subjects with relapsed/refractory 
DLBCL, PMBCL, and transformed FL treated with autologous CAR T cells, the ORR was 72%, 
with a DOR of 9.2 months. The CR rate was 51% and the DOR has not yet been established. 
Grade ≥3 CRS and neurologic events occurred in 13% and 28% of subjects, respectively 
(Yescarta USPI, 2017).
The efficacy and safety of tisagenlecleucel was evaluated in an open-label, multicenter, 
single-arm trial in adult subjects with relapsed or refractory DLBCL who had received at least 
2 lines of chemotherapy. Of the 160 subjects enrolled, 106 subjects received tisagenlecleucel, 
including 92 subjects who were followed for at least 3 months or discontinued earlier. Of the 
160 subjects enrolled, 49 did not receive tisagenlecleucel due to manufacturing failures, death, 
adverse events (AEs), or physician’s choice. Among the efficacy evaluable population of 
68 subjects, efficacy was established based on CR rate and DOR. The ORR was 50% and CR 
rate was 32%. With a median follow-up of 9.4 months, median DOR in responders and subjects 
who achieved CR has not been reached. Grade ≥3 CRS and neurotoxicity occurred in 23% and 
18% of subjects, respectively (Kymriah USPI, 2017).
The approval of lisocabtagene maraleucel is based on the efficacy and safety results from the 
Transcend NHL001 pivotal trial results in which 268 subjects with relapsed/refractory large B 
cell lymphoma received the treatment, including subjects with broad range histologies and 
high-risk disease. In the study, 192 subjects were treated at the dose of 50 to 110 × 106 CAR+
viable T cells and evaluated for efficacy. Of these subjects, 73% achieved a response (95% 
confidence interval [CI]: 67%-80%), including 54% who had minimal or no detectable 
lymphoma remaining following treatment (CR; 95% CI: 47%-61%) and 19% who achieved a 
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partial response (PR; 95% CI: 14%-26%). Median DOR was 16.7 months in all responders (95% 
CI: 5.3 – not reached [NR]). For subjects who achieved a CR, median DOR was NR (95% CI: 
16.7 – NR), and for subjects with a best response of PR, median DOR was 1.4 months (95% CI: 
1.1 – 2.2). Of 104 subjects treated with lisocabtagene maraleucel who achieved a best overall 
response of CR, 65% had remission lasting at least 6 months and 62% had remission lasting at 
least 9 months. In the study, 268 subjects treated with lisocabtagene maraleucel were evaluated 
for safety. Any grade CRS occurred in 46% (122/268) of subjects using the Lee grading system 
(Lee et al., 2014). Grade ≥3 CRS and grade ≥3 neurological toxicities occurred in 4% (11/268) 
and 12% (31/268) of subjects, respectively (Breyanzi USPI, 2021).
These approvals have paved the way to further exploration of CAR T cell therapies and have 
identified further areas of improvement in which an off-the-shelf allogeneic product could have 
appropriate use. 
1.5.2.
Allogeneic CAR T Cells
Allogeneic CAR T cells (manufactured from T cells collected from a healthy donor) have also 
been investigated for hematological malignancies such as pediatric ALL. Whereas allogeneic 
HSCT requires a human leukocyte antigen (HLA)–matched donor, gene editing allows the 
removal of cell surface proteins most likely to cause graft vs host or host vs graft reactions. 
Early phase clinical studies are ongoing evaluating UCART19, an allogeneic CAR T cell therapy 
that combines lentiviral-driven expression of a CD19 CAR with the use of TALEN (transcription 
activator-like effector nucleases) gene editing to knock out the T cell receptor (TCR) and CD52 
(ClinicalTrials.gov Identifiers: NCT02808442, NCT02746952; Section 1.3). Study data 
demonstrate the safety of the approach, with only 2 reported cases of mild (grade 1) skin graft vs 
host disease (GvHD) in the 21 subjects treated, although the incidence of CRS and neurotoxicity 
remain similar to autologous CD19-directed CAR T cell therapy. No other GvHD has been 
reported in those studies, and 14 of 21 (67%) evaluable subjects demonstrated a CR or CRi 
(Benjamin et al., 2020). This approach demonstrates the safety of the allogeneic CAR T cells, 
with only 2 reported cases of mild GvHD in the 21 subjects treated. The risk of CRS and 
neurotoxicity remain and will continue to be managed as with autologous CAR T cell treatment. 
In the Phase 1 clinical trial evaluating another allogeneic CAR T therapy PBCAR019 in B cell 
malignancies (Jacobson et al., 2019); Section 1.3), early findings include no serious adverse 
events (SAEs) or dose-limiting toxicities (DLTs), and no cases of GvHD, with 7 of 9 subjects 
(78%) with objective evidence of tumor shrinkage at any time point. In the B cell ALL cohort, 
3 subjects (mean age: 56 years; range: 48-72 years) treated at dose level (DL) 2 achieved Day 
28+ ORR of 33% (1/3 patients at DL 2), comprising 1 CR. These subjects had received a median 
of 4 prior lines of therapy, and all 3 subjects were refractory to their last treatment, with 2 
subjects having poor prognostic indicators at trial entry.
An overview of several external allogeneic CAR T cell programs in clinical development are 
presented in Table 2. Overall, initial data demonstrate the safety of the allogeneic CAR T cell 
approach. Compared to autologous CD19-directed CAR T cell therapy, the incidence of CRS 
and neurotoxicity remains similar and the events are less severe. In addition, studies of 
allogeneic CAR T cells demonstrate efficacy similar to that seen with autologous CAR T cells.
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Table 2:
Overview of Key Allogeneic CAR T Programs by Other Sponsors
Target
AntigenIndication
Engineering/
Modality
Dose Levels
Efficacy
Safety
Program and 
ClinicalTrials.gov
Identifier #
Sponsor
Reference
CD19
R/R 
LBCL or 
FL 
TALEN 
TCR and 
CD52 KO for 
selective LD 
with ALLO-
647
ALLO-501
DL1: 40 × 
106
DL2: 120 × 
106
DL3: 360 × 
106
DL2 
Consol.: 120 
× 106 Day 0 
and D28 for 
≥SD
ALLO-501a
DL1: 40 × 
106
DL2: 120 × 
106
DL2 
Consol.: 120 
× 106 Day 0 
and D28 for 
≥SD
ALLO-
501
ORR 75% 
(24/32), 
CR 50% 
(16/32) 
ALLO-
501a
ORR 56% 
(5/9), CR 
56% (5/9) 
ALLO-501
27% CRS any 
grade, no grade 
≥3 CRS, 2% 
ICANS (any 
grade and grade 
≥3), no GvHD
ALLO-501a
15% CRS any 
grade, 8% CRS 
grade ≥3, no 
ICANS, no 
GvHD
ALLO-501
(ALPHA Study)
NCT03939026
ALLO-501a
(ALPHA2 Study)
NCT04416984
Allogene 
CD19 
Forum1
(Neelapu et 
al., 2020)
BCMA R/R MM TALEN 
TCR and 
CD52 KO for 
selective LD 
with ALLO-
647 
DL1: 40 × 
106
DL2: 160 × 
106
DL3: 320 × 
106
DL4: 480 × 
106
ORR 60% 
(6/10) in 
DL3
45% (14/31) CRS 
grade 1 or 2, no 
ICANS, no 
GvHD
ALLO-715
(UNIVERSAL 
Study)
NCT04093596
Allogene
(ASH 2020 
Abstract)
(Mailankody 
et al., 2020)2
CD19
R/R B-
ALL
TALEN 
TCR and 
CD52 KO for 
selective LD 
with 
alemtuzumab
(CALM)
DL1: 6 × 
106/kg
DL2: 6-8 × 
107/kg
DL3: 1.8-
2.4 × 108/kg
(PALL)
1.1-2.3 × 
106/kg
67% 
subjects 
(14/21) 
achieved 
CR or 
CRi
CRS any grade: 
91% (19/21); 
grade 3 or 4 CRS: 
14% (3/21); grade 
1 or 2 neurotox: 
38% (8/21); acute 
skin GvHD: 10% 
(2/21); grade 4 
prolonged 
cytopenia: 32% 
(6/21) 
UCART19
(CALM Study)
NCT02746952
(PALL Study)
NCT02808442
Cellectis
(Benjamin 
et al., 2020)
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Target
AntigenIndication
Engineering/
Modality
Dose Levels
Efficacy
Safety
Program and 
ClinicalTrials.gov
Identifier #
Sponsor
Reference
CD22
R/R B-
ALL
TALEN 
TCR and 
CD52 KO for 
selective LD 
with ALLO-
647
DL1: 1 × 
105/kg
DL2: 1 × 
106/kg
2 of 3 
subjects 
at DL1 
achieved 
CRi and 
CR 
3/5 subjects with 
CRS, no ICANS, 
no GvHD
UCART22
(BALLI-01 Study)
NCT04150497
Cellectis
(ASH 2020 
Abstract)
(Jain et al., 
2020)
CD19
NHL
B-ALL
Meganuclease 
TCR KO
DL1: 
3 × 105/kg
DL2: 
1 × 106/kg
DL3: 
3 × 106/kg
NHL: 
ORR:11 
subjects 
(100%)
CR: 
8 subjects 
(73%)
NHL: 56% (9/16) 
subjects with 
grade 1 or 2 CRS,
31% (5/16) 
subjects with 
grade 1 or 2 
ICANS, 
no GvHD
B-ALL: 45% 
(5/11) subjects 
with grade 1 or 2 
CRS,
18% (2/11) 
subjects with 
grade 1 or 2 
ICANS, no 
GvHD
PBCAR0191
(Phase 1/2 Study)
NCT03666000
(Precision 
Biosciences, 
2022)3
CD19
R/R
B-NHL
PD-1 KO
DL1: 
40 x 106
DL2: 
80 x `106
CR: 
40% at 
6 months
100% 
best 
response
Longest 
measured 
CR: 
9 months
4 (67%) subjects 
with 17-related 
grade ≥3 TEAEs 
(neutropenia; 
1 (17%); 
thrombocytopenia 
3 (50%); WBC 
decreased 
3 (50%); 
lymphocyte 
decreased 
1 (17%); LDH 
increased 
1 (17%))
Any grade:
CRS 2 (33%)
ICANS 1 (17%) 
(grade 3)
Infection 2 (33%) 
(grade 3: 1 (17%)
CB-010 
(ANTLER)
NCT04637763
Caribou 
Biosciences
(Nastoupil 
et al., 2022)
(EHA 2022 
Poster)
ASCO: American Society of Clinical Oncology; ASH: American Society of Hematology; B-ALL: B cell acute 
lymphoblastic leukemia; BCMA: B cell maturation antigen; Consol.: consolidation; CR: complete response; CRi: 
CR with incomplete hematologic recovery; CRS: cytokine release syndrome; DL: dose level; DLT: dose-limiting 
toxicity; DoR: duration of response; FL: follicular lymphoma; GvHD: graft vs host disease; ICANS: immune 
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effector cell–associated neurotoxicity syndrome; KO: knockout; LBCL: large B cell lymphoma; LD: 
lymphodepletion; MM: multiple myeloma; NHL: non-Hodgkin lymphoma; ORR: objective response rate; PDL-1: 
programmed death ligand 1; PR: partial response; R/R: relapsed/refractory; SD: stable disease; TALEN: 
transcription activator-like effector nucleases; TCR: T cell receptor; WBC: white blood cell.
1 Allogene Therapeutics CD19 Forum 19 May 2021 presentation available at https://ir.allogene.com/static-
files/7a26a1c0-55f9-4474-a362-9a49b598c43c.
2 Oral presentation available at: 
https://www.allogene.com/resources/download/Anti_BCMA_ALLO_715_And_Anti_CD52_Mab_ALLO_647.pdf
3 Data disclosure available at: https://investor.precisionbiosciences.com/static-files/717d82d7-d304-4428-ba22-
1a19c965d8d5
In addition, CRISPR Therapeutics currently has allogeneic CAR T cell programs in clinical 
development, including CTX110. Preliminary clinical data from CTX110 targeting CD19 being 
evaluated in subjects with relapsed or refractory B cell malignancies (Study CRSP-ONC-001; 
ClinicalTrials.gov identifier NCT04035434) are summarized in Section 1.8 and Section 5.3.1.1.
1.6.
CRISPR Technology
CRISPR (clustered regularly interspaced short palindromic repeats) are found in many bacteria 
and archaea flanking foreign DNA sequences. CRISPR are an important part of an adaptive 
bacterial defense system using RNA-guided DNA-cleaving enzymes (Barrangou et al., 2007; 
Hale et al., 2009). The RNAs expressed from CRISPR sequences direct the sequence-specific 
binding of CRISPR-associated protein 9 (Cas9) proteins. These key bacterial defense systems 
were adapted as a programmable RNA-directed CRISPR-Cas9 system for editing genomes 
(Jinek et al., 2012). 
CRISPR-Cas9 systems can be directed by a complex of 2 distinct RNAs: crisprRNA (crRNA) 
and trans-activating crRNA (tracrRNA), or by a single-guide RNA (sgRNA) containing the 
crRNA and tracrRNA joined by a loop (Jinek et al., 2012). Delivery of Cas9 nuclease and 
sgRNA into a cell results in cutting the cell’s genomic DNA at sequences specified by the 
sgRNA 5’ sequence (Figure 1) and leaving double-stranded breaks (DSBs). These DSBs are 
repaired by the cell’s own DNA repair machinery. Repair of DSBs by the cellular 
nonhomologous end-joining (NHEJ) pathway often results in insertions or deletions, which lead 
to gene disruptions and knockouts. Alternatively, when donor DNA is supplied, DSBs can be 
repaired by a process of homology-directed repair (HDR) in which the donor DNA sequence is 
used to replace the genomic DNA sequence spanning the site of the DSB (Figure 2). HDR results 
in precise modification of the genomic sequence and can be used to correct mutations or 
introduce novel sequences at specific sites.
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Figure 1:
Schematic of the CRISPR-Cas9 Complex
A CRISPR-Cas9 complex containing an sgRNA wherein the crRNA and tracrRNA are joined by a linker loop.
Cas9: CRISPR-associated protein 9; CRISPR: clustered regularly interspaced short palindromic repeats; crRNA: 
crispr RNA; PAM: protospacer-adjacent motif; sgRNA: single-guide RNA; tracrRNA: trans-activating crRNA.
Figure 2:
CRISPR-Cas9–Mediated Genome Editing Strategies
CRISPR-Cas9–mediated DNA cleavage creates a DSB at the target locus that is repaired either by the cells’ NHEJ 
or HDR (denoted in the figure as Homologous Recombination) pathways. Once the sgRNA/Cas9 nuclease complex 
is bound to DNA at a target site, 2 independent nuclease domains in Cas9 (shown as scissors) each cleave 1 of the 
DNA strands 3 bases upstream of the protospacer-adjacent motif site, leaving a blunt-end DNA DSB. Formation of 
the site-specific DSB is the first key step in genome editing, followed by cellular repair.
Cas9: CRISPR-associated protein 9; CRISPR: clustered regularly interspaced short palindromic repeats; DSB: 
double-stranded break; HDR or HR: homology-directed repair; NHEJ: nonhomologous end-joining; sgRNA: single-
guide RNA.
Target sites for CRISPR-Cas9 systems are distributed throughout the genome. The only 
requirement is that the target sequence, homologous to the 5’ end of the sgRNA, is followed by a 
protospacer-adjacent motif (PAM) sequence (Horvath et al., 2008; Mojica et al., 2009; Shah et 
al., 2013). For Streptococcus pyogenes Cas9, this is any nucleotide followed by a pair of 
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guanines (marked as NGG). Typically, the specificity-determining region of the sgRNA is 
20 nucleotides in length. 
The Cas9 nuclease searches for the PAM site and adjacent sequence matching the sgRNA 5’ end 
before cleaving the DNA. Therefore, target-site specificity results from a required combination 
of the site matching the sgRNA adjacent to a PAM site. The Cas9 nuclease does not bind to 
sequences without being complexed to a matching sgRNA. The Cas9 nuclease and sgRNA will 
not bind or cut unless the target sequence is adjacent to the PAM. 
Multiple guide sequences can be targeted to enable simultaneous or sequential editing of 
different sites within the genome (Cong et al., 2013). The resulting multiplex editing can employ 
different editing methods, such as NHEJ at one site(s) and HDR at another site(s) (González et 
al., 2014). CRISPR systems therefore present a very promising means of creating multiple sets of 
complex edits.
1.7.
CTX110
CTX110 is a CD19-directed T cell immunotherapy comprised of allogeneic T cells that are 
genetically modified ex vivo using CRISPR-Cas9 gene editing components (guide RNA and 
Cas9 nuclease). The modifications include disruption of the T cell receptor alpha constant and 
beta-2 microglobulin (B2Μ) loci, and the simultaneous insertion of an anti-CD19 CAR transgene 
into the TRAC locus. The CAR is comprised of a murine scFv specific for CD19, followed by a 
CD8 hinge and transmembrane region that is fused to the intracellular signaling domains for 
CD28 and CD3 ζ. The gene knockouts are intended to reduce the probability of GvHD, redirect 
the modified T cells towards CD19-expressing tumor cells, and increase the persistence of the 
allogeneic cells. 
The drug product is prepared from healthy donor peripheral blood mononuclear cells (PBMCs) 
obtained via a standard leukapheresis procedure. The mononuclear cells are enriched for T cells 
and activated with anti-CD3/CD28 antibody–coated beads, then electroporated with CRISPR-
Cas9 ribonucleoprotein complexes, and transduced with a CAR gene–containing recombinant 
adeno-associated virus (AAV) vector. The modified T cells are expanded in cell culture, purified, 
formulated into a
and 
The product will be stored onsite and thawed 
immediately prior to administration.
A summary of CTX110 production is depicted in Figure 3. Nonclinical data supporting the 
clinical use of CTX110 are summarized in the Investigator Brochure. 
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Figure 3:
Schematic of CTX110 Production
CTX110 is an allogeneic CRISPR-Cas9–edited T cell product that uses Cas9 nuclease protein and 2 guide RNAs for 
gene editing. The first guide RNA targets the TRAC locus (encoding the TCR) to direct homology-directed repair 
mechanisms to insert an anti-CD19 CAR expression cassette (delivered via a recombinant AAV vector) into the 
TRAC locus and disrupt the TCR. Disruption of the TCR is intended to minimize the probability of GvHD when the 
allogeneic T cell product is delivered into patients. The second guide RNA targets the %2M locus for disruption by 
nonhomologous end-joining. Disruption of the %2M (a component of MHC class I molecules) is intended to 
minimize the host’s immune rejection of the allogeneic T cell product mediated by the MHC molecules when the 
allogeneic T cell product is delivered into patients, and thus improve persistence of CTX110 following dosing. Both 
guide RNAs and Cas9 nuclease protein are delivered by electroporation. 
AAV: adeno-associated virus; E2M/B2M: beta-2 microglobulin; CAR: chimeric antigen receptor; Cas9: CRISPR-
associated protein 9; Chr: chromosome; CRISPR: clustered regularly interspaced short palindromic repeats; EF1D: 
elongation factor 1 alpha; gRNA/sgRNA: guide RNA/single-guide RNA; LHA: left homology arm; MHC: major 
histocompatibility complex; RHA: right homology arm; RNP: ribonucleoprotein; scFv: single-chain variable 
fragment; TCR: T cell receptor; TCRαβ: T cell receptor alpha and beta chain complex; TRAC: T cell receptor alpha 
constant.
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1.8.
Study Rationale
Outcomes for patients with relapsed/refractory B cell malignancies are historically poor. 
However, the use of autologous CAR T cell therapy in this setting has produced complete and 
durable responses where previous treatment options were palliative (June et al., 2018; Maus and 
June, 2016; Neelapu et al., 2017; Schuster et al., 2019; Schuster et al., 2017). Autologous CAR 
T cell therapies require patient-specific cell collection and manufacturing. Unfortunately, some 
patients are not candidates to undergo leukapheresis, or they experience disease progression or 
death while awaiting treatment. An allogeneic off-the-shelf CAR T cell product such as CTX110 
could provide the benefit of immediate availability, reduce manufacturing variability, and 
prevent individual subject manufacturing failures. 
Further, patients treated with multiple rounds of chemotherapy may have T cells with exhausted 
or senescent phenotypes. The low response rates in patients with CLL treated with autologous 
CAR T cell therapy have been partially attributed to the exhausted T cell phenotype (Fraietta et 
al., 2018; Riches et al., 2013). By starting with chemotherapy-naïve T cells from a healthy donor, 
allogeneic approaches could increase the consistency and potency of CAR T therapy 
as compared to autologous products. This could lead to improved efficacy and facilitate the 
identification of biomarkers that predict clinical benefit.
The main barrier to the use of allogeneic CAR T cells has been the risk of GvHD. 
CRISPR-Cas9 gene-editing technology allows for reliable multiplex cellular editing. The 
CTX110 manufacturing process couples the introduction of the CAR construct to the disruption 
of the TRAC locus through homologous recombination. The delivery and precise insertion of the 
CAR at the TRAC genomic locus using an AAV-delivered DNA donor template and HDR 
contrasts with the random insertion of genetic material using lentiviral and retroviral transduction 
methods. CAR gene insertion at the TRAC locus results in elimination of TCR in nearly all cells 
expressing the CAR, which minimizes risk of GvHD. Furthermore, manufacturing from healthy 
donor cells removes the risk of unintentionally transducing malignant B cells (Ruella et al., 
2018). 
This first-in-human trial in subjects with relapsed/refractory B cell malignancies aims to evaluate 
the safety as well as efficacy of CTX110 with this CRISPR-Cas9–modified allogeneic CAR T 
cell approach. Refer to CTX110 Investigator's Brochure for the details of the preliminary safety 
data from Part A of the study. 
The preliminary clinical safety data with CTX110 are largely consistent with other 
CD19-directed CAR T cell therapies. As of 10 April 2022 (the data cutoff date for CTX110 
Investigator’s Brochure Version 6.0), there have been no events of GvHD among 61 subjects 
who had received CTX110 in Phase 1, including 42 subjects with NHL (Cohort A [inclusive of 
legacy Cohort F] and Cohort C) and 6 subjects with adult B cell ALL (Cohort D) in Part A (dose 
escalation) and 13 subjects with NHL in Part B (expansion of the Cohort A regimen). 
Preliminary study data have shown that the treatment-emergent adverse events (TEAEs) 
observed are consistent with the underlying disease condition of lymphoma or LD 
chemotherapy. CTX110-related AEs are consistent with known pharmacological class effects of 
CAR T cell therapies and include CRS and immune effector cell–associated neurotoxicity 
syndrome (ICANS), and hematologic events. All cases of CRS resolved with supportive care, 
tocilizumab, and/or steroids, including 2 events of grade 3 CRS that occurred in 1 subject in 
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Part B Cohort A (1 event after a first CTX110 infusion and 1 after a second CTX110 infusion), 
both of which resolved within 6 days of onset. Four subjects had events of ICANS (3 subjects in 
Part A Cohort A and 1 subject in Part A Cohort C), including 1 event of serious grade 5 ICANS 
and human herpesvirus 6 (HHV-6) encephalitis with the outcome of death in 1 subject in Cohort 
A DL4 (1 DLT), and 1 subject with ICANS that started as grade 1 on Day 5 and worsened to 
grade 4, with subsequent recovery to grade 1 on Day 10 followed by resolution on Day 12. In 
Part A Cohort D, 1 subject had an SAE assessed as related to CTX110, a grade 2 infusion related 
reaction that occurred during CTX110 administration. No events of other AESIs specified in the 
study protocol, such as tumor lysis syndrome, B cell aplasia, secondary malignancy, or 
uncontrolled T cell proliferation, were reported in either part of the study (Phase 1 Part A and 
Part B) as of the data cutoff date. 
The preliminary data with CTX110 from Part A of the clinical study also demonstrate the safety 
of a second CTX110 infusion. Eighteen subjects with NHL received a second infusion of 
CTX110, 9 of whom received the second infusion as part of the first course of treatment and 9 of
whom received a second course of treatment. The occurrence and severity of AESIs was similar 
after first vs second infusion and no DLTs were reported in subjects who received a second 
CTX110 infusion. See Section 5.3.1.1 that supports the rationale for additional CTX110 
infusions within the first course of treatment.
2.
STUDY OBJECTIVES
Phase 1
Primary objective, Part A (dose escalation): To assess the safety of escalating doses of 
CTX110 in combination with various lymphodepletion agents in subjects with relapsed or 
refractory B cell malignancies to determine the recommended Part B or Phase 2 dose and cohort
Primary objective, Part B (cohort expansion): To assess the preliminary efficacy of CTX110 
in subjects with relapsed or refractory B cell malignancies, as measured by objective response 
rate
Secondary objectives (dose escalation and cohort expansion): 
x
To further characterize the efficacy, safety, and PK of CTX110
x
To evaluate the changes over time in patient-reported outcomes (PROs) associated 
with CTX110
Exploratory objectives 
 
 
Phase 2
Primary objective: To assess the efficacy of CTX110 in subjects with select NHL subtypes, 
as measured by objective response rate (ORR)
Secondary objectives:
x
To further characterize the efficacy, safety, and pharmacokinetics (PK) of CTX110
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x
To evaluate the changes over time in patient-reported outcomes (PROs) associated with 
CTX110
Exploratory objectives:
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3.
SUBJECT ELIGIBILITY
The eligibility criteria below are for enrollment in the study. Eligibility criteria for a second 
CTX110 infusion are provided in Section 5.3.1.3, and eligibility criteria for a second course of 
treatment after disease progression are provided in Section 5.3.1.4.
3.1.
Inclusion Criteria
To be considered eligible to participate in this study, a subject must meet all the inclusion criteria 
listed below, which apply to all cohorts in Phase 1 and for subjects with NHL in Phase 2 unless 
otherwise specified.
1. Age ≥18 years (Phase 1 Cohorts A, B, and C and Phase 2), or ≥18 to ≤70 years (Phase 1 
Cohort D) 
2. Able to understand and comply with protocol-required study procedures and voluntarily 
sign a written informed consent document
3. Diagnosed with 1 of the following B cell malignancies:
Phase 1 Cohorts A, B, and C (C1 and C2) and Phase 2: Histologically confirmed B 
cell NHLs: DLBCL NOS, high-grade B cell lymphoma with MYC and BCL2 and/or 
BCL6 rearrangements, transformed FL, grade 3b FL, or PMBCL
x
Confirmation of tumor histology from local pathology lab (archival tissue from 
last relapse/progression [within 3 months of enrollment] or biopsy during 
screening [or within 28 days prior to CTX110 infusion, if a recent sample was 
collected as part of standard of care])
x
At least 1 measurable lesion that is fluorodeoxyglucose positron emission 
tomography (PET)–positive, as defined by Lugano criteria (Deauville score of 4 
or 5 on Lugano criteria 5-point scale; Appendix A). Note: Previously irradiated 
lesions will be considered measurable only if progression is documented 
following completion of radiation therapy.
Phase 1 Cohort D: Histologically confirmed B cell ALL
x
Subcohort D1: Bone marrow involvement with ≥5% blasts (see investigational 
plan in Section 4.1).
x
Subcohort D2: Bone marrow MRD-positive (defined as >1 × 10-4 cells detected 
by flow cytometry or polymerase chain reaction [PCR] or next-generation 
sequencing [NGS] including ClonoSeq or positive BCR-ABL transcript for Ph+ 
disease) in subjects with bone marrow with ≤5% blasts. Subjects in Subcohort D2 
may be enrolled with local baseline MRD results pending, as long as qualifying 
results within 3 months of enrollment are available.
4. Refractory or relapsed disease, as evidenced by the following cohort-specific criteria:
Phase 1 Cohorts A, B, and C (NHL) and Phase 2 (NHL): 2 or more prior therapies, 
including an anti-CD20 monoclonal antibody and an anthracycline-containing regimen. 
Subjects who have received
 must have recovered from
toxicities.
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x
Refractory disease is defined as subjects with PD on last therapy or have stable 
disease (SD) following at least 2 cycles of therapy.
x
For subjects with transformed FL, subjects must have received at least 1 line of 
chemotherapy for disease after transformation to DLBCL.
x
For Phase 1 Cohort B, subjects must meet the following criteria:

Received prior treatment with an approved autologous CD19-directed CAR T cell 
therapy (e.g., axicabtagene ciloleucel, tisagenlecleucel, lisocabtagene maraleucel) 
≥12 months prior to enrollment

Achieved a CR for ≥4 months duration from that prior treatment.

No grade ≥2 ICANS from prior CAR T cell therapy

No history of grade 4 CRS 

No other prior or residual toxicity from prior CAR T cell therapy that, in the 
investigator’s judgement, would place subject at increased risk of toxicity from a 
subsequent CAR T cell therapy

Age <70 years old

No elevated lactate dehydrogenase (LDH) (per institutional normal range)
Note: Subjects with relapse after autologous CAR T cell therapy <6 months and/or 
6 to 12 months prior to enrollment, those with elevated LDH, and those >70 years old 
may be considered after SRC review of safety and efficacy data from at least 
6 subjects in Cohort B.
Phase 1 Cohort D (adult B cell ALL):
x
2 or more prior therapies, or
x
Any bone marrow relapse after allogeneic HSCT; or
x
Philadelphia chromosome–positive if subjects are intolerant to or ineligible for 
tyrosine kinase inhibitor (TKI) therapy or have progressed after at least 1 line of 
TKI therapy
5. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 (Appendix B)
6. Meets criteria to undergo LD chemotherapy (all Phase 1 cohorts and Phase 2), CAR T 
cell infusion (all Phase 1 cohorts and Phase 2), and daratumumab administration (Phase 1 
Cohort C only)
7. Adequate organ function:
x
Renal: Estimated glomerular filtration rate >50 mL/min/1.73 m2
x
Liver: Aspartate transaminase (AST) or alanine transaminase (ALT) <3 × upper limit 
of normal (ULN); total bilirubin <1.5 × ULN (for subjects with Gilbert's syndrome, 
total bilirubin <2 mg/dL)
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x
Cardiac: Hemodynamically stable and left ventricular ejection fraction ≥45% by 
echocardiogram
x
Pulmonary: Oxygen saturation level on room air >91% per pulse oximetry
8. Female subjects of childbearing potential (postmenarcheal with an intact uterus and at 
least 1 ovary, who are less than 1 year postmenopausal) must agree to use acceptable 
method(s) of contraception from enrollment through at least 12 months after the most 
recent CTX110 infusion (Appendix C).
9. Male subjects must agree to use effective acceptable method(s) of contraception from 
enrollment through at least 12 months after the most recent CTX110 infusion 
(Appendix C).
3.2.
Exclusion Criteria
To be eligible for entry into the study, the subject must not meet any of the exclusion criteria 
listed below, which apply to all cohorts in Phase 1 and for subjects with NHL in Phase 2 unless 
otherwise specified.
1. Treatment with the following therapies as described below:
x
Prior treatment with any gene therapy or genetically modified cell therapy, including 
CAR T cells. Exception: Phase 1 Cohort B will enroll subjects who received prior 
treatment with an approved autologous CD19-directed CAR T cell therapy.
x
Prior treatment with a CD19-directed therapy (e.g., CD19-directed antibody, 
bispecific T cell engager, or antibody-drug conjugate, unless there is confirmed CD19 
expression (by immunohistochemistry or flow cytometry) after progression or relapse 
following most recent CD19-directed treatment. The requirement to confirm CD19 
expression is optional in Phase 1 Subcohort D2. Subjects in Phase 1 Cohort B should 
demonstrate confirmed CD19 expression.
2. Prior allogeneic HSCT. Exception: For subjects with B cell ALL (Phase 1 Cohort D), 
prior allogeneic HSCT is permissible if it has been more than 6 months from HSCT at the 
time of enrollment; there is no evidence of acute or chronic GvHD; and the subject has 
recovered from HSCT-related toxicities, has been off immunosuppressive therapies for at 
least 3 months prior to enrollment, and has not received donor lymphocyte infusion for at 
least 2 months prior to enrollment. 
3. Diagnosis of Burkitt’s lymphoma/leukemia 
4. Known contraindication to daratumumab (Phase 1 Cohort C only), cyclophosphamide, 
fludarabine, or any of the excipients of CTX110 product
5. Prior CNS disease
x
For NHL subjects: Detectable malignant cells from CSF or magnetic resonance 
imaging (MRI) indicating brain metastases during screening, or a history of central 
nervous system (CNS) involvement by malignancy (CSF or imaging).
x
For B cell ALL subjects: a prior history of CNS involvement with no evidence of 
current CNS disease during screening and/or those with CNS-2 disease, which is 
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defined as the presence of blast cells in CSF containing <5 white blood cells/μl per 
National Comprehensive Cancer Network (NCCN) guidelines V2.2021 (NCCN, 
2021), without neurological symptoms are eligible for the study. The SRC will review 
the first 2 subjects with CNS-2 ALL to allow additional subjects with CNS disease to 
be enrolled.
6. History of a seizure disorder, major cerebrovascular ischemia/hemorrhage, dementia, 
cerebellar disease, or any autoimmune disease with CNS involvement 
7. Unstable angina, clinically significant arrhythmia, or myocardial infarction within 
6 months of enrollment, or grade 3 or higher pericardial effusion at the time of enrollment
8. Presence of active bacterial, viral, or fungal infection that is uncontrolled, based on 
investigator judgment in consultation with the medical monitor
9. Positive for presence of human immunodeficiency virus (HIV) type 1 or 2, or active 
hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. Subjects with prior history 
of HBV or HCV infection who have documented undetectable viral load (by quantitative 
PCR or nucleic acid testing) are permitted. Infectious disease testing (HIV-1, HIV-2, 
HCV antibody and PCR, HBV surface antigen, HBV surface antibody, HBV core 
antibody) performed within 45 days of enrollment may be considered for subject 
eligibility
10. Previous or concurrent malignancy, except basal cell or squamous cell skin carcinoma, 
adequately resected and in situ carcinoma of cervix, or a previous malignancy that was 
completely resected and has been in remission for ≥5 years of enrollment.
11. Radiation therapy within 14 days of enrollment
12. For Phase 1 Cohorts A, B, and C (NHL) and Phase 2 (NHL): Use of systemic antitumor 
therapy or investigational agent within 14 days or 5 half-lives, whichever is longer, of 
CTX110 infusion. Exceptions: 1) prior inhibitory/stimulatory immune checkpoint 
molecule therapy, which is prohibited within 3 half-lives of CTX110 infusion; and 2) 
rituximab, other anti-CD20 monoclonal antibodies, or polatuzumab vedotin use within 30 
days prior to CTX110 infusion is prohibited (however PET/CT needs to occur at least 2 
weeks after last dose).
For Phase 1 Cohort D (adult B cell ALL): Use of systemic antitumor therapy within 
7 days of CTX110 infusion. Exceptions: 1) immunotherapy agents (i.e., rituximab, 
inotuzumab) must be stopped at least 14 days prior to CTX110 infusion; 2) long-acting 
chemotherapy agents (e.g., pegylated asparaginase, methotrexate >25 mg/m2) must be 
stopped at least 14 days prior to CTX110 infusion; 3) Hydroxyurea must be stopped 
≥72 hours before CTX110 infusion; and 4) investigational agent(s) must be stopped after 
5 half-lives have passed before CTX110 infusion. Subjects must have recovered to 
grade 1 Common Terminology Criteria for Adverse Events (CTCAE; National Cancer 
Institute, version 5.0) from acute toxicity (except hematological) of all previous therapy 
prior to CTX110 infusion. 5) Steroids are permitted until the day before starting LD 
chemotherapy for maintenance or to allow for control of peripheral blood blasts.
13. Primary immunodeficiency disorder or active autoimmune disease requiring steroids 
and/or other immunosuppressive therapy. 
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14. Diagnosis of significant psychiatric disorder or other medical condition that, in the 
opinion of the investigator, could impede the subject’s ability to participate in the study
15. Women who are pregnant or breastfeeding
16. Life expectancy of less than 6 weeks
17. For Phase 1 Subcohort D2 only: Exclusion of isolated extramedullary disease (defined as 
any subject with ≤5% blasts in the bone marrow and confirmation of the presence of 
clonal blasts in any tissue other than the medullary compartments)
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4.
STUDY DESIGN
This is an open-label, multicenter, Phase 1/2 study evaluating the safety and efficacy of CTX110 
in subjects with relapsed or refractory B cell malignancies. Phase 1 of the study will be divided 
into 2 parts: dose escalation (Part A) followed by cohort expansion (Part B). Phase 2 will further 
explore efficacy in cohorts that have been evaluated in Phase 1.
4.1.
Phase 1 Investigational Plan
In Phase 1, dose escalation (Part A) and cohort expansion (Part B) will be conducted separately 
for each cohort and performed according to the criteria outlined in Section 4.1.4. An SRC, 
consisting of investigators and sponsor representatives, will review all available safety data and 
make decisions regarding dose escalation (or de-escalation), additional CTX110 infusion, LD 
chemotherapy dose regimen, and daratumumab (Darzalex®, Janssen) dose regimen to determine 
the recommended Part B dose for cohort expansion and/or the recommended Phase 2 dose. The 
SRC may also propose revisions to the DLT definitions and dosing schema during dose 
escalation. 
The study is designed to enroll adult subjects with 1 of the following NHL subtypes: DLBCL 
NOS, high-grade B cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, grade 3b 
FL, transformed FL, or PMBCL (Cohorts A, B, and C); and subjects with adult B cell ALL 
(Cohort D). Cohorts C and D are divided into Subcohorts C1 and C2 and D1 and D2, 
respectively. See Table 3 for CTX110, LD chemotherapy, and daratumumab (if applicable) dose 
regimens for each cohort. 
Cohort B will enroll subjects with NHL who have achieved a CR on prior approved autologous 
CD19-directed CAR T cell therapy and subsequently experienced disease progression. The dose 
regimen will be the same as for Cohort A, and LD chemotherapy will comprise co-
administration of fludarabine 30 mg/m2 and cyclophosphamide 750 mg/m2 IV daily for 3 days. 
The higher dose of cyclophosphamide is intended to improve peak cell expansion and 
persistence in this pre-treated population (Section 5.2.1). Initially, enrollment will be restricted to 
subjects who are ≥12 months from prior CAR T cell therapy, are age <70 years old, and have 
LDH in the normal range. However, after at least 6 subjects have been treated in Cohort B, the 
SRC may review of safety and efficacy data and determine that a broader population of post 
autologous CAR T cell therapy subjects may be enrolled.
To provide immunomodulatory effects to induce an immune environment amenable to allogeneic 
CAR T cells, subjects in Cohort C will receive daratumumab with or without LD chemotherapy 
(see Table 3). 
 
 
 
 
 
This study will allow for up to 3 infusions of CTX110 for each subject. 
For all cohorts (except Subcohort C1), a second infusion of CTX110 with the respective LD 
regimen will be administered on Day 35 (-7 days/+21 days) to subjects who achieve SD or better 
at the Day 28 evaluation (Table 3). This additional infusion of CTX110 may be administered 
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without LD chemotherapy if a subject is experiencing significant cytopenias, as described in 
Section 5.3.1.3. 
As shown in the STUDY SCHEMA and Table 3, the first course of treatment encompasses the 
initial CTX110 infusion with respective LD regimen and the second infusion with LD regimen, 
if applicable.
For all cohorts, if the subject has demonstrated clinical benefit after the initial CTX110 infusion 
but then has disease progression, an optional second course of treatment with a single infusion 
of CTX110 after PD will be administered with standard LD chemotherapy (i.e., without 
daratumumab for subjects in Phase 1 Cohort C) within 18 months of the initial CTX110 infusion 
and ≥4 weeks from the prior CTX110 infusion. See Table 3 for additional details regarding all 
Part A cohorts.
In Phase 1 Part A, for cases in which a dose level has been cleared in a cohort and dose 
escalation is permitted, the sponsor, in consultation with the SRC, may decide to enroll 
additional subjects at a given dose level. In any dose escalation cohort or subcohort (e.g., D1, or 
D2), 6 additional subjects (up to 12 total subjects) may receive study treatment at or below the 
highest cleared dose level. Further, with SRC approval, 12 additional subjects (24 total) may 
receive study treatment in any one cohort or subcohort (A, B, C1, C2, D1, or D2) at or below the 
highest cleared dose level to gather additional safety information prior to cohort expansion. Dose 
escalation for other cohorts may continue in parallel to cohort expansion and Phase 2 enrollment. 
Dose escalation for subjects with adult B cell ALL is anticipated to continue in parallel to cohort 
expansion and Phase 2 enrollment for NHL cohorts.
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Table 3:
Lymphodepletion Regimen and CTX110 Infusion Schedule (Part A Dose 
Cohorts)
Cohort
Disease Subtype
First Course of Treatment
A
NHL: Adult subjects with 
DLBCL NOS, high-grade 
B cell lymphoma with 
MYC and BCL2 and/or 
BCL6 rearrangements, 
grade 3b FL, transformed 
FL, or PMBCL
Stage 2A
LD chemotherapy: Co-administration of fludarabine 30 mg/m2 + 
cyclophosphamide 500 mg/m2 IV daily for 3 days; both agents 
should be started on the same day and administered for 
3 consecutive days and completed at least 48 hours (but no more 
than 7 days) prior to CTX110 infusion.
Stage 2B
x
Initial CTX110 infusion on Day 1 starting at DL1
x
A second infusion of CTX110 on Day 35 (-7 days/+21 days) 
administered with LD chemotherapy for subjects who 
achieve SD or better at Day 28 scan (based on Lugano 
criteria).
B*
Same as Cohort A, with 
additional inclusion criteria 
related to prior autologous 
CAR T cell therapy
Stage 2A
LD chemotherapy: Co-administration of fludarabine 30 mg/m2 + 
cyclophosphamide 750 mg/m2 IV daily for 3 days; both agents 
should be started on the same day and administered for 
3 consecutive days and completed at least 48 hours (but no more 
than 7 days) prior to CTX110 infusion. 
Stage 2B
x
Initial CTX110 infusion on Day 1 starting at DL4
x
A second infusion of CTX110 on Day 35 (-7 days/+21 days) 
with LD chemotherapy (co-administration of fludarabine 
30 mg/m2 + cyclophosphamide 500 mg/m2 IV daily for 
3 days) to subjects who achieve SD or better at Day 28 scan 
(based on Lugano criteria). 
C
(Subcohorts 
C1 and C2)
Same as Cohort A
Stage 2A
LD regimen: Daratumumab + LD chemotherapy
Daratumumab administration: One dose of daratumumab1
16 mg/kg by IV infusion or 1800 mg by SC injection ≥1 day prior 
to starting LD chemotherapy and within 10 days prior to CTX110 
infusion. To facilitate administration, the first 16 mg/kg IV dose 
may be split (to 8 mg/kg) over 2 consecutive days.
LD chemotherapy: Co-administration of fludarabine 30 mg/m2 + 
cyclophosphamide 500 mg/m2 IV daily for 3 days; both agents 
should be started on the same day and administered for 
3 consecutive days and completed at least 48 hours (but no more 
than 7 days) prior to CTX110 infusion.
Stage 2B
Cohort C1
x
Initial CTX110 infusion on Day 1 starting at DL3
x
No second infusion of CTX110 on Day 35
x
For subjects who achieve SD or better on Day 28, 
2 additional doses of daratumumab (16 mg/kg by IV infusion 
or 1800 mg by SC injection) will be administered at Day 28 
(± 4 days) and Month 2 (± 4 days) visits.
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Cohort
Disease Subtype
First Course of Treatment
Cohort C2
x
Initial CTX110 infusion on Day 1 starting at or below the DL 
cleared in Cohort C1
x
A second infusion of CTX110 on Day 35 (-7 days/+21 days) 
administered with daratumumab2 and LD chemotherapy to 
subjects who achieve SD or better at Day 28 scan (based on 
Lugano criteria). 
D
(Subcohorts 
D1 and D2)
Adult B cell ALL
D1: BM involvement with 
≥5% blasts. 
D2:  BM <5% blasts and 
MRD-positive (>1 × 10-4 
cells detected by flow 
cytometry or PCR or NGS 
including ClonoSEQ or 
positive BCR-ABL 
transcript for Ph+ disease).
Stage 2A
LD chemotherapy: Co-administration of fludarabine 30 mg/m2 + 
cyclophosphamide 500 mg/m2 IV daily for 3 days; both agents 
should be started on the same day and administered for 
3 consecutive days and completed at least 48 hours (but no more 
than 7 days) prior to CTX110 infusion.3
Stage 2B
Cohort D1 (BM involvement with ≥5% blasts)
x
Initial CTX110 infusion on Day 1 starting at DL2 or DL3
x
A second infusion of CTX110 on Day 35 (-7 days/+21 days) 
with LD chemotherapy if subject has a decrease in BM blast 
count at Day 28 of ≥50% but blast count remains ≥5% or is 
MRD-positive. 
Cohort D2 (BM involvement with <5% blasts and MRD-positive)
x
CTX110 infusion on Day 1 starting at or below the DL 
cleared in D1
x
Second infusion of CTX110 on Day 35 for subjects who have 
demonstrated a reduction in detectable MRD and remain 
MRD positive.
ALL: acute lymphoblastic leukemia; BM: bone marrow; CAR: chimeric antigen receptor; DL: Dose Level; DLBCL: 
diffuse large B cell lymphoma; FL: follicular lymphoma; IV: intravenous(ly); LD: lymphodepleting; MRD: minimal 
residual disease; NGS: next-generation sequencing; NHL: Non-Hodgkin Lymphoma; NOS: not otherwise specified; 
PCR: polymerase chain reaction; PMBCL: primary mediastinal large B cell lymphoma; SC: subcutaneous; SD: 
stable disease.
Note: Subjects in legacy Cohort F (discontinued in Version 6.0 of the protocol) have been merged with Cohort A.
Note: Subjects should meet the criteria specified in the protocol prior to both the initiation of LD chemotherapy and 
infusion of CTX110 and should meet criteria specified for second or subsequent infusions prior to receiving any 
additional doses of CTX110. Criteria for LD chemotherapy should be confirmed prior to infusion of daratumumab 
as applicable. The CTX110 infusion on Day 35 (-7 days/+21 days), if applicable, may be administered without LD 
chemotherapy if subject is experiencing significant cytopenias (see Section 5.3.1.3.1).
Subjects in all cohorts have the option to receive an additional infusion of CTX110 with LD chemotherapy (co-
administration of fludarabine 30 mg/m2 + cyclophosphamide 500 mg/m2 IV daily for 3 days) after PD, as a second 
course of treatment, if subjects had response after prior infusion. Additional infusion after PD must be within 
18 months of the initial CTX110 infusion and ≥4 weeks after last infusion. 
* Cohort B will enroll subjects only at selected investigative sites, at the sponsor’s discretion.
1. Daratumumab may be administered as an SC injection (1800 mg/30,000 units of hyaluronidase-fihj) or as an IV 
infusion of 16 mg/kg, per local prescribing information.
2. For subjects in Cohort C2 who respond to treatment (i.e., achieve SD or better on Day 28), an additional dose of 
daratumumab will be administered at the Day 28 visit and an additional infusion of CTX110 will be administered 
on Day 35. A second additional daratumumab dose will be administered as part of the LD regimen for Day 35 
unless within 14 days of the previous Day 28 dose (Section 5.1).
3. In Cohort D, additional subjects may be enrolled to explore alternative LD dose regimen in which 
cyclophosphamide may be administered at a dose of 750 mg/m2 IV daily for 3 days, starting at a CTX110 dose 
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level at or below the highest dose level that has been cleared with LD dose containing 500 mg/m2 IV daily for 
3 days and if it has been agreed by the SRC and the sponsor. Additional subjects enrolled will follow dose 
escalation rules as described in Section 4.1.4. In that instance, for the second infusion on Day 35 (where 
applicable), the cyclophosphamide dose in LD chemotherapy will be 500 mg/m2.
4.1.1.
Phase 1 Study Design
The study will consist of 3 main stages: screening, treatment, and follow-up. The dose escalation 
part of the study will involve 4 cohorts of subjects: Cohorts A, B, C, and D. Cohorts C and D 
include Subcohorts C1 and C2 and D1 and D2, respectively.
Enrollment and allocation of subjects to each cohort will be at the sponsor’s discretion. Subjects 
with B cell ALL will be exclusively assigned to Cohort D in parallel with other cohorts. 
The 3 main stages of the study will be as follows:
Stage 1 – Screening to determine eligibility for treatment (1-2 weeks)
Stage 2 – Treatment (Stage 2A + Stage 2 B). See Table 3 for treatment by cohort. 
Stage 3 – Follow-up for all cohorts (up to 5 years after the last CTX110 infusion)
Note: Subjects’ clinical eligibility should be reconfirmed according to the criteria in Sections 5.2
and 5.3 prior to both the initiation of LD chemotherapy (all cohorts), infusion of CTX110 (all 
cohorts), and prior to administration of daratumumab (Cohort C).
Criteria for additional CTX110 infusions are described in Section 5.3.1.
For Phase 1 Part A (dose escalation), subjects must remain within proximity of the investigative 
site (i.e., 1-hour transit time) for 28 days after each CTX110 infusion. For Phase 1 Part B (cohort 
expansion), subjects must remain within proximity of the investigative site (i.e.,1-hour transit 
time) for 28 days after the first CTX110 infusion and at least 14 days for subsequent CTX110 
infusions, or longer if justified by subject’s clinical status or as required by local regulation or 
site practice. During this acute toxicity monitoring period, subjects will be routinely assessed for 
AEs, including CRS, neurotoxicity, and GvHD. Toxicity management guidelines are provided in 
Section 6. During dose escalation, all subjects will be hospitalized for the first 7 days following 
each CTX110 infusion, or longer if required by local regulation or site practice (Appendix D).
After the acute toxicity monitoring period, subjects will be subsequently followed for up to 
5 years after the last CTX110 infusion with physical exams, regular laboratory and imaging 
assessments, and AE evaluations.
4.1.2.
Phase 1 Study Subjects
Approximately 100 subjects will be treated in Part A (dose escalation), depending on which 
cohorts are enrolled and the number of dose levels explored. 
Up to 30 subjects will be treated in Part B (cohort expansion) of Cohort A. If other cohorts 
expand, the sample size estimation for the first cohort expansion will also apply to the 
subsequent cohort expansion, thus increasing the total number of enrolled subjects in Part B.
Section 7.1.3 describes the assignment of subjects to treatment cohorts.
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4.1.3.
Phase 1 Study Duration
Subjects will participate in this study for up to 5 years after the last CTX110 infusion. All 
subjects will also be asked to participate in a separate long-term follow-up study for an 
additional 10 years to assess long-term safety and survival.
4.1.4.
Phase 1 Part A Dose Escalation
In Phase 1 Part A, the following doses of CTX110, based on number of CAR+ T cells, may be 
evaluated in this study (Table 4).
Table 4:
Dose Escalation of CTX110
Dose Level
Total CAR+ T Cell Dose
−1
1 × 107
1
3 × 107
2
1 × 108
3
3 × 108
3.5*
4.5 × 108
4
6 × 108
5**
9 × 108
CAR: chimeric antigen receptor; DL: Dose Level. 
* DL3.5 is an optional de-escalation dose level.
**Note: The sponsor, with approval of the safety review committee, may explore DL5 (9 × 108 cells) in parallel 
to cohort expansion.
Dose escalation will be performed using a standard 3+3 design in which 3 to 6 subjects will be 
enrolled at each dose level depending on the occurrence of DLTs, as defined in Section 4.1.4.2. 
The SRC will review available data when the DLT observation period ends for the last subject 
enrolled in each cohort. The SRC will be responsible for making dose escalation decisions based 
on review of all available safety and PK data. Throughout dose escalation, for cases in which a 
dose had been cleared in a cohort or subcohort (e.g., Subcohort D1) and dose escalation is 
permitted, the sponsor in consultation with the SRC may alternatively decide to enroll an 
additional number of subjects for a total of up to 24 at the current dose level to gather additional 
safety data. Based on an ongoing assessment of benefit and risk, the SRC may stop dose 
escalation before a maximum tolerated dose (MTD) is determined.
The doses of CTX110 presented in Table 4, based on the total number of CAR+ T cells, may be 
evaluated in this study. The starting dose for escalation will be selected separately for each 
cohort and will reflect the cumulative safety data across all cohorts for each study population 
(NHL, adult B cell ALL). Whenever escalation begins in a new cohort, the sponsor and SRC will 
discuss and agree on the starting dose level, which will not exceed the highest dose level cleared 
in Cohort A. There will be a dose limit of
TCR+ cells/kg for all dose levels, which will 
determine the minimum weight for dosing.
The DLT evaluation period will begin with the initial CTX110 infusion and last for 28 days. 
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In addition to a formal assessment of DLTs following the first dose of CTX110, the sponsor will 
systematically review safety for each dosing regimen, including for subjects who receive:
1. Second infusion of CTX110 at Day 35 with or without LD chemotherapy (see 
Section 5.3.1.3)
2. Day 28 and Month 2 doses of daratumumab (Cohort C1) (see Section 5.1)
3. A second course of study treatment after disease progression (see Section 5.3.1.4)
Events that could be considered DLTs in any of these settings will be brought to the SRC for 
review and discussion. Further, the incidence and severity of long-term cytopenias will be 
monitored and summarized by dosing regimen, and subject to the same DLT definition as 
outlined in Section 4.1.4.2. The sponsor will collect and monitor AEs, SAEs, and adverse events 
of special interest (AESIs) per protocol and analyze safety information relative to the first dose 
and compare the safety information relative to the second dose for the subjects who receive 
additional infusions, in addition to the cumulative safety data analysis for subjects who receive 
single and additional infusions in each cohort. The sponsor will also continue to share and 
discuss with the SRC on a regular basis the safety profile of subjects who receive a single 
infusion of CTX110 and of subjects who have received additional infusions. These data will be 
reviewed on an ongoing basis by the DSMB. The sponsor will apply the DLT criteria defined in 
Section 4.1.4.2 to assess safety in addition to the frequency and severity of AEs and AESIs 
collected during the immediate 28-day period after each additional CTX110 infusion. The 
sponsor will discuss the results with the SRC after the first 3 subjects have received an additional 
infusion of CTX110 within each cohort, and at regular intervals as more subjects receive 
additional CTX110 infusions.
For Cohort A: In DL1 (and DL-1, if required), subjects will be treated in a staggered manner 
such that the second and third subjects will only receive CTX110 after the previous subject has 
completed the DLT evaluation period. In subsequent dose levels or for additional subjects 
enrolled at the same dose level, cohorts of up to 3 subjects may be enrolled and dosed 
concurrently. 
For Cohorts B, C, and D: The first 2 subjects within each cohort will be treated in a staggered 
manner at the starting dose level and at each subsequent dose level, such that the second subject 
will only receive CTX110 after the previous subject has completed the DLT evaluation period. 
For additional subjects enrolled at the same dose level, cohorts of up to 3 subjects may be 
enrolled and dosed concurrently. 
For Cohort D: The first 2 subjects at each dose level of Subcohort D1 (adult B cell ALL subjects 
with ≥5% blasts) will be treated in a staggered manner such that the second subject will only 
receive CTX110 after the previous subject has completed the DLT evaluation period. However, 
in Subcohort D2 (adult B cell ALL subjects with <5% blasts and MRD positive), up to 3 subjects 
may be enrolled and dosed concurrently if the dose level has been cleared by the SRC in 
Subcohort D1. The opposite will not be allowed. If 3 subjects in Subcohort D2 are cleared, then 
Subcohort D2 alone will advance to the next dose level.
The sponsor considers this approach to subject enrollment appropriate for this first-in-human 
study with CTX110, given that dose escalation will only be performed in centers with extensive 
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experience administering cell therapies, and the existence of comprehensive toxicity 
management algorithms based on CD19-directed autologous CAR T cell therapy (Section 6). 
Dose escalation will be performed according to the following rules:
x
If 0 of 3 subjects experience a DLT, escalate to the next dose level.
x
If 1 of 3 subjects experiences a DLT, expand the current dose level to 6 subjects.
o
If 1 of 6 subjects experiences a DLT, escalate to the next dose level.
o
If ≥2 of 6 subjects experience a DLT:

For Cohort A, if in DL-1, evaluate alternative dosing schema or declare 
inability to determine recommended Part B dose.

For Cohort A, if in DL1, de-escalate to DL-1. For Cohort D, if in DL2, 
de-escalate to DL1.

For all cohorts, if in DL 2, 3, 3.5, 4, or 5 declare previous dose level the 
MTD.
x
If ≥2 of 3 subjects experience a DLT:
o
For Cohort A, if in DL-1, evaluate alternative dosing schema or declare inability 
to determine recommended Part B dose.
o
For Cohort A, if in DL1, decrease to DL-1. For Cohort D, if in DL2, de-escalate 
to DL1.
o
For all cohorts, if in DL 2, 3, 3.5, 4, or 5 declare previous dose level the MTD.
The sponsor will declare the recommended dose for Part B cohort expansion or Phase 2 at or 
below the MTD (if determined). At least 6 subjects will be administered CTX110 in the trial 
before a recommended Part B dose is declared.
4.1.4.1.
CTX110 Dose Rationale: Part A
Nonclinical safety models are limited in part because the CD19-directed CAR does not recognize 
murine CD19, and therefore these studies cannot evaluate CD19-dependent toxicities. 
Additionally, the PK profile of CTX110 cannot be evaluated in CD19 antigen–free mouse 
models, or in immunocompetent nonhuman primate models in which rapid clearance would be 
expected, as CTX110 is a human cell. Therefore, the starting dose of CTX110 is predominantly 
informed by published clinical studies of other autologous and allogeneic CD19-directed CAR T 
cell therapies (Table 5). In clinical trials, CAR T cells have been administered as 1 specific 
CAR+ T cell dose or as per kilogram dosing, depending on the clinical trial and product.
Table 5:
CAR+ T Cell Doses
Product
Indication
Dosing 
(CAR+ T cells)
Tisagenlecleucel
Pediatric/young 
adult ALL
Subjects >50 kg: Range of doses, 
maximum 2.5 × 108 
Subjects <50 kg: 0.2-6.0 × 106
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Product
Indication
Dosing 
(CAR+ T cells)
Tisagenlecleucel
NHL
5 × 108
Axicabtagene ciloleucel
NHL
2 × 106/kg, maximum 2 × 108
Lisocabtagene maraleucel
NHL
5 ×x 107 and 1 × 108
ALL: acute lymphoblastic leukemia; CAR: chimeric antigen receptor; NHL: non-Hodgkin lymphoma.
CTX110 will be administered IV using a flat dosing schema based on the number of CAR+ T 
cells. The starting dose will be 3 × 107 CAR+ T cells, which is approximately 1 log lower than 
the doses of autologous CAR T cells currently approved for NHL, reflecting a conservative 
approach given this study is the first clinical experience with CTX110. Prior CAR T cell studies 
have failed to demonstrate a strong dose-response relationship for either safety or efficacy 
outcomes (Mueller et al., 2017). Some studies report ≤100,000-fold expansion of CAR T cells in 
subjects after infusion, resulting in highly variable systemic exposure to CAR T cells even at the 
same dose (Maude et al., 2015; Schuster et al., 2019; Schuster et al., 2017). Toxicities associated 
with autologous CAR T cells are likely due to several factors in addition to dose such as the 
malignancy being treated, disease status (including tumor burden) at the time of infusion, and, 
potentially, LD chemotherapy doses. 
4.1.4.2.
DLT Definitions
Toxicities will be graded and documented according to National Cancer Institute CTCAE 
version 5.0 (Appendix E), except as provided in Section 6.2.4 for CRS (American Society for 
Transplantation and Cellular Therapy [ASTCT] criteria (Lee et al., 2019), Section 6.2.5 for 
neurotoxicity (Lee et al., 2019), and Section 6.2.9 for GvHD (Harris et al., 2016). 
A DLT will be defined as any of the following events occurring during the DLT evaluation 
period that persists beyond the specified duration (relative to the time of onset):
x
Grade ≥2 GvHD that is steroid-refractory (e.g., PD after 3 days of steroid treatment 
[e.g., 1 mg/kg/day], SD after 7 days, or PR after 14 days of treatment)
x
Death during the DLT period (except due to disease progression)
x
Grade 4 neurotoxicity of any duration that is related or possibly related to CTX110
x
Any CTX110-related grade 3 or 4 toxicity that is clinically significant according to 
the investigator’s judgment and does not improve within 72 hours
The following will NOT be considered as DLTs: 

Grade 3 or 4 CRS that improves to grade ≤2 within 72 hours

Grade 3 neurotoxicity (e.g., encephalopathy, confusion) that improves to grade ≤2 
within 14 days

Grade 3 or 4 fever 

Bleeding in the setting of thrombocytopenia (platelet count <50 × 109/L); 
documented bacterial infections or fever in the setting of neutropenia (absolute 
neutrophil count [ANC] <1000/mm3)
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
Hypogammaglobulinemia

Grade 3 or 4 pulmonary toxicity that resolves to grade ≤2 within 7 days. For 
subjects intubated due to fluid overload from supportive care, this may be 
extended to 14 days.

Grade 3 or 4 liver function studies that improve to grade ≤2 within 14 days

Grade 3 or 4 renal insufficiency that improves to grade ≤2 within 21 days

Grade 3 or 4 thrombocytopenia, neutropenia, anemia, or lymphopenia will be 
assessed retrospectively. After at least 6 subjects are infused, if ≥50% of subjects 
have prolonged cytopenias (i.e., lasting more than 28 days post infusion) dose 
escalation will be suspended pending SRC review. For Cohort D: Grade ≥3 
cytopenias that were present at the start of LD chemotherapy may not be 
considered a DLT pending SRC review and identification of another etiology.
Subjects must receive CTX110 to be evaluated for DLT. If a subject discontinues the study any 
time prior to the initial CTX110 infusion, the subject will not be evaluated for DLT and a 
replacement subject will be enrolled at the same dose level as the discontinued subject. If a 
subject has a potential DLT for which the protocol definition allows time for improvement or 
resolution, the DLT evaluation period will be extended accordingly before a DLT is declared. 
AEs occurring outside the DLT evaluation period that are assessed by the investigator and/or 
sponsor as related to CTX110 will be considered by the SRC when making dose escalation 
decisions. AEs that have no plausible causal relationship with CTX110 will not be considered 
DLTs. A DLT occurring in one cohort will not impact enrollment in another cohort unless the 
sponsor and SRC consider there is an increased overall safety risk.
4.1.4.3.
Rationale for DLT Definitions
The DLT definitions used in this study are informed by prior experience with autologous CAR T 
cell therapies. The clinical data from tisagenlecleucel and axicabtagene ciloleucel in NHL 
(including DLBCL) indicate that although CAR T cell therapies can cause grade 3-4 toxicities in 
approximately 13-40% of subjects, most toxicities respond to treatment and resolve with no 
sequelae (Table 6). 
Table 6:
Frequency of Severe AEs Reported With Tisagenlecleucel and Axicabtagene 
Ciloleucel in Subjects With NHL
Adverse Event
Tisagenlecleucel1
Axicabtagene Ciloleucel2
Grade ≥3 cytokine release 
syndrome
Frequency: 23% 
Median duration: 8 days (range: 1-36)
Frequency: 13%
Median duration: 7 days (range: 2-58)
Grade ≥3 neurological toxicities
Frequency: 18%
Median duration: 14 days
Frequency: 31%
Median duration: 17 days
Prolonged grade ≥3 cytopenias 
At day 28 post infusion:
40% thrombocytopenia
25% neutropenia
At day 30 post infusion: 
18% thrombocytopenia
15% neutropenia 
1. From tisagenlecleucel package insert (Kymriah USPI, 2017).
2. From axicabtagene ciloleucel package insert (Yescarta USPI, 2017).
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The sponsor, in consultation with participating investigators experienced in the administration of 
CAR T cell therapies, have developed protocol DLT definitions that allow time for select AEs to 
improve with appropriate medical management as well as reflect risks that are specific to an 
allogeneic product (e.g., GvHD; see Section 6.2.9). The protocol provides extensive guidance 
regarding how to identify and treat AEs that were previously seen with autologous CAR T cell 
therapies (Section 6). Subjects in Phase 1 Part A (dose escalation) will be hospitalized or remain 
in proximity of the investigative site (i.e., 1-hour transit time) for at least 28 days after each 
CTX110 infusion to ensure appropriate safety monitoring. 
The SRC will closely monitor the evolving safety data from CTX110 during dose escalation, 
including potential DLTs that occur outside the DLT evaluation period, and may adjust the DLT 
criteria further with input from the DSMB.
The sponsor considers this approach appropriate to balance the principal goal of protecting 
subject safety while reducing the likelihood that dose escalation is stopped prematurely, thereby 
allowing adequate opportunity to demonstrate efficacy in a high-risk oncology population with 
limited treatment options.
4.1.5.
Phase 1 Part B Cohort Expansion and Recommended Dose
Cohort expansion (Part B) will begin with Cohort A to further evaluate the safety and efficacy of 
CTX110 in NHL subjects. Cohort expansion can be performed for any cohorts that have 
completed dose escalation and for which the Part B dose has been determined per the protocol-
specified criteria, with agreement from the SRC, DSMB, and at the sponsor’s discretion. 
Alternatively, the sponsor, in agreement with the SRC and DSMB, may begin Phase 2 for any 
NHL cohort that has completed dose escalation (Section 4.2), after selection of a recommended 
Phase 2 dose.
Recommended Part B Dose Rationale (Cohort A)
As of 22 December 2021, the study had enrolled a total of 34 subjects in Cohort A (inclusive of 
legacy Cohort F in the global version of the protocol) and had completed dose escalation for 
Cohort A. Among the 34 enrolled subjects, 32 received CTX110 infusion. Three subjects were 
treated with CTX110 in DL1 (3 × 107 CAR+ T cells), 3 in DL2 (1 × 108 CAR+ T cells), 6 in DL3 
(3 × 108 CAR+ T cells), 6 in DL3.5 (4.5 × 108 CAR+ T cells), and 14 in DL4 (6 × 108 CAR+ T 
cells).
The selection of DL4 (6 × 108 CAR+ T cells) as the recommended Part B dose for NHL subjects 
in Cohort A was based on preliminary efficacy results comparable to available autologous 
CAR T cell therapies, lack of DLTs, and an overall acceptable safety profile.
Based on the totality of safety and efficacy data obtained from these subjects, the sponsor in 
agreement with the SRC and an independent data safety monitor board (DSMB) has selected 
6 ×108 CAR+ T cells (DL4) as the recommended Part B dose for cohort expansion to further 
evaluate the safety and efficacy of CTX110 in NHL subjects. The dose regimen for expansion 
will be the same as for Part A Cohort A, as described in Table 3.
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4.2.
Phase 2 Investigational Plan
Following dose escalation of any Phase 1 cohort, the sponsor may begin enrollment in Phase 2 to 
evaluate efficacy and safety of CTX110 in a larger population of subjects. Enrollment to Phase 2 
will be at the sponsor’s discretion, with agreement from the SRC and DSMB.
Phase 2 will begin with subjects with NHL at the recommended dose and regimen determined in 
Phase 1 for Cohort A, to further evaluate the efficacy and safety of CTX110 in subjects with 
NHL (see Section 4.2.4). Approximately 97 subjects with NHL will be enrolled. Where required, 
regulatory approval will be obtained prior to enrolling any subjects from that region into Phase 2.
Phase 2 may be conducted in parallel with Phase 1 dose escalation or cohort expansion of other 
cohorts in the study. 
One interim analysis is planned in Phase 2 for early efficacy and futility based on the total 
population of the expanded cohort for NHL and will be performed by an independent statistician 
and reviewed by the DSMB. This interim analysis will occur when 50% of the expected subjects 
in the total population have received CTX110 infusion and have 3 months of evaluable tumor 
response data or discontinued earlier. For Phase 2, a sample size of 97 subjects is planned. 
4.2.1.
Phase 2 Study Design
The study will consist of 3 main stages: 
x
Screening to determine eligibility for treatment (1-2 weeks)
x
Treatment:

LD chemotherapy: Co-administration of fludarabine 30 mg/m2 + 
cyclophosphamide 500 mg/m2 IV daily for 3 days; both agents should be started 
on the same day and administered for 3 consecutive days and completed at least 
48 hours (but no more than 7 days) prior to CTX110 infusion

Initial CTX110 infusion on Day 1 (6 × 108 CAR+ T cells)

A second infusion of CTX110 (6 × 108 CAR+ T cells) on Day 35 (-7 days/ 
+21 days) administered with LD chemotherapy for subjects who achieve SD or 
better at Day 28 scan (based on Lugano criteria). The second infusion may be 
administered without LD chemotherapy if the subject is experiencing significant 
cytopenias (see Section 5.3.1.3.1).
x
Follow-up (up to 5 years after the last CTX110 infusion)
Each subject will have the option to receive an additional infusion of CTX110 with LD 
chemotherapy (co-administration of fludarabine 30 mg/m2 + cyclophosphamide 500 mg/m2 IV 
daily for 3 days) after PD, as a second course of treatment, if the subject had response after the 
initial infusion. The additional infusion after PD must be within 18 months of the first CTX110 
infusion and ≥4 weeks after the first infusion.
Subjects’ clinical eligibility should be reconfirmed according to the criteria in Sections 5.2 and 
5.3 prior to both the initiation of LD chemotherapy and infusion of CTX110, and according to 
the criteria in Section 5.3.1 for the second and any subsequent infusion of CTX110. 
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Subjects must remain within proximity of the investigative site (i.e., 1-hour transit time) for 
28 days after the first CTX110 infusion and at least 14 days for subsequent CTX110 infusions, or 
longer if justified by the subject’s clinical status, or required by local regulation or site practice. 
During this acute toxicity monitoring period, subjects will be routinely assessed for AEs, 
including CRS, neurotoxicity, and GvHD. Toxicity management guidelines are provided in 
Section 6. 
After the acute toxicity monitoring period, subjects will be subsequently followed for up to 
5 years after the last CTX110 infusion with physical exams, regular laboratory and imaging 
assessments, and AE evaluations.
4.2.2.
Phase 2 Study Subjects
Approximately 97 subjects with NHL will be treated in Phase 2 with the Cohort A dose regimen, 
contingent upon the outcome of an interim analysis (Section 10.5).
4.2.3.
Phase 2 Study Duration
As in Phase 1 (see Section 4.1.3), Phase 2 subjects will participate in this study for up to 5 years 
after the last CTX110 infusion. All subjects will also be asked to participate in a separate long-
term follow-up study for an additional 10 years to assess long-term safety and survival.
4.2.4.
Phase 2 Dose Rationale
Based on the acceptable safety profile of CTX110 and available clinical data from Part B for 
subjects with NHL, the recommended CTX110 infusion and LD chemotherapy dose regimen 
will be further evaluated for efficacy and safety in the Phase 2 part of the study. See
Section 4.2.1 for LD regimen and CTX110 infusion plan.
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5.
STUDY TREATMENT
5.1.
Daratumumab Administration in Phase 1 
Subjects in Cohort C will receive 1 dose of daratumumab 16 mg/kg by IV infusion or 1800 mg 
by subcutaneous (SC) injection administered at least 1 day prior to starting LD chemotherapy 
and within 10 days of CTX110 infusion (see Table 3). For NHL subjects in Cohort C1 who 
respond to treatment (i.e., achieve SD or better on Day 28), 2 additional doses of daratumumab 
(16 mg/kg) will be administered at the Day 28 (± 4 days) and M2 (± 4 days) visits. For subjects 
in Cohort C2 who respond to treatment (i.e., achieve SD or better on Day 28), an additional dose 
of daratumumab will be administered at the Day 28 visit and an additional infusion of CTX110 
will be administered on Day 35. A second additional daratumumab dose will be administered as 
part of the LD regimen for Day 35 unless within 14 days of the previous Day 28 dose. 
The first dose of daratumumab will be delayed if any of the criteria for delayed lymphodepletion 
as described in Section 5.2 are present.
To be considered for any additional doses of daratumumab, subjects must meet the following 
criteria at the time of daratumumab dosing:
x
No severe or unmanageable toxicity with prior daratumumab doses
x
No ongoing uncontrolled infection
x
Platelet count ≥25,000 cells/μL (nontransfused)
Daratumumab administration (including pre- and postdose medications, preparation, infusion 
rates when administered by IV infusion, postdose monitoring) will be performed according to the 
approved prescribing information. To facilitate administration, the first 16 mg/kg IV dose may 
be split (to 8 mg/kg) over 2 consecutive days. 
After at least 3 subjects are treated at a specific CTX110 dose with daratumumab, the sponsor 
along with the SRC will review the total safety and efficacy data and may decide to enroll 
additional subjects at a specific dose level with a lower dose of daratumumab (8 mg/kg IV). 
Confirmation of tumor response will be based on the PET/computed tomography (CT) scan at 
the Day 28 visit, and the scan must be read before repeat dosing with daratumumab. 
5.1.1.
Daratumumab Infusion Reactions
To reduce the risk of infusion reactions with daratumumab, 1 to 3 hours prior to administration 
subjects will be premedicated with corticosteroids (e.g., IV methylprednisolone 100 mg or 
equivalent), antipyretics (e.g., oral acetaminophen [paracetamol] 650 to 1,000 mg, or equivalent), 
and antihistamines (e.g., oral or IV diphenhydramine hydrochloride [or another H1-
antihistamine] 25 to 50 mg, or equivalent).
If alternative premedication methods are preferred, the site needs to discuss these with and gain 
approval from the medical monitor.
Subjects will be monitored frequently during the entire administration of each dose of 
daratumumab. For infusion reactions of any grade/severity, infusion will be interrupted 
immediately, and symptoms managed. If an anaphylactic reaction or life-threatening (grade 4) 
reaction occurs, therapy will be permanently discontinued, and appropriate emergency care will 
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be administered. For subjects with grade 1, 2, or 3 reactions, after symptom resolution, the 
infusion rate will be reduced when restarting the infusion as described in approved prescribing 
information or per site practice. 
To reduce the risk of delayed infusion reactions, oral corticosteroids (20 mg methylprednisolone 
or equivalent dose of an intermediate-acting or long-acting corticosteroid in accordance with 
local standards) will be administered to subjects following infusion as per prescribing 
information. 
For the second or third dose of daratumumab, intermediate-acting corticosteroids 
(i.e., prednisone, methylprednisone) should be preferentially used to reduce the risk of 
interference with CTX110. 
If a subject has an unresolved infusion reaction after daratumumab treatment, LD chemotherapy 
should be delayed and discussed with the medical monitor prior to proceeding.
5.1.2.
Additional Considerations
Daratumumab has been associated with herpes zoster (2%) and hepatitis B (1%) reactivation in 
patients with multiple myeloma. To prevent herpes zoster reactivation, initiate antiviral 
prophylaxis within 1 week after infusion and continue for 3 months following treatment. For 
subjects with latent hepatitis B, consider hepatitis B prophylaxis prior to initiation of 
daratumumab and for 3 months following treatment (King et al., 2018). 
Supportive care should be provided according to the approved prescribing information.  
Daratumumab binds to CD38 on red blood cells and results in a positive indirect antiglobulin test 
(indirect Coombs test). Blood type and screen per the approved prescribing information to 
prevent interference with blood compatibility testing.
5.1.3.
Daratumumab Dose Rationale
Daratumumab is a human immunoglobulin G1 monoclonal antibody that targets CD38 surface 
antigen. CD38 is overexpressed in hematologic malignancies, including multiple myeloma, and 
daratumumab is thought to exert anticancer efficacy through several mechanisms, including 
antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity, and 
apoptosis via cross-linking. CD38 is also expressed on various immune cell populations, 
including regulatory and activated T cells, B cells, myeloid-derived suppressor cells, and NK 
cells, and daratumumab has several demonstrated immunoregulatory modes of actions (Casneuf 
et al., 2017; Castella et al., 2019; Krejcik et al., 2016).
The goal of daratumumab administration in this study is to utilize these immunomodulatory 
effects to induce an immune environment amenable to allogeneic CAR T cells.
 
 
The use of a monoclonal antibody (median [± standard deviation] half-life of 
18 ± 9 days) is intended to deepen and prolong the immunosuppressive effects achieved with 
LD chemotherapy alone. Analogous strategies of combining a biologic (e.g., alemtuzumab, an 
anti-CD52 monoclonal antibody) with chemotherapy-based lymphodepletion have been 
successfully pursued in other allogeneic CAR T studies (Benjamin et al., 2020). However, given 
the broad expression of CD52 across the immune system and the known significant 
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immunosuppression associated with alemtuzumab, 
 
 As mentioned in Section 1.6, CTX110 is an 
allogeneic CAR T cell with disruption of the B2M locus, resulting in elimination of MHC class I 
expression on the cell surface, NK cells can potentially detect and clear these “nonself” MHC 
class I negative cells (Paul and Lal, 2017).
 
 
 
 
 
 
 
 
 
 
 
 
Daratumumab was previously evaluated for safety and efficacy in a Phase 2, proof-of-concept 
trial in subjects with relapsed/refractory NHL, including DLBCL, FL, and mantle cell lymphoma 
(MCL; N = 138). Daratumumab (16 mg/kg; 28-day cycles) was administered IV weekly for 
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2 cycles, every 2 weeks for 4 cycles, and every 4 weeks thereafter. Median CD38 expression 
across treated subjects was 70%. The ORR was 6.7%, 12.5%, and not evaluable in the DLBCL, 
FL, and MCL cohorts, respectively. The most common grade 3 or 4 treatment-emergent adverse 
event (TEAE) was thrombocytopenia (11.1%), and 4 (11.1%) subjects discontinued treatment 
because of TEAEs. Infusion-related reactions occurred in 72.2% of subjects, and the most 
common reaction was cough (DLBCL cohort: 26.7%; FL cohort: 25.0%; MCL cohort: 80.0%). 
One subject in each cohort reported a grade 3 infusion-related reaction on Cycle 1, Day 1, which 
included 2 cases of hypertension, 1 case of pharyngeal edema, and 1 swollen tongue. No grade 4 
infusion-related reactions were reported. All infusion-related reactions occurred during the first 
infusion and recovered/resolved on the same onset date. In conclusion, although this study failed 
to demonstrate clinically meaningful activity of single-agent daratumumab in the NHL patient 
population, it did confirm that there were no safety concerns with use of daratumumab in 
subjects with NHL. All subjects with evaluable samples were found to be negative for
 and the PK of daratumumab were found to be consistent with the results 
observed in multiple myeloma studies (Salles et al., 2019). 
The proposed daratumumab dosage (16 mg/kg IV) used in this protocol is consistent with the 
doses investigated in the 2 registrational clinical trials in subjects with relapsed or refractory 
multiple myeloma (Lokhorst et al., 2015; Lonial et al., 2016) and in the proof-of-concept trial in 
subjects with relapsed or refractory NHL subtypes (Salles et al., 2019). Daratumumab is also 
available as an SC injection of 1800 mg that is co-formulated with 30,000 units of 
hyaluronidase-fihj, which increases permeability of the SC tissue by depolymerizing hyaluronan. 
The daratumumab and hyaluronidase-fihj SC formulation has been shown to be noninferior to 
the IV formulation and is approved for the treatment of patients with multiple myeloma. In 
summary, the IV and SC formulations were shown to be comparable in terms of efficacy and PK, 
with fewer infusion reactions based on a noninferiority trial in multiple myeloma (Mateos et al., 
2020). Daratumumab administered SC was noninferior to daratumumab 16 mg/kg administered 
IV, as measured by ORR (41% vs 37%, respectively) and maximum Ctrough (593 ± 306 μg/mL vs 
522 ± 226 μg/mL, respectively; geometric mean ratio of 108%). The incidence of 
administration-related reactions was significantly lower with SC daratumumab (13%) compared 
with IV daratumumab (34%) (Mateos et al., 2020).  
5.2.
Lymphodepleting Chemotherapy
Phase 1 
All subjects in all cohorts will receive LD chemotherapy prior to infusion of first CTX110 
infusion and before additional infusions, as specified in Section 5.3.1. 
Prior to first CTX110 infusion for Cohorts A, C, and D, and prior to additional CTX110 
infusions for all cohorts, LD chemotherapy will consist of:
x
Fludarabine 30 mg/m2 IV daily for 3 doses AND
x
Cyclophosphamide 500 mg/m2 IV daily for 3 doses.
For Cohort B, LD chemotherapy prior to first CTX110 infusion will consist of:
x
Fludarabine 30 mg/m2 IV daily for 3 doses AND
x
Cyclophosphamide 750 mg/m2 IV daily for 3 doses.
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Phase 2
Prior to first CTX110 infusion and prior to additional CTX110 infusions, LD chemotherapy will 
consist of:
x
Fludarabine 30 mg/m2 IV daily for 3 doses AND
x
Cyclophosphamide 500 mg/m2 IV daily for 3 doses.
Phase 1 and Phase 2
Both LD agents (fludarabine and cyclophosphamide) will be started on the same day and 
administered for 3 consecutive days. Subjects should start LD chemotherapy (or daratumumab 
administration) within 7 days of study enrollment. Adult subjects with moderate impairment of 
renal function (creatinine clearance 30-70 mL/min/1.73 m2) may receive a reduced dose of 
fludarabine in accordance with applicable prescribing information.
Reference the current full prescribing information for fludarabine and cyclophosphamide for 
guidance regarding the storage, preparation, administration, supportive care instructions, and 
toxicity management associated with LD chemotherapy. 
For subjects in all cohorts, LD chemotherapy or first daratumumab dose (subjects in Phase 1 
Cohort C) will be delayed if any of the following signs or symptoms are present:
x
Significant worsening of clinical status that, according to the investigator, increases 
the potential risk of AEs associated with LD chemotherapy
x
Requirement for supplemental oxygen to maintain a saturation level >91%
x
New uncontrolled cardiac arrhythmia
x
Hypotension requiring vasopressor support
x
Active infection: Positive blood cultures for bacteria, fungus, or virus not responding 
to treatment, or negative culture but active infection based on investigator judgment 
in consultation with the medical monitor
x
Grade ≥2 acute neurological toxicity
x
Unresolved infusion reaction due to daratumumab treatment (Phase 1 Cohort C only)
See Section 5.3.1.3 and Section 5.3.1.3.1 for additional criteria that may affect administration of 
LD chemotherapy.
During Phase 1, Part A (dose escalation), if LD chemotherapy is delayed more than 30 days or 
the subject starts
the subject will be replaced. For subjects whose toxicity(ies) 
are driven by underlying disease and require
 they must subsequently meet 
disease inclusion criteria, treatment washout, and end organ function criteria before restarting LD 
chemotherapy. Additionally, any subject who received
after enrollment 
(besides LD chemotherapy for all cohorts or daratumumab for Cohort C) must have disease 
evaluation (including PET/CT scan) performed prior to starting LD chemotherapy (Cohorts A, B, 
and D) or daratumumab (Cohort C).
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5.2.1.
Lymphodepleting Chemotherapy Dose Rationale
The goal of lymphodepletion is to allow for significant CAR T cell expansion following 
infusion. LD chemotherapy consisting of fludarabine and cyclophosphamide across different 
doses has been successfully utilized in several autologous CAR T cell trials. The rationale for the 
use of LD chemotherapy is to eliminate regulatory T cells and other competing elements of the 
immune system that act as 
enhancing the availability of
such as 
(Dummer et al., 2002; Gattinoni et al., 2005). Additionally, it is 
postulated that naïve T cells begin to proliferate and differentiate into memory-like T cells when 
total numbers of naïve T cells are reduced below a certain threshold (Dummer et al., 2002). 
Cohorts A, C, and D will use cyclophosphamide (500 mg/m2) and fludarabine (30 mg/m2) at 
doses that are consistent with doses used in registrational clinical trials of axicabtagene 
ciloleucel. Cohort B will use a higher dose of cyclophosphamide (750 mg/m2) prior to first 
CTX110 infusion to evaluate whether increased intensity of lymphodepletion may facilitate 
expansion of an allogeneic CAR T cell product in subjects who received prior treatment with an 
approved autologous CD19-directed CAR T cell therapy. Doses of cyclophosphamide within this 
range (total of >120 mg/kg or 3 g/m2) have been used in prior CAR T cell therapy studies in 
hematological malignancies (Brentjens et al., 2011; Kochenderfer et al., 2015; Turtle et al., 
2016). When used as a part of higher intensity LD chemotherapy, increased doses of 
cyclophosphamide are associated with improved efficacy (Hirayama et al., 2019). In preliminary 
results from a study of the allogeneic CAR T cell therapy PBCAR0191 in relapsed autologous 
CAR T cell therapy subjects, an LD regimen of 30 mg/m2 fludarabine for 4 days + 750 mg/m2
cyclophosphamide for 3 days (similar to the LD regimen for Cohort B) showed peak expansion 
of PBCAR0191 and resulted in 100% ORR (11/11 subjects) and 73% CR (8/11 subjects) 
(Precision Biosciences, 2022).
5.3.
Administration of CTX110
CTX110 consists of allogeneic T cells modified with CRISPR-Cas9,
A flat dose of CTX110 (based 
on CAR T cells) will be administered as a single IV infusion. A dose limit of 
TCR+
cells/kg will be imposed for all dose levels. 
Infusion should preferably occur through a central venous catheter. A leukocyte filter must 
not be used.  
Prior to the start of CTX110 infusion, the site pharmacy must ensure that 2 doses of tocilizumab 
and emergency equipment are available for each specific subject treated. Subjects should be 
premedicated per the site standard of practice with acetaminophen PO (i.e., paracetamol or its 
equivalent per site formulary) and diphenhydramine hydrochloride IV or PO (or another 
H1-antihistamine per site formulary) approximately 30 to 60 minutes prior to CTX110 infusion. 
Prophylactic systemic corticosteroids should not be administered, as they may interfere 
with the activity of CTX110.
Refer to Section 5.4.2 for a list of medications that must be discontinued prior to CTX110 
infusion. 
Each CTX110 infusion will be delayed if any of the following signs or symptoms are present: 
x
New active uncontrolled infection
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x
Worsening of clinical status compared to prior to start of LD chemotherapy that, in 
the opinion of the investigator, places the subject at increased risk of toxicity
x
Grade ≥2 acute neurological toxicity
Each CTX110 infusion will be administered at least 48 hours (but no more than 7 days) after the 
completion of LD chemotherapy. If CTX110 infusion is delayed by more than 10 days, LD
chemotherapy must be repeated. Contact the CRISPR medical monitor if a subject’s CTX110 
infusion is delayed. Refer to Section 5.3.1 for information regarding additional CTX110 
infusions.
Refer to the Infusion Manual for detailed instructions on preparation, storage, handling, and 
administration of CTX110.
5.3.1.
Additional CTX110 Infusion(s)
5.3.1.1.
Rationale for CTX110 Additional Infusions
Subjects dosed with CTX110 have achieved objective responses without multi-log CAR T cell 
expansion in peripheral blood, suggesting a different biology and cell behavior than autologous 
CAR T cells. 
 
 
As allogeneic CAR T cells may be 
susceptible to more rapid clearance than autologous CAR T cells upon lymphocyte recovery, it 
therefore may be necessary to administer more than a single infusion to clear any remaining 
cancerous cells. In order to achieve greater responses and prolonged durability, the sponsor is 
proposing additional CTX110 infusions in subjects who do not experience significant toxicity 
following the first CTX110 infusion. 
Additional infusions of CTX110 are proposed based on the safety profile demonstrated in Study 
CRSP-ONC-001 as of 10 April 2022, which includes 61 subjects treated at 5 different dose 
levels (DL1, DL2, DL3, DL3.5, and DL4) in Phase 1 of the study, and which is largely 
consistent with other CD19-directed CAR T cell therapies. See Section 1.8 and refer to the 
CTX110 Investigator’s Brochure for the preliminary clinical safety data for CTX110. 
As of the data cutoff date of 10 April 2022, 18 subjects with NHL had received a second infusion 
of CTX110 in Phase 1 of the study. Nine of these subjects received the second infusion as part of 
the dose regimen of the first course of treatment (4 in Part A Cohort A, 1 in Part A Cohort C, and 
4 in Part B cohort expansion). The other 9 subjects responded to the initial CTX110 infusion, 
subsequently had disease progression, and received the second CTX110 infusion as a second 
course of treatment (all in Part A Cohort A). The incidence and severity of AEs was similar after 
first and second infusion. In Part A Cohort A (inclusive of legacy Cohort F), AESIs were 
reported in 14 of 32 subjects (43.8%) after first CTX110 infusion and in 6 of 13 subjects (46.2%) 
after second CTX110 infusion. CRS was reported in 13 subjects (40.6%) after the first infusion 
and in 6 subjects (46.2%) after second infusion, all grade 1 or grade 2 per Lee 2019 criteria. 
After first infusion, ICANS was reported in 3 subjects (9.4%), opportunistic or invasive 
infections in 3 subjects (9.4%), and hypogammaglobulinemia in 1 subject (3.1%). After second 
infusion, opportunistic or invasive infection was reported in 1 subject (7.1%) and there were no 
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reports of ICANS or hypogammaglobulinemia. The sponsor considers this an acceptable safety 
profile to investigate the potential efficacy improvements that may come from a second CTX110 
infusion.
Preliminary data from other allogeneic anti-CD19 CAR T cell development programs have also 
suggested multiple infusions may have a favorable benefit-risk profile. Notably, it was recently 
reported that a subject with relapsed/refractory DLBCL who responded and subsequently 
progressed after their first infusion of ALLO-501 achieved a CR upon receiving a second 
infusion of allogeneic CAR T cells (Neelapu et al., 2020) ClinicalTrials.gov Identifier: 
NCT03939026). Of 6 subjects who received 2 infusions of ALLO-501A in the ALPHA2 trial, 
none experienced CRS, ICANS, or GvHD (Allogene Therapeutics, 2021). Recently, data were 
presented from another subject, with adult B cell ALL, who received a second infusion of 
PBCAR0191 on Day 10 without LD chemotherapy. The subject tolerated the second infusion 
and received a third infusion of PBCAR0191 on Day 28 with LD chemotherapy. The subject did 
not experience ICANS or GvHD. Out of 11 adult ALL subjects treated on that trial, 5 had grade 
1 or 2 CRS; however, it is unclear from the available information if any of those subjects 
received multiple infusions of CAR T cells (Precision Biosciences, 2020). 
Taken together, the sponsor believes that the current benefit-risk profile of CTX110 in addition 
to the available clinical data with CTX110 and other allogeneic CAR T cell therapies collectively 
support further investigating the safety and efficacy of multiple infusions in order to enhance 
clinical responses and prolong durability within this patient population.
5.3.1.2.
Administration Schedule for Subsequent Infusions of CTX110
This study will allow for up to 3 infusions of CTX110 for each subject. 
The additional CTX110 infusions after Day 1 will occur in the following 2 scenarios: 
1. In the first course of treatment, additional infusions will be based on disease response 
criteria. In Phase 1, these additional infusions will be administered in all cohorts except 
Subcohort C1 (see tabulation below and details in Section 5.3.1.3).
Cohort
Additional CTX110 Infusions after Day 1 Within the First Course of 
Treatment
A and B
A second infusion of CTX110 on Day 35 (-7 days/+21 days) administered with 
LD chemotherapy to subjects who achieve SD or better at Day 28 scan (based 
on Lugano criteria). Note: For LD chemotherapy for Cohort B, 
cyclophosphamide dose will be 750 mg/m2 prior to first CTX110 infusion, and 
500 mg/m2 prior to subsequent CTX110 infusion.
C2
A second infusion of CTX110 on Day 35 (-7 days/+21 days) administered with 
daratumumab and LD chemotherapy to subjects who achieve SD or better at 
Day 28 scan (based on Lugano criteria). 
D1 and D2
A second infusion of CTX110 on Day 35 (-7 days/+21 days) administered with 
LD chemotherapy if the subject has a decrease in BM blast count at Day 28 of 
≥50% or is MRD-positive (Subcohort D1) or has demonstrated a reduction in 
detectable MRD and remain MRD positive (Subcohort D2). 
Note: In all cohorts described above, a subject may receive the Day 35 infusion without the LD regimen if 
experiencing significant cytopenias.
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2. For all Phase 1 cohorts and in Phase 2, a second course of treatment consisting of a single 
CTX110 infusion with LD chemotherapy may be administered after PD if the subject has 
demonstrated clinical benefit after the first course of treatment. The additional infusion 
after PD must be within 18 months of the initial CTX110 infusion and ≥4 weeks from the 
prior CTX110 infusion (Section 5.3.1.4). Subjects in Cohort D who are
and become MRD-positive without increase in BM blast count may be considered for a 
second course of treatment. 
To receive an additional CTX110 infusion after Day 1, subjects must meet the criteria and repeat 
some of the screening assessments specified in Sections 5.3.1.3 and 5.3.1.4. All CTX110 
infusions subsequent to Day 1 should be discussed in advance with the medical monitor.
Phase 2 will follow the same additional infusions for the first course of treatment and a second 
course of treatment as determined for Cohort A expansion in Part B of Phase 1 (see Section 4.2.1
for the Phase 2 dose regimen, including additional CTX110 infusions). 
5.3.1.3.
Criteria for Day 35 CTX110 Infusions Within the First Course of Treatment 
For second infusions of CTX110 in Phase 1 Cohorts A, B, C2, and D and in Phase 2 (Day 35), 
subjects must meet the following criteria: 
x
No prior DLT during dose escalation (if applicable)
x
No prior grade ≥3 CRS without resolution to grade ≤2 within 72 hours following 
CTX110 infusion per ASTCT criteria 
x
No prior GvHD following initial CTX110 infusion
x
Grade 1, 2, or 3 ICANS must have resolved more than 14 days prior to a subsequent 
CTX110 infusion
x
No prior grade 4 ICANS
Additionally, at the time of LD chemotherapy and prior to second infusion (Day 35), subjects 
must meet the following criteria:
x
ECOG performance status 0 or 1
x
No requirement for supplemental oxygen to maintain a saturation level >91% 
x
No new uncontrolled cardiac arrhythmia 
x
No hypotension requiring vasopressor support or fluid bolus
x
No active uncontrolled infection (positive blood cultures for bacteria, fungus, or virus 
not responding to treatment)
x
Renal: Estimated glomerular filtration rate >50 mL/min/1.73 m2
x
Liver: AST or ALT <3 × ULN; total bilirubin <1.5 × ULN (for subjects with 
Gilbert’s syndrome, total bilirubin <2 mg/dL)
x
No worsening of clinical status compared to prior CTX110 infusion that, in the 
opinion of the investigator, places the subject at increased risk of toxicity.
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x
No new neurological symptoms suggesting CNS disease involvement. In the case of a 
normal finding on lumbar puncture or brain MRI and following resolution of 
neurologic symptoms, additional CTX110 infusions could be considered.
x
Women who are pregnant or breastfeeding are not eligible for additional CTX110 
infusions.
Local laboratory testing performed within 14 days of planned start of lymphodepletion may be 
used to confirm eligibility for subsequent CTX110 infusions. Not all central lab screening 
samples may be required; refer to Laboratory Manual for details.
In the first course of treatment, prior to second CTX110 infusion, LD chemotherapy may be 
omitted for subjects with platelet count <25,000 cells/μL or ANC <500/mm3 (unless alternative 
etiologies for cytopenias are provided; see Section 5.3.1.3.1 for further details).
Subjects who receive an additional infusion should be followed per the schedule of assessments 
in Table 16, consistent with their initial infusion, with the following considerations:
x
Echocardiogram (unless new cardiac signs or symptoms), brain MRI, and lumbar 
puncture (unless new neurological symptoms concerning for progression) are not 
required.
x
The requirement to confirm CD19 expression is optional in Subcohort D2.
x
PET/CT must be performed within 4 weeks of the additional infusion.
x
Bone marrow biopsy and aspirate must be repeated within 28 days of the additional 
infusion in subjects with NHL and B cell ALL with initial bone marrow involvement.  
The investigator may choose not to administer the second CTX110 infusion if there is a concern 
for increased risk or lack of benefit to the subject based on the subject’s current clinical status.
5.3.1.3.1. Cytopenia and LD Chemotherapy
During the first course of treatment, in subjects with significant cytopenias (ANC <500/mm3
and/or platelets <25,000 cells/μL), the investigator may omit LD chemotherapy prior to the 
second CTX110 infusion (Day 35). Individual cases may be discussed with medical monitor, if 
there is strong evidence of cytopenias being due to alternative etiologies or expected recovery 
(including underlying malignancy especially for subjects with B cell ALL).
The sponsor will continue to evaluate subjects who receive additional infusions with LD 
chemotherapy for prolonged cytopenias. After at least 6 subjects receive an additional infusion 
with LD chemotherapy in cohort expansion, if >50% of subjects have prolonged grade 3 or 4 
cytopenias (i.e., lasting more than 28 days post infusion), use of LD chemotherapy prior to 
additional infusions will be reconsidered while the sponsor and the SRC reassess current schema 
and propose an alternate regimen. 
In cohort expansion, in subjects who on Day 28 had SD or better and subsequently receive an 
additional CTX110 infusion without LD chemotherapy, if 8 subjects are infused and all have 
progressive disease or there is no improvement in response observed based on imaging 28 days 
after the last infusion, the option of subsequent infusions without LD chemotherapy will be 
removed and subsequent subjects will receive additional infusions of CTX110 with LD 
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chemotherapy or will not receive additional infusions of CTX110. See Section 5.2 for LD 
chemotherapy details.
5.3.1.4.
Second Course of Treatment After Progressive Disease for All Cohorts
For all Phase 1 cohorts and in Phase 2, a subject may receive an additional infusion of CTX110 
after PD if the subject has a clinical response after the first course of treatment. Subjects must 
have achieved evidence of clinical benefit, as demonstrated by a decrease in tumor size and/or 
FDG-avidity on a PET/CT scan after CTX110 infusion for subjects with NHL and by ≥50% 
decrease in BM blasts or achieving
remission for subjects with adult B cell ALL, 
and either concurrently or subsequently progressed or relapsed. The additional infusion after PD 
must be within 18 months of the initial CTX110 infusion and ≥4 weeks from the prior CTX110 
infusion. The additional CTX110 infusion will be administered only if the extent of disease is 
less than what was documented prior to the initial CTX110 infusion and will proceed only after 
consultation with the medical monitor. Subjects with B cell ALL who have become MRD-
positive after achieving
remission may also be considered for a second course of 
treatment. The second course of treatment will be administered with standard lymphodepletion 
(i.e., without daratumumab) for subjects in Phase 1 Cohort C. 
The earliest time at which a subject could be receive a CTX110 infusion after PD is ≥4 weeks 
following last CTX110 infusion. The additional infusion in subjects with grade 3 or 4 
neutropenia or thrombocytopenia who are ≥4 weeks after last CTX110 infusion will not be 
permitted unless the cytopenias can be clearly attributed to PD or other reversible cause. 
To receive the second course of treatment with an additional CTX110 infusion, subjects must 
meet the following criteria: 
x
Confirmation tumor (NHL) or bone marrow (ALL) remains CD19+ at relapse (by 
flow cytometry or immunohistochemistry); the requirement to confirm CD19 
expression is optional in subjects with B cell ALL with only MRD positive disease.
x
No prior DLT during dose escalation (if applicable)
x
No prior grade ≥3 CRS without resolution to grade ≤2 within 72 hours following 
CTX110 infusion
x
No prior GvHD following CTX110 infusion
x
No prior grade ≥2 ICANS following CTX110 infusion
x
Meet initial study inclusion criteria (#1, #2, #5 through#9) and exclusion criteria (#1 
[except prior treatment with CTX110] through #14), as described in Section 3
x
Meet criteria for LD chemotherapy and CTX110 infusion, as described in 
Sections 5.2 and 5.3, respectively
x
Subjects who are reinfused after PD should be followed per the schedule of 
assessments in Table 16. 
All Stage 1 screening assessments (see Schedule of Assessments) must be repeated, including the 
following additional considerations:
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x
Brain MRI and lumbar puncture to be repeated if at high risk for CNS recurrence 
based on International Prognostic Index criteria (Schmitz et al., 2016) or signs of 
CNS involvement are present at the time of the additional infusion. All subjects with 
adult B cell ALL must have a repeat of lumbar puncture (LP) prior to additional 
infusion.
x
Echocardiogram may be omitted if the additional infusion occurs within 3 months of 
last CTX110 infusion when echocardiogram was performed and if no new cardiac 
symptoms have occurred. 
x
For NHL cohorts: The PET/CT scan demonstrating disease relapse/progression will 
serve as the new baseline for tumor response evaluation. The additional infusion must 
occur within 28 days of that scan. Bone marrow aspirate and biopsy must be repeated 
if it was not performed at the time of relapse/progression. 
x
For adult B cell ALL cohorts: Bone marrow aspirate and biopsy (as well as imaging 
for subjects with extramedullary disease) within 28 days of LD chemotherapy. 
Subjects who receive an additional CTX110 infusion after PD will receive a lymphodepletion 
regimen according to their initial cohort design and a CTX110 dose that at the time of the 
additional infusion has been deemed safe by the SRC. Exception will be made for subjects in 
Cohort B or C, who may receive lymphodepletion similar to Cohort A after discussion with 
medical monitor. 
In subjects who have more than 1 infusion prior to disease progression, disease response 
assessments will continue using the baseline PET/CT scan and bone marrow biopsy performed 
during screening. For subjects who receive an additional CTX110 infusion after PD, disease 
response will be assessed relative to the most recent PET/CT scan and bone marrow prior to the 
additional infusion.
5.3.2.
CTX110 Postinfusion Monitoring
Following CTX110 infusion, subject’s vitals should be monitored every 30 minutes for 2 hours 
after infusion or until resolution of any potential clinical symptoms.
Subjects in Phase 1 Part A will be hospitalized for a minimum of 7 days after CTX110 infusion, 
or longer if required by local regulation or site practice (Appendix D). In Phase 1 Part A (dose 
escalation, subjects must remain in proximity of the investigative site (i.e., 1-hour time) for at 
least 28 days after CTX110 infusion. For Phase 1 Part B (cohort expansion) and Phase 2, 
subjects must remain within proximity of the investigative site (i.e., 1-hour transit time) for 
28 days after the first CTX110 infusion and at least 14 days for subsequent CTX110 infusions, or 
longer if justified by subject’s clinical status or as required by local regulation or site practice.
Management of acute CTX110-related toxicities should occur ONLY at the study site.
Subjects will be monitored for signs of CRS, TLS, neurotoxicity, GvHD, and other AEs 
according to the schedule of assessments (Table 16, Table 17, and Table 18).
Guidelines for the management of CAR T cell–related toxicities are described in Section 6. 
Subjects should remain hospitalized until CTX110-related nonhematologic toxicities (e.g., fever, 
hypotension, hypoxia, ongoing neurological toxicity) return to grade 1. Subjects may remain 
hospitalized for longer periods if considered necessary by the treating investigator.
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5.3.3.
Investigational Product Accountability
The investigator and sponsor are responsible for accountability and traceability of CTX110 
clinical supply.
The investigator will ensure that CTX110 is used in accordance with this protocol. Detailed 
accountability records indicating CTX110 inventory at each clinical site, use by each subject, 
and disposal will be maintained by the clinical sites. These records will document which subjects 
were provided the CTX110 dose as specified in the protocol and will reconcile CTX110 received 
by the subject. To maintain compliance, the sponsor or its designee will review CTX110 clinical 
supply accountability records at the clinical sites on an ongoing basis during monitoring visits.
All excess material containing CTX110 will be considered hazardous waste and disposed of in 
compliance with applicable regulations and standard hospital procedures. Destruction will be 
adequately documented and reviewed regularly by the sponsor or its designee and the 
investigator.
In cases in which daratumumab is supplied by the sponsor, the investigator and sponsor are 
responsible for accountability and traceability of daratumumab clinical supply in a manner 
similar to that for CTX110, as described above. 
5.4.
Prior and Concomitant Medications
5.4.1.
Allowed Medications
Necessary supportive measures for optimal medical care will be given throughout the study, 
including IV antibiotics to treat infections, growth factors, blood components, etc., except for 
prohibited medications listed in Section 5.4.2.
All concurrent therapies, including prescription and nonprescription medication, must be 
recorded from the date of signed informed consent through 3 months after CTX110 infusion. 
Beginning 3 months post-CTX110 infusion, only the following selected concomitant 
medications will be collected: IV immunoglobulins, vaccinations,
immunosuppressants (including steroids), and 
any investigational agents. 
5.4.2.
Prohibited Medications
The following medications are prohibited during certain periods of the study as specified below:
x
Corticosteroid therapy at a pharmacologic dose (>10 mg/day of prednisone or 
equivalent doses of other corticosteroids) and other immunosuppressive drugs should 
be avoided after CTX110 administration unless medically indicated to treat new 
toxicity or as part of management of CRS or neurotoxicity associated with CTX110, 
as described in Section 6. Use of oral corticosteroids before and after daratumumab 
administration is permitted to prevent infusion reactions, as described in Section 5.1.
x
Granulocyte-macrophage colony-stimulating factor (GM-CSF) following CTX110 
infusion due to the potential to worsen symptoms of CRS
x
Granulocyte colony-stimulating factor (G-CSF) is prohibited following CTX110 
infusion but may be administered ≥10 days following CTX110 infusion if subject 
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shows no signs of CRS. In addition, for cohorts that receive 2 CTX110 infusions with 
LD chemotherapy in a regimen, proactive use of G-CSF starting ≥10 days following 
the first CTX110 infusion is recommended to support the second round of LD 
chemotherapy.
x
Intrathecal CNS prophylaxis must be stopped at least 7 days prior to CTX110 
infusion.
6.
TOXICITY MANAGEMENT
6.1.
General Guidance
Subjects must be closely monitored for at least 28 days after CTX110 infusion. Significant 
toxicities have been reported with autologous CAR T cell therapies and investigators are 
required to proactively monitor and treat all adverse events in accordance with protocol 
guidance. 
Although this is a first-in-human study and the clinical safety profile of CTX110 has not been 
described, the following general recommendations are provided based on prior experience with 
CD19-directed autologous CAR T cell therapies:
x
Fever is the most common early manifestation of CRS; however, subjects may also 
experience weakness, hypotension, or confusion as first presentation. 
x
Diagnosis of CRS should be based on clinical symptoms and NOT laboratory values.
x
In subjects who do not respond to CRS-specific management, always consider sepsis 
and resistant infections. Subjects should be continually evaluated for resistant or 
emergent bacterial infections, as well as fungal or viral infections.
x
CRS, HLH, and TLS may occur at the same time following CAR T cell infusion. 
Subjects should be consistently monitored for signs and symptoms of all the 
conditions and managed appropriately.
x
Neurotoxicity may occur at the time of CRS, during CRS resolution, or following 
resolution of CRS. Grading and management of neurotoxicity will be performed 
separately from CRS.
x
Tocilizumab must be administered within 2 hours from the time of order.
The safety profile of CTX110 will be continually assessed throughout the study, and 
investigators will be updated on a regular basis with new information regarding the identification 
and management of potential CTX110-related toxicity (refer to the CTX110 Investigator’s 
Brochure).
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6.2.
Toxicity-Specific Guidance
6.2.1.
Infusion Reactions
Infusion reactions have been reported in autologous CD19-directed CAR T cell trials, including 
transient fever, chills, and/or nausea. Acetaminophen (paracetamol) and diphenhydramine 
hydrochloride (or another H1-antihistamine) may be repeated every 6 hours after CTX110 
infusion, as needed, if an infusion reaction occurs.
Nonsteroidal anti-inflammatory medications may be prescribed, as needed, if the subject 
continues to have fever not relieved by acetaminophen. Systemic steroids should not be 
administered except in cases of life-threatening emergency, as this intervention may have a 
deleterious effect on CAR T cells.
6.2.2.
Febrile Reaction and Infection Prophylaxis 
Infection prophylaxis should occur according to the institutional standard of care. 
In the event of febrile reaction, an evaluation for infection should be initiated and the subject 
managed appropriately with antibiotics, fluids, and other supportive care as medically indicated 
and determined by the treating physician. Viral and fungal infections should be considered 
throughout a subject’s medical management if fever persists. If a subject develops sepsis or 
systemic bacteremia following CTX110 infusion, appropriate cultures and medical management 
should be initiated. Additionally, consideration of CRS should be given in any instances of fever 
following CTX110 infusion within 30 days post infusion.
For Phase 1 Cohort C, prophylaxis for herpes zoster and hepatitis B reactivation in the setting of 
daratumumab treatment is strongly recommended, as per prescribing information. 
For subjects receiving multiple CTX110 infusions with LD chemotherapy, pneumocystis 
jirovecii prophylaxis is recommended per local guidelines.
6.2.3.
Tumor Lysis Syndrome 
Subjects receiving CAR T cell therapy are at increased risk of TLS. Subjects should be closely 
monitored for TLS via laboratory assessments and symptoms from the start of LD chemotherapy 
until 28 days following CTX110 infusion.
All subjects at risk for TLS should receive prophylactic allopurinol (or a nonallopurinol 
alternative, such as febuxostat, per institutional guidelines) and increased oral/IV hydration 
during screening and before initiation of LD chemotherapy. Prophylaxis can be stopped after 28 
days following CTX110 infusion or once the risk of TLS passes. 
Sites should monitor and treat TLS as per their institutional standard of care, or according to 
published guidelines (Cairo and Bishop, 2004). TLS management, including administration of 
rasburicase, should be instituted promptly when clinically indicated.  
6.2.4.
Cytokine Release Syndrome
CRS is a major toxicity reported with autologous CD19-directed CAR T cell therapy. CRS is due 
to hyperactivation of the immune system in response to CAR engagement of the target antigen, 
resulting in multi-cytokine elevation from rapid T cell stimulation and proliferation (Frey et al., 
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2014; Maude et al., 2014a). When cytokines are released, a variety of clinical signs and 
symptoms associated with CRS may occur, including cardiac, gastrointestinal (GI), neurological, 
respiratory (dyspnea, hypoxia), skin, cardiovascular (hypotension, tachycardia), and 
constitutional (fever, rigors, sweating, anorexia, headaches, malaise, fatigue, arthralgia, nausea, 
and vomiting) symptoms, and laboratory (coagulation, renal, and hepatic) abnormalities. 
The goal of CRS management is to prevent life-threatening sequelae while preserving the 
potential for the antitumor effects of CTX110. Symptoms usually occur 1 to 14 days after 
autologous CAR T cell therapy, but the timing of symptom onset has not been fully defined for 
allogeneic CAR T cells. 
CRS should be identified and treated based on clinical presentation and not laboratory cytokine 
measurements. If CRS is suspected, grading should be applied according to the ASTCT 
(formerly known as American Society for Blood and Marrow Transplantation) consensus 
recommendations (Lee et al., 2019) (Table 7), and management should be performed according 
to the recommendations in Table 8.
At the time of the original protocol version (V1.0), the well-known Lee 2014 CRS grading 
criteria (Lee et al., 2014) were applied to Part A. However, this has been updated to the ASTCT 
criteria (Lee et al., 2019), which have become the worldwide standard for CRS grading. Starting 
with Protocol Version 6.0 (Amendment 5), only the ASTCT criteria will be used during both 
Parts A and Part B (cohort expansion) of the trial. CRS events previously graded using the Lee 
criteria (Lee et al., 2014) will be re-graded according to the ASTCT criteria for the purposes of 
aggregate safety reporting.
Neurotoxicity will be graded and managed as described in Section 6.2.5.
Table 7:
Grading of CRS According to ASTCT Consensus Criteria
CRS Parameter
Grade 1
Grade 2
Grade 3
Grade 4
Fever1
Temperature ≥38°C
Temperature ≥38°C
Temperature ≥38°C
Temperature ≥38°C
With hypotension
None
Not requiring 
vasopressors
Requiring a 
vasopressor with or 
without vasopressin
Requiring multiple 
vasopressors 
(excluding 
vasopressin)
And/or 
Hypoxia2
None
Requiring low-flow 
nasal cannula3 or 
blow-by
Requiring high-flow 
nasal cannula3, 
facemask, 
nonrebreather mask, 
or Venturi mask
Requiring positive 
pressure (e.g., CPAP, 
BiPAP, intubation, 
and mechanical 
ventilation)
ASTCT: American Society for Transplantation and Cellular Therapy; BiPAP: bilevel positive airway pressure; 
C: Celsius; CPAP: continuous positive airway pressure; CRS: cytokine release syndrome; CTCAE: Common 
Terminology Criteria for Adverse Events.
Note: Organ toxicities associated with CRS may be graded according to CTCAE v5.0 but they do not influence CRS 
grading.
1. Fever is defined as temperature ≥38°C not attributable to any other cause. In subjects who have CRS then receive 
antipyretics or
such as tocilizumab or steroids, fever is no longer required to grade 
subsequent CRS severity. In this case, CRS grading is driven by hypotension and/or hypoxia.
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2. CRS grade is determined by the more severe event: hypotension or hypoxia not attributable to any other cause. For 
example, a subject with temperature of 39.5°C, hypotension requiring 1 vasopressor, and hypoxia requiring low-
flow nasal cannula is classified as grade 3 CRS.
3. Low-flow nasal cannula is defined as oxygen delivered at ≤6 L/minute. Low flow also includes blow-by oxygen 
delivery, sometimes used in pediatrics. High-flow nasal cannula is defined as oxygen delivered at >6 L/minute.
Table 8:
CRS Management Guidance
CRS Severity1
Tocilizumab
Corticosteroids
Grade 1
Tocilizumab2 may be considered per 
investigator’s discretion in 
consultation with the medical 
monitor
N/A
Grade 2
Administer tocilizumab 8 mg/kg IV 
over 1 hour (not to exceed 800 mg) 2
Repeat tocilizumab every 8 hours as 
needed if not responsive to IV fluids 
or increasing supplemental oxygen.
Limit to ≤3 doses in a 24-hour 
period; maximum total of 4 doses.
If no improvement within 24 hours 
after starting tocilizumab, 
administer methylprednisolone 
1 mg/kg IV twice daily. 
Continue corticosteroid use until the 
event is grade ≤1, then taper over 
3 days. 
Grade 3
Per grade 2
Per grade 2 
Grade 4
Per grade 2
If no response to multiple doses of 
tocilizumab and steroids, consider 
using other
(e.g., siltuximab, anakinra).
Per grade 2
CRS: cytokine release syndrome; IV: intravenously; N/A: not applicable.
1. See Lee et al., 2019.
2. Refer to tocilizumab prescribing information.
Throughout the duration of CRS, subjects should be provided with supportive care consisting of 
antipyretics, IV fluids, and oxygen. Subjects who experience grade ≥2 CRS (e.g., hypotension, or 
hypoxia requiring supplemental oxygenation) should be monitored with continuous cardiac 
telemetry and pulse oximetry. For subjects experiencing grade 3 CRS, consider performing an 
echocardiogram to assess cardiac function. For grade 3 or 4 CRS, consider intensive care 
supportive therapy. Intubation for airway protection due to neurotoxicity (e.g., seizure) and not 
due to hypoxia should not be captured as grade 4 CRS. Similarly, prolonged intubation due to 
neurotoxicity without other signs of CRS (e.g., hypoxia) is not considered grade 4 CRS. 
Investigators should always consider the potential of an underlying infection in cases of severe 
CRS, as the presentation (fever, hypotension, hypoxia) is similar. Resolution of CRS is defined 
as resolution of fever (temperature ≥38 °C), hypoxia, and hypotension (Lee et al., 2019).
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6.2.5.
Neurotoxicity
Neurotoxicity has been observed with autologous CD19-directed CAR T cell therapies. Signs 
and symptoms can be progressive and may include headache, aphasia, altered level of 
consciousness, impairment of cognitive skills, motor weakness, seizures, and cerebral edema. 
Neurotoxicity may occur at the time of CRS, during the resolution of CRS, or following 
resolution of CRS, and its pathophysiology is unclear. The ASTCT consensus further defined 
neurotoxicity associated with CRS as ICANS, a disorder characterized by a pathologic process 
involving the CNS following any immune therapy that results in activation or engagement of 
endogenous or infused T cells and/or other immune effector cells (Lee et al., 2019). Potential 
etiologies of neurotoxicity include ICANS or viral infection. Guidance for differential diagnosis 
and management follows (see Section 6.2.5.1 for ICANS and Section 6.2.5.2 for viral 
encephalitis).
Evaluation of any new onset neurotoxicity should include a neurological examination, including 
ICE assessment tool (Table 10), brain MRI, and examination of the CSF (via LP), as clinically 
indicated. If a brain MRI is not possible, all subjects should receive a noncontrast CT to rule out 
intracerebral hemorrhage. LP is required for any grade ≥3 neurotoxicity and is strongly 
recommended for grade 1 and grade 2 events, if clinically feasible. LP must be performed within 
48 hours of symptom onset, unless not clinically feasible. Electroencephalogram should also be 
considered as clinically indicated. Endotracheal intubation may be needed for airway protection 
in severe cases.
Nonsedating, antiseizure prophylaxis (e.g., levetiracetam) should be considered in all subjects for 
at least 21 days following CTX110 infusion or upon resolution of neurological symptoms (unless 
the investigator considers the antiseizure medication to be contributing to the detrimental 
symptoms). For severe or life-threatening neurologic toxicities, intensive care supportive therapy 
should be provided. Neurology consultation should always be considered. Monitor platelets and 
for signs of coagulopathy and transfuse blood products appropriately to diminish risk of 
intracerebral hemorrhage. For subjects who receive active steroid management for more than 
3 days, antifungal and antiviral prophylaxis is recommended to mitigate a risk of severe infection 
with prolonged steroid use. Consideration for antimicrobial prophylaxis should also be given 
(see Section 6.2.2).
In cases of suspected ICANS, subjects should be graded according to the ICANS grading table 
(Table 9) which incorporates assessment of level of consciousness, presence/absence of seizures, 
motor findings, presence/absence of cerebral edema, and overall assessment of neurologic 
domains by using a modified assessment tool called the ICE (immune effector cell–associated 
encephalopathy) assessment tool (Table 10).
Headache, which may occur in a setting of fever or after chemotherapy, is very common but is a 
nonspecific symptom. Headache alone may not necessarily be a manifestation of ICANS and 
further evaluation should be performed. Weakness or balance problem resulting from 
deconditioning and muscle loss are excluded from definition of ICANS. Similarly, intracranial 
hemorrhage with or without associated edema may occur due to coagulopathies in these subjects 
and are also excluded from definition of ICANS. These and other neurotoxicities should be 
captured in accordance with CTCAE v5.0.
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6.2.5.1.
ICANS
If ICANS is diagnosed, management should be performed according to Table 11 depending on 
the ICANS grade (Table 9) and whether the subject has concurrent CRS or not. In addition, 
nonsteroidal agents (e.g., anakinra, etc.) may be considered for ICANS management after 
discussion with the CRISPR medical monitor (Neill et al., 2020). Subjects who experience 
ICANS grade ≥2 should be monitored with continuous cardiac telemetry and pulse oximetry.
Table 9:
ICANS Grading
Neurotoxicity 
Domain
Grade 1
Grade 2
Grade 3
Grade 4
ICE score1
7-9
3-6
0-2
0 (subject is unarousable 
and unable to undergo 
ICE assessment)
Depressed level of 
consciousness2
Awakens 
spontaneously
Awakens to 
voice
Awakens only to tactile 
stimulus
Subject is unarousable 
or requires vigorous or 
repetitive tactile stimuli 
to arise; stupor or coma
Seizure
N/A
N/A
Any clinical seizure, 
focal or generalized, that 
resolves rapidly, or 
nonconvulsive seizures 
on EEG that resolve 
with intervention
Life-threatening 
prolonged seizure 
(>5 min) or repetitive 
clinical or electrical 
seizures without return 
to baseline in between 
Motor findings3
N/A
N/A
N/A
Deep focal motor 
weakness such as 
hemiparesis or 
paraparesis
Elevated ICP/ 
cerebral edema
N/A
N/A
Focal/local edema on
neuroimaging 4
Diffuse cerebral edema 
on neuroimaging, 
decerebrate or 
decorticate posturing, 
cranial nerve VI palsy, 
papilledema, or 
Cushing’s triad
CTCAE: Common Terminology Criteria for Adverse Events; EEG: electroencephalogram; ICANS: immune effector 
cell–associated neurotoxicity syndrome; ICE: immune effector cell–associated encephalopathy (assessment tool); 
ICP: intracranial pressure; N/A: not applicable.
ICANS grade is determined by the most severe event (ICE score, level of consciousness, seizure, motor findings, 
raised ICP/cerebral edema) not attributable to any other cause. 
1. A subject with an ICE score of 0 may be classified as grade 3 ICANS if awake with global aphasia, but a subject 
with an ICE score of 0 may be classified as grade 4 ICANS if unarousable.
2. Depressed level of consciousness should be attributable to no other cause (e.g., sedating medication).
3. Tremors and myoclonus associated with immune effector therapies should be graded according to CTCAE v5.0 
but do not influence ICANS grading.
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Table 10:
ICE Assessment 
Domain
Assessment
Maximum Score
Orientation
Orientation to year, month, city, hospital
4 points
Naming
Name 3 objects (e.g., point to clock, pen, button)
3 points
Following 
command
Ability to follow commands (e.g., “Show me 2 fingers” or “Close your 
eyes and stick out your tongue”)
1 point
Writing
Ability to write a standard sentence (includes a noun and verb)
1 point
Attention
Ability to count backward from 100 by 10
1 point
ICE score will be reported as the total number of points (0-10) across all assessments.
See Section 7.2.12.
Table 11:
ICANS Management Guidance
Severity
Management
Grade 1
If less than 72 hours after infusion, consider dexamethasone 10 mg IV every 12 to 24 hours
for up to 3 days in consultation with the medical monitor
Grade 2
Consider administering dexamethasone 10 mg IV every 6 hours (or equivalent 
methylprednisolone) unless subject already on equivalent dose of steroids for CRS.
Continue dexamethasone use until event is grade ≤1, then taper over 3 days.
Cohorts D and G (B cell ALL only): Strongly consider administration of dexamethasone 
10 mg IV every 6 hours.
Grade 3
Administer dexamethasone 10 mg IV every 6 hours, unless subject already on equivalent dose 
of steroids for CRS.
Continue dexamethasone use until event is grade ≤1, then taper over 3 days.
Grade 4
Administer methylprednisolone 1000 mg IV per day for 3 days; if improves, manage as above.    
CRS: cytokine release syndrome; ICANS: immune effector cell–associated neurotoxicity syndrome; IV: intravenously.
6.2.5.2.
Viral Encephalitis
Reactivation of chronic latent infections has been reported in patients who are highly 
immunosuppressed, including those who have undergone hematopoietic stem cell transplantation 
(HSCT) or CAR T cell therapy (Handley et al., 2021; Rebechi et al., 2021). Specifically, there 
have been 8 reported cases of human herpesvirus 6 (HHV-6) encephalitis following CAR T cell 
infusion (Spanjaart et al., 2022).
Viral encephalitis can be distinguished from ICANS based on the characteristics described in 
Table 12. In addition, encephalitis should be considered in subjects who initially respond to 
ICANS treatment, but subsequently worsen.
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Table 12:
Differentiating Between ICANS and HHV-6 Encephalitis After CAR T Cell 
Therapy
Neurotoxicity After CAR T Cell 
Therapy (ICANS)
HHV-6 Encephalitis
Clinical presentation
Tremor, dysphagia, expressive aphasia, 
impaired attention, apraxia, and lethargy
Headache, confusion, or delirium; 
progresses to anterograde then 
retrograde amnesia
Timing
Very early (usually within first 3 to 
10 days)
Typically within the first 21 days
Progression
Rapidly over hours to days
More slowly, over several days
Associated symptoms
Cytokine release syndrome
Fever is uncommon
Seizures
Less common
Very common
CSF findings
Often normal, may have mildly elevated 
protein
Mildly abnormal (minimal pleocytosis, 
slightly elevated protein, normal 
glucose)
CSF HHV-6
PCR negative
PCR positive
EEG abnormalities
Diffuse slowing
Epileptiform activity
Imaging findings 
(MRI)
Usually normal, although vasogenic 
edema, leptomeningeal enhancement, and 
microhemorrhages
T2/FLAIR/DWI hyperintensities in the 
medial temporal lobes, especially the 
amygdala and the hippocampus
Treatment
Corticosteroids and/or 
 
Antivirals (ganciclovir, foscarnet, 
cidofovir)
Outcomes
Highly variable, ranges from complete 
recovery to significant residual disability 
and death
Highly variable, ranges from complete 
recovery to disability and death; 
majority recover
CAR: chimeric antigen receptor; CSF: cerebrospinal fluid; EEG: electroencephalogram; HHV-6, human 
herpesvirus 6;
 MRI: magnetic resonance imaging; PCR: polymerase chain reaction; 
T2/FLAIR/DWI: T2-weighted fluid attenuated inversion recovery/diffusion-weighted imaging.
Source: Adapted from (Rebechi et al., 2021).
In cases of suspected viral encephalitis, the following diagnostic tests are required:
x
brain MRI,
x
blood (plasma preferred) for HHV-6 DNA PCR, and
x
LP for:

HHV-6 DNA PCR (should be performed within 48 hours of symptoms if 
clinically feasible),

the standard panel performed at site (which should include at least cell count, 
Gram stain, and Neisseria meningitidis), and

CSF PCR analysis for herpes simplex virus (HSV) -1 and -2, enterovirus, 
varicella zoster virus (VZV), cytomegalovirus (CMV), and HHV-6. 
Baseline serology samples will be collected and sent to a central lab and may be tested in the 
event of viral infection to distinguish between primary infection and reactivation.
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Results from the infectious disease panel should be available within 5 business days of the LP in 
order to appropriately manage the subject. If a site is unable to perform the panel tests, it must be 
discussed with the medical monitor. For any suspected case of viral encephalitis, the CRISPR 
medical monitor must be contacted within 24 hours.
HHV-6 management should include the following:
x
Primary therapy should include foscarnet and ganciclovir, and second-line therapy 
should include cidofovir.
x
Recommended duration of therapy is 3 weeks. Treatment duration can be increased to 
6 weeks in the event of persistent clinical manifestations or ongoing detectable 
HHV-6 copies in the CSF or peripheral blood.
x
An infectious disease consultation is recommended.
6.2.6.
B Cell Aplasia
B cell aplasia may occur and will be monitored by following IgG blood levels. IV 
gammaglobulin should be administered for clinically significant hypogammaglobulinemia 
(systemic infections, <400 mg/dL) according to institutional standard of care.
6.2.7.
Hemophagocytic Lymphohistiocytosis
HLH has been reported after treatment with autologous CD19-directed CAR T cells (Barrett et 
al., 2014; Maude et al., 2014b; Maude et al., 2015; Porter et al., 2015; Teachey et al., 2013). 
HLH is a clinical syndrome that is a result of an inflammatory response following infusion of 
CAR T cells in which cytokine production from activated T cells leads to excessive macrophage 
activation. Signs and symptoms of HLH may include fevers, cytopenias, hepatosplenomegaly, 
hepatic dysfunction with hyperbilirubinemia, coagulopathy with significantly decreased 
fibrinogen, and marked elevations in ferritin and C-reactive protein (CRP). Neurologic findings 
have also been observed (Jordan et al., 2011; La Rosée, 2015).
CRS and HLH may possess similar clinical syndromes with overlapping clinical features and 
pathophysiology. HLH will likely occur at the time of CRS or as CRS is resolving. HLH is 
considered an overlap syndrome with CRS and should be treated according to the CRS 
management guidelines. 
The diagnosis of HLH will be confirmed in subjects who meet the criteria in Table 13.
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Table 13:
Criteria for Diagnosis of HLH
Subjects must meet the following criteria
Peak serum ferritin level of >10,000 ng/mL during the CRS phase of CAR T cell therapy (typically the 
first 5 days after cell infusion)
AND
Subsequently developed any 2 of the following:
x
Grade ≥3 increase in serum bilirubin, aspartate 
aminotransferase, or alanine aminotransferase 
levels
x
Grade ≥3 oliguria or increase in serum 
creatinine levels
x
Grade ≥3 pulmonary oedema
x
Presence of hemophagocytosis in bone 
marrow or organs based on histopathological 
assessment of cell morphology and/or CD68 
immunohistochemistry
CAR: chimeric antigen receptor; CD: cluster of differentiation; CRS: cytokine release syndrome
Adapted from (Neelapu et al., 2018).
HLH may be suspected in the presence of unexplained elevated liver function tests or cytopenias 
with or without other evidence of CRS. In the event of a suspicion or diagnosis of HLH, the 
following should be collected:
x
serum soluble interleukin-2 receptor (soluble CD25)
x
bone marrow biopsy and aspirate may be collected if safe to conduct, for further 
confirmation. Where feasible, excess bone marrow samples should be sent to a central 
laboratory. Details of sample preparation and shipment are contained in the 
Laboratory Manual.
If HLH is suspected or confirmed:
x
Frequently monitor coagulation parameters, including fibrinogen. These tests may be 
done more frequently than indicated in the schedule of assessments, and frequency 
should be driven based on laboratory findings.
x
Fibrinogen should be maintained ≥100 mg/dL to decrease risk of bleeding.
x
Coagulopathy should be corrected with blood products.
x
Check for soluble CD25 and triglycerides
x
If possible, perform bone marrow biopsy to assess for hemophagocytosis. 
x
Given the overlap with CRS, subjects should also be managed per CRS treatment 
guidance in Table 8. The
inhibitor anakinra or other
may also be considered following discussion with the 
medical monitor.
Suspected cases of HLH should be discussed with the sponsor’s medical monitor.
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6.2.8.
Cytopenias 
Grade 3 neutropenia and thrombocytopenia, at times lasting more than 28 days post infusion, 
have been reported in subjects treated with autologous CD19-directed CAR T cell products 
(Kymriah USPI, 2017; Yescarta USPI, 2017). Therefore, subjects receiving CTX110 should be 
monitored for such toxicities and appropriately supported. Consideration should be given to 
antimicrobial and antifungal prophylaxis for any subject with prolonged neutropenia. For 
subjects experiencing grade ≥3 neutropenia, thrombocytopenia, or anemia that has not resolved 
within 28 days of CTX110 infusion, a complete blood count with differential should be 
performed more frequently until resolution to grade ≤2 or administration of a new systemic 
 They should be performed weekly until 3 months after each CTX110 
infusion and then should be performed at least monthly.
G-CSF may be considered in cases of grade 4 neutropenia 10 days post–CTX110 infusion, when 
the risk of CRS has passed. G-CSF administration may be considered earlier but must first be 
discussed with the medical monitor. In addition, for cohorts that receive 2 CTX110 infusions 
with LD chemotherapy in a regimen, proactive use of G-CSF starting ≥10 days following the 
first CTX110 infusion is recommended to support the second round of LD chemotherapy. 
Antimicrobial and antifungal prophylaxis should be considered for any subject with prolonged 
neutropenia or on high doses of steroids.
For Phase 1 Cohort C, daratumumab may increase neutropenia and/or thrombocytopenia induced 
by background therapy. Monitor complete blood cell counts periodically during treatment 
according to the manufacturer’s prescribing information for background therapies. Monitor 
subjects with neutropenia for signs of infection. Daratumumab dose delay may be required to 
allow recovery of neutrophils and/or platelets, as per prescribing information. Consider 
supportive care with growth factors for neutropenia or transfusions for thrombocytopenia.
6.2.9.
Graft vs Host Disease
GvHD is seen in the setting of allogeneic HSCT and is the result of immunocompetent donor 
T cells (the graft) recognizing the recipient (the host) as foreign. The subsequent immune 
response activates donor T cells to attack the recipient to eliminate foreign antigen–bearing cells. 
GvHD is divided into acute, chronic, and overlap syndromes based on both the time from 
allogeneic HSCT and clinical manifestations. Signs of acute GvHD may include a 
maculopapular rash; hyperbilirubinemia with jaundice due to damage to the small bile ducts, 
leading to cholestasis; nausea, vomiting, and anorexia; and watery or bloody diarrhea and 
cramping abdominal pain (Zeiser and Blazar, 2017).
To support the proposed clinical study, a nonclinical Good Laboratory Practice–compliant 
GvHD and tolerability study was performed in immunocompromised mice at 2 doses that exceed 
all proposed clinical dose levels by at least 10-fold. Further, due to the specificity of CAR 
insertion at the TRAC locus, it is highly unlikely for a T cell to be both CAR+ and TCR+. 
Remaining TCR+ cells are removed during the manufacturing process by immunoaffinity 
chromatography on an anti-TCR antibody column to achieve ≤0.15% TCR+ cells in the final 
product. A limit of
TCR+ cells/kg will be imposed for all dose levels. This limit is lower 
than the limit of 1 × 105 TCR+ cells/kg based on published reports on the number of allogeneic 
cells capable of causing severe GvHD during HSCT with haploidentical donors (Bertaina et al., 
2014). Through this specific editing, purification, and strict product release criteria, the risk of 
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GvHD following CTX110 should be low, although the true incidence is unknown. Subjects 
should be monitored closely for signs of acute GvHD following infusion of CTX110. The timing 
of potential symptoms is unknown. However, given that CAR T cell expansion is antigen-driven 
and will likely occur only in TCR– cells, it is unlikely that the number of TCR+ cells will 
appreciably increase above the number infused.
Diagnosis and grading of GvHD should be based on published criteria (Harris et al., 2016), as 
outlined in Table 14. 
Table 14:
Criteria for Grading Acute GvHD
Stage
Skin 
(active erythema only)
Liver 
(bilirubin mg/dL)
Upper GI
Lower GI 
(stool output/day)
0
No active (erythematous) 
GvHD rash
<2
No or intermittent 
nausea, vomiting, or 
anorexia
<500 mL/day or 
<3 episodes/day
1
Maculopapular rash 
<25% BSA
2-3
Persistent nausea, 
vomiting, or 
anorexia
500-999 mL/day or 
3-4 episodes/day
2
Maculopapular rash 
25-50% BSA
3.1-6
–
1000-1500 mL/day or 
5-7 episodes/day
3
Maculopapular rash 
>50% BSA
6.1-15
–
>1500 mL/day or 
>7 episodes/day
4
Generalized erythroderma 
(>50% BSA) plus bullous 
formation and 
desquamation >5% BSA
>15
–
Severe abdominal pain with 
or without ileus, or grossly 
bloody stool (regardless of 
stool volume)
BSA: body surface area; GI: gastrointestinal; GvHD: graft vs host disease.
Overall GvHD grade will be determined based on most severe target organ involvement.
x
Grade 0: No stage 1-4 of any organ
x
Grade 1: Stage 1-2 skin without liver, upper GI, or lower GI involvement
x
Grade 2: Stage 3 rash and/or stage 1 liver and/or stage 1 upper GI and/or stage 1 
lower GI
x
Grade 3: Stage 2-3 liver and/or stage 2-3 lower GI, with stage 0-3 skin and/or stage 
0-1 upper GI
x
Grade 4: Stage 4 skin, liver, or lower GI involvement, with stage 0-1 upper GI
Potential confounding factors that may mimic GvHD such as infections and reactions to 
medications should be ruled out. Skin and/or GI biopsy should be obtained for confirmation 
before or soon after treatment has been initiated. In instance of liver involvement, liver biopsy 
should be attempted if clinically feasible. Sample(s) of all biopsies will also be sent to a central 
laboratory for pathology assessment. Details of sample preparation and shipment are contained 
in the Laboratory Manual.
Recommendations for management of acute GvHD are outlined in Table 15. To allow for 
intersubject comparability at the end of the trial, investigators should follow these 
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recommendations except in specific clinical scenarios in which following them could put the 
subject at risk. 
Table 15:
Acute GvHD Management
Grade
Management
1
Skin: Topical steroids or immunosuppressants; if stage 2: methylprednisolone 1 mg/kg 
(or equivalent dose).
2-4
Initiate methylprednisolone 2 mg/kg daily (or equivalent dose). 
IV form of steroid such as methylprednisolone should be considered if there are 
concerns with malabsorption.
Steroid taper may begin after improvement is seen after ≥3 days of steroids. Taper 
should be 50% decrease of total daily steroid dose every 5 days. 
GI: In addition to steroids, start anti-diarrheal agents per standard practice.
GI: gastrointestinal; IV: intravenous.
Decisions to initiate second-line therapy should be made sooner for subjects with more severe 
GvHD. For example, secondary therapy may be indicated after 3 days with progressive 
manifestations of GvHD, after 1 week with persistent grade 3 GvHD, or after 2 weeks with 
persistent grade 2 GvHD. Second-line systemic therapy may be indicated earlier in subjects who 
cannot tolerate high-dose glucocorticoid treatment (Martin et al., 2012). Choice of secondary 
therapy and when to initiate will be based on the treating investigator’s clinical judgment and 
local practice. 
Management of refractory acute GvHD or chronic GvHD will be per institutional guidelines. 
Anti-infective prophylaxis measures should be instituted per local guidelines when treating 
subjects with immunosuppressive agents (including steroids). 
The CRISPR medical monitor should be contacted if a case of GvHD is suspected.
6.2.10.
Hypotension and Renal Insufficiency
Hypotension and renal insufficiency have been reported with CAR T cell therapy and should be 
treated with IV administration of normal saline boluses according to institutional practice 
guidelines. Dialysis should be considered when appropriate. 
6.2.11.
Special Consideration During COVID-19 Pandemic
Subjects enrolled in this study undergo LD chemotherapy, are immunocompromised, and at 
increased risk of infections. Hence, the clinical study protocol requires exclusion of subjects in 
the case of any ongoing active infection during screening, prior to LD chemotherapy, and prior 
to CTX110 infusion, or delayed infusions (see Section 3.2).
This measure will include subjects with active infection with Severe Acute Respiratory 
Syndrome Coronavirus-2 (SARS-CoV-2), the causal agent of COVID-19 (coronavirus 
disease-2019). Due to the rapidly changing evidence as well as locoregional differences, the 
sponsor defers to local regulations and institutional guidelines if the current situation allows a 
safe conduct of the study for an individual subject at a given time. Whenever possible, a 
COVID-19 vaccine or booster should not be administered within 4 weeks prior to scheduled 
imaging for disease assessment. Additionally, the minimal requirements by the sponsor are to be 
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defined in a memorandum to the study centers that is periodically updated as evidence and 
guidelines evolve.
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7.
STUDY PROCEDURES
Both the dose escalation and expansion parts of the study will consist of 3 distinct stages: 
(1) screening and eligibility confirmation; (2) treatment, consisting of LD chemotherapy (with or 
without daratumumab) and CTX110 infusion; and (3) follow-up. During the screening stage, 
subjects are assessed according to the eligibility criteria outlined in Section 3. 
After enrollment, subjects in Phase 1 Cohorts A, B, and D and Phase 2 will receive LD 
chemotherapy followed by infusion of CTX110; subjects in Phase 1 Cohort C will receive 
daratumumab followed by LD chemotherapy, then CTX110 infusion. Additional CTX110 
infusion may be administered with or without respective LD regimen as specified in Table 3 and 
Section 5.3.1. During follow-up, subjects will be assessed for tumor response, disease 
progression, and survival. Throughout all study stages, subjects will be regularly monitored for 
safety.
A complete schedule of assessments is provided in Table 16 for Phase 1 (Parts A and B), 
Table 17 for Phase 2, and Table 18 for both phases. Descriptions of all required study procedures 
are provided in this section. In addition to protocol-mandated assessments, subjects should be 
followed per institutional guidelines, and unscheduled assessments should be performed when 
clinically indicated, as determined by the investigator. Refer to the Study Reference Manual for 
specific details and guidance related to additional CTX110 infusions. 
Missed evaluations should be rescheduled and performed as close to the original scheduled date 
as possible. An exception is made when rescheduling becomes, in the investigator’s opinion, 
medically unnecessary or unsafe because it is too close in time to the next scheduled evaluation. 
In that case, the missed evaluation should be abandoned.
For the purposes of this protocol, there is no Day 0. All visit dates and windows are to be 
calculated using Day 1 as the date of first CTX110 infusion. 
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Table 16:
Phase 1 Schedule of Assessments (Screening to Month 24) 
Study Stage
Screening 
(Stage 1)1
Treatment 
(Stage 2)
Follow-up 
(Stage 3)
Day
D −10 
to 
D−62
D −5 
to 
D−3
D13
D2
D3
±1d
D5
±2d
D8 
±2d
D10
±2d
D14
±2d
D21
±2d
D28
±4d
M2
±7d
M3
±14d
M6
±14d
M9
±14d
M12
±14d
M15
±14d
M18
±14d
M24
±21d
Informed consent
X
Confirm eligibility4
X
X
X
X
X
Enrollment
X
Medical history5
X
Physical exam
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs6
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Height, weight7
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy test8
X
X
X
ECOG status
X
X
X
X
Brain MRI
X
Lumbar puncture9
X
Echocardiogram
X
12-lead ECG10
X
X
X
X
X
ICE assessment11
X
X
X
X
X
X
X
Patient-reported 
outcomes12
X
X
X
X
X
X
X
X
X
Concomitant 
meds13
Continuous
Adverse events14
Continuous
Hospital utilization
Continuous
Treatment
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Study Stage
Screening 
(Stage 1)1
Treatment 
(Stage 2)
Follow-up 
(Stage 3)
Day
D −10 
to 
D−62
D −5 
to 
D−3
D13
D2
D3
±1d
D5
±2d
D8 
±2d
D10
±2d
D14
±2d
D21
±2d
D28
±4d
M2
±7d
M3
±14d
M6
±14d
M9
±14d
M12
±14d
M15
±14d
M18
±14d
M24
±21d
Daratumumab15
X
X
X
LD chemotherapy16
X17
X18
CTX110 infusion 
18,19
X17
X18
NHL Disease Response/Assessment (Central and Local)
PET scan/CT with 
IV contrast20
X
X
X21
X
X
X
X
X
BM aspirate/ 
biopsy22
X
X
Tumor 
biopsy/pathology23
X24
X23
Adult B Cell ALL Disease Response/Assessment 
BM biopsy and 
aspirate (central and 
local)21
X
X
X25
X
X
X26
BCR-ABL1 in 
peripheral blood (if 
Ph+)
X
X
X25
X
X
X26
Imaging for 
extramedullary 
disease 
(if applicable)
X
X27
Post-screening 
lumbar puncture
X28
Peripheral blood 
chimerism (local)29
X
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Study Stage
Screening 
(Stage 1)1
Treatment 
(Stage 2)
Follow-up 
(Stage 3)
Day
D −10 
to 
D−62
D −5 
to 
D−3
D13
D2
D3
±1d
D5
±2d
D8 
±2d
D10
±2d
D14
±2d
D21
±2d
D28
±4d
M2
±7d
M3
±14d
M6
±14d
M9
±14d
M12
±14d
M15
±14d
M18
±14d
M24
±21d
Laboratory Assessments (Local)30
CBC w/ differential
X
X
X
X
X
X
X
X
X
X
X
X30
X
X
X
X
X
X
X
X
Serum chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Coagulation 
parameters
X
X
X
X
X
X
X
X
X
X
X
Viral serology31
X
Immunoglobulins
X
X
X
X
X
X
X
X
X
X
X
Ferritin, CRP
X
X
X
X
X
X
X
X
X
X
B cells (CD19, 
CD20)
X
X
X
X
X
X
X
X
X
X
X
Blood type, Ab 
screen33
X
Biomarkers (Blood, Central)30
CTX110 PK34, 35
X
X36
pre
/post
X
X
X
X
X
X
X
X
X
X
X
X
X
Daratumumab 
PK36,39
X
X
X
X
X
X
DNA36
X
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Ab: antibody; AE: adverse event; AESI: adverse event of special interest; ALL: acute lymphoblastic leukemia; B-ALL: B cell acute lymphoblastic leukemia; 
BM: bone marrow: CBC: complete blood count; CNS: central nervous system; CR: complete response; CRP: C-reactive protein; CRS: cytokine release 
syndrome; CT: computed tomography; D or d: day; ECG: electrocardiogram; ECOG: Eastern Cooperative Oncology Group; HBV: hepatitis B virus; HCV: 
hepatitis C virus; HIV-1/-2: human immunodeficiency virus type 1 or 2; HLH: hemophagocytic lymphohistiocytosis; HSCT: hematopoietic stem cell transplant; 
ICE: immune effector cell–associated encephalopathy; IPI: International Prognostic Index; IV: intravenously;  LD: lymphodepleting; LP: lumbar puncture; M: 
month; MRD: minimal residual disease; MRI: magnetic resonance imaging; NHL: non-Hodgkin lymphoma; PCR: polymerase chain reaction; PET: positron 
emission tomography; Ph+: Philadelphia chromosome-positive; PK: pharmacokinetic(s); PRO: patient-reported outcome; SAE: serious adverse event; SC: 
subcutaneous; SD: stable disease;
Note: Study visits cannot be combined, even if visit windows allow overlap (e.g., D3 ±1 day could overlap with D2 or D5 ±2 days, but separate visits are 
required for D2, D3, and D5 visits.)
Note: Certain assessments for visits after D8 may be performed as in-home or alternate-site visits. Assessments include hospital utilization, changes in health 
and/or changes in medications, body system assessment, vital signs, weight, PRO questionnaire distribution, and blood sample collections for local and central 
laboratory assessments. 
1. Screening assessments completed up to 14 days after informed consent. Subjects allowed 1-time rescreening within 3 months of initial consent, or longer if 
specific approval is obtained from the medical monitor.
2. Only for Cohort C. All procedures will be performed prior to daratumumab administration.
3. All baseline assessments on Day 1 are to be performed prior to CTX110 infusion unless otherwise specified; refer to Laboratory Manual for details.
4. Study eligibility to be confirmed before enrollment. Eligibility for treatment based on clinical status to be confirmed before start of LD chemotherapy (Cohorts 
A, B, and D) or daratumumab (Cohort C) and before CTX110 infusion (see Sections 5.1, 5.2, and 5.3).
5. Includes complete surgical and cardiac history.
6. Includes sitting blood pressure, heart rate, respiratory rate, pulse oximetry, and temperature.
7. Height at screening only.
8. For female subjects of childbearing potential. Serum pregnancy test at screening. Serum or urine pregnancy test within 72 hours before start of LD 
chemotherapy (Cohorts A, B, and D) or daratumumab (Cohort C) or additional CTX110 infusions (Cohorts A, B, C2, and D) when administered without 
daratumumab or LD chemotherapy. 
9. Mandatory for Cohort D subjects. For Cohorts A, B, and C: LP at screening for subjects with high risk for CNS involvement (e.g., high-grade B cell lymphoma 
with MYC and BCL2 and/or BCL6 rearrangements or double-expressor lymphoma, subjects with testicular involvement of lymphoma, or subjects with high-
risk CNS IPI score). For LPs performed during neurotoxicity, samples should be sent to central laboratory for CTX110 PK and
10.Prior to daratumumab infusion (Cohort C), prior to LD chemotherapy (Cohorts A, B, and D), and prior to CTX110 infusion (all cohorts). 
11.On Day 1 prior to CTX110 administration, then all listed time points. If CNS symptoms persist, ICE assessment should continue to be performed 
approximately every 2 days until symptom resolution to grade 1 or baseline.
12.PRO surveys should be administered before any visit-specific procedures are performed. See Section 7.2.13.
13.All concomitant medications will be collected ≤3 months post-CTX110, after which only select concomitant medications will be collected (Section 5.4.1).
14.Collect all AEs from informed consent to 3 months after each CTX110 infusion and collect only SAEs, AESIs, and nonserious AEs related to LD 
chemotherapy from 3 months after last CTX110 infusion through Month 24 visit. After Month 24 to Month 60 or after a subject starts a new
anytime on the study, only SAEs and AESIs related to LD chemotherapy, study procedure, or CTX110 and new malignancies will be reported. See Section 8.7, 
Table 21 for details.
15.Cohort C only: 1 dose of daratumumab 16 mg/kg IV or 1800 mg SC administered ≥1 day prior to starting LD chemotherapy and within 10 days prior to 
CTX110 infusion (Section 5.1). The first 16 mg/kg IV dose may be split (to 8 mg/kg) over 2 consecutive days. For subjects in Subcohort C1 who achieve SD 
or better on Day 28, 2 additional doses of daratumumab (16 mg/kg IV or 1800 mg SC) will be administered at the Day 28 (± 4 days) and Month 2 (± 4 days) 
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visits. Confirmation of SD state based on PET/CT scan measurement will be required before repeat dosing with daratumumab. If a subject experiences severe 
or unmanageable AEs with prior daratumumab doses, redosing with daratumumab will not be permitted. 
16.For first CTX110 infusion, start LD chemotherapy within 7 days of study enrollment. After completion of LD chemotherapy, ensure washout period of 
≥48 hours (but ≤7 days) before CTX110 infusion. Physical exam, weight, and coagulation laboratories performed prior to first dose of LD chemotherapy. Vital 
signs, CBC, clinical chemistry, and AEs/concomitant medications assessed and recorded daily (i.e., 3 times) during LD chemotherapy. 
17.This study will allow for a second CTX110 infusion for subjects in Cohorts A, B, C2, D1, and D2 per the criteria in Section 5.3.1.3 and Section 5.3.1.4. 
Subjects who receive the second CTX110 infusion should be followed per the schedule of assessments consistent with the initial dosing. All procedures 
(screening through Day 28) must be repeated, with exceptions for screening assessments specified in Section 5.3.1.3 and Section 5.3.1.4. Month 2 visit 
procedures do not need to be repeated if they have been performed as part of a visit occurring within 28 days of the second CTX110 infusion. 
18.A second infusion of CTX110 on Day 35 (-7 days/+21 days) administered with LD chemotherapy for subjects who achieve objective response at Day 28 
assessment. The second infusion may be administered without LD chemotherapy if subject is experiencing significant cytopenias (see Section 5.3.1.3.1). In 
addition, this study will allow for a second course of treatment with a single CTX110 infusion with LD chemotherapy after PD. See Section 5.3.1 for the 
eligibility and additional considerations for screening assessments. All subjects will be followed according to Table 16 after additional CTX110 infusions. 
19.For first CTX110 infusion and additional CTX110 infusions with LD chemotherapy, CTX110 will be administered 48 hours to 7 days after completion of LD 
chemotherapy. 
20.Baseline disease assessment (PET scan/CT of diagnostic quality for subjects with NHL or BM biopsy with imaging for extra medullary disease (if applicable) 
for subjects with B-ALL) to be performed within 28 days prior to CTX110 infusion. BM for B-ALL may be assessed locally and centrally at any time prior to 
the 14-day window for screening, with appropriate consent. In Subcohort D2, if MRD results are pending at the time of enrollment, it is acceptable for 
eligibility purposes to enroll based on BM performed during screening that confirms BM blast count <5% accompanied by qualifying MRD results performed 
within the past 3 months. MRI with contrast allowed if CT is clinically contraindicated, or as required by local regulation. Additional imaging at Month 2 
allowed per investigator discretion. 
21.For all subjects who receive a second CTX110 infusion on Day 35 (-7 days/+21 days), a PET/CT scan is required 28 days after that infusion to assess efficacy. 
It is permissible for that scan to replace the Month 3 imaging.
22.To be performed ± 5 days of visit date. BM at Day 28 is required for NHL subjects with BM involvement at screening. Additional BM biopsy and aspirate 
must be performed to confirm CR as part of disease evaluation for NHL subjects with BM involvement at screening and to evaluate CTX110 trafficking. BM 
biopsy and aspirate may also be performed at time of disease relapse. Samples from all BM biopsy and aspirate should be sent for CTX110 PK and
 If HLH is suspected, BM biopsy and aspirate to be performed as specified in Section 6.2.7. 
23.Optional: For subjects who have disease amenable to biopsy and who provide separate consent. To be performed ± 5 days of visit date.
24.It is preferred that subjects undergo tumor biopsy during screening. However, if a biopsy of relapsed/refractory disease was performed within 3 months prior to 
enrollment and after the most recent line of therapy, archival tissue may be used (see Laboratory Manual for details). If relapse occurs on study, every attempt 
should be made to obtain biopsy of relapsed tumor and send to central pathology. Tumor biopsy refers to tissue other than bone marrow. 
25.Assessments optional at Month 2 to confirm CR if not achieved at Month 1. 
26.For Subcohort D2 only.
27.If applicable, imaging for extramedullary disease at baseline, Day 28, and at subsequent visits as clinically indicated or to confirm CR.
28.For subjects with baseline CNS disease: to confirm CR and when clinically indicated.
29.To be performed only in subjects who have received prior allogeneic HSCT.
30.All local and central laboratory assessments should be performed prior to dosing, unless otherwise specified. Assessments at Month 6 or later may be delayed 
or moved ahead of the visit window to accommodate holidays, vacations, and unforeseen delays.
31.For subjects experiencing grade ≥3 neutropenia, thrombocytopenia, or anemia that has not resolved within 28 days of CTX110 infusion, a CBC with 
differential must be performed more frequently until resolution to grade ≤2 or administration of a new systemic
 They should be performed 
weekly until 3 months after each CTX110 infusion and then should be performed at least monthly.
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32.Infectious disease testing (HIV-1, HIV-2, HCV antibody/PCR, HBV surface antigen, HBV surface antibody, HBV core antibody) ≤45 days of enrollment may 
be considered for subject eligibility.
33.
assessment at screening, before daratumumab infusion (Cohort C), before start of first day of LD chemotherapy (Cohorts A, B, and D), before 
CTX110 infusion (all cohorts), then all listed time points. 
34.Blood type and
prescribing information to prevent interference with blood compatibility testing for subjects in Cohort C 
after cohort allocation is confirmed, and before daratumumab infusion.
35.Samples for CTX110 PK should be sent from any LP, BM aspirate, or tissue biopsy performed following CTX110 infusion. In subjects experiencing signs or 
symptoms of CRS, neurotoxicity, or suspected HLH, additional blood samples should be drawn at intervals outlined in the laboratory manual. Samples for 
CRS PK should only be collected between scheduled visits. If samples are already being collected as part of a scheduled visit, no additional samples are 
required to be collected for CRS PK on the same day of the scheduled visit.
 
37.Two samples collected on Day 1: One pre–CTX110 infusion and one 20 (±5) minutes after the end of CTX110 infusion.
 
 
 
 
 
41.Prior to first day of LD chemotherapy only.
Table 17:
Phase 2 Schedule of Assessments (Screening to Month 24) 
Study Stage
Screening1
Treatment
Follow-up
Day
D −5 
to 
D−3
D1(2)
D2
D3
±1d
D5
±2d
D8 
±2d
D10
±2d
D14
±2d
D21
±2d
D28
±4d
M2
±7d
M3
±14d
M6
±14d
M9
±14d
M12
±14d
M15
±14d
M18
±14d
M24
±21d
Informed consent 
X
Confirm eligibility3
X
Enrollment
X
Medical history4
X
Physical exam
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs5
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
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Study Stage
Screening1
Treatment
Follow-up
Day
D −5 
to 
D−3
D1(2)
D2
D3
±1d
D5
±2d
D8 
±2d
D10
±2d
D14
±2d
D21
±2d
D28
±4d
M2
±7d
M3
±14d
M6
±14d
M9
±14d
M12
±14d
M15
±14d
M18
±14d
M24
±21d
Height, weight6
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Pregnancy test7
X
X
ECOG status
X
X
X
X
Brain MRI
X
Lumbar puncture8
X
Echocardiogram
X
12-lead ECG9
X
X
X
X
ICE assessment10
X
X
X
X
X
X
X
Patient-reported 
outcomes11
X
X
X
X
X
X
X
X
X
Concomitant 
meds12
Continuous
Adverse events13
Continuous
Hospital utilization
Continuous
Treatment
LD chemotherapy14
X15
X16
CTX110 infusion14, 
16, 17
X15
X16
Disease Response/Assessment (Central and Local)
PET scan/CT with 
IV contrast18
X
X
X19
X
X
X
X
X
BM aspirate/ 
biopsy20
X
X
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Study Stage
Screening1
Treatment
Follow-up
Day
D −5 
to 
D−3
D1(2)
D2
D3
±1d
D5
±2d
D8 
±2d
D10
±2d
D14
±2d
D21
±2d
D28
±4d
M2
±7d
M3
±14d
M6
±14d
M9
±14d
M12
±14d
M15
±14d
M18
±14d
M24
±21d
Tumor 
biopsy/pathology21, 
22
X22
X21
Laboratory Assessments (Local)23
CBC w/ differential
X
X
X
X
X
X
X
X
X
X
X24
X
X
X
X
X
X
X
X
Serum chemistry 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Coagulation 
parameters
X
X
X
X
X
X
X
X
X
X
Viral serology25
X
Immunoglobulins
X
X
X
X
X
X
X
X
X
X
X
Ferritin, CRP
X
X
X
X
X
X
X
X
X
X
B cells (CD19, 
CD20)
X
X
X
X
X
X
X
X
X
X
X
Biomarkers (Blood, Central)23
CTX110 PK27,28
X
X29
pre
/post
X
X
X
X
X
X
X
X
X
X
X
X
X
DNA28
X
Ab: antibody; AE: adverse event; AESI: adverse event of special interest; BM: bone marrow: CBC: complete blood count; CNS: central nervous system; CR: 
complete response; CRP: C-reactive protein; CRS: cytokine release syndrome; CT: computed tomography; D or d: day; ECG: electrocardiogram; ECOG: Eastern 
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Cooperative Oncology Group; HBV: hepatitis B virus; HCV: hepatitis C virus; HIV-1/-2: human immunodeficiency virus type 1 or 2; HLH: hemophagocytic 
lymphohistiocytosis; HSCT: hematopoietic stem cell transplant; ICE: immune effector cell–associated encephalopathy; IPI: International Prognostic Index; IV: 
intravenously; LD: lymphodepleting; LP: lumbar puncture; M: month; MRD: minimal residual disease; MRI: magnetic resonance imaging; PCR: polymerase 
chain reaction; PET: positron emission tomography; Ph+: Philadelphia chromosome-positive; PK: pharmacokinetic(s); PRO: patient-reported outcome; SAE: 
serious adverse event;
Note: Study visits cannot be combined, even if visit windows allow overlap (e.g., D3 ±1 day could overlap with D2 or D5 ±2 days, but separate visits are 
required for D2, D3, and D5 visits.)
Note: Certain assessments for visits after D8 may be performed as in-home or alternate-site visits. Assessments include hospital utilization, changes in health 
and/or changes in medications, body system assessment, vital signs, weight, PRO questionnaire distribution, and blood sample collections for local and central 
laboratory assessments. 
1. Screening assessments completed up to 14 days after informed consent. Subjects allowed 1-time rescreening within 3 months of initial consent, or longer if 
specific approval is obtained from the medical monitor.
2. All baseline assessments on Day 1 are to be performed prior to CTX110 infusion unless otherwise specified; refer to Laboratory Manual for details.
3. Study eligibility to be confirmed before enrollment. Eligibility for treatment based on clinical status to be confirmed before start of LD chemotherapy and 
before CTX110 infusion (see Sections 5.2 and 5.3).
4. Includes complete surgical and cardiac history.
5. Includes sitting blood pressure, heart rate, respiratory rate, pulse oximetry, and temperature.
6. Height at screening only.
7. For female subjects of childbearing potential. Serum pregnancy test at screening. Serum or urine pregnancy test within 72 hours before start of LD 
chemotherapy or additional CTX110 infusions when administered without LD chemotherapy. 
8. LP at screening for subjects with high risk for CNS involvement (e.g., high-grade B cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements or 
double-expressor lymphoma, subjects with testicular involvement of lymphoma, or subjects with high-risk CNS IPI score). For LPs performed during 
neurotoxicity, samples should be sent to central laboratory for CTX110 PK and 
whenever possible. 
9. Prior to LD chemotherapy and prior to CTX110 infusion. 
10.On Day 1 prior to CTX110 administration, then all listed time points. If CNS symptoms persist, ICE assessment should continue to be performed 
approximately every 2 days until symptom resolution to grade 1 or baseline.
11.PRO surveys should be administered before any visit-specific procedures are performed. See Section 7.2.13.
12.All concomitant medications will be collected ≤3 months post-CTX110, after which only select concomitant medications will be collected (Section 5.4.1).
13.Collect all AEs from informed consent to 3 months after each CTX110 infusion and collect only SAEs, AESIs, and nonserious AEs related to LD 
chemotherapy from 3 months after last CTX110 infusion through Month 24 visit. After Month 24 to Month 60 or after a subject starts a new
anytime on the study, only SAEs and AESIs related to LD chemotherapy, study procedure, or CTX110 and new malignancies will be reported. See Section 8.7, 
Table 21 for details.
14.For first CTX110 infusion, start LD chemotherapy within 7 days of study enrollment. After completion of LD chemotherapy, ensure washout period of 
≥48 hours (but ≤7 days) before CTX110 infusion. Physical exam, weight, and coagulation laboratories performed prior to first dose of LD chemotherapy. Vital 
signs, CBC, clinical chemistry, and AEs /concomitant medications assessed and recorded daily (i.e., 3 times) during LD chemotherapy. 
15.Subjects will receive a second CTX110 infusion if they meet the criteria in Section 5.3.1.3 and Section 5.3.1.4. All procedures (screening through Day 28) 
must be repeated, with exceptions for screening assessments specified in Section 5.3.1.3 and Section 5.3.1.4. Month 2 visit procedures do not need to be 
repeated if they have been performed as part of a visit occurring within 28 days of the second CTX110 infusion.
16.A second infusion of CTX110 on Day 35 (-7 days/+21 days) will be administered with LD chemotherapy for subjects who achieve an objective response at the 
Day 28 assessment. The second infusion may be administered without LD chemotherapy if subject is experiencing significant cytopenias (see 
Section 5.3.1.3.1). In addition, a second course of treatment with a single CTX110 infusion with LD chemotherapy may be administered after PD for subjects 
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who achieve a response to the first course of treatment. See Section 5.3.1 for the eligibility and additional considerations for screening assessments. All 
subjects will be followed according to Table 17 after additional CTX110 infusions. 
17.For first CTX110 infusion and additional CTX110 infusions with LD chemotherapy, CTX110 will be administered 48 hours to 7 days after completion of 
LD chemotherapy. 
18.Baseline disease assessment (PET scan/CT of diagnostic quality to be performed within 28 days prior to CTX110 infusion. MRI with contrast allowed if CT is 
clinically contraindicated, or as required by local regulation. Additional imaging at Month 2 allowed per investigator discretion. 
19.For all subjects who receive a second CTX110 infusion on Day 35 (-7 days/+21 days), a PET/CT scan is required 28 days after that infusion to assess efficacy. 
If that PET/CT scan from the second CTX110 infusion occurs within 14 days of the initial Month 3 scan (including window), it is permissible for that scan to 
replace the Month 3 imaging.
20.To be performed ± 5 days of visit date. BM at Day 28 is required for subjects with BM involvement at screening. Additional BM biopsy and aspirate must be 
performed to confirm CR as part of disease evaluation for subjects with BM involvement at screening and to evaluate CTX110 trafficking. BM biopsy and 
aspirate may also be performed at time of disease relapse. Samples from all BM biopsy and aspirate should be sent for CTX110 PK and 
If HLH is suspected, BM biopsy and aspirate to be performed as specified in Section 6.2.7. 
21.Optional: For subjects who have disease amenable to biopsy and who provide separate consent. To be performed ± 5 days of visit date.
22.It is preferred that subjects undergo tumor biopsy during screening. However, if a biopsy of relapsed/refractory disease was performed within 3 months prior to 
enrollment and after the most recent line of therapy, archival tissue may be used (see Laboratory Manual for details). If relapse occurs on study, every attempt 
should be made to obtain biopsy of relapsed tumor and send to central pathology. Tumor biopsy refers to tissue other than bone marrow. 
23.All local and central laboratory assessments should be performed prior to dosing, unless otherwise specified. Assessments at Month 6 or later may be delayed 
or moved ahead of the visit window to accommodate holidays, vacations, and unforeseen delays.
24.For subjects experiencing grade ≥3 neutropenia, thrombocytopenia, or anemia that has not resolved within 28 days of CTX110 infusion, a CBC with 
differential must be performed more frequently until resolution to grade ≤2 or administration of a new systemic
They should be performed 
weekly until 3 months after each CTX110 infusion and then should be performed at least monthly.
25.Infectious disease testing (HIV-1, HIV-2, HCV antibody/PCR, HBV surface antigen, HBV surface antibody, HBV core antibody) ≤45 days of enrollment may 
be considered for subject eligibility.
26.
assessment at screening, before start of first day of LD chemotherapy, before CTX110 infusion, then all listed time points.
27.Samples for CTX110 PK should be sent from any LP, BM aspirate, or tissue biopsy performed following CTX110 infusion. In subjects experiencing signs or 
symptoms of CRS, neurotoxicity, or suspected HLH, additional blood samples should be drawn at intervals outlined in the laboratory manual. Samples for 
CRS PK should only be collected between scheduled visits. If samples are already being collected as part of a scheduled visit, no additional samples are 
required to be collected for CRS PK on the same day of the scheduled visit.
29.Two samples collected on Day 1: One pre-CTX110 infusion and one 20 (±5) minutes after the end of CTX110 infusion.
30.
samples should be collected daily for the duration of CRS. Day 1 samples to be collected prior to CTX110 infusion. During neurotoxicity 
and suspected HLH
will be collected (see Laboratory Manual for specific information). Samples for CRS should only be collected 
between scheduled visits. If samples are already being collected as part of a scheduled visit, no additional samples are required to be collected for CRS on the 
same day of the scheduled visit.
32.Prior to first day of LD chemotherapy only.
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Table 18:
Phase 1 and Phase 2 Schedule of Assessments (Months 30-60)
Assessments
M30 
(± 21 days)
M36
(± 21 days)
M42
(± 21 days)
M48
(± 21 days)
M54
(± 21 days)
M60
(± 21 days)
Progressive 
Disease
Secondary 
Follow-Up1
Vital signs2
X
X
X
X
X
X
X
X
Physical exam
X
X
X
X
X
X
X
X
Concomitant medications3
X
X
X
X
X
X
X
X
Survival status
X
X
X
X
X
X
X
X
Disease assessment4
X
X
X
X
X
X
X
Tumor biopsy4
X
CBC with differential5
X
X
X
X
X
X
X
X
Serum chemistry5
X
X
X
X
X
X
X
X
Immunoglobulins5,6
X
X
X
X
X
X
X
CTX110 persistence (central)6,7
X
X
X
X
X
Patient-reported outcomes
X
X
X
X
X
X
X
Adverse events8
X
X
X
X
X
X
X
X
Ab: antibody; AE: adverse event; AESI: adverse event of special interest; ALL: acute lymphoblastic leukemia; BM: bone marrow; CBC: complete blood count; 
CRS: cytokine release syndrome; CT: computed tomography; GvHD: graft vs host disease; HLH: hemophagocytic lymphohistiocytosis; LD: lymphodepleting; 
M: month; NHL: non-Hodgkin lymphoma; PET: positron emission tomography; PK: pharmacokinetic; PRO: patient-reported outcome; SAE: serious adverse 
event;
NOTE: Certain assessments for visits after Day 8 may be performed as in-home or alternate-site visits. Assessments include hospital utilization, changes in 
health and/or changes in medications, body system assessment, vital signs, weight, PRO questionnaire distribution, and blood sample collections for local and 
central laboratory assessments. 
1. Subjects with progressive disease or who receive a subsequent line of 
 will discontinue the normal schedule of assessments and attend 
annual study visits. The first secondary follow-up visit will occur 1 year (±6 weeks) after the progressive disease visit. Survival status, AEs, and 
 
 should be assessed every 6 months during secondary follow-up (by telephone, medical record review, or search of publicly available records [see 
Section 7.1.5] for time points that fall between scheduled visits). Subjects who have entered secondary follow-up in this protocol can roll over into the CRISPR 
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long-term follow-up protocol if the long-term follow-up protocol is approved and activated at the investigative site. Subjects who partially withdraw consent 
will undergo these procedures at minimum. 100-day transplant-related outcomes will be collected from subjects with B cell ALL who undergo stem cell 
transplant. These may include survival rate, nonrelapse survival rate, and rate of GvHD. 
2. Includes temperature, blood pressure, pulse rate, and respiratory rate.
3. Only select concomitant medications will be collected (Section 5.4.1).
4. Disease assessment will consist of investigator review of physical exam, CBC, clinical chemistry, and lactate dehydrogenase for NHL subjects, and of physical 
exam, CBC with differential, and clinical chemistry for B cell ALL. NHL subjects with suspected malignancy will undergo PET/CT imaging and/or a BM 
biopsy to confirm relapse. B cell ALL subjects with suspected malignancy will undergo bone marrow biopsy and aspirate, imaging of extramedullary lesions, 
and lumbar puncture for disease assessment. Every attempt should be made to obtain a biopsy of the relapsed tumor in subjects who progress. 
5. Assessed at local laboratory
Samples for CTX110 PK analysis should be sent to the central laboratory from any lumbar puncture, BM biopsy, or tissue biopsy performed following 
CTX110 infusion. 
8. SAEs, AESIs and nonserious AEs related to LD chemotherapy, study procedure, or CTX110 should be reported until last study visit. Only SAEs and AESIs 
related to LD chemotherapy, study procedure, or CTX110 will be reported after Month 24 to Month 60 or if a subject starts new
anytime 
≥3 months after CTX110 infusion. See Section 8.7, Table 21 for details.
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7.1.
Subject Screening, Enrollment, and Withdrawal
7.1.1.
Subject Screening and Enrollment
Investigators will keep a log of all potential subjects reviewed and evaluated for study 
participation. The screening log will capture limited information such as date of screening, date 
of enrollment, and reason why a subject failed screening. If at any time in the screening period a 
subject fails to meet the eligibility criteria, the subject will be designated a screen failure. 
The screening period begins on the date that the subject informed consent form (ICF) and 
continues through confirmation of eligibility and enrollment into the study. Once informed 
consent has been obtained, the subject will be screened to confirm study eligibility as outlined in 
the schedule of assessments (Table 16 and Table 17). Screening assessments are to be completed 
up to 14 days after a subject signs the ICF.
After screening is completed, a subject is deemed enrolled in the study upon the principal 
investigator’s confirmation of eligibility, and the sponsor’s approval of enrollment. Subjects 
should start LD chemotherapy within 7 days after study enrollment.
Subjects will be allowed a one-time rescreening, which may take place within 3 months of the 
initial consent.
7.1.2.
Subject Identification
A unique subject number will be assigned when an individual subject signs the study ICF. 
Subjects will be identified by a subject number consisting of:
Last 3 digits of protocol number (001), 3-digit site number, sequential 3-digit subject number 
(e.g., 001-XXX-YYY)
Subject numbers will be assigned via an interactive web response system. Once a number is 
assigned, it cannot be reassigned to a different subject. Rescreened participants will keep the 
same participant number assigned during the initial screening process.
7.1.3.
Assignment of Subjects to Treatment Cohorts
Cohorts A, B, and C will comprise subjects with NHL, including DLBCL NOS, high-grade B 
cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, transformed FL, grade 3b FL, 
and PMBCL. Enrollment and allocation of subjects to Cohorts A, B, and C will be at the 
sponsor’s discretion. Subjects with B cell ALL will be exclusively assigned to Cohort D in 
parallel with other cohorts. The starting dose for escalation will be selected separately for each 
cohort and will reflect the cumulative safety data across all cohorts for each study population 
(NHL, adult B cell ALL). Whenever escalation begins in a new cohort, the sponsor and SRC will 
discuss and agree on the starting dose level, which will not exceed the highest dose level cleared 
in Cohort A. There will be a dose limit of
TCR+ cells/kg for all dose levels, which will 
determine the minimum weight for dosing. Dosing will be staggered as described in 
Section 4.1.4. 
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7.1.4.
Replacement of Subjects
During Phase 1 Part A, subjects who withdraw or are lost to follow-up before completing the 
DLT evaluation period will be replaced. In addition, during Part A, if LD chemotherapy is 
delayed more than 30 days or the subjects starts
the subject will be replaced. 
During Part B, subjects who withdraw from the study before receiving LD chemotherapy in 
Cohorts A, B, or D, or before daratumumab in Cohort C may be replaced. Subjects who 
discontinue from the study at any other time for any other reason will not be replaced.
7.1.5.
Subject Withdrawal or Removal
Subjects may voluntarily withdraw from the study at any time. Withdrawal of full consent means 
that the subject does not wish to receive further protocol-required therapy, undergo study 
procedures, or continue any further study follow-up. The sponsor will be notified of all study 
withdrawals. Subject data and samples collected up to the date of withdrawal of consent will be 
retained and included in the analyses. Where permitted by local regulations, publicly available 
data (e.g., death records) may be included after withdrawal of consent. 
Subjects can also decide to stop receiving selected protocol assessments, procedures, and/or 
treatments but otherwise continue to participate in the study (i.e., partial withdrawal of consent). 
In this case, the site and subject should discuss and agree to a plan for further study participation 
and document this plan in source documents, clearly specifying the protocol activities that will 
continue to be performed.
The investigator will specify reason for removal from the study as follows:
x
Subject withdrawal of consent
x
Investigator decision
x
Loss to follow‐up
x
Death
For subjects who are lost to follow-up, the investigator should attempt to search publicly 
available records (where permitted and allowed by local law) to ascertain survival status. 
Attempts should also be made to collect information related to hospitalizations from other 
sources for the duration of the study.
Subjects who enter secondary follow-up due to disease progression, investigator decision / start 
of new
should attend annual visits through Month 60 to collect safety 
inform
in Table 17 under secondary follow-up visit. Subjects who have 
entered secondary follow-up in this protocol can roll over into the CRISPR long-term follow-up 
protocol if the long-term follow-up protocol is approved and activated at the investigative site.
7.2.
Study Assessments
Refer to the schedule of assessments in Table 16, Table 17, and Table 18 for the timing of the 
required procedures.
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7.2.1.
Informed Consent 
The investigator at each center will ensure that the subject is given full and adequate oral and 
written information about the nature, purpose, and possible risk and benefit of the study. Subjects 
must also be notified that they are free to discontinue from the study at any time. The subject 
should be given the opportunity to ask questions and allowed time to consider the information
provided.
The subject’s signed and dated ICF must be obtained before conducting any study procedures.
The investigator must maintain the original, signed ICF. A copy of the signed ICF must be given 
to the subject.
Whenever important new information becomes available that may be relevant to the subject’s 
consent, the written ICF and any other written information provided to subjects will be revised 
by the sponsor or designee and be submitted again to the institutional review board (IRB)/ethics 
committee (EC) for review and favorable opinion. The agreed upon, revised information will be 
provided to each subject in the study for signing and dating. The investigator will explain the 
changes to the previous version.
7.2.2.
Medical History
Demographic data will be collected. Medical history, including a full history of the subject’s 
disease, previous cancer treatments, and response to treatment from date of diagnosis will be 
obtained. Cardiac, neurological, and surgical history will be obtained.
For trial entry, all subjects must fulfill all inclusion criteria described in Section 3.1, and have 
none of the exclusion criteria described in Section 3.2.
7.2.3.
Physical Exam
Physical examination, including examination of major body systems, including general 
appearance, skin, neck, head, eyes, ears, nose, throat, heart, lungs, abdomen, lymph nodes, 
extremities, and nervous system, will be performed at every study visit and the results 
documented. Changes noted from the exam performed at screening will be recorded as an AE.
7.2.4.
Vital Signs, Including Height and Weight
Vital signs will be recorded at every study visit and include sitting blood pressure, heart rate, 
respiratory rate, oxygen saturation by pulse oximetry, temperature, and height. Weight will be 
obtained according to the schedule in Table 16 and Table 17, and height will only be obtained at 
screening.
7.2.5.
Pregnancy Test
Female subjects of childbearing potential (women who have reached menarche or women who 
have not been postmenopausal 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 serum pregnancy test performed at the time of 
screening, and a serum or urine pregnancy test within 72 hours of beginning LD chemotherapy 
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(Cohorts A, B, and D), daratumumab (Cohort C), or additional infusion of CTX110, if 
applicable, when administered without daratumumab or LD chemotherapy.
Contraception requirements for both male and female subjects are outlined in Appendix C.
7.2.6.
ECOG Performance Status
Performance status will be assessed at the screening, CTX110 infusion (Day 1), Day 28, and 
Month 3 visits. Performance status will be assessed using the ECOG scale to determine the 
subject’s general well-being and ability to perform activities of daily life (Appendix B).
7.2.7.
Echocardiogram
A transthoracic cardiac echocardiogram (for assessment of left ventricular ejection fraction) will 
be performed and read by trained medical personnel at screening to confirm eligibility. 
Additional cardiac assessment is recommended during grade 3 or 4 CRS for all subjects who 
require >1 fluid bolus for hypotension, who are transferred to the intensive care unit for 
hemodynamic management, or who require any dose of vasopressor for hypotension (Brudno 
and Kochenderfer, 2016).
7.2.8.
Electrocardiogram
Twelve (12)-lead electrocardiograms (ECGs) will be obtained during screening, prior to 
daratumumab infusion (Cohort C), prior to LD chemotherapy on the first day of treatment 
(Cohorts A, B, and D), prior to CTX110 administration on Day 1 (all cohorts), and on Day 28. 
QTc and QRS intervals will be determined from ECGs. Additional ECGs may be obtained at the 
investigator’s discretion.
7.2.9.
NHL Tumor Pathology
Histopathological diagnosis of NHL subtype will be based on local laboratory assessment. It is 
preferred that subjects undergo tumor biopsy during screening. However, if a biopsy of 
relapsed/refractory disease was performed after completion of last line of therapy and within 
3 months prior to enrollment, archival tissue may be used. Bone biopsies and other decalcified 
tissues are not acceptable due to interference with downstream assays.
Portions of the tissue biopsy will be submitted to a central laboratory for analysis. Requirements 
for tissue preparation and shipping can be found in the Laboratory Manual. If archival tissue is of 
insufficient volume or quality to fulfill central laboratory requirements, a biopsy during 
screening must be performed. Archival tumor tissue samples may be analyzed for markers of 
aggressive NHL (e.g., MYC, BCL2, BCL6) as well as immune markers in the tumor and 
surrounding microenvironment (e.g., programmed cell death protein 1, programmed cell death-
ligand 1).
If relapse occurs on study, every attempt should be made to obtain biopsy of relapsed tumor and 
send to central pathology. Tumor biopsy refers to tissue other than bone marrow (see Table 16
and Table 17). 
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7.2.10.
Brain MRI
To rule out CNS metastasis, a brain MRI will be performed during the screening. Requirements 
for the acquisition, processing, and transfer of this MRI will be outlined in the Imaging Manual.
7.2.11.
Lumbar Puncture
A lumbar puncture will be performed at screening according to institutional standard procedures 
in all subjects with adult B cell ALL (Cohort D) to assess presence of malignancy. For Cohorts 
A, B, and C, lumbar puncture at screening will be performed in subjects at high risk for CNS 
involvement. These include subjects with high-grade B cell lymphoma with MYC and BCL2
and/or BCL6 rearrangement or double-expressor lymphoma; subjects with testicular involvement 
of lymphoma; or subjects with high-risk scores on the CNS International Prognostic Index, a tool 
used to estimate risk of CNS relapse/progression in patients with DLBCL treated with R-CHOP 
(Schmitz et al., 2016).
If clinically feasible, for lumbar punctures performed during neurotoxicity,
and for presence of CTX110 (by 
PCR). Whenever lumbar puncture is performed in the setting of neurotoxicity evaluation, in 
addition to the standard panel performed at the site (which should include at least cell count, 
Gram stain, and Neisseria meningitidis) the following viral panel must be performed (see 
Section 6.2.5): CSF PCR analysis for HSV-1 and -2, enterovirus, VZV, CMV, and HHV-6.
Results of viral panel should be available within 5 business days from draw to support 
appropriate management of a subject. 
A lumbar puncture on Day 28 for analysis of CSF may also be required to confirm CR after 
CTX110 administration in subjects with B cell ALL with CNS disease at baseline (Table 16).
7.2.12.
Immune Effector Cell–associated Encephalopathy (ICE) Assessment
Neurocognitive assessment will be performed using the ICE assessment. The ICE assessment is a 
slightly modified version of the CARTOX-10 screening tool, which now includes a test for 
receptive aphasia. The ICE assessment (Table 10) examines various areas of cognitive function: 
orientation, naming, following commands, writing, and attention.
The ICE assessment will be performed at screening, before administration of CTX110 on Day 1, 
and on Days 2, 3, 5, 8, and 28. If a subject experiences CNS symptoms, the ICE assessment 
should continue to be performed approximately every 2 days until resolution of symptoms. To 
minimize variability, whenever possible the assessment should be performed by the same 
research staff member who is familiar with or trained in administration of the ICE assessment.
7.2.13.
Patient-reported Outcomes
For Cohorts A, B, and C, 3 PRO surveys, the Functional Assessment of Chronic Illness Therapy 
(FACIT) Measurement System’s Functional Assessment of Cancer Therapy (FACT)–specific 
subscale for lymphoma (FACT-Lym v 4.0), the Short Form Survey Instrument (SF-36 v 2.0), 
and EuroQoL Group 5-Dimension (EQ-5D-5L) questionnaire, and will be administered 
according to the schedule in Table 16 and Table 17. For Cohort D, FACT for leukemia 
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(FACT-Leu v4.0), and EQ-5D-5L will be administered. Questionnaires should be completed 
(self-administered in the language the subject is most familiar) before clinical assessments are 
performed.
FACT-Lym is a standardized tool based on the validated general FACT assessment in oncology, 
the FACT-G (Cella et al., 1993). The FACT-Lym evaluates the 4 domains of quality of life: 
physical, social/family, emotional, and functional well-being in the FACT-G, along with a 
15-question subscale specific to lymphoma. The subscale component is designed to capture 
patient concerns and clinical issues specific to patients undergoing treatment for lymphoma 
(Cella et al., 2005). 
The FACT-Leu is a standardized tool also based on the validated general FACT assessment in 
oncology, the FACT-G (Cella et al., 1993). In addition to the FACT-G subscales, it comprises a  
17-question leukemia-specific subscale designed to capture concerns and symptoms specific to 
patients undergoing treatment for acute or chronic disease (Cella et al., 2012).
The SF-36 is a 36-item health survey assessing 8 facets of health: physical functionality, pain, 
activity limitation due to physical health problems, activity limitation from personal or emotional 
health issues, emotional well-being, social function, energy/fatigue, and perceptions of general 
health, as well as a single question that addresses the subject’s perception of changes to his/her 
health (Ware and Sherbourne, 1992).
The EQ-5D-5L comprises a 5-item descriptive system questionnaire and a visual analogue scale 
(VAS). The descriptive system assesses health on the dimensions of mobility, self-care, usual 
activities, pain/discomfort, and anxiety/depression, with each dimension including 5 levels of 
severity: no problems, slight problems, moderate problems, severe problems, and extreme 
problems. The VAS assesses self-rated health on a 20-cm vertical scale from 0 (worst imaginable 
health) to 100 (best imaginable health). 
7.2.14.
Hospitalizations and Health Care Resource Utilization
Data on hospitalization, including intensive care unit stay and outpatient day use, will be 
collected during the first 2 months after each CTX110 infusion. 
7.2.15.
PET/CT and Radiologic Disease Response Assessments for NHL
PET/CT scans of all sites of disease (including the neck, chest, abdomen, and pelvis) are 
required. The CT portion of PET/CT should be of diagnostic quality. MRI with contrast may be 
used when CT is clinically contraindicated or as required by local regulation. The baseline 
PET/CT must be performed within 28 days prior to administration of CTX110, and postinfusion 
scans will be conducted per the schedule of assessments in Table 16 and Table 17. If a subject 
has symptoms consistent with possible disease progression, an unscheduled PET/CT should be 
performed. Additional detail on imaging required for disease assessments can be found in the 
imaging manual. 
For all subjects who receive a second CTX110 infusion on Day 35 (-7 days/+21 days), a PET/CT 
scan is required 28 days after that infusion to assess efficacy. It is permissible for that scan to 
replace the Month 3 imaging.
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Requirements for the acquisition, processing, and transfer of scans will be outlined in the 
Imaging Manual. When possible, the imaging modalities, machines, and scanning parameters 
used to acquire PET/CT should be kept consistent during the study. All radiological images 
available for the site investigators will be transmitted by the sites to a central imaging vendor 
designated by the sponsor. 
Tumor burden will be quantified at baseline according to Lugano criteria (Appendix A). Tumor 
burden assessments are to include the SPD calculated by aggregating the dimensions of each 
target lesion (nodal or extranodal) for a maximum of 6 target lesions, by multiplying the 
2 longest perpendicular diameters of lesions. Target lesions should be selected from those with 
the largest size that can be reproducibly measured, representing overall tumor burden across 
multiple sites and organs.
Tumor response will be determined according to Lugano criteria (Appendix A) and will be 
assessed by both the local investigators and a central imaging review. The determination of study 
eligibility and decisions regarding subject management and disease progression will be made by 
the investigator. Postbaseline imaging will be compared against baseline imaging to determine a 
response; however, imaging indicative of progression may be compared against the nadir. 
7.2.15.1.
Imaging of Extramedullary Disease in B cell ALL
Adult B cell ALL subjects with known extramedullary disease at baseline will be assessed with 
imaging within 28 days prior to administration of CTX110, and postinfusion imaging will be 
conducted per the schedule of assessments in Table 16 and Table 17. A modality appropriate for 
the anatomical location of disease will be used with the same imaging modality for the duration 
of participation. Extramedullary disease will be assessed as described in Appendix F .
7.2.16.
Bone Marrow Biopsy and Aspirate for NHL
A bone marrow biopsy and aspirate will be performed at screening (or within 28 days prior to 
CTX110 infusion, if a recent sample was collected as part of standard of care) and at Day 28 to 
evaluate extent of disease. A bone marrow biopsy at Day 28 is required for NHL subjects with 
BM involvement at screening. Subjects with history of bone marrow involvement who achieve a 
CR as determined on PET/CT scan will have a bone marrow biopsy to confirm response 
assessment. If a subject shows signs of relapse, the biopsy collection should be repeated. A 
sample of aspirate for presence of CTX110 (detected via PCR) should be sent for central 
laboratory evaluation at any point when bone marrow analysis is performed. Standard 
institutional guidelines for the bone marrow biopsy should be followed. Further instructions on 
processing and shipment are provided in the Laboratory Manual.
7.2.17.
Optional Tumor Biopsy for NHL
To understand more about the trafficking of CTX110 into the tumor tissue and the impact of 
tumor environment on the function of CTX110, optional tumor biopsies will be obtained from 
subjects with tumor amenable to biopsy and who provide separate consent for this procedure. 
The optional tumor biopsy will be performed at Day 28. Standard institutional guidelines for the 
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tumor biopsy should be followed. Further instructions on processing and shipment are provided 
in the Laboratory Manual. 
7.2.18.
Bone Marrow Biopsy and Aspirate for B Cell ALL
A bone marrow biopsy and aspirate will be performed during the screening window or within 
28 days of CTX110 infusion with appropriate consent. Samples will be assessed locally to 
confirm disease pathology, evaluate extent of disease, and assign cohorts. Samples will also be 
assessed (locally and centrally) for MRD by multicolor flow cytometry or molecular approaches 
(e.g., PCR, NGS). Subjects in Subcohort D2 may be enrolled with local baseline MRD results 
pending, as long as qualifying results within 3 months of enrollment are available.
Additional bone marrow aspirates and biopsy will be performed at subsequent visits per the 
schedule of assessments in Table 16. If a subject shows signs of relapse, the biopsy and aspirate 
collection should be repeated. Disease assessments will be performed according to criteria in 
Appendix F. A sample for presence of CTX110 (detected via PCR) should be sent for central 
laboratory evaluation at any point when bone marrow analysis is performed. 
Standard institutional guidelines for bone marrow biopsy and aspirate collection should be 
followed. Further instructions on processing and shipment are provided in the Laboratory 
Manual. 
7.2.19.
Laboratory Tests
Laboratory samples will be collected and analyzed according to the schedule of assessment in 
Table 16, Table 17, and Table 18. Local laboratories meeting Clinical Laboratory Improvement 
Amendments requirements will be utilized to analyze all tests listed in Table 19 according to 
standard institutional procedures.
Table 19:
Local Laboratory Tests
Hematology
Hematocrit, hemoglobin, red blood cell count, white blood cell count, 
neutrophils, lymphocytes, monocytes, basophils, eosinophils, platelet count, 
absolute neutrophil count, ABO type,1
peripheral blasts in 
Cohort D 
Serum Chemistry
ALT (SGPT), AST (SGOT), total bilirubin, albumin, alkaline phosphatase, 
bicarbonate, blood urea nitrogen, calcium, chloride, creatinine, eGFR, glucose, 
lactate dehydrogenase, magnesium, phosphorus, potassium, sodium, total 
protein, CRP, ferritin
Coagulation
Prothrombin time, activated partial thromboplastin time, international 
normalized ratio, fibrinogen
Infectious Disease
HIV-1, HIV-2, hepatitis C virus antibody and PCR, hepatitis B surface antigen, 
hepatitis B surface antibody, hepatitis B core antibody
Immunological2
CD19, CD20, IgA, IgG, IgM
Serum or Urine Pregnancy3
Human chorionic gonadotropin
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ALT: alanine aminotransferase; AST: aspartate aminotransferase; CD: cluster of differentiation; CRP: C-reactive 
protein; eGFR: estimated glomerular filtration rate; HIV-1/-2: human immunodeficiency virus type 1 or 2; HLH: 
hemophagocytic lymphohistiocytosis; IgA/G/M: immunoglobulin A, G, or M; LD: lymphodepleting; PCR: 
polymerase chain reaction; SGOT: serum glutamic oxaloacetic transaminase; SGPT: serum glutamic pyruvic 
transaminase;
1. For Cohort C only, if necessary.
2. CD19 and CD20 should be evaluated in the same assay to detect CD19 antigen loss.
3. For females of childbearing potential only. Serum pregnancy test required at screening. Serum or urine pregnancy 
test within 72 hours of start of LD chemotherapy (Phase 1 Cohorts A, B, and D and Phase 2) or daratumumab 
(Phase 1 Cohort C) or additional infusion of CTX110, if applicable, when administered without daratumumab or 
LD chemotherapy. See Section 7.2.5 for additional details.
7.3.
Biomarkers
Blood, bone marrow, tumor, and CSF samples (only in subjects with ICANS) will be collected to 
The following labs will be drawn for analysis at a central laboratory. Reference the Laboratory 
Manual for information regarding the blood draw and sample handling for tests sent to the 
central laboratory for processing.
7.3.1.
CTX110 Pharmacokinetic Analysis
PK analysis of CTX110 cells will be performed on blood samples collected according to the 
schedule described in Table 16, Table 17, and Table 18. In subjects experiencing signs or 
symptoms of CRS, neurotoxicity, and HLH, additional blood samples should be drawn in 
intervals outlined in the laboratory manual. The time course of the disposition of CTX110 in 
blood (Tsai et al., 2017) will be described using a PCR assay that measures copies of CAR 
construct per μg DNA. Complementary analyses using flow cytometry to confirm the presence 
of CAR protein on the cellular surface may also be performed.
The trafficking of CTX110 in CSF, bone marrow, or tumor tissues may be evaluated in any of 
these samples collected as per protocol-specific sampling.
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8.
SAFETY, ADVERSE EVENTS, AND STUDY OVERSIGHT
The investigator will monitor each subject for clinical and laboratory evidence of AEs on a 
routine basis throughout the study. The investigator will assess and record details, including the 
date of onset, event diagnosis (when known) or signs and symptoms, time course (end date, 
ongoing, intermittent), relationship to the study therapies or procedure, action(s) taken, and 
outcome. AEs in response to a query, observed by site personnel, or reported spontaneously by 
the subject will be recorded. The investigator is responsible for ensuring that any AEs observed 
by the Investigator or reported by the subject are recorded in the subject’s medical record in the 
sponsor’s electronic data capture system. 
8.1.
Adverse Events 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and which does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unfavorable or unintended sign (including an 
abnormal laboratory finding, for example), symptom, or disease temporally associated with the 
use of a medicinal (investigational) product whether or not considered related to the medicinal 
(investigational) product [(GCP) E6(R2)]. In clinical studies, an AE can include an undesirable 
medical condition occurring at any time, including baseline or washout periods, even if no study 
treatment has been administered. 
The investigator will assess and record information pertaining to the AE, which includes but is 
not limited to the following: date of onset, event diagnosis (when known) and/or signs and 
symptoms, duration, severity, seriousness, relationship to the study therapy or procedure, 
action(s) taken, and outcome. 
Additional criteria defining an AE are described below.
The following are considered to be AEs: 
x
Aggravation of a pre-existing disease or permanent disorder (any clinically significant 
worsening in the nature, severity, frequency, or duration of a pre-existing condition)
x
Events resulting from protocol-mandated procedures (e.g., complications from 
invasive procedures)
The following are not considered to be AEs: 
x
Medical or surgical procedures including elective or preplanned procedures such as 
surgery, endoscopy, tooth extraction, and transfusion. These should be recorded in the 
relevant eCRF.

Note: An untoward medical event occurring during the prescheduled elective 
procedure or routinely scheduled treatment should be recorded as an AE or SAE.
x
Pre-existing diseases or conditions that do not worsen during or after administration 
of the investigational medicinal product
x
Hospitalization planned for study treatment infusion or observation
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x
The malignancy under study or signs and symptoms associated with the disease 
(except signs and symptoms of disease progression that meet seriousness criteria 
within 3 months after CTX110 administration) as well as progression or relapse of the 
underlying malignancy (see Section 8.10 disease progression)
The investigator is responsible for reviewing laboratory test results and determining whether an 
abnormal value in an individual study subject represents a clinically significant change from the 
subject’s baseline value. Only abnormal laboratory results considered by the investigator to be 
clinically significant should be reported as AEs (e.g., an abnormal laboratory finding associated 
with clinical symptoms, of prolonged duration, or that requires additional monitoring and/or 
medical intervention). Whenever possible, these should be reported as a clinical diagnosis rather 
than the abnormal parameter itself (i.e., neutropenia vs neutrophil count decreased). Abnormal 
laboratory results without clinical significance should not be recorded as AEs. 
Adverse events can occur before, during, or after treatment, and can be either treatment-emergent 
(AEs that start or worsen on or after CTX110 infusion) or non–treatment-emergent. A non–
treatment-emergent AE is any new sign or symptom, disease, or other untoward medical event 
that occurs after written informed consent has been obtained and before the subject has received 
CTX110.
8.2.
Serious Adverse Event
An AE of any untoward medical consequence must be classified as an SAE if it meets any of the 
following criteria:
x
Results in death
x
Is life-threatening (i.e., an AE that, in the opinion of the investigator, places the 
subject at immediate risk of death)
x
Requires in-patient hospitalization or prolongs an existing hospitalization 
(hospitalizations for scheduled medical or surgical procedures or to conduct 
scheduled treatments do not meet these criteria)
x
Results in persistent or significant disability or incapacity
x
Results in a congenital anomaly or birth defect in the newborn
x
Other important/significant medical events. Important medical events that may not 
result in death, be life-threatening, or require hospitalization may be considered 
serious when, based upon appropriate medical judgment, they may jeopardize the 
patient or subject and may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition. 
Hospitalization for study treatment infusions, or planned hospitalizations following CTX110 
infusion, are not considered SAEs. Furthermore, hospitalizations for observation or prolongation 
of hospitalization for observation alone should not be reported as an SAE unless they are 
associated with a medically significant event that meets other SAE criteria as assessed by the 
investigator.
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8.3.
Adverse Events of Special Interest
An AESI, whether serious or nonserious, is one of scientific and medical concern specific to the 
sponsor’s product or program for which ongoing monitoring and rapid communication by the 
investigator to the sponsor may be appropriate.
Based on the reported clinical experience of autologous CAR T cells, considered to be in the 
same pharmacological class, the sponsor has identified the following AESIs:
x
CTX110 infusion reactions 
x
Grade ≥ 3 infections 
x
Tumor lysis syndrome 
x
Cytokine release syndrome
x
ICANS 
x
B cell aplasia 
x
Hemophagocytic lymphohistiocytosis
x
Hypogammaglobulinemia 
x
Graft vs host disease 
x
Secondary malignancy 
x
Uncontrolled T cell proliferation
x
Any new hematological or autoimmune disorder that the investigator determines is 
possibly related or related to CTX110. 
Additional information on the required AESI reporting collection period is detailed in Table 21.
8.4.
Adverse Event Severity
The investigator is obligated to grade AEs according to CTCAE version 5.0 (Appendix E), with 
the exception of CRS, neurotoxicity, and GvHD, which will be graded according to the criteria in 
Section 6.2.4, Section 6.2.5, and Section 6.2.9, respectively.
When a CTCAE grade or protocol-specified criteria are not available, the investigator will use 
the toxicity grading in Table 20. 
Table 20:
Adverse Event Severity
Grade 1
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated.
Grade 2
Moderate; minimal, local, or noninvasive intervention indicated; limiting age-
appropriate instrumental ADL.1
Grade 3
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care ADL.2
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Grade 4
Life-threatening consequences; urgent intervention indicated.
Grade 5
Death related to AE.
ADL: Activities of Daily Living; AE: adverse event. 
1. Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing 
money, etc.
2. Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not 
bedridden.
8.5.
Adverse Event Causality
The investigator must assess the relationship between each AE and CTX110, LD chemotherapy, 
daratumumab infusion, and any protocol-mandated study procedure (all assessed individually). 
The assessment of relationship will be made based on the following definitions:
Related: There is a clear causal relationship between the study treatment or procedure and 
the AE.
Possibly related: There is some evidence to suggest a causal relationship between the study 
treatment or procedure and the AE, but alternative potential causes also exist.
Not related: There is no evidence to suggest a causal relationship between the study 
treatment or procedure and the AE.
Investigators should consider the temporal association between the timing of the event and 
administration of the treatment or procedure, a plausible biological mechanism, and other 
potential causes of the event (e.g., concomitant therapy, underlying disease) when making their 
assessment of causality.
If an SAE is assessed to be not related to any study intervention, an alternative etiology must be 
provided in the CRF.
If the relationship between the SAE and the investigational product is determined to be 
“possible,” a rationale for the assessment must be provided by the reporting investigator.
8.6.
Outcome
The outcome of an AE or SAE classified and reported as follows:
x
Fatal
x
Not recovered/not resolved
x
Recovered/resolved
x
Recovered/resolved with sequelae
x
Recovering/resolving
x
Unknown
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8.7.
Adverse Event Collection Period
The safety-related information of all subjects enrolled in this study will be recorded from the 
time of ICF signing until end of study; however, there are different reporting requirements for 
the different time periods in the study. Table 21 describes the AEs that should be reported at each 
time period of the study.
Table 21:
Adverse Event Collection by Study Time Period
Time Period
AE Reporting Requirements
Informed consent to 3 months after each CTX110 
infusion1
x
All AEs2
3 months after last CTX110 infusion through Month 24 
visit
x
Nonserious AEs related to LD 
chemotherapy, study procedure,3 or CTX110
x
SAEs
x
AESIs
Month 24 to Month 60 visit OR any time a subject starts 
a new
x
SAEs related to LD chemotherapy, study 
procedure,3 or CTX110
x
AESIs related to LD chemotherapy, study 
procedure,3 or CTX110
x
New malignancies 
AE: adverse event; AESI: adverse event of special interest; LD: lymphodepleting; SAE: serious adverse event. 
1. If additional infusion of CTX110 occurs after the 3-month post-CTX110 infusion period, then the AE reporting for 
any additional CTX110 infusion begins with daratumumab or LD chemotherapy administration, as applicable.
2. SAEs related to disease progression, including SAEs related to disease progression with outcome of death, will be 
reported up to 3 months. SAEs related to disease progression will not be collected after 3 months. Deaths due to 
disease progression after 3 months must be reported as outlined Section 8.11 .
3. AEs related to study procedure include events related to, e.g., laboratory procedures, radiography, biopsies, bone 
marrow aspirates, or IV treatment infusions, and may occur at any time starting at screening and continuing 
through the duration of the study.
If a subject does not receive CTX110 therapy after enrollment, the AE reporting period ends 
30 days after last study-related treatment or procedure (e.g., biopsy, imaging, LD chemotherapy).
8.8.
Adverse Event Reporting
All AEs will be recorded in the appropriate section of the electronic case report form (eCRF). 
Subjects withdrawn from the study because of AEs will be followed by the investigator until the 
outcome is determined. When appropriate, additional written reports and documentation will be 
provided.
AE reporting should occur as per the study period designated in Table 21. If a reportable SAE or 
AESI occurs, the SAE/AESI form provided to investigators should be completed and submitted 
to the sponsor or its designee immediately (i.e., no more than 24 hours after the investigator 
becomes aware of the event) by scanning and emailing the paper report form using the email 
address provided to the investigators. In particular, if the SAE is fatal or life-threatening, the 
report form must be submitted immediately, irrespective of the extent of available AE 
information. The time frame also applies to additional, new information (follow-up) on 
previously reported SAE/AESI reports.
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In the rare event that the investigator does not become aware of the occurrence of a reportable 
SAE/AESI immediately (e.g., a study subject initially seeks treatment elsewhere), the 
investigator is to report the event within 24 hours of learning of the event and document the date 
and time of awareness of the event.
In addition, an investigator may be requested to obtain specific additional follow-up information 
in an expedited fashion (e.g., autopsy finding). The information collected for SAEs/AESIs is 
more detailed than that captured on the AE CRF. In general, this will include a description of the 
event in sufficient detail, as well as concomitant medications and any relevant medical details to 
allow for a complete medical assessment of the case and causality assessment by the investigator 
and the sponsor. Information on the other possible causes of the event, such as concomitant 
medications and illnesses must be provided.
The investigator must complete, sign, and date the SAE/AESI form, verify the accuracy of the 
information recorded on the SAE/AESI form with the corresponding source documents, and send 
a copy by email or fax to the sponsor or designee. Subsequently, all SAEs will be reported to the 
health authorities per local reporting guidelines.
It is the principal investigator’s responsibility to notify the IRB/EC of all SAEs that occur at his 
or her site as per local policies. Investigators will also be notified of all unexpected, serious, 
drug-related events that occur during the clinical trial. Each site is responsible for notifying its 
IRB/EC of these additional SAEs.
8.9.
Pregnancy
Certain information, although not considered an AE or SAE, must be recorded, reported, and 
followed as indicated for an SAE (see Section 8.8), including pregnancies.
Pregnancies (both those of female subjects and female partners of male subjects) must be 
reported to the sponsor or designee within 24 hours of the investigator’s knowledge using the 
Investigational Product Pregnancy Report. All pregnancies will be followed through to outcome 
and the outcome must be reported to the sponsor or designee using the Pregnancy outcome 
section of Investigational Product Pregnancy Report. 
Pregnancies themselves are not considered AEs or SAEs. However, any AEs or SAEs occurring 
during pregnancy are to be reported following AE and SAE reporting guidelines.
8.10.
Disease Progression
Progression of malignancy is not considered an adverse event, and the term “disease 
progression” or similar should not be reported as an AE. However, within 3 months after 
CTX110 administration, signs and symptoms of disease progression meeting seriousness criteria 
should be reported as SAEs (including SAEs with the outcome of death), as per Table 21. 
Whenever possible, the event should be reported as a clinical diagnosis (e.g., respiratory failure 
or pulmonary hemorrhage). For reporting of disease progression with outcome of death 
≥3 months after CTX110 administration, refer to Section 8.11.
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8.11.
Reporting Deaths
Regardless of relationship to study drug, all deaths on study should be recorded in the relevant 
eCRF. 
-
In addition, all outcomes of death must be reported to the sponsor according to the AE 
collection periods described in Section 8.7 and according to the information provided in 
Section 8.8. 
-
For any death that does not meet reporting criteria in Section 8.7, the death must be 
reported on the Death Report Form. An example of a situation where the Death Report 
Form should be used would be a death due to disease progression that occurs more than 
90 days after CTX110 infusion.
8.12.
Study Oversight
8.12.1.
Safety Review Committee
During dose escalation, an SRC composed of Part A investigators and sponsor representatives 
will meet before each dose escalation decision and before initiating a new dose cohort. The SRC 
will review and discuss all AEs and determine if they meet DLT criteria and/or study stopping 
rules (Section 4.1.4.2 and Section 9). After 3 or 6 subjects are enrolled in a dose level, the SRC 
will review aggregate safety data and decide whether to dose escalate, de-escalate, or confirm the 
recommended Part B dose according to the rules in Section 4.1.4. The SRC may consult with the 
DSMB via the sponsor regarding emergent safety data and discuss potential revisions to DLT 
criteria or alternate dosing schema.
In Part B, the SRC may continue to meet regularly to discuss one or more of the following: 
single subject case studies, aggregate safety and/or biomarker data, toxicity management 
algorithms, and review and discuss the possibility of expanding the study to include other 
malignancies.
8.12.2.
Independent Data Safety Monitoring Board
An independent DSMB comprised of at least 2 physicians and 1 statistician with appropriate 
scientific and medical expertise to monitor the study will be established during Part A. The 
DSMB will perform interim analyses of safety and efficacy data according to Section 10.5 and 
will monitor stopping rules to pause enrollment. The DSMB will also review expedited reports 
of any SAEs, including expedited SAEs or SAEs resulting in death. The DSMB may recommend 
that the sponsor amend the protocol, stop enrollment, or discontinue the study at any time if 
concerns about safety of the subjects are encountered. The roles and responsibilities of the 
DSMB will be further described in the DSMB charter.
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9.
STOPPING RULES AND STUDY TERMINATION
9.1.
Stopping Rules
A Phase 1 cohort will be paused if one or more of the following events occur: 
x
Life-threatening (grade 4) toxicity attributable to CTX110 that is unmanageable, 
unexpected, and unrelated to LD chemotherapy
x
Death related to CTX110 within 30 days of infusion
x
Grade 3 or higher GvHD
x
After at least 12 subjects are enrolled in cohort expansion and at least 1 of the 
following occurs:

>35% grade 3 or 4 neurotoxicity not resolving within 2 weeks to grade ≤2

>20% grade ≥2 GvHD that is steroid refractory.

>30% grade 4 CRS
x
New malignancy (distinct from recurrence/progression of previously treated 
malignancy)
x
Lack of efficacy, defined as 2 or fewer objective responses (per central review) after 
15 subjects in cohort expansion (Phase 1 Part B) have 3 months of post-CTX110 
assessment.
If there is any such event(s), enrollment will be suspended, all available data will be reviewed, 
and health authorities will be notified as required. A meeting will take place with the SRC, 
members of the study team, and sponsor medical monitor. Meeting minutes will be taken to 
capture the review of any ongoing investigations, including next steps in management of the 
subject and any proposed changes to the protocol for forwarding to the DSMB. After evaluation 
and following a review of the data with the DSMB, the sponsor may decide to restart enrollment 
in a cohort, amend the study, or permanently suspend enrollment and remove all subjects who 
have not received CTX110 from the study. Discontinuation or suspension of enrollment in one 
particular disease subset or cohort may not be applicable to others. 
For Phase 2, the DSMB will review available safety data on at least a semi-annual basis and 
make trial conduct recommendations based on analysis of the risk-benefit balance. The DSMB 
may request additional safety data or may recommend modifying the study conduct if safety 
concerns are identified. The DSMB will also review safety data in parallel to the interim analysis 
for futility and efficacy (Section 10.5.1). The overall study will be paused if the sponsor or health 
authorities decide for any reason that patient safety may be compromised by continuing the 
study.
In the event enrollment is permanently suspended, subjects who are already enrolled in the study 
will not proceed with daratumumab infusion (Phase 1 Cohort C), LD chemotherapy (all Phase 1 
cohorts and Phase 2), and CTX110 infusion (all Phase 1 cohorts and Phase 2). Subjects who have 
already been treated with CTX110 will remain in the study and continue to be followed per the 
study protocol or will be transitioned to a long-term safety follow-up study.
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If enrollment is suspended after a subject (or subjects) has received daratumumab (Cohort C) or 
LD chemotherapy before they have received CTX110 (all cohorts), the decision to infuse 
CTX110 will be at the investigator’s discretion after discussion of the potential risks with the 
subject. The investigator should inform the CRISPR medical monitor of the decision before 
infusion of CTX110.
If enrollment is permanently suspended, the sponsor will immediately inform all appropriate 
parties, including principal investigators, ECs, IRBs, and competent authorities.
9.2.
Stopping Rules for Individual Subjects
Stopping rules for individual subjects are as follows: 
x
Any medical condition that, in the opinion of the investigator, would put the subject 
at risk during continuing study-related treatments or follow-up
x
If a subject is found not to have met eligibility criteria or has a major protocol 
deviation before the start of LD chemotherapy (Cohorts A, B, D), or before the start 
of daratumumab infusion (Cohort C)
x
If a subject has unresolved infusion reaction due to daratumumab treatment 
(Cohort C)
9.3.
End of Study Definition
The end of the study is defined as the time at which the last subject completes the Month 60 visit, 
is considered lost to follow-up, withdraws consent, or dies. The primary analyses of Phase 2 will 
be conducted after the 97 subjects have completed the 6-month disease response assessment, are 
lost to follow-up, withdraw from the study, or die, whichever occurs first.
9.4.
Study Termination
This study may be discontinued at any time due to safety concerns, failure to meet expected 
enrollment goals, administrative reasons, or at the discretion of the sponsor. In the event of study 
termination, the sponsor will immediately inform all appropriate parties, including principal 
investigators, ECs, IRBs, and competent authorities. In the event this study is terminated early, 
subjects who have received CTX110 will be asked to participate in a separate long-term follow-
up study for up to 15 years after the last CTX110 infusion.
9.5.
Long-Term Follow-up Study
The long-term follow-up study is a separate, noninterventional safety study. Subjects in the 
current study (CRSP-ONC-001) will be asked to consent to be followed for safety for up to 15 
years from their last CTX110 infusion. Subjects may be rolled over into the long-term follow-up 
study once they have entered secondary follow-up in CRSP-ONC-001, if the long-term follow-
up study has been approved at the investigative site. Details regarding the long-term follow-up 
study requirements will be specified in a separate protocol.
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10.
STATISTICAL ANALYSES
10.1.
Study Objectives and Hypotheses
Phase 1
The primary objective of Part A is to assess the safety of escalating doses of CTX110 in 
combination with various lymphodepletion agents in subjects with relapsed or refractory B cell 
malignancies to determine the recommended Part B dose and cohort.
The primary objective of Part B is to assess the preliminary efficacy of CTX110 in subjects with 
relapsed or refractory B cell malignancies, as measured by ORR.
Phase 2
The primary objective of Phase 2 is to assess the efficacy of CTX110 in subjects with select 
NHL subtypes, as measured by ORR.
10.2.
Study Endpoints
10.2.1.
Primary Endpoints
Phase 1
Part A (dose escalation) for all cohorts: The incidence of AEs, defined as DLTs for each of the 
cohorts (A, B, C, and D).
Part B (cohort expansion) and Phase 2: The ORR (CR + PR) per the Lugano Response 
Criteria for Malignant Lymphoma (Cheson et al., 2014), as determined by independent central 
review.
10.2.2.
Secondary Efficacy Endpoints (Phase 1 and Phase 2)
Duration of response/remission (DOR) based on central read/assessment will be reported only 
for subjects who have had objective response events. This will be assessed using the time 
between the first objective response and the first disease progression or death due to any cause 
after the first objective response. 
Duration of clinical benefit (DOCB) based on central read/assessment will be calculated as the 
time between the first objective response and the last disease progression or death. 
Treatment-failure–free survival (TFFS) will be calculated as the time between the first CTX110 
infusion and the last disease progression or death due to any cause.  
Progression-free survival (PFS) will be calculated as the time between the first CTX110 infusion 
and the first disease progression or death due to any cause. 
Overall survival (OS) will be calculated as the time between date of first CTX110 infusion and 
death due to any cause. 
For secondary efficacy endpoints DOR, DOCB, TFFS and PFS, the subjects who have not 
progressed and are still on study at the data cutoff date will be censored at their last response 
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assessment date. For OS, the subjects who are alive at the data cutoff date will be censored at 
their last date known to be alive. 
For adult B cell ALL (Phase 1 Cohort D), ORR (complete remission + CRi) will be assessed.
10.2.3.
Secondary Safety Endpoints (Phase 1 and Phase 2)
The frequency and severity of AEs and clinically significant laboratory abnormalities will be 
summarized and reported according to CTCAE version 5.0, except for CRS (ASTCT criteria, 
Section 6.2.4), neurotoxicity (ICANS, Section 6.2.5, and CTCAE v5.0), and GvHD (Mount Sinai 
Acute GVHD International Consortium [MAGIC] criteria, Section 6.2.9).
10.2.4.
Pharmacokinetics (Phase 1 and Phase 2)
Pharmacokinetic data will include levels of CTX110 in blood over time as assessed by a PCR 
assay that measures copies of CAR construct. Analysis of CTX110 in blood may also occur 
using flow cytometry that detects CAR protein on the cellular surface. Such analysis may be 
used to confirm the presence of CTX110 in blood and to further characterize other cellular 
immunophenotypes.
10.2.5.
Secondary Patient-reported Outcome Endpoint (Phase 1 and Phase 2)
Change over time in PROs associated with CTX110 will be evaluated and analyzed as in 
Section 10.6.5. See Section 7.2.13 for the PRO surveys administered to subjects in various 
cohorts. 
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10.3.
Analysis Sets
The following analysis sets will be evaluated and used for presentation of the data. 
Phase 1 Part A (Dose Escalation)
DLT evaluable set (DES): All subjects who receive CTX110 and complete the DLT 
evaluation period or discontinue early after experiencing a DLT. The DLT evaluation period 
will begin with first CTX110 infusion and last for 28 days. The DES will be used for 
determination of the recommended Part B or Phase 2 dose. 
Phase 1 Part A and Part B (Dose Escalation and Cohort Expansion) and Phase 2
Enrolled set: All subjects enrolled in the study. The enrolled set will be classified according 
to the assigned dose level of CTX110.
Treated set: All subjects who received any study treatment in the study. The subjects in the 
treated set will be classified according to the received study treatment.
Full analysis set (FAS): All subjects who received CTX110 infusion. The subjects in FAS 
will be classified according to the assigned dose regimen of CTX110. Only subjects in the 
FAS who are assigned to the dose regimen for Phase 2 will be used for the primary efficacy 
analysis.
Safety analysis set (SAS): All subjects who received CTX110 infusion. The subjects in SAS 
will be classified according to the received dose level of CTX110. The SAS will be the 
primary analysis set for the characterization of CTX110 safety profile.
10.4.
Sample Size
The sample size in Phase 1 Part A (dose escalation) of the study will be approximately 100, i.e., 
approximately 70 subjects with NHL and approximately 30 subjects with B cell ALL, depending 
on the number of dose levels and cohorts evaluated, and the occurrence of DLTs. The sample 
size in Phase 1 Part B (cohort expansion) will be up to 30. 
To test for efficacy, group sequential design with alpha-spending function (Lan and DeMets, 
1983) will be employed. One interim analysis is planned for both futility and early efficacy. It 
will be performed at an information level of 0.5 (proportion of total subjects), and boundaries 
based on error-spending function will be used for the interim analysis.
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10.5.
Interim Analyses
10.5.1.
Efficacy Interim Analysis
10.5.2.
Safety Interim Analyses
The DSMB will review safety data from dose escalation (Phase 1 Part A) and endorse the 
recommended Part B or Part 2 dose before the study advances to cohort expansion or Phase 2. 
The DSMB will review safety data twice a year until the last treated subject in Part B or Phase 2 
is at least 2 years after last CTX110 infusion. The sponsor or SRC may request additional 
reviews by the DSMB if safety concerns are identified. Data submitted to the DSMB may be 
monitored or unmonitored to facilitate timely DSMB review.
10.6.
Planned Method of Analyses
The primary analysis of efficacy will occur after all subjects in the FAS in Phase 2 of the study 
have had the opportunity to be assessed for response 6 months after CTX110 infusion. A final 
analysis will occur when all subjects complete or withdraw from the study. 
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Tabulations will be produced for appropriate disposition, demographic, baseline, efficacy, and 
safety parameters. By-subject listings will be provided for all data, unless otherwise specified.
10.6.1.
Efficacy Analysis
The primary endpoint of ORR for all analyses (interim and primary) will be based on 
independent central review of disease assessments in the FAS.
Sensitivity analyses of ORR based on investigator review of disease assessments will be 
performed. For NHL, Lugano response criteria (Cheson et al., 2014) will be used and ORR refers 
to the rate of CR + PR (Appendix A). For B cell ALL, ORR refers to the rate of complete 
remission + CRi (Appendix F).
Objective response rate will be summarized as a proportion with exact 95% confidence intervals.
For time-to-event variables such as DOR, DOCB, TFFS, PFS, and overall survival, medians with 
95% confidence intervals will be calculated using Kaplan-Meier methods.
10.6.2.
Safety Analysis
All subjects who receive CTX110 will be included in the safety analysis set. Clinical AEs will be 
graded according to CTCAE version 5.0, except for CRS, which will be graded according to 
ASTCT (Lee et al., 2019), neurotoxicity, which will be graded according to ICANS (Lee et al., 
2019) and CTCAE, and GvHD, which will be graded according to MAGIC criteria (Harris et al., 
2016). AEs, SAEs, and AESIs will be summarized and reported according to the collection by 
study time period described in Table 21. 
Treatment-emergent adverse events are defined as AEs that start or worsen on or after the initial 
CTX110 infusion.
Vital signs will be listed. Summary tables will be prepared to examine the distribution of 
laboratory measures over time.
Frequencies of subjects experiencing at least 1 AE will be reported by body system and preferred 
term according to Medical Dictionary for Regulatory Activities (MedDRA) terminology. 
Detailed information collected for each AE will include description of the event, duration, 
whether the AE was serious, intensity, relationship to study drug, action taken, clinical outcome, 
and whether or not it was a DLT. Emphasis in the analysis will be placed on AEs classified as 
dose-limiting.
10.6.3.
Pharmacokinetic and Pharmacodynamic Analyses
Incidence of
 levels of CTX110 CAR+ T cells in blood, and levels of 
in serum will be summarized.
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10.6.5.
Patient-reported Outcomes
Descriptive statistics will be presented for PRO, both as reported and as change from baseline. 
Further analyses may be performed on an ad hoc basis.
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11.
DATA MANAGEMENT
11.1.
Data Recording and eCRF Processing 
The investigator is required to maintain adequate and accurate medical records designed to 
record all observations and data pertinent to the study for each subject. Study data for each 
consented subject will be entered into a CRF by site personnel using a secure, validated (21 CFR 
Part 11 compliant), web-based electronic data capture application. Instances of missing, 
discrepant, or uninterpretable data will be queried by the sponsor or designee for resolution. Any 
changes to study data will be made to the eCRF and documented in an audit trail maintained 
within the clinical database. CRFs must be reviewed and electronically signed and dated by the 
investigator.
An audit may be performed at any time during or after completion of the clinical study by 
sponsor personnel or their designee. All study-related documentation must be made available to 
the designated auditor.
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12.
ADMINISTRATIVE
12.1.
Institutional Review Board/Ethics Committee
This protocol and the proposed ICF must be reviewed and approved by the appropriate IRB/EC 
prior to the start of the study. During the study, the investigator shall make timely and accurate 
reports to the IRB/EC on the progress of the trial, at intervals not exceeding 1 year, as well as 
satisfying any other local IRB/EC regulations regarding reporting. Copies of all reports to and 
correspondence with and from the IRB/EC must be provided to the sponsor or its designee.
Any significant changes or revisions in the study protocol or any changes that may alter subject 
risk must be approved in writing by the IRB/EC prior to implementation. A protocol change 
intended to eliminate an apparent immediate hazard may be implemented immediately provided 
that the sponsor is immediately notified, and an amendment is subsequently provided by the 
sponsor and approved by the IRB/EC.
It is the investigator’s obligation to maintain an IRB/EC correspondence file, and to make this 
available for review by sponsor representatives or their designee as part of the study monitoring 
process.
12.2.
Study Conduct
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with International Conference on Harmonisation 
(ICH) Guidelines for Good Clinical Practice (GCP) and applicable regulatory requirements.
12.3.
Subject Privacy
To maintain subject confidentiality and to comply with applicable data protection and privacy 
laws and regulations, all data provided to the sponsor or designee, study reports, and 
communications relating to the study will identify subjects by assigned subject numbers, and 
access to subject names linked to such numbers shall be limited to the site and the study 
physician and shall not be disclosed to the sponsor or designee. As required by applicable laws 
and regulations in the countries in which the study is being conducted, the investigator will allow 
the sponsor and/or its representatives access to all pertinent medical records to allow for the 
verification of data gathered and the review of the data collection process. The regulatory 
authorities in other jurisdictions, including the IRB/EC, may also request access to all study 
records, including source documentation, for inspection.
12.4.
Written Informed Consent
The investigator will be responsible for obtaining written informed consent from potential 
subjects prior to any study-specific screening and entry into the study. A copy of the signed 
document will be provided to the subject, and a copy will be maintained with the subject’s
records. The original will be retained by the investigator. The source documents for each subject 
shall document that the informed consent was obtained prior to participation in the study.
The investigator at each center will ensure that the subject is given full and adequate oral and 
written information about the nature, purpose, and possible risk and benefit of the study. Subjects 
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must also be notified that they are free to discontinue from the study at any time. The subject 
should be given the opportunity to ask questions and allowed time to consider the information 
provided. The subject’s signed and dated ICF must be obtained before conducting any study 
procedures. The investigator must maintain the original, signed ICF. A copy of the signed ICF 
must be given to the subject. Whenever important new information becomes available that may 
be relevant to the subject’s consent, the written ICF and any other written information provided 
to subjects will be revised by the sponsor or designee and be submitted again to the IRB/EC for 
review and favorable opinion. The agreed upon, revised information will be provided to each 
subject in the study for signing and dating. The investigator will explain the changes to the 
previous version.
12.5.
Delegation of Investigator Responsibilities
The investigator will ensure that all persons involved in the conduct of the study are informed 
about the protocol, protocol amendments, study procedures, and study-related duties.
12.6.
Study Files
Documentation concerning investigators’ credentials and experience, and IRB approval of 
protocol and ICF, and other documentation are required prior to shipment of study drug to the 
study site. Copies of these documents as well as supplemental information, such as the 
Investigator’s Brochure, will be kept onsite in an investigator study file binder. This file also will 
contain drug accountability (receipt/dispensing) records, sponsor/investigator correspondence, 
IRB correspondence, changes to the protocol, information regarding monitoring activities, 
subject exclusion records, and biological sample records.
12.7.
Retention of Study Documents
All study documents, including records of drug receipt and disposition, copies of eCRFs, as well 
as supporting documentation and administrative records, must be retained by the investigator for 
a minimum of 2 years following notification that the appropriate regulatory authority has 
approved the product for the indication under study, notification that the entire clinical 
investigation will not be used in support of a marketing application, or notification that the 
marketing application was not approved. No study documents will be destroyed or moved to a 
new location without prior written approval from the sponsor. If the investigator relocates, 
retires, or withdraws from the clinical study for any reason, all records required to be maintained 
for the study should be transferred to an agreed upon designee, such as the study monitor, 
another investigator, or the institution where the study was conducted. The sponsor should be 
notified in writing at least 30 days prior to the disposal of any study records related to this 
protocol.
12.8.
Protocol Compliance
No modifications to the protocol will be made without the approval of both the investigator and 
the sponsor. Changes that significantly affect the safety of the subjects, the scope of the 
investigation, or the scientific quality of the study (e.g., efficacy assessments) will require 
IRB/EC notification before implementation, except where the modification is necessary to 
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eliminate an apparent immediate hazard to human subjects. The sponsor will submit all protocol 
modifications to the required regulatory authorities.
Emergency departures from the protocol that eliminate an apparent immediate hazard to a 
particular subject and that are deemed crucial for the safety and well-being of that subject may be 
instituted for that subject only. The investigator or other attending physician also will contact the 
sponsor as soon as possible in the case of such a departure. These departures do not require 
preapproval by the IRB; however, the IRB and sponsor must be notified in writing as soon as 
possible after the departure has been made. In addition, the investigator will document the 
reasons for protocol deviation and the ensuing events.
12.9.
Monitoring Functions and Responsibility
Before an investigational site can enter a subject into the study, a representative of CRISPR will 
visit the investigational study site to:
x
Determine the adequacy of the facilities
x
Discuss with the investigator(s) and other personnel their responsibilities with regard 
to protocol adherence, and the responsibilities of CRISPR or its representatives. This 
will be documented in a Clinical Study Agreement between CRISPR and the 
investigator.
During the study, a monitor from CRISPR or representative will have regular contacts with the 
investigational site to:
x
Provide information and support to the investigator(s)
x
Confirm that facilities remain acceptable
x
Confirm that the investigational team is adhering to the protocol, that data are being 
accurately recorded in the CRFs, and that investigational product accountability 
checks are being performed
x
Perform source data verification. This includes a comparison of the data in the CRFs 
with the subject’s medical records at the hospital or practice, and other records 
relevant to the study. This will require direct access to all original records for each 
subject (e.g., clinic charts).
x
Record and report any protocol deviations not previously sent to CRISPR
x
Confirm AEs and SAEs have been properly documented on CRFs and confirm any 
SAEs have been forwarded to CRISPR and those SAEs that met criteria for reporting 
have been forwarded to the IRB
The monitor will be available between visits if the investigator(s) or other staff needs 
information or advice.
12.10.
Quality Control and Quality Assurance
Authorized representatives of CRISPR, a regulatory authority, an EC, or an IRB may visit the 
site to perform audits or inspections, including source data verification. The purpose of a 
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CRISPR audit or inspection is to systematically and independently examine all study-related 
activities and documents to determine whether these activities were conducted, and data were 
recorded, analyzed, and accurately reported per the protocol, ICH/GCP guidelines, and any 
applicable regulatory requirements. The investigator should contact CRISPR immediately if 
contacted by a regulatory agency about an inspection.
12.11.
Disclosure of Data
All information obtained during the conduct of this study will be regarded as confidential. 
Disclosures (i.e., any release of information to any third party not noted herein) of any, not 
previously known to be public, information and/or results of the investigation for publication or 
by capsules or poster presentation shall not be made earlier than 30 days after submission of the 
proposed material to the sponsor for inspection, unless the sponsor consents to earlier disclosure. 
The investigator will take appropriate cognizance of the sponsor’s suggestions before disclosure 
for publication or presentation consistent with protection of the sponsor’s right to its confidential 
data.
12.12.
Confidentiality and Publication
All scientific, commercial, and technical information disclosed by CRISPR in this protocol or 
elsewhere will be considered the confidential and proprietary property of CRISPR. The 
investigator will hold such information in confidence and shall not disclose the information to 
any third party except to such of the investigator’s employees and staff as have been made aware 
that the information is confidential and who are bound to treat it as such and to whom disclosure 
is necessary to evaluate that information. The investigator will not use such information for any 
purpose other than determining mutual interest in performing the study and, if the parties decide 
to proceed with the study, for the purpose of conducting the study.
The investigator understands that the information developed from this clinical study will be used 
by CRISPR in connection with the development of the study drug and other drugs and 
diagnostics, and therefore may be disclosed as required to other clinical investigators, business 
partners and associates, the FDA, and other government agencies. The investigator also 
understands that to allow for the use of the information derived from the clinical study, the 
investigator has the obligation to provide CRISPR with complete test results and all data 
developed in the study.
Authorship of publications will be determined based on the Recommendations for Conduct, 
Reporting, Editing, and Publication of Scholarly Work in Medical Journals, which states that 
authorship should be based on the following 4 criteria:
1. Substantial contributions to conception and design, acquisition of data, or analysis and 
interpretation of data; 
2. Drafting of the article or revising it critically for important intellectual content; 
3. Final approval of the version to be published; and
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4. Agreement to be accountable for all aspects of the work in ensuring that questions related 
to the accuracy or integrity of any part of the work are appropriately investigated and 
resolved.
An individual must meet all criteria to be an author on any publication containing data from this 
study.
No publication or disclosure of study results will be permitted except under the terms and 
conditions of a separate written agreement between CRISPR and the investigator and/or the 
investigator’s institution.
12.13.
Clinical Study Report
After completion of the study, a clinical study report, written by the sponsor or designee in 
accordance with the ICH E3 Guideline, will be submitted in accordance with local regulations.
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13.
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Allogene Therapeutics, U. (2021). Allogene Therapeutics CD19 forum highlights positive results 
from Phase 1 studies of ALLO-501 and ALLO-501A in relapsed/refractory non-Hodgkin 
lymphoma and plan to initiate pivotal study in 2021. Presentation available at 
https://ir.allogene.com/static-files/7a26a1c0-55f9-4474-a362-9a49b598c43c.
Bains, P., Al Tourah, A., Campbell, B.A., Pickles, T., Gascoyne, R.D., et al. (2013). Incidence of 
transformation to aggressive lymphoma in limited-stage follicular lymphoma treated with 
radiotherapy. Ann Oncol 24, 428-432.
Barrangou, R., Fremaux, C., Deveau, H., Richards, M., Boyaval, P., et al. (2007). CRISPR 
provides acquired resistance against viruses in prokaryotes. Science 315, 1709-1712.
Barrett, D.M., Teachey, D.T., and Grupp, S.A. (2014). Toxicity management for patients 
receiving novel T-cell engaging therapies. Curr Opin Pediatr 26, 43-49.
Barrington, S.F., Mikhaeel, N.G., Kostakoglu, L., Meignan, M., Hutchings, M., et al. (2014). 
Role of imaging in the staging and response assessment of lymphoma: consensus of the 
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14.
APPENDICES
14.1.
Appendix A: Lugano Response Evaluation Criteria in Lymphoma
The Lugano Classification (Cheson et al., 2014) provides a standardized way to assess imaging 
in lymphoma subjects. It is comprised of radiologic assessments of tumor burden on diagnostic 
CT, and metabolic assessments on F18 FDG-PET for FDG-avid histologies. 
Table 23:
Lugano Classification Assessment Components
Diagnostic CT/MRI
F18 FDG-PET
Target Lymph Nodes and Extra Nodal Lesions 
Up to 6 of the largest target nodes, nodal masses, or 
other lymphomatous lesions that are measurable in 
two diameters (longest diameter [LDi] and shortest 
diameter) should be identified from different body 
regions representative of the subject’s overall disease 
burden and include mediastinal and retroperitoneal 
disease, if involved.
x
Nodal disease: Must have an LDi >1.5 cm
x
Extranodal disease: Must have an LDi >1.0 cm
Non-Measured Lesions
All other lesions (including nodal, extranodal, and 
assessable disease) should be followed as 
nonmeasured disease (e.g., cutaneous, GI, bone, 
spleen, liver, kidneys, pleural or pericardial effusions, 
ascites).
Organ Enlargement (Spleen)
The spleen is considered enlarged (splenomegaly) 
when >13 cm in the cranial to caudal dimension.
New Lesions
x
Nodal disease: Must have an LDi >1.5 cm
x
Extranodal disease: Any size
5 Point Scale (Deauville) PET Score 
(Lymph Nodes and Extra Lymphatic Sites )1
The 5-point scale scores the site of the most intense 
FDG uptake for the time point, as follows:
Score
Criteria
1
No uptake 
2
Uptake ≤ mediastinum
3
Uptake > mediastinum but ≤ liver
4
Uptake moderately higher than liver 
(moderately indicates uptake greater than 
normal liver)
5
Uptake markedly higher than liver 
(markedly indicates much higher than 
normal liver) 
and/or 
New lesions
X
New areas of uptake unlikely to be 
related to lymphoma
Bone Marrow: FDG uptake assessed as
x
No FDG uptake consistent with lymphoma
x
Focal FDG uptake consistent with lymphoma
x
Diffuse FDG uptake consistent with lymphoma
CT: computed tomography; F18 FDG: fluorodeoxyglucose F18; LDi: longest diameter; MRI: magnetic resonance 
imaging; PET: positron emission tomography.
1. See (Barrington et al., 2014)
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Table 24:
Lugano Criteria for Response Assessment
At each follow-up time point, a PET-based response and a CT-based response will be made per 
the definitions below.
Response and Site
PET-based Response
CT-based Response
COMPLETE
Complete Metabolic Response1
ALL of the following
Complete Radiologic Response
ALL of the following
Lymph nodes, 
extranodal lesions
Score of 1, 2, or 31
x
Lymph nodes: All <1.5 cm in 
longest diameter.
x
Extralymphatic disease absent.
Nonmeasured lesion
N/A
Absent
Organ enlargement
N/A
Spleen: normal size
New lesions
No new metabolically active lesions 
(new lesions drive score 5)
None
Bone marrow
No FDG-avid disease in marrow
Normal by morphology; if 
indeterminate, IHC negative.
PARTIAL
Partial Metabolic Response
Partial Remission
ALL of the following
Lymph nodes, 
extranodal lesions
Score of 4, or 5 with reduced uptake from 
baseline and residual masses of any size
≥50% decrease in SPD of all 
target lesions from baseline
Nonmeasured lesion
N/A
Absent, normal, or regressed, 
but no increase
Organ enlargement
N/A
Spleen: ≥50% decrease from 
baseline in enlarged portion
New lesions
None
None
Bone marrow
Residual uptake higher than uptake in 
normal marrow but reduced compared with 
baseline (e.g., persistent focal changes in 
the marrow with nodal response)
N/A
NO RESPONSE/STABLE DISEASE
No Metabolic Response
Stable Disease
Lymph nodes, 
extranodal lesions
Score of 4, or 5 with no significant change 
in FDG uptake from baseline
x
<50% decrease in SPD of all 
target lesion from baseline
x
No progression
Nonmeasured lesion
N/A
No increase consistent with 
progression
Organ enlargement
N/A
Spleen: No increase 
consistent with progression
New lesions
None
None
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Response and Site
PET-based Response
CT-based Response
Bone marrow
No change from baseline
N/A
PROGRESSION
Progressive Metabolic Response
Progressive Disease
ANY of the following
Lymph nodes, 
extranodal lesions
x
Lymph nodes/nodal masses: Score of 4 
or 5 with increased uptake compared to 
baseline.
x
Extranodal lesions: New FDG avid foci 
consistent with lymphoma.
PPD Progression
An individual node/extranodal lesion 
must be abnormal (nodal disease with 
LDi >1.5 cm, extranodal disease with 
and LDi >1.0 cm) with: 
x
Increase of ≥50% from the 
product of the perpendicular 
diameters (PPD) from nadir AND 
x
Increase in LDi or SDi from nadir 
x
≥0.5 cm for lesions ≤2 cm 
x
≥1.0 cm for lesions >2 cm
Nonmeasured lesion
None
Unequivocal progression
Organ enlargement
None
x
Progression of pre-existing 
splenomegaly: Splenic length 
must increase by 50% of the 
extent of its prior increase beyond 
baseline (e.g., a 15-cm spleen 
must increase to 16 cm). 
x
New splenomegaly: Spleen must 
increase by at least 2 cm from 
baseline
Or
x
Recurrent splenomegaly
New lesions
New FDG-avid foci consistent with 
lymphoma rather than another etiology
x
Regrowth of previously resolved 
lesions 
x
New node >1.5 cm in any axis 
x
New extranodal site >1.0 cm in 
any axis 
x
New extranodal site <1.0 cm in 
any axis or 
unequivocal/attributable to 
lymphoma
x
New assessable disease 
unequivocal/ attributable to 
lymphoma of any size
Bone marrow
New/recurrent FDG-avid foci
New or recurrent involvement
FDG: fluorodeoxyglucose; IHC: immunohistochemistry; LDi: longest diameter; N/A: not applicable; 
PPD: perpendicular diameters; SDi: shortest diameter; SPD: sum of the products of diameters.
Note: It is recognized that in Waldeyer’s ring or extranodal sites with high physiologic uptake or with 
activation within spleen or marrow (e.g., with chemotherapy or myeloid colony-stimulating factors), 
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uptake may be greater than normal mediastinum and/or liver. In this circumstance, complete metabolic 
response may be inferred if uptake at sites of initial involvement is no greater than surrounding normal 
tissue even if the tissue has high physiologic uptake.
1. Deauville score of 3 will represent a complete metabolic response (Barrington et al., 2014).
14.2.
Appendix B: Eastern Cooperative Oncology Group Performance 
Status Scale
Grade
ECOG Performance Status
0
Fully active, able to carry on all pre-disease performance without restriction 
1
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work
2
Ambulatory and capable of all self-care but unable to carry out any work activities; 
up and about more than 50% of waking hours
3
Capable of only limited self-care; confined to bed or chair more than 50% of 
waking hours
4
Completely disabled; cannot carry on any self-care; totally confined to bed or chair
5
Dead
Developed by the Eastern Cooperative Oncology Group, Robert L. Comis, MD, Group Chair (Oken et al., 1982).
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14.3.
Appendix C: Contraception Requirements
Female subjects of childbearing potential must agree to use acceptable, highly effective methods 
of contraception to avoid pregnancy from the time of signing the informed consent form through 
at least 12 months after CTX110 infusion. 
Nonsterile male subjects who are or may become sexually active with female partners of 
childbearing potential must agree to use acceptable, highly effective methods of contraception to 
avoid fathering a child from consent through at least 12 months after CTX110 infusion. 
Acceptable methods of contraception for subjects and their partners are listed below. If 
applicable, additional contraception requirements may need to be followed according to local 
regulations and/or requirements.
Contraception for the couple is waived for the following:
x
True abstinence for the subject, when this is in line with the preferred and usual 
lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, 
postovulation methods) and withdrawal are not acceptable methods of contraception.
x
If the male is infertile (e.g., bilateral orchiectomy). Infertility may be documented 
through examination of a semen specimen or by demonstration of the absence of the 
vas deferens by ultrasound before mobilization.
x
If the female is of nonchildbearing potential, as described below
Female Subjects
Acceptable, highly effective methods of contraception to avoid pregnancy must be used from 
consent through at least 12 months after CTX110 infusion.
x
Female bilateral tubal ligation performed at least 6 months previously
x
Female continuous use of an intrauterine device (non–hormone-releasing or hormone-
releasing) for at least 90 days before informed consent
x
Female combined (estrogen- and progestogen–containing) or progestogen-only oral 
hormonal contraception associated with inhibition of ovulation if successfully used 
for at least 60 days before informed consent or with a second form of approved 
contraception for at least 60 days after beginning hormonal contraception
Male Subjects
Acceptable contraceptive methods must be used from consent through at least 12 months after 
CTX110 infusion and include the following:
x
Condom with spermicide (either as a single product if commercially available and/or 
allowed according to local regulations; otherwise condom and spermicide as separate 
products). Local regulations may require use of an additional acceptable method of 
contraception. 
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x
Vasectomy (with a negative sperm postvasectomy semen analysis) at least 6 months 
before start of mobilization, and 1 barrier method of contraception
Acceptable contraceptive methods for female partners of male subjects:
x
Bilateral tubal ligation performed at least 6 months previously
x
Continuous use of an intrauterine device for at least 90 days before consent
x
Hormonal contraceptives, if successfully used for at least 60 days before consent
Additional notes:
x
Female condom cannot be used with male condom (as a double method of 
contraception) due to risk of tearing.
x
The use of birth control methods does not apply if the female partner has had a 
bilateral oophorectomy, hysterectomy, or is postmenopausal (as defined below).
x
Male subjects who are not sexually active at the time of screening must agree to 
follow the contraceptive requirements of this study if they become sexually active 
with a partner of the opposite sex.
x
If applicable, additional contraception requirements may need to be followed 
according to local regulations and/or requirements.
x
Male subjects must not donate sperm after consent, throughout the study, and for 12 
months following CTX110 infusion.
x
Unique situations that may not fall within the above specifications may be discussed 
with the CRISPR medical monitor or designee on an individual basis.
Female Subjects of Nonchildbearing Potential
Female subjects of nonchildbearing potential will not be required to use contraception. To be 
considered of nonchildbearing potential, female subjects must meet at least 1 of the following 
criteria:
x
Postmenopausal: Female subjects who have been amenorrheic for at least 2 years and 
have a serum follicle-stimulating hormone level within the laboratory’s reference 
range for postmenopausal females
x
Documented hysterectomy and/or bilateral oophorectomy
Note: All other female subjects (including subjects with tubal ligations and subjects who do not 
have a documented hysterectomy) will be considered to be of childbearing potential.
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14.4.
Appendix D: Postinfusion Hospitalization
In Part A and Part B, the length of hospitalization post infusion may be extended where required 
by local regulation or site practice. 
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14.5.
Appendix E: National Cancer Institute Common Terminology 
Criteria for Adverse Events Version 5.0
National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 can be 
found at the following website: https://evs.nci.nih.gov/ftp1/CTCAE/About.html
Inquiries specifically regarding the Common Toxicity Criteria should be addressed to: 
ncictephelp@ctep.nci.nih.gov
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14.6.
Appendix F: B Cell Acute Lymphoblastic Leukemia Response 
Evaluation
Table 25:
B Cell ALL Disease Response 
Disease Response
Definition
If Extramedullary Disease is 
Present at Baseline
Complete remission 
(CR)
x
≤5% blasts in the bone marrow; and
x
No evidence of disease; and
x
Full recovery of peripheral blood 
counts (platelets ≥100,000/μL and 
ANC ≥1,000/μL)
x
Disappearance of measurable and 
nonmeasurable nodal lesions: 
x
Nodal masses >1.5 cm in GTD 
at baseline must have regressed 
to ≤1.5 cm in GTD 
x
Nodes that were 1.1 to 1.5 cm 
in their long axis and >1.0 cm 
in their short axis before 
treatment must have decreased 
to 1.0 cm in their short axis 
after treatment 
AND
x
If testes, spleen, and/or liver 
involvement, they must be normal 
size by imaging or physical 
examination 
AND
x
No new lesions
Complete remission 
with incomplete blood 
count recovery (CRi)
x
≤5% blasts in the bone marrow; and
x
No evidence of disease; and 
x
Incomplete recovery of peripheral 
blood counts (platelets <100,000/μL or 
ANC <1000/μL)
Complete remission 
with partial 
hematologic recovery 
(CRh)
x
≤5% blasts in the bone marrow; and
x
No evidence of disease; and
x
Partial recovery of peripheral blood 
counts (platelets ≥50,000/μL, and 
ANC ≥500/μL)
Blast-free hypoplastic 
or aplastic bone 
marrow
x
≤5% blasts in the bone marrow; and 
x
No evidence of disease; and
x
Does not meet the criteria for 
peripheral blood counts for CR, CRi or 
CRh
Partial Response
x
Meets criteria in blood and bone 
marrow for CR, Cri, or CRh
x
≥50% decrease in SPD of up to 6 of 
the largest dominant masses. 
Dominant masses should be clearly 
measurable in ≥2 perpendicular 
dimensions, and should be from 
different regions of the body if 
possible
AND
x
No increase in size of liver or spleen 
by imaging or physical exam
AND
x
If multiple splenic and hepatic 
nodules are present, they must 
regress by ≥50% in SPD. There 
must be a >50% decrease in GTD 
for a single nodule
AND
x
No new lesions
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Disease Response
Definition
If Extramedullary Disease is 
Present at Baseline
Progressive disease 
(PD)
x
≥25% increase in absolute number of 
circulating or bone marrow blasts, or 
development of extramedullary 
disease (including CNS disease)
x
≥50% increase from nadir in the 
sum of the products of at least 2 
lymph nodes, or if a single node is 
involved ≥50% increase in the 
product of the diameters of this one 
node; OR
x
≥50% increase in the longest 
diameter of any single previously 
identified node >1 cm in its short 
axis; OR
x
≥50% increase in size of splenic, 
hepatic or any other 159onmodal 
lesion; OR
x
Development of new lesions
Relapsed disease
x
Reappearance of blasts in blood or 
bone marrow (>5%) after a CR; or
x
New development of CNS-2 or CNS-3 
status or clinical signs of CNS 
leukemia such as facial nerve palsy, 
brain/eye involvement, or 
hypothalamic syndrome without 
another explanation will be considered 
a CNS relapse.
Non-response
x
Not fitting the definition of CR, Cri, CRh, blast-free hypoplastic or aplastic bone 
marrow, or PD, and not having relapsed disease
Unknown
x
Assessment is not done, incomplete, or indeterminate
ALL: acute lymphoblastic leukemia; ANC: absolute neutrophil count; CNS: central nervous system; CNS-3: total 
nucleated cell count ≥5 × 106/L with blasts on cytocentrifuge; CR: complete remission; CRh: complete remission 
with partial hematologic recovery; Cri: complete remission with incomplete blood count recovery; GTD: greatest 
traverse diameter; PD: progressive disease; SPD: sum of the product diameter.
Adapted from National Comprehensive Cancer Network guidelines for treatment of acute lymphoblastic leukemia 
Version 2.2021(NCCN, 2021).
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14.7.
Appendix G: Protocol History and Summary of Changes to Protocol 
CRSPONC001 
14.7.1.
Summary of Changes to the Current Protocol Version 7.0, Amendment 6 
(Global or Rest of World)
The previous version of this protocol (Version 6.0, 30 July 2021) was amended to create the 
current version (Version 7.0, 12 September 2022). The most significant changes are listed below 
and all key changes made in the current version of the protocol are summarized in the table 
below.
x
Added Phase 2 to further evaluate the efficacy and safety of CTX110 in subjects with 
NHL. As a result, reduced the number of subjects in Cohort A Part B (cohort 
expansion) and moved the interim and final primary efficacy analyses to Phase 2.
x
Removed Cohort E (NHL subjects administered CTX110 on Days 1, 8, and 35 with 
daratumumab in the LD regimen) and Cohort G (adult B Cell ALL subjects with 
daratumumab in the LD regimen). As a result, reduced the number of subjects in 
Phase 1 Part A from 162 to 100.
x
Revised Phase 1 Cohort B to include subjects who received prior approved 
autologous CAR T cell therapy.
x
Removed N1/N2 stratification for enrollment of subjects with NHL and removed 
hierarchical analysis.
x
Added PMBCL to NHL inclusion criteria
x
Removed the inclusion requirement for prior 
(failed, ineligible, or 
refused) and removed the exclusion criterion “eligible for and agrees to 
x
Updated AE collection periods, reporting procedures, and instructions for reporting 
disease progression and death. 
Change and Rationale
Affected Section(s)
Title Page
Updated sponsor address due to change in location.
Title Page 
Updated study title to indicate addition of Phase 2
Title Page, SYNOPSIS
Introduction
Updated background on adult B cell ALL CAR T cell therapies to reflect more 
recent study data and regulatory approval.
Section 1.3, Table 1
Removed the specific number of allogeneic CAR T cell programs in development 
by the sponsor.
Section 1.5.2
Updated the CTX110 data in the study rationale section to reflect a more recent 
data cut-off date.
Section 1.8
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Study Objectives
Added objectives for the new Phase 2 part of the study. Specified that the primary 
objective for Phase 1 Part B (cohort expansion) is to assess the preliminary efficacy 
of CTX110.
SYNOPSIS, Section 2
Subject Eligibility
Added PMBCL to the types of NHL allowed for inclusion (#3).
SYNOPSIS, Section 3.1, 
Section 4.1 , Table 3
For subjects with refractory or relapsed disease (#4), removed the requirement for 
prior
(failed, ineligible, or refused) in response to regulatory 
feedback from FDA. 
Also, removed exclusion criterion #1: Eligible for and agrees to
SYNOPSIS, Section 3.1, 
Section 3.2
Changed the inclusion criteria requirement (#4) for subjects with NHL or adult B 
cell ALL from 2 or more lines of prior therapy to 2 or more prior therapies to 
broaden the inclusion. 
SYNOPSIS, Section 3.1
In definition of refractory disease (#4), removed the provision that duration of SD 
up to 6 months is considered refractory disease, as this is not standardly included in 
the definition of refractory LBCL, per FDA feedback.
SYNOPSIS, Section 3.1
Revised Cohort B to explore CTX110 in subjects with relapse after prior 
autologous CAR T cell therapy (inclusion criterion #4). Added requirements for 
prior treatment with approved autologous CD-19-directed CAR T cell therapy, 
history of response, and toxicity to the therapy and age.
Also, added an exception for Cohort B to the exclusion criterion for prior 
autologous CAR T therapy (#1, formerly #2), and required that subjects in 
Cohort B demonstrate confirmed CD19 expression. 
Initial dose to be explored in Cohort B revised to DL4.
SYNOPSIS, Section 3.1, 
Section 3.2, Table 3, 
Section 4.1
Revised the exclusion criteria for central nervous system involvement (#5, formerly 
#6) to clarify which criteria apply to subjects with NHL vs B cell ALL. Also, 
updated text for subjects with B cell ALL with CNS involvement because the 
SRC’s review after the first 2 patients with CNS are treated (as required in protocol 
V6.0) has occurred. Subjects with a prior history of CNS involvement with no 
evidence of current CNS disease during screening and/or those with CNS-2 disease 
without neurological symptoms are now eligible for the study.
SYNOPSIS, Section 3.2
For therapies that must not be used just prior to study participation (exclusion 
criterion #12, formerly #13), changed the time window for immune checkpoint 
therapy and rituximab to be calculated from enrollment CTX110 infusion. Also, 
specified that hydroxyurea must be stopped  ≥72 hours (half-life [2-4 hours]) 
before CTX110 infusion to minimize overlapping toxicities with this prior 
treatment. 
SYNOPSIS, Section 3.2
Study Design: Investigational Plan
Added a Phase 2 part of the study to further explore efficacy in cohorts that have 
been evaluated in Phase 1. As a result, reduced the sample size for Cohort A Part B 
to up to 30 subjects and moved the interim and final primary efficacy analyses to 
Phase 2. 
SYNOPSIS, Section 1.8, 
Section 4.1, Section 4.2, 
minor global revisions
Removed Cohort E and Cohort G, due to the sponsor’s decision not to enroll 
subjects in these cohorts.
SYNOPSIS, Section 3.1,
Section 4.1, Section 5, 
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Change and Rationale
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Section 7, minor global 
revisions
Added that subjects in Phase 1 Part B or Phase 2 must remain within proximity of 
the investigative site (i.e.,1-hour transit time) for and at least 14 days for 
subsequent CTX110 infusions, or longer if justified by subject’s clinical status or 
as required by local regulation or site practice.
SYNOPSIS, Section 4.1.1, 
Section 4.1.4.3, 
Section 5.3.2
Revised the number of subjects in Phase 1 Part A from approximately 162 to 
approximately 100 to reflect the removal of Cohort E and Cohort G
SYNOPSIS, Section 4.1.2, 
Section 10.4
For clarity, consolidated repeated text within the table into a single footnote: 
The CTX110 infusion on Day 35 (-7 days/+21 days), if applicable, may be 
administered without LD chemotherapy if subject is experiencing significant 
cytopenias (see Section 5.3.1.3.1 ).
SYNOPSIS, Section 4.1, 
Table 3
Removed the note for D1 and D2 regarding the SRC review to determine if 
subjects with B cell ALL with prior history of CNS involvement may be included, 
as this SRC meeting has already occurred, and these subjects may enroll.
SYNOPSIS, Section 4.1, 
Table 3
In Cohort D2, added the possibility for a second infusion of CTX110 on Day 35 for 
subjects who have demonstrated a reduction in detectable MRD and remain MRD 
positive.
SYNOPSIS, Section 4.1, 
Table 3, Table 16
Shortened the footnote explanation of legacy Cohort F (discontinued in Version 6.0 
of the protocol and merged with Cohort A).
SYNOPSIS, Section 4.1, 
Table 3
Included DL5 in the rules for dose escalation.
Section 4.1.4
Revised to allow Phase 1 Part B cohort expansion to apply to the adult B cell ALL 
subcohorts (D1 and D2) (Part B was formerly for NHL cohorts only).
SYNOPSIS, Section 4.1, 
Section 4.1.5, Section 10.2.1
Allowed for additional subjects (up to 24) to enroll in any Part A cohort (not just 
any NHL cohort) prior to cohort expansion. Also, clarified that this option to enroll 
additional subjects up to 24 total applies to each subcohort (e.g., D1 or D2) 
separately.
SYNOPSIS, Section 4.1, 
Section 4.1.4
In the description of staggered dosing, made the revision “in subsequent dose levels 
or expansion of for additional subjects enrolled at the same dose level …” to clarify 
that this refers to additional Part A subjects, not subjects in Part B cohort 
expansion. Likewise, revised “In expansion of For additional subjects enrolled at
the same dose level, cohorts of up to …” in the following paragraph.
SYNOPSIS, Section 4.1.4
To the DLT definitions, added anemia to the list of cytopenias that will be assessed 
retrospectively, for consistency with the definition of prolonged cytopenias. 
SYNOPSIS, Section 4.1.4.2
Updated the protocol to reflect that the recommended Part B dose for Cohort A had 
been chosen and added a rationale for the decision. Also, moved the explanation of 
Part B cohort expansion to a higher-level subsection separate from Part A.
Section 4.1.5
Removed the stratification of subjects into the primary population (N1) and bulky-
refractor population (N2), per FDA feedback. 
SYNOPSIS, Section 4.1, 
Section 7.1.3
Clarified that the DSMB will perform review the interim analysis in Phase 2.
SYNOPSIS
Study Treatment
Rephrased the instructions for multiple doses of daratumumab in Cohort C2 who 
respond to treatment to read: “an additional dose of daratumumab will be 
administered at the Day 28 visit and an additional infusion of CTX110 will be 
SYNOPSIS, Table 3, 
Section 5.1
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administered on Day 35 and the Day 28. A second additional daratumumab dose
will be repeated administered as part of the LD regimen for Day 35 unless received
within 14 days prior to of the additional CTX110 previous Day 28 dose” in order to 
add clarity based on feedback in the ongoing study. 
Revised the recommendation for LD chemotherapy as follows: “Adult subjects 
with moderate impairment of renal function (creatinine clearance 
30-70 mL/min/1.73 m2) should may receive a reduced dose of fludarabine in 
accordance with applicable prescribing information”.
Section 5.2
Added Phase 2 LD chemotherapy regimen
Section 5.2
Updated LD chemotherapy rationale to acknowledge inclusion of subjects who 
received prior treatment with an autologous CD-19 directed CAR T cell therapy 
and to present supporting data from subjects with prior treatment with a previous 
allogeneic CAR T cell therapy.
Section 5.2.1
For the CTX110 formulation, removed the brief name of the 
 
 which does not fully describe the product and is subject to change. 
Updated formulation information is maintained in the CTX110 Investigator’s 
Brochure.
Section 5.3
Updated the rationale for CTX110 additional infusions with more recent study 
data.
Section 5.3.1.1
In the criteria for Day 35 CTX110 infusions, revised the ICANS criteria to be more 
stringent, as required by the DSMB.
V6.0 criteria
•  No prior grade ≥2 ICANS following CTX110 infusion that did not resolve (in 
Cohort E for Day 8 infusion: no prior event of ICANS)
V7.0 criteria
•  Grade 1, 2, or 3 ICANS must have resolved more than 14 days prior to a 
subsequent CTX110 infusion
•  No prior grade 4 ICANS
Section 5.3.1.3
In order to reduce the burden on study participants, removed the requirement for 
tissue biopsy (NHL) or bone marrow sample (B cell ALL) to be obtained whenever 
possible to demonstrate CD19 expression prior to an additional CTX110 infusion 
on Day 35.
Section 5.3.1.3
Clarified that in order for subjects to receive an additional CTX110 infusion after 
PD, the subject must have achieved clinical benefit/response “after the first 
infusion course of treatment,” to allow for a response after a second or third 
CTX110 infusion in multi-dose regimens.
Section 5.3.1.2, 
Section 5.3.1.4
Added that the optional second course of treatment will be administered with 
standard lymphodepletion (i.e., without daratumumab) for subjects in Phase 1 
Cohort C, and removed the phrase “consistent with their initial infusion” from the 
bullets for second course of treatment eligibility criteria to clarify.
Schema, Section 4.1, 
Section 5.3.1.4
Raised the limit for prohibited corticosteroid therapy from >5 mg/day to 
>10 mg/day based on relevant clinical trial experience.
Section 5.4.2
Clarified that, while G-CSF is prohibited following CTX110 infusion, “…for 
cohorts that receive 2 CTX110 infusions with LD chemotherapy in a regimen, 
Section 5.4.2, Section 6.2.8
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proactive use of G-CSF starting ≥10 days following the first CTX110 infusion is 
strongly recommended to support the second round of LD chemotherapy.” 
Toxicity Management
Per FDA feedback, revised the protocol to require that HLH be diagnosed, 
managed, and graded separately from CRS. Added diagnosis criteria and guidance 
specific to HLH.
Section 6.1, Section 6.2.7
For the management of TLS, clarified that the recommendation for prophylactic 
allopurinol is only for subjects at risk for TLS and that nonallopurinol alternatives, 
such as febuxostat, should be administered per institutional guidelines.
Section 6.2.3
Revised the CRS management section to remove text related to the previous 
grading system (Lee 2014) used in previous versions of the protocol, because 
ASTCT criteria (Lee 2019) are used for CRS grading in all parts of the study as of 
V6.0. Also, removed “Part A and Part B” from the title of the CRS Grading and 
Management Guidance because the guidance applies to all parts of the study.
Section 6.2.4, Table 7, 
Table 8
Reorganized and revised the toxicity management section for neurotoxicity to 
provide clearer guidance to investigators and to update literature references. Added 
guidance for differentiating between ICANS and HHV-6 encephalitis and updated 
Table 12.
Section 6.2.5, Table 10, 
Table 12
For cytopenia management, clarified instructions regarding frequency of 
performing a complete blood count with differential in patients with cytopenia 
grade ≥3 that has not resolved within 28 days of CTX110 infusion. Also clarified 
proactive use of G-CSF in cohorts that receive 2 CTX110 infusions with LD 
chemotherapy.
Section 6.2.8, Table 16
For COVID-19 considerations, added that “Whenever possible, a COVID-19 
vaccine or booster should not be administered within 4 weeks prior to scheduled 
imaging for disease assessment” to avoid potential conflict in imaging analysis due 
to a common side effect of the COVID-19 vaccines: swollen lymph nodes. 
Section 6.2.11
Study Procedures
Added separate rows in the schedule of assessments tables for confirmation of 
eligibility and enrollment, and an associated footnote, to clarify the sequence of 
events.
Table 16
In the schedule of assessments, consolidated the rows for tumor biopsy and tumor 
pathology to clarify that, while the sample may be used for different purposes, this 
is a single procedure. 
Table 16
In the schedule of assessments, added a note in the footnotes to specify that study 
visits cannot be combined, even if visit windows allow overlap (e.g., D3 ±1 day 
could overlap with D2 or D5 ±2 days, but separate visits are required for D2, D3, 
and D5 visits).
Table 16
Revised footnote to clarify that screening assessments should be completed within
up to 14 days of after informed consent. Also, allowed for a subject to be 
rescreened after 3 months of initial consent if specific approval is obtained from the 
medical monitor.
Table 16
Added double expressor lymphoma to the examples of disease types that are at 
high risk for CNS involvement
Table 16, Section 7.2.11
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Clarified that for baseline disease assessment, PET scan/CT should be of diagnostic 
quality and removed the phrase “with IV contrast.” Also added a reference to the 
imaging manual for details.
Table 16, Section 7.2.15
For BM aspirate/biopsy for NHL subjects, provided clearer direction on which 
subjects require BM assessment at Day 28 and to confirm CR (BM involvement at 
screening), and removed the optional assessment for subjects with no BM 
involvement at screening.
Table 16, Section 7.2.16
Added a reference to the laboratory manual for details on using archival tissue for 
tumor biopsy at screening.
Table 16
Added a footnote to clarify that all local and central laboratory assessments should 
be performed prior to dosing, unless otherwise specified. Also, to better 
accommodate study subjects, added that assessments at Month 6 or later may be 
delayed or moved ahead of the visit window to accommodate holidays, vacations, 
and unforeseen delays.
Table 16
Added “if consecutive tests are negative for
 to clarify the 
example of a reason for the sponsor to request discontinuation of sample collection. 
Also, added this option to discontinue sample collection to all central laboratory 
assessments, not just CTX110 PK samples.
Table 16
Clarified that in the event of CRS, additional samples for CTX110 PK and 
should only be collected between scheduled visits. If samples are already 
being collected as part of a scheduled visit, no additional samples are required to be 
collected on the same day of the scheduled visit.
Table 16
Added a schedule of assessments for Phase 2 for subjects with NHL with the 
Phase 1 Cohort A recommended Part B dose and regimen.
Table 17
In the schedule of assessments for Months 30-60, updated the footnote for 
secondary follow-up to apply to any subject who receives a different line of anti-
cancer therapy, not just subjects who undergo stem cell transplant. Also, clarified 
timing of the first secondary follow-up visit, added requirement for assessments 
between in-person visits, and added that subjects in secondary follow-up may be 
moved to a long-term follow-up study under a separate protocol.
Table 18
In the schedule of assessments (Months 30-60), removed the word “blood” from 
the assessment rows for CTX110 persistence and
because 
the assessment may include other samples (e.g., from lumbar puncture or BM 
biopsy), as detailed in the footnotes. Also added a footnote for the
assessment to align with the Schedule of Assessments (Screening to 
Table 18
In the schedule of assessments (Months 30-60), added rows for survival status and 
subsequent
to emphasize the need to perform these assessments.
Table 18
In the schedule of assessments (Months 30-60), applied the footnote that allows the 
sponsor to request discontinuation of sample collection to
collection.
Table 18
Clarified that enrollment begins after screening is completed, and that the sponsor’s 
approval of enrollment must occur after the investigator confirms eligibility. Also 
clarified that screening assessments are to be completed within up to 14 days of 
after signing the informed consent form. Additionally, specified that subjects 
should start LD chemotherapy within 7 days after study enrollment.
Section 7.1.1
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Updated the text for selecting a starting dose to align with text in the synopsis and 
Section 4.1.4.
Section 7.1.3
Added that subjects who have entered secondary follow-up in this protocol can roll 
over into the CRISPR long-term follow-up protocol if the long-term follow-up 
protocol is approved and activated at the investigative site.
Section 7.1.5
Removed the specification that PET/CT scan should be with IV contrast Also, 
added that additional detail can be found in the imaging manual. 
Section 7.2.15
Added that post-baseline imaging will be compared against baseline imaging to 
determine a response; however, imaging indicative of progression may be 
compared against the nadir. 
Section 7.2.15
Revision to indicate bone marrow biopsy is required at Day 28 in subjects with 
NHL with BM involvement at screening. 
Section 7.2.16
Removed direct bilirubin from the local laboratory tests, as this test was often 
missed by sites and is not required. For immunological tests, added a footnote to 
clarify that CD19 and CD20 should be evaluated in the same assay to detect CD19 
antigen loss.
Section 7.2.19, Table 19
To
added the option for collecting prior autologous CAR T 
cell levels in applicable subjects, due to the revision of Cohort B to enroll subjects 
with prior autologous CAR T cell therapy.
Section 7.3.5.1
Safety, Adverse Events, and Study Oversight
Removed the sentence “All AEs will be followed to a satisfactory conclusion” due 
to ambiguity.
Section 8
AE collection was revised to add the requirement to collect all signs and symptoms 
of disease progression that meet seriousness criteria (including deaths) for 
3 months after CTX110 administration 
Section 8.1 , Section 8.7, 
Table 21, Section 8.10
Clarified that treatment-emergent refers to events (occurring post- AEs that start or 
worsen on or after CTX110 infusion) to align the text with the definition of TEAEs 
in Section 10.6.2.
Section 8.1
Per FDA feedback, added HLH to the list of AESIs separate from CRS.
Section 8.3
Per EMA feedback, revised the collection of AEs from 3 months after last CTX110 
infusion through Month 24 visit to add the collection of nonserious AEs related to 
LD chemotherapy, study procedure, or CTX110.
Also, added a footnote to specify which events are considered related to study 
procedure and that these events may occur at any time on the study starting at 
screening.
Section 8.7, Table 21, 
Table 16, Table 18
Per EMA feedback, revised the collection of AEs from Month 24 to Month 60 visit 
OR any time a subject starts a new
to add collection of SAEs 
and AESIs related to LD chemotherapy and study procedure, not just SAEs and 
AESIs related to CTX110. 
Section 8.7, Table 21, 
Table 16, Table 18
Clarified that if a subject does not receive CTX110 therapy after enrollment, the 
AE reporting period ends 30 days after last study-related treatment or procedure
Section 8.7
Updated the AE reporting procedures to reflect a change in vendor. Specifically, 
replaced contact information for PrimeVigilance with instructions for reporting 
AEs to the sponsor. Also, added instructions for reporting SAEs or AESIs, 
Section 8.8
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including in the rare event that the investigator does not become aware of the 
occurrence immediately, as well as the requirement to submit follow-up 
information in an expedited fashion if requested by the sponsor.
Revised the disease progression text to align with the new reporting requirement 
for collection of serious signs and symptoms of disease progression for 3 months 
after CTX110 administration and with revisions to the AE collection periods. 
Deleted bulleted text, as both bulleted items are covered elsewhere in the protocol.
Section 8.10
For reporting deaths, added references to relevant safety sections for reporting 
deaths due to SAEs, and included a new requirement for the use of a Death Report 
Form for deaths not due to SAEs.
Section 8.11
Stopping Rules and Study Termination
Clarified the language for Stopping Rules: 
Deleted: Grade >2 GvHD in subjects who receive
TCR+ cells/kg prior to 
the initiation of any new 
New: Grade 3 or higher GvHD
Section 9.1
Added stopping rules for Phase 2
Section 9.1
Updated subject numbers required for end of study to reflect the addition of 
Phase 2.
Section 9.3
Added a section to describe the long-term follow-up study.
Section 9.5
Statistical Analyses 
Updated Statistical Analyses to reflect addition of Phase 2 and deletion of 
Cohorts E and G including adjustment of objectives, analysis sets, sample size, 
interim analyses, safety, and efficacy assessment.
Section 10
Deleted Dose Escalation and Cohort Expansion from Secondary Efficacy 
Endpoints and Exploratory Endpoints headings because these endpoints apply to all 
parts of the study, including the new Phase 2.
Section 10.2.2
Section 10.2.6
Changed the definition of the safety analysis set to include only subjects who 
receive CTX110 (not LD chemotherapy and/or daratumumab), i.e., the 
investigational product, and in accordance with the definition of treatment-
emergent AEs in Section 10.6.2.
Section 10.6.2
Appendices
Removed the original Appendix F: Use of High-dose Vasopressors in CRS 
Management because it is related to Lee 2014 CRS grading criteria, which are no 
longer used in the study with the change to Lee 2019 ASTCT criteria. Also 
removed reference to Appendix F from footnote of Table 7.
Table 7, Section 14  
Added blast-free hypoplastic or aplastic bone marrow to the B cell ALL disease 
response table, in order to add more specificity consistent with other similar 
clinical trials of ALL.
Section 14.6
Minor editorial and formatting changes were made as applicable throughout for accuracy and consistency.
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14.7.2.
Summary of Changes to Protocol Version 6.0, Amendment 5 (Global or Rest of 
World)
The previous version of this protocol (Version 5.0, 12 February 2021) was amended to create the 
current version (Version 6.0, 30 July 2021). The most significant changes are listed below, and 
all key changes made in the current version of the protocol are summarized in the table below. 
x
Incorporated Cohort F clinical response criteria for additional CTX110 infusion (i.e., 
CR) into Cohort A and discontinued Cohort F, thus allowing subjects in Cohort A to 
receive additional CTX110 at SD or better.
x
Added Cohort G for adult B cell ALL with inclusion of daratumumab in the 
lymphodepletion regimen
x
Clarified daratumumab may be administered by intravenous infusion or subcutaneous 
administration.
x
Added group sequential hierarchical analysis for Part B cohort expansion with one 
interim analysis for both efficacy and futility. Added that the interim analysis will be 
performed when 39 (~50% of 77 subjects in Part Cohort expansion) receive CTX110 
infusion and complete 3 months follow-up or discontinue earlier. 
x
Added that enrollment with be stratified into 2 categories: Primary population (N1) 
and Bulky-refractory population (N2); defined the populations.
x
Simplified FAS definition to be "all subjects who receive CTX110 infusion." Added 
Treatment-failure-free survival as an efficacy endpoint.
x
Revised grading of CRS in both Parts A and B to ASTCT criteria (Lee et al., 2019)
Change and Rationale
Affected Section(s)
Title Page
Updated medical monitor name and contact information.
Title Page
Introduction
Added newly published data to Table 1 CAR T Cell Clinical Trial Results in ALL 
and Table 2 Overview of Key Allogeneic CAR T Cell Programs by Other 
Sponsors.
Section 1.3 and 1.5.1, 
Table 1, Table 2
Added approvals for lisocabtagene maraleucel.
Section 1.5.1
Replaced summary of Part A preliminary safety data for CTX110 with reference to 
Investigator’s Brochure.
Section 1.8
Study Objectives and Endpoints
Added recommended Part B dose and cohort to Primary Objective (Part A).
PROTOCOL SYNOPSIS, 
Section 2, Section 10.1 
PROTOCOL SYNOPSIS, 
Section 2, Section 0, Section 
7.3.5.1
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Protocol CRSP-ONC-001
CTX110 for B Cell Malignancies
Version 7.0, 12 September 2022
Confidential 
Page 169 of 194
Change and Rationale
Affected Section(s)
Clarified that the primary endpoint for cohort expansion applies only to the NHL 
cohorts (Cohorts A, B, C, and E).
PROTOCOL SYNOPSIS, 
Section 10.2.1
In secondary efficacy endpoints, added new endpoint of of treatment-failure–free 
survival; removed event-free survival; removed requirement for central 
read/assessment for PFS; and clarified that the adult B cell ALL ORR endpoint 
applies to Cohorts D and G.
PROTOCOL SYNOPSIS, 
Sections 10.2.2, 10.6.1
Defined
in an
PROTOCOL SYNOPSIS, 
Section 10.2.6
Subject Eligibility
Revised Inclusion Criterion #1 to clarify the eligible age for Cohort G. 
PROTOCOL SYNOPSIS, 
Section 3.1
Revised Inclusion Criterion #3 to clarify that Subcohorts C1 and C2 will enroll 
subjects with histologically confirmed B cell NHL and that Cohort G will enroll 
subjects with B cell ALL; and that Subcohort G1 is the same as Subcohort D1, and 
Subcohort G2 is the same as Subcohort D2. Specified that MRD status may also be 
confirmed by NGS including ClonoSeq.
PROTOCOL SYNOPSIS, 
Section 3.1
Added Cohort G to the description of refractory or relapsed disease for adult B cell 
ALL in Inclusion Criterion #4.
PROTOCOL SYNOPSIS, 
Section 3.1
Specified in Inclusion Criterion #6 that subjects in Cohorts C, E, and G must meet 
criteria to receive daratumumab.
PROTOCOL SYNOPSIS, 
Section 3.1
In Inclusion Criteria #8 and #9, specified that acceptable methods of contraception 
must be used from enrollment through ≥12 months after the most recent CTX110 
infusion.
PROTOCOL SYNOPSIS, 
Section 3.1
In Exclusion Criterion #2, added that the requirement to confirm CD19 expression 
is optional in Subcohorts D2 and G2. 
PROTOCOL SYNOPSIS, 
Section 3.2
Added new Exclusion Criterion #4 as subjects with the diagnosis of Burkitt’s 
lymphoma/leukemia will not be included in the study
4.
Diagnosis of Burkitt’s lymphoma/leukemia 
PROTOCOL SYNOPSIS, 
Section 3.2
In Exclusion Criterion #5, clarified that no known contraindication to daratumumab 
applies to Cohorts C, E, and G.
PROTOCOL SYNOPSIS, 
Section 3.2
Clarified Exclusion Criterion #6 to allow enrollment of subjects with B cell ALL 
with CNS-2 disease without neurological symptoms and noted that the SRC will 
review the first 2 subjects with CNS-2 ALL to determine whether to allow 
additional subjects with CNS disease. Also specified that subjects with B cell ALL 
and prior grade 4 neurotoxicity associated with CD19-directed therapy are 
excluded unless otherwise indicated by the SRC based on safety data from the first 
6 subjects with B cell ALL.
PROTOCOL SYNOPSIS, 
Section 3.2
Specified in Exclusion Criterion #13 that the description of prior therapy for B cell 
ALL applies to Cohort G in addition to Cohort D. For Cohorts A, B, C, and E, 
clarified that rituximab, other anti-CD20 monoclonal antibodies, or polatuzumab 
vedotin must not be used within 30 days prior to enrollment.
PROTOCOL SYNOPSIS, 
Section 3.2
Added new Exclusion Criterion #18 for Subcohorts D2 and G2 only: Exclusion of 
isolated extramedullary disease (≤5% blasts in BM and confirmation of presence of 
clonal blasts in any tissue other than the medullary compartments).
PROTOCOL SYNOPSIS, 
Section 3.2
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Protocol CRSP-ONC-001
CTX110 for B Cell Malignancies
Version 7.0, 12 September 2022
Confidential 
Page 170 of 194
Change and Rationale
Affected Section(s)
Study Design: Investigational Plan
Updated all study schemas to reflect updated study design.
STUDY SCHEMA
Revised table (Table S1 and Table 3) describing lymphodepletion regimen and 
CTX110 to reflect updated study design.
PROTOCOL SYNOPSIS, 
Table 3
Incorporated Cohort F into Cohort A and eliminated Cohort F. Cohort F, 
introduced in Protocol Version 5.0, received LD chemotherapy followed by 
CTX110 infusion and allowed for reinfusion for subjects who achieved SD, PR, or 
CR at the Day 28 PET/CT scan. In Protocol Version 6.0, Cohort A allows for a 
second infusion for all subjects with SD or better, which encompasses the Cohort F 
regimen.
PROTOCOL SYNOPSIS, 
STUDY SCHEMA, 
Table 3, Sections 4.1, 4.1.1, 
7, 7.1.3
Added new cohort, Cohort G, to investigate escalating doses of CTX110 with 
daratumumab + LD chemotherapy in subjects with B cell ALL.
PROTOCOL SYNOPSIS, 
STUDY SCHEMA, 
Sections 4.1, 4.1.1, 7, 7.1.3
Clarified that subjects will participate in the study for up to 5 years after the last
CTX110 infusion.
PROTOCOL SYNOPSIS, 
Sections 4.1.1, 4.1.3
Expanded investigation in Part A to escalating doses of CTX110 and different LD 
regimens and to allow preliminary evaluation of efficacy, as well as safety and PK 
of CTX110, with or without additional CTX110 infusions.
PROTOCOL SYNOPSIS
Clarified that for cases in which a dose level has been cleared, the sponsor, in 
consultation with the SRC, may decide to enroll additional subjects at a given dose 
level. In any dose escalation cohort, 6 additional subjects (up to 12 total subjects) 
may receive study treatment at or below the highest cleared dose level. Further, 
with SRC approval, 12 additional subjects (24 total) may receive study treatment in 
any one NHL cohort (A, B, C, or E) at or below the highest cleared dose level to 
gather additional safety information prior to cohort expansion. 
PROTOCOL SYNOPSIS, 
Sections 4.1, 4.2
Clarified that dose escalation rules and staggering will apply to all cohorts, and that 
for subjects who receive additional infusions of CTX110 based on disease response 
criteria and eligibility, the dose level for the additional CTX110 infusion will be at 
or below the highest CTX110 dose that has been cleared by the SRC and the 
sponsor with the planned LD regimen.
PROTOCOL SYNOPSIS, 
Section 4.2
Clarified that for all cohorts, both LD chemotherapy agents should be started on the 
same day and administered for 3 consecutive days.
PROTOCOL SYNOPSIS, 
Table 3, Section 5.2
For Cohort B, removed the exploration of an increased dose of cyclophosphamide.
PROTOCOL SYNOPSIS, 
Section 4.1
For Cohorts A, B, C2, D1, E, and G1, incorporated an additional CTX110 infusion 
on Day 35 with LD chemotherapy for subjects who achieve clinical response at 
Day 28, and noted that this additional CTX110 infusion may be administered 
without LD chemotherapy if the subject is experiencing significant cytopenias. 
Also clarified that in Cohort B, the cyclophosphamide dose for the additional 
CTX110 infusion will be 500 mg/m2 (vs 750 mg/m2 used with the initial CTX110 
infusion). The DL for the additional CTX110 infusion will be at or below the 
highest CTX110 doses that has been cleared by the SRC and the sponsor with the 
planned LD regimen. 
PROTOCOL SYNOPSIS, 
STUDY SCHEMA, 
Table 3, Table 14, Table 16, 
Sections 4.1, 5.2, 5.2.1, 
5.3.1.2, 5.3.1.3, 5.3.1.3.1, 
5.3.1.3.2
Added 1 dose of daratumumab to the LD regimen for Cohorts C, E, and G, 
administered by IV infusion (16 mg/kg) or SC injection (1800 mg) ≥1 day prior to 
starting LD chemotherapy and within 10 days prior to CTX110 infusion. 
PROTOCOL SYNOPSIS, 
STUDY SCHEMA, 
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Protocol CRSP-ONC-001
CTX110 for B Cell Malignancies
Version 7.0, 12 September 2022
Confidential 
Page 171 of 194
Change and Rationale
Affected Section(s)
Table 3, Table 14, Table 16, 
Sections 4.1, 5.1
Divided Cohort C into Subcohorts C1 and C2. For NHL subjects in Subcohort C1, 
initial CTX110 infusion on D1 starts at DL3, and subjects who achieve SD or 
better at the D28 scan receive 2 additional doses of daratumumab at D28 and M2 
visits. For Subcohort C2, initial CTX110 infusion on D1 starts at or below the DL 
cleared in Subcohort C1, and subjects who achieve SD or better at the D28 scan 
receive a second infusion of CTX110 on D35 with daratumumab and LD 
chemotherapy. Subjects with adult B cell ALL in Subcohort G2 (BM involvement 
with <5% blasts) will not receive additional doses of daratumumab at Day 28 (± 4 
days) and Month 2 (± 4 days) visits.
PROTOCOL SYNOPSIS, 
STUDY SCHEMA, 
Table 3, Sections 4.1, 5.1
Divided Cohort D (B cell ALL) into Subcohorts D1 and D2. 
Subcohort D1 includes subjects with BM involvement with ≥5% blasts. Initial 
CTX110 infusion on Day 1 starts at DL2 or DL3, and subjects with a decrease in 
BM blast count at Day 28 of ≥50% but blast count remains >5% or is MRD-
positive receive a second infusion of CTX110 on D35 with LD chemotherapy.
Subcohort D2 includes subjects with BM <5% blasts and are MRD-positive (>1 × 
10-4 cells detected by flow cytometry or PCR or NGS including ClonoSEQ). Initial 
CTX110 infusion on Day 1 starts at or below the DL cleared in Subcohort D1. No 
second infusion of CTX110 for subjects in this subcohort. 
PROTOCOL SYNOPSIS, 
STUDY SCHEMA, 
Table 3, Sections 4.1, 5.1
Revised CTX110 dosing in Cohort E. Second planned dose of CTX110 
administered without LD regimen for subjects meeting safety parameters moved to 
Day 8 (from 3 weeks post initial CTX110). Added third CTX110 infusion on D35 
administered with daratumumab and LD chemotherapy for subjects who achieve 
SD or better at D28 scan.
PROTOCOL SYNOPSIS, 
STUDY SCHEMA, 
Table 3, Table 16, Sections 
4.1, 5.1, 5.3.1.2, 5.3.1.3, 
5.3.1.3.2
Provided details for Cohort G (B cell ALL), which includes Subcohorts G1 and G2. 
Subcohorts G1 and G2 are defined the same as Subcohorts D1 and D2, 
respectively.  
PROTOCOL SYNOPSIS, 
STUDY SCHEMA, Table 3
Added that for Cohorts D and G, additional subjects may be enrolled to explore 
alternative LD dose regimen in which cyclophosphamide may be administered at a 
dose of 750 mg/m2 IV daily for 3 days, starting at a CTX110 dose level at or below 
the highest dose level that has been cleared with LD dose containing 
cyclophosphamide 500 mg/m2 IV daily for 3 days and if it has been agreed by the 
SRC and the sponsor. In that instance, for the second infusion on Day 35 (where 
applicable), the cyclophosphamide dose in LD chemotherapy will be 500 mg/m2.
PROTOCOL SYNOPSIS, 
Table 3
To further evaluate the safety and efficacy of CTX110, allowed parallel cohort 
expansion (Part B) for any NHL cohorts that have completed dose escalation and 
have determined the Part B dose per the protocol-specified criteria. Dose escalation 
for subjects with adult B cell ALL may continue in parallel to cohort expansion for 
NHL cohorts.
PROTOCOL SYNOPSIS, 
Sections 4.1, 4.1.1, 4.3
Addition of detailed description of enrollment and safety data as of a data cutoff of 
10 April 2021 and discussion of influence on dose rationale for redosing.
Section 5.3.1.1
Study Treatment
Added option for daratumumab to be administered as 16 mg/kg by IV infusion or 
1800 mg by subcutaneous injection.
PROTOCOL SYNOPSIS, 
STUDY SCHEMA, 
Table 3, Table 14, Table 16, 
Sections 4.1, 5.1, 5.1.3
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Protocol CRSP-ONC-001
CTX110 for B Cell Malignancies
Version 7.0, 12 September 2022
Confidential 
Page 172 of 194
Change and Rationale
Affected Section(s)
Applied list of signs or symptoms that would delay LD chemotherapy for all 
cohorts to initiation of first daratumumab dose in Cohorts C, E, and G. Clarified the 
following criterion:
Active infection: Positive blood cultures for bacteria, fungus, or virus not 
responding to treatment, or negative culture but active infection based on 
investigator judgment in consultation with the medical monitor
PROTOCOL SYNOPSIS, 
Section 5.2
Included additional criteria for Cohort E regarding signs and symptoms that would 
prevent administration of the second CTX110 infusion on Day 8.
PROTOCOL SYNOPSIS, 
Section 5.3.1.3
Clarified that DL3.5 is an optional de-escalation dose level and noted that a DL5 
(9 × 108 CAR+ T cells) may also be explored with SRC approval.
PROTOCOL SYNOPSIS, 
Table 4, Section 5.3.1.3.2
Defined first and second courses of treatment:
First course of treatment: Initial CTX110 infusion with respective LD regimen and 
the second infusion with LD regimen (Cohorts A, B, C2, D1, and G1) or without 
LD regimen (Cohort E). In the case of Cohort E, the third CTX110 infusion with or 
without LD regimen is also part of the first course of treatment.
Second course of treatment (optional): For all cohorts, an additional single infusion 
of CTX110 after PD, administered with LD chemotherapy.  
STUDY SCHEMA, Section 
4.1
Added alternative premedication methods for daratumumab following discussion 
with medical monitor, and recommendation for preferential use of intermediate-
acting corticosteroids for second or third doses of daratumumab to reduce risk of 
interference with CTX110.
Section 5.1.1
Expanded rationale for daratumumab dosing to suppress specific NK cells, which 
may reduce the potential host immune response to allogeneic CAR T cell product 
and allow increased expansion and persistence of CTX110. Inclusion of supportive 
data for subcutaneous dosing of daratumumab.
Section 5.1.3
Specified that all subjects in all cohorts will receive LD chemotherapy before 
additional CTX110 infusions except for the Day-8 CTX110 infusion for Cohort E.
Section 5.2
Added new Section 5.3.1 Additional CTX110 Infusions and provided rationale, 
administration schedule, and criteria for additional CTX110 infusions, and 
considerations. 
Sections 5.3.1, 5.3.1.1, 
5.3.1.2, 5.3.1.3, 5.3.1.3.1, 
5.3.1.3.2, 5.3.1.4
Added option to receive an additional infusion of CTX110 infusion with LD 
chemotherapy after PD if the subject had a prior response. 
Table 3, Section 5.3.1.4
Toxicity Management
Clarified that HLH-observed signs and symptoms are a manifestation of CRS and 
will not be graded separately.
Section 6.1
Expanded recommendation for herpes zoster and hepatitis prophylaxis to Cohorts 
C, E, and G. Also recommended pneumocystis jirovecii prophylaxis per local 
guidelines for subjects receiving multiple CTX110 infusions with LD 
chemotherapy.
Section 6.2.2
Recommended dexamethasone 10 mg IV every 6 hours for any grade 2 ICANS in 
subjects with adult B cell ALL (Cohorts D and G).
Section 6.2.5.1, Table 11
To reflect recently published data, added management recommendations for grade 
1 ICANS
Table 11
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Protocol CRSP-ONC-001
CTX110 for B Cell Malignancies
Version 7.0, 12 September 2022
Confidential 
Page 173 of 194
Change and Rationale
Affected Section(s)
Clarified that although subjects may meet some of the criteria for HLH or 
macrophage activation syndrome after CTX110 infusion, this is part of CRS and 
that given the overlap with CRS, subjects with HLH should also be managed per 
CRS treatment guidance. Recommended that anakinra or other
may also be considered following discussion 
with the medical monitor.
Section 6.2.7
For subjects experiencing grade ≥3 neutropenia, thrombocytopenia, or anemia that 
has not resolved within 28 days of CTX110 infusion, a complete blood count with 
differential should be performed weekly until resolution to grade ≤2 or 
administration of a new systemic
weekly until Month 3 after 
each dose of CTX110, then a minimum of monthly until in accordance with 
institutional practice. Also decreased the amount of time necessary between 
allowing G-CSF administration for grade 4 neutropenia from 21 to 10 days post–
CTX110 infusion, when the risk of CRS has passed; and applied recommendations 
for monitoring for daratumumab-associated cytopenias to Cohorts C, E, and G.
Section 6.2.8
Study Procedures
Updated schedule of assessments to reflect revised study design, including updates 
to Table 16 for assessments specific to Cohort E to reflect the addition of 
daratumumab and to move the second CTX110 infusion from Day 21 to Day 8.
Table 14, Table 15, 
Table 16
Added assessment of BCR-ABL1 in peripheral blood if Ph+.
Table 14
Clarified that female subjects of childbearing potential must have a serum 
pregnancy test performed at the time of screening, and a serum or urine pregnancy 
test within 72 hours of beginning LD chemotherapy (Cohorts A, B, and D), 
daratumumab (Cohorts C, E, and G), or additional infusion of CTX110 (Cohorts A, 
B, C2, D1, E, and G1) when administered without daratumumab or LD 
chemotherapy.
Table 14, Table 16, 
Table 17, Section 7.2.5
Updated procedures for subjects who are lost to follow-up and subjects who enter 
secondary follow-up.
Section 7.1.5
Specified separate timing for ECOG performance status assessment for Cohort E: 
screening, CTX110 infusion (Day 1), and Day 28 visits.
Table 16, Section 7.2.6
Specified that ECG prior to daratumumab infusion applies to Cohorts C, E, and G
and ECG prior to LD chemotherapy applies to Cohorts A, B, and D.
Table 14, Table 16, Section 
7.2.8
Added that if relapse occurs during the study, every effort should be made to obtain 
a biopsy of the relapsed tumor.
Section 7.2.9
Specified that LP is required at screening for all subjects with B cell ALL (Cohorts 
D and G), and that CSF analysis may be required to confirm CR after CTX110 
administration in subjects with B cell ALL with baseline CNS disease.
Table 14, Section 7.2.11
Included additional ICE assessments for Cohort E on Days 10, 12, 14, and 16.
Table 16, Section 7.2.12
Specified that PRO surveys for subjects with B cell ALL will be administered to 
Cohorts D and G.
Table 14, Table 15, 
Table 16, Section 7.2.13
Clarified that tumor burden will be quantified at baseline according to Lugano 
criteria and provided specifics regarding calculating tumor burden assessments.
Section 7.2.15
Added new Section 7.2.15.1 Imaging of Extramedullary Disease in B cell ALL for 
subjects with B cell ALL with known extramedullary disease at baseline.
Table 14, Table 15, Section 
7.2.15.1
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Protocol CRSP-ONC-001
CTX110 for B Cell Malignancies
Version 7.0, 12 September 2022
Confidential 
Page 174 of 194
Change and Rationale
Affected Section(s)
Removed cell-free DNA testing due to the change in the MRD testing plan for this 
protocol version, since higher yields from whole blood are preferred over the 
limited DNA collected from cell-free DNA samples.
Table 14, Table 15, 
Table 16
Clarified that baseline BM biopsy and aspirate for subjects with NHL can be 
performed at screening or within 28 days prior to CTX110 infusion, if a recent 
sample was collected as part of standard of care.
Section 7.2.16
Clarified that baseline BM biopsy and aspirate for subjects with B cell ALL can be 
performed at screening or within 28 days of CTX110 infusion with appropriate 
consent, and will be assessed locally to confirm pathology, assess extent of disease,
and assign cohorts. Specified that MRD will be assessed locally and centrally, and 
that subjects in Subcohorts D2 and G2 may be enrolled with local baseline MRD 
results pending as long as qualifying results within 3 months of enrollment are 
available.
Section 7.2.18
Added local laboratory test for peripheral blasts in Cohorts D and G for cohort 
determination.
Table 17
Safety, Adverse Events, and Study Oversight
Revised CRS grading in both Parts A and B to ASTCT criteria (Lee et al., 2019). 
PROTOCOL SYNOPSIS, 
Table 7, Table 8, Sections 
4.2.2, 6.2.4, 10.2.3, 10.6.2
Clarified that for Cohort E, the DLT evaluation period will last for 28 days after the 
second infusion (Day 8), for a total of approximately 35 days (7 days from initial 
infusion + 28 days from second infusion). Also clarified that for all cohorts, 
subjects who receive a subsequent CTX110 infusion on Day 35 and/or after disease 
progression will be monitored for frequency and severity of AEs and AESIs during 
the immediate 28-day period after each additional CTX110 infusion in addition to 
the assessment of safety per the DLT criteria defined in the protocol.
PROTOCOL SYNOPSIS, 
Sections 4.1.1, 4.2, 10.3
Clarified the DLT definition regarding neurotoxicity: Grade 4 neurotoxicity of any 
duration that is related or possibly related to CTX110.
Also specified that the following should not be considered DLTs:
Hypogammaglobulinemia of any grade (vs grade 3 or 4 only)
For Cohorts D and G: Grade ≥3 cytopenias present at start of LD chemotherapy, 
pending SRC review and identification of another etiology
PROTOCOL SYNOPSIS, 
Section 4.2.2 
Revised DSMB requirement to include review of any SAEs, including expedited 
SAEs.
PROTOCOL SYNOPSIS, 
Section 8.12.2
Specified that for Cohorts D and G, the first 2 subjects at each dose level of 
Subcohorts D1 and G1 (adult B cell ALL subjects with >5% blasts) will be treated 
in a staggered manner such that the second subject will only receive CTX110 after 
the previous subject has completed the DLT evaluation period. However, in 
Subcohorts D2 and G2 (adult B cell ALL subjects with <5% blasts and MRD+), up 
to 3 subjects may be enrolled and dosed concurrently if the dose level has been 
cleared by the SRC in Subcohort D1 or G1, respectively. The opposite will not be 
allowed. If 3 subjects in Subcohort D2 or G2 are cleared, then Subcohort D2 or G2 
alone will advance to the next dose level.
Section 4.2
Clarified that a subject will be replaced and not evaluated for DLT if a subject 
discontinues the study any time prior to the first CTX110 infusion.
Section 4.2.2
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Protocol CRSP-ONC-001
CTX110 for B Cell Malignancies
Version 7.0, 12 September 2022
Confidential 
Page 175 of 194
Change and Rationale
Affected Section(s)
Added safety parameters for additional doses of daratumumab.
Section 5.1
Clarified that G-CSF is prohibited following CTX110 infusion but may be 
administered ≥2110 days following CTX110 infusion if subject shows no signs of 
CRS.
Section 5.4.2
To increase subject safety and potentially reduce risk of GvHD, lowered 
manufacturing threshold from <0.5% TCR+ cells to ≤0.15% TCR+ cells in final 
CTX110 product.
Section 6.2.9
Revised AE definition to reflect GCP E6(R2).
Section 8.1
Clarified that all grade ≥3 infections are to be considered AESIs (vs 
opportunistic/invasive infections), and that CRS is an AESI, including cases with
overlapping manifestations of HLH. Removed HLH as a separate AESI.
Section 8.3
To improve safety data collection, modified timeframe for collection of CTX110-
related SAEs, CTX110-related AESIs, and new malignancies as follows: Month 24 
to Month 60 visit OR after a subject receives a new
after Month 
3 visit any time a subject starts a new 
d collection 
of SAEs resulting in death regardless of relationship to CTX110 from Month 24 to 
Month 60 timeframe
Table 14, Table 15, 
Table 16, Table 19
Clarified that if additional infusion of CTX110 occurs after the 3-month post–
CTX110 infusion period, AE reporting for any additional CTX110 infusion begins 
with daratumumab or LD chemotherapy administration, as applicable, and that 
disease progression resulting in death only needs to be reported as an SAE for 30 
days after CTX110 infusion (Section 8.10 for exceptions).
Table 19
To ensure comprehensive and timely collection of safety data, deleted the 
following: 
Events that are clearly consistent with the expected progression of disease under 
study and are captured in the eCRF, will be considered as anticipated and not 
subject to expedited reporting.
Section 8.8
Added new Sections 8.10 and 8.11 to clarify procedures regarding reporting events 
related to disease progression and deaths, respectively.
Sections 8.10 and 8.11
Clarified that a cohort will be paused in the event of grade >2 GvHD in subjects 
who receiv
TCR+ cells/kg prior to the initiation of any new
Section 9.1
Clarified that daratumumab-specific guidance regarding stopping rule for cohorts 
or subjects applies to Cohorts C, E, and G.
Sections 9.1, 9.2
Statistical Analyses 
Increased sample size of Part A from 6-66 subjects to approximately 162 subjects 
(approximately 90 subjects with NHL and approximately 60 subjects with B cell 
ALL), and of Part B from 77 subjects to approximately 97 subjects. Clarified that 
the sample size estimation for the first cohort expansion will also apply to any 
subsequent cohort expansions, thus increasing the total number of enrolled subjects 
in Part B.
PROTOCOL SYNOPSIS, 
Sections 4.1, 4.1.2, 10.3, 
10.4
Defined 2 categories for Part B enrollment:
Primary population (N1; approximately 77 subjects): Subjects with SPD <50 cm2
for target lesions (pre–LD chemotherapy) as assessed by local and/or central 
PROTOCOL SYNOPSIS, 
Sections 4.1, 7.1.3, 10.4
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Protocol CRSP-ONC-001
CTX110 for B Cell Malignancies
Version 7.0, 12 September 2022
Confidential 
Page 176 of 194
Change and Rationale
Affected Section(s)
analysis, and initiation of first line of 
for subjects with NHL 
>7 months prior to enrollment.
Bulky-refractory population (N2; approximately 20 subjects): Subjects with SPD 
≥50 cm2 for target lesions (pre–LD chemotherapy) as assessed by local and/or 
central analysis; or initiation of the first line of 
for subjects with 
NHL ≤7 months prior to enrollment.
The maximum number of 20 added subjects with refractory NHL and bulky disease 
(N2) will not be included in the primary population (N1) to prevent over-
representation of subjects with refractory disease with bulky presentation in a 
cohort and limit the exposure of the investigational product for subjects who are 
relatively less likely to benefit from it.
Revised cohort expansion design from optimal Simon 2-stage to an enrichment 
design with hierarchical testing strategy. Hierarchical hypothesis testing for 
efficacy will be performed with the first testing in the primary population (N1) and, 
if positive, followed by a second testing in the total population (N1 + N2) 
containing both primary and bulky-refractory populations. Group sequential design 
with alpha-spending function will be employed to test for efficacy in N1.
PROTOCOL SYNOPSIS, 
Sections 10.4, 10.6.1
Added one interim analysis for futility and efficacy planned when 39 of 77 subjects 
in the primary population have received CTX110 infusion and completed ≥3 
months of follow-up or discontinued earlier. At the interim analysis, the study may 
be stopped for futility if ≤10 of the first 39 subjects in the primary population 
achieve objective response (CR or PR); otherwise the study will continue to enroll 
an additional 38 subjects (total N1 = 77) in the second stage. If ≥20 of the first 39 
subjects in the primary population achieve OR, early efficacy can be claimed at the 
interim analysis.
PROTOCOL SYNOPSIS, 
Sections 4.1.2, 9.3, 10.4, 
10.5.1, 10.6.1
Specified that subjects who have not progressed and are still on study at the data 
cutoff date will be censored at their last response assessment date. Also clarified 
secondary efficacy endpoint definitions as follows:
DOR: Time between first objective response and first disease progression or death 
due to any cause after the first objective response.
DOCB: Time between first objective response and last disease progression or death 
that followed the last objective response a subject ever achieved.
TFFS: Time between first CTX110 infusion and the last disease progression or 
death due to any cause.
Clarified that the secondary efficacy endpoint of ORR for subjects with adult B cell 
ALL applies to Cohorts D and G.
Section 10.2.2
Appendices
Linked Appendix F: Use of High-dose Vasopressors in CRS Management to 
Table 7: Grading of CRS According to ASTCT Consensus Criteria. Added 
Footnote #2. See Appendix F for information on high-dose vasopressors.
Section 14.6; Appendix F
Updated Appendix G: B Cell Acute Lymphoblastic Leukemia Response Evaluation 
to include criteria for extramedullary disease present at baseline, partial response, 
and unknown response.
Appendix G; Table 24
Minor editorial and formatting changes were made as applicable throughout for accuracy and consistency.
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14.7.3.
Summary of Changes to Protocol Version 5.0, Amendment 4 (Global or Rest of 
World)
Version 4.0 (17 June 2020) was amended to create the Version 5.0 (12 February 2021). The 
country-specific protocol version 4.1 for United States (22 June 2020) has also merged into 
Version 5.0. The most significant changes are listed below, and all key changes made in the 
current version of the protocol are summarized in the table below. 
x
Added 2 new cohorts, Cohorts E and F, to evaluate safety and effect of planned 
redosing of CTX110 without and with LD chemotherapy in subjects with NHL. 
Added planned redosing for Cohort A.
x
Added new DLT of grade 4 neurotoxicity of any duration that is possibly related to 
CTX110.
x
Added viral encephalitis management.
x
Removed the weight threshold from the eligibility criterion (per Version 4.1 United 
States) with the intent of applying a dose limit of
TCR+ cells/kg for all dose 
levels.
x
Added evaluation of changes over time in patient-reported outcomes associated with 
CTX110 as a secondary study objective.
x
Updated definition of a TEAE.
x
Modified AE reporting requirements and study time period.
Change and Rationale 
Affected 
Section(s)
Removed number of study centers as the number is prone to changes.
PROTOCOL 
SYNOPSIS
Added secondary objective:
To evaluate the changes over time in patient-reported outcomes associated with CTX110
and secondary endpoint:
Change over time in patient-reported outcomes
PROTOCOL 
SYNOPSIS
Sections 2, 
10.2.5, 10.6.5
Removed requirement for subsequent participation in long-term follow-up trial, and accordingly 
removed inclusion criterion #10 (“Agree to participate in an additional long-term follow-up 
study after completion of this study”).
PROTOCOL 
SYNOPSIS
Sections 3.1, 
4.1.3, 9.3
In inclusion criterion #1, the age limit for Cohort D was raised from 60 to 70 years based on the 
acceptable safety data observed to date in the clinical study and to facilitate the inclusion of 
elderly subjects in Cohort D. Also removed weight requirement of >50 kg (from protocol 
version 4.1 United States) with the availability of a highly sensitive TCR screening assay for 
CTX110 and given the dose limit of
TCR+ cells/kg applicable for all dose levels. 
PROTOCOL 
SYNOPSIS
Section 3.1
In inclusion criterion #3, for NHL cohorts clarified that FDG PET positivity is defined by a 
Deauville score of 4 or 5 on the Lugano criteria 5-point scale.
PROTOCOL 
SYNOPSIS
Section 3.1
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Change and Rationale 
Affected 
Section(s)
Updated details of inclusion criterion #3 for Cohort D (histologically confirmed B cell ALL) 
from “bone marrow involvement with ≥5% blast” to include the following subcohort-specific 
criteria:
D1: Bone marrow involvement with ≥5% blasts (see additional details in Section 4.1)
•
D2: Bone marrow MRD-positive (defined as >1 × 10-4 cells detected by flow 
cytometry or PCR) with ≤5% blasts.
Removed an element of inclusion criterion #4 for Cohort D (adult B cell ALL) by deleting the 
following bullet as more details are now included in criterion #3 as specified above: 
Bone marrow blast <50% at time of screening
Removed inclusion criterion #10 (“Agree to participate in an additional long-term follow-up 
study after completion of this study”) since the subject will be asked (not required) to participate 
in the long-term follow-up study.
PROTOCOL 
SYNOPSIS
Section 3.1
Clarified timing for exclusion criteria #3, #9, #10, and #12 to indicate timeframes are based on 
time of enrollment, not screening or informed consent.
Added the following condition to Exclusion Criterion #5 for subjects with B cell ALL with a 
prior history of CNS involvement: Subjects with B cell ALL with a prior history of CNS 
involvement with no evidence of current CNS disease during screening may be included after 
SRC approval, based on safety data from the first 6 B cell ALL subjects with no CNS disease 
history treated in the dose escalation part of the study.
PROTOCOL 
SYNOPSIS
Section 3.2
Table 14
Clarified exclusion criterion #6 to specify that disqualifying cerebrovascular 
ischemia/hemorrhage should be “major.”
PROTOCOL 
SYNOPSIS
Section 3.2
To increase subject safety, added “grade 3 or higher pericardial effusion at the time of 
enrollment” to exclusion criterion #7.
PROTOCOL 
SYNOPSIS
Section 3.2
Revised exclusion criterion #8 as indicated below to clarify parameters for determining if an 
infection is “uncontrolled”:
Presence of active bacterial, viral, or fungal infection that is uncontrolled, or requires IV anti-
infectives based on investigator judgement in consultation with the medical monitor
PROTOCOL 
SYNOPSIS
Section 3.2
In exclusion criterion #9, expanded allowable timeframe for prior infectious disease testing use 
in determining eligibility from “within 30 days of signing the ICF” to “within 45 days of 
enrollment.”
PROTOCOL 
SYNOPSIS
Section 3.2
In exclusion criterion #12, clarified that existing information regarding prohibition of systemic 
antitumor therapy applies to NHL cohorts, and added/expanded exceptions:
For Cohorts A, B, C, E, and F (NHL): Use of systemic antitumor therapy or investigational 
agent within 14 days or 5 half-lives, whichever is longer, of enrollment. Exceptions are made 
for: 1) prior inhibitory/stimulatory immune checkpoint molecule therapy, which is prohibited 
within 3 half-lives of enrollment; and 2) rituximab use within 30 days prior to screening
enrollment is prohibited (however PET/CT needs to occur at least 2 weeks after last rituximab 
dose).
Also added ALL-specific criteria:
For Cohort D (adult B cell ALL): Use of systemic antitumor therapy within 7 days of 
enrollment. Exceptions: 1) immunotherapy agents (i.e., rituximab, inotuzumab) must be stopped 
within 14 days of enrollment; 2) long-acting chemotherapy agents (e.g., pegylated asperigenase, 
methotrexate >25 mg/m2) must be stopped within 14 days of enrollment; and 3) investigational 
PROTOCOL 
SYNOPSIS
Section 3.2
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Change and Rationale 
Affected 
Section(s)
agent must be stopped after 5 half-lives have passed before enrolling. Subjects must have 
recovered to grade 1 CTCAE from acute toxicity (except hematological) of all previous therapy 
prior to enrollment. Steroids are permitted until 2 days before starting LD chemotherapy for 
maintenance or to allow for control of peripheral blood blasts.
To improve feasibility, added exclusion criterion #16: Life expectancy of less than 6 weeks.
PROTOCOL 
SYNOPSIS
Section 3.2
Updated number of subjects in Part A from approximately 6-54 to approximately 6-66 to reflect 
added cohorts.
PROTOCOL 
SYNOPSIS
Sections 4.1.2, 
10.4
Updated table summarizing treatment by cohort with the following underlined text to reflect 
added cohorts and added options for redosing:
Cohort
Disease Subset
Treatment
A
Adult subjects 
with DLBCL 
NOS, high-grade 
B cell lymphoma 
with MYC and 
BCL2 and/or 
BCL6 
rearrangements, 
grade 3b FL, and 
transformed FL 
LD chemotherapy: Co-administration of fludarabine 
30 mg/m2 + cyclophosphamide 500 mg/m2 IV daily 
for 3 days; completed at least 48 hours (but no more 
than 7 days) prior to CTX110 infusion
CTX110 starting at DL1
Second planned dose of CTX110 with LD 
chemotherapy administered 48 weeks after first 
CTX110 infusion to subjects who achieve SD or PR 
at Day 28 scan after first CTX110 infusion. Option to 
redose without LD chemotherapy if subject is 
experiencing significant cytopenias. 
Option to redose CTX110 with LD chemotherapy 
after PD if subject had prior response
B
Same as Cohort 
A
LD chemotherapy: Co-administration of fludarabine 
30 mg/m2 + cyclophosphamide 750 mg/m2 IV daily 
for 3 days; completed at least 48 hours (but no more 
than 7 days) prior to CTX110 infusion
CTX110 starting at DL2 DL3 
Option to redose CTX110 with LD chemotherapy 
after PD if subject had prior response
C
Same as Cohort 
A
One dose of daratumumab 16 mg/kg administered at 
least 1 day prior to starting LD chemotherapy and 
within 10 days of CTX110 infusion. For subjects who 
achieve SD or better on Day 28, 2 additional doses of 
daratumumab (16 mg/kg) will be administered at the 
Day 28 (± 4 days) and Month 2 (± 4 days) visits. To 
facilitate administration, the first 16 mg/kg dose may 
be split (to 8 mg/kg) over 2 consecutive days.
PROTOCOL 
SYNOPSIS
Section 4.1
Table 3
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Change and Rationale 
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LD chemotherapy: Co-administration of fludarabine 
30 mg/m2 + cyclophosphamide 500 mg/m2 IV daily 
for 3 days; completed at least 48 hours (but no more 
than 7 days) prior to CTX110 infusion
CTX110 starting at DL2 DL3
Option to redose CTX110 with LD chemotherapy 
after PD if subject had prior response (can redose 
without daratumumab)
D
Adult B cell ALL
LD chemotherapy: Co-administration of fludarabine 
30 mg/m2 + cyclophosphamide 500 mg/m2 IV daily 
for 3 days; completed at least 48 hours (but no more 
than 7 days) prior to CTX110 infusion
CTX110 starting at DL2 or DL3
Option to redose CTX110 with LD chemotherapy 
after PD if subject had prior response or if subject is 
MRD-positive
E
Same as Cohort 
A
LD chemotherapy: Co-administration of fludarabine 
30 mg/m2 + cyclophosphamide 500 mg/m2 IV daily 
for 3 days; completed at least 48 hours (but no more 
than 7 days) prior to CTX110 infusion
CTX110 starting at DL3.5 or DL4
Second dose of CTX110 administered without LD 
chemotherapy 3 weeks after first CTX110 infusion
• Option to redose CTX110 with LD chemotherapy 
after PD if subject had prior response 
F
Same as Cohort 
A
•
LD chemotherapy: Co-administration of 
fludarabine 30 mg/m2 + cyclophosphamide 500 
mg/m2 IV daily for 3 days; completed at least 48 
hours (but no more than 7 days) prior to CTX110 
infusion
• CTX110 starting at DL3.5 or DL4
Second dose of CTX110 administered with LD 
chemotherapy 4-8 weeks after first CTX110 infusion 
to subjects who achieve SD, PR, or CR at Day 28 
scan after first CTX110 infusion. Option to redose 
without LD chemotherapy if subject is experiencing 
significant cytopenias. 
Option to redose CTX110 with LD chemotherapy 
after PD if subject had prior response
Per memoranda dated 17 November 2020 and 14 December 2020, increased starting dose levels 
for Cohorts B and C from DL2 to “DL3.” In Cohort A, DL3 
(3 × 108 CAR+ T cells) was cleared in July 2020 with no DLTs. In total, 5 subjects have been 
PROTOCOL 
SYNOPSIS
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dosed in DL3, with no CRS, ICANS, or GvHD. Significantly more antitumor activity has been 
observed at DL3 relative to DL2. For these reasons, the SRC recommended that dose escalation 
in Cohorts B and C begin at DL3.
Table 3
Sections 4.1, 
4.2, 7.1.3
To reflect significantly more antitumor activity observed at DL3 relative to DL2, increased start 
dose level of Cohorts B and C from DL2 to DL3 and for Cohort D to “DL2 or DL3.”
PROTOCOL 
SYNOPSIS
Table 3
Sections 4.1, 
4.2
To reflect addition of repeat dosing, specified that follow-up will continue for up to 5 years after 
the last CTX110 infusion, that subjects must remain within proximity of the investigative site 
for 28 days after each CTX110 infusion, and that subjects in dose escalation will be hospitalized 
for the first 7 days following each CTX110 infusion.
PROTOCOL 
SYNOPSIS
Sections 4.1, 
4.2.3
Clarified that after Cohort expansion (Part B) will begin with Cohort A at the current version of 
the protocol to further evaluate the safety and efficacy of CTX110.  Regulatory approval will be 
obtained, where required, prior to enrolling any subjects from that region into cohort expansion. 
Cohort A expansion may be followed by the expansion of other cohorts, as those complete the 
dose escalation part of the study, with agreement from the SRC and at the sponsor's discretion.
PROTOCOL 
SYNOPSIS
Section 4.1
To increase subject safety, the dose limit of TCR+ cells/kg imposed for all dose levels was 
reduced from 1 × 105 to
TCR+ cells/kg, and the weight threshold was removed for the 
highest dose level, DL4, in any of the cohorts. This dose limit of TCR+ cells/kg was previously 
applicable for V4.1 United States.
PROTOCOL 
SYNOPSIS
Sections 4.2, 
5.3, 6.2.9
To reflect addition of repeat dosing, specified that the DLT evaluation period begins with initial
CTX110 infusion and lasts for 28 days, and that for Cohort E, the DLT evaluation period will 
last for 28 days after the second infusion (a total of approximately 7 weeks).
PROTOCOL
SYNOPSIS
Section 4.2
Clarified timing of enrollment and treatment for cohorts as follows:
For Cohort A: In DL1 (and DL-1, if required), subjects in each cohort will be treated in a 
staggered manner, such that the second and third subjects will only receive CTX110 after the 
previous subject has completed the DLT evaluation period.
For Cohorts B, C, D, E, and F: The first 2 subjects within each cohort will be treated in a 
staggered manner at the starting dose level, such that the second subject will only receive 
CTX110 after the previous subject has completed the DLT evaluation period. In subsequent 
dose levels or expansion of the same dose level, cohorts of up to 3 subjects may be enrolled and 
dosed concurrently.
PROTOCOL 
SYNOPSIS
Section 4.2
Per a memorandum dated 20 November 2020, a new DLT was added based on regulatory 
feedback regarding a grade 5, possibly CTX110-related neurotoxicity SAE at DL4:
Grade 4 neurotoxicity of any duration that is possibly related to CTX110
Also removed grade 4 from the DLT neurotoxicity exception:
Grade 3 or 4 neurotoxicity (e.g., encephalopathy, confusion) that improves to grade ≤2 within 
14 days
PROTOCOL 
SYNOPSIS
Section 4.2.2
Clarified that grade 3 or 4 toxicity that is clinically significant according to the investigator’s 
judgement and does not improve within 72 hours must be CTX110-related to be considered a 
DLT.
PROTOCOL 
SYNOPSIS
Section 4.2.2
Added revision from a memorandum dated 11 September 2020 that clarified the change to 
redosing criteria was consistent with the original intent of this language, that a consideration for 
PROTOCOL 
SYNOPSIS
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redosing required conclusive demonstration that CTX110 had antitumor activity in a subject 
after the first dose. This is typically reflected as an objective response according to the Lugano 
criteria, which was why the original language references PR or CR. However, specific 
circumstances may occur when many individual sites of disease respond (e.g., decrease in tumor 
size and/or FDG-avidity on a PET/CT scan), but a new or worsening lesion leads to an overall 
determination of PD. In such cases, the investigator may determine a response to CTX110 was 
achieved and that redosing is appropriate.
Added text in italics:
For all cohorts, a subject may receive a maximum of 3 doses of CTX110. Redosing may occur 
in 2 scenarios:
1.
Planned redosing with or without LD chemotherapy based on timing or disease 
response criteria: this includes redosing scenarios in Cohorts A, E, and F, as tabulated below
Cohort
CTX110 Redosing
A
Second planned dose of CTX110 administered with LD chemotherapy 
4-8 weeks after first CTX110 infusion to subjects who achieve SD or 
PR at Day 28 scan after first CTX110 infusion. Option to redose 
without LD chemotherapy if subject is experiencing significant 
cytopenias. 
E
Second planned dose of CTX110 administered without LD 
chemotherapy 3 weeks after first CTX110 infusion
F
Second planned dose of CTX110 administered with LD chemotherapy 
4-8 weeks after first CTX110 infusion to subjects who achieve SD, PR, 
or CR at Day 28 scan after first CTX110 infusion. Option to redose 
without LD chemotherapy if subject is experiencing significant 
cytopenias. 
Redosing after progression of disease (PD) if the subject has had initial response after the first 
CTX110 infusion – includes all cohorts. 
Any redosing should be discussed in advance with the medical monitor. 
To be redosed with CTX110, subjects must meet the redosing criteria and repeat some of the 
screening assessments specified in the protocol.
Original:
This study will allow for one-time redosing of NHL subjects with CTX110 based on the 
investigator’s decision in consultation with the CRISPR Therapeutics medical monitor. To be 
considered for redosing, subjects must have either 1) achieved a PR or CR after CTX110 
infusion and subsequently progressed or relapsed within 12 months of the initial CTX110 
infusion, or 2) remain in PR (but not CR) at the Month 3 visit.
Confirmation tumor (NHL) or bone marrow (ALL) remains CD19+ at relapse (by flow 
cytometry or immunohistochemistry).
Section 4.3.2 
Section 4.3.4
Table 15
STUDY 
SCHEMA
To enhance the effect of CTX110, changed when redosing can occur. For subjects in Cohort A 
who achieve SD or PR at the D28 scan after the first CTX110 infusion, a second CTX110 
infusion will be administered 4-8 weeks after first CTX110 infusion (changed from 3 months 
postinfusion). Clarified that the earliest time at which a subject could be redosed is ≥3 weeks 
after initial CTX110 infusion (based on dosing schedule for Cohort E). To increase subject 
safety, provided option to redose without LD chemotherapy if subject is experiencing significant 
cytopenias.
PROTOCOL 
SYNOPSIS
Sections 4.1.1, 
4.3.2
Table 3, Table 
15
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STUDY 
SCHEMA
To provide the benefit of added effect for deep and lasting response, added the option for 
redosing with CTX110 after PD if the subject had prior response for all cohorts.
PROTOCOL 
SYNOPSIS
Section 4.1.1
Section 4.3.4
Table 3
STUDY 
SCHEMA
Clarified that for all cohorts, each CTX110 infusion would be delayed if any of the following 
signs or symptoms are present: 
•
New active uncontrolled infection
•
Worsening of clinical status compared to prior to start of LD chemotherapy that, in the 
opinion of the investigator, places the subject at increased risk of toxicity
•
Grade ≥2 acute neurological toxicity
PROTOCOL 
SYNOPSIS
Section 5.3
Clarified that the existing primary endpoint for cohort expansion (ORR [CR+PR] per Lugano 
criteria, as determined by IRC) is specifically for Cohort A.
Clarified that the primary endpoint for cohort expansion would be determined by independent 
central radiology review.
PROTOCOL 
SYNOPSIS
Sections 
10.2.1, 10.6.1
Added secondary efficacy endpoint of duration of clinical benefit.
Duration of clinical benefit (DOCB) will be calculated as the time between the first objective 
response and the disease progression or death that followed the last objective response a subject 
ever achieved.
Details about the endpoints will be provided in the statistical analysis plan.
PROTOCOL 
SYNOPSIS
Sections 
10.2.2, 10.6.1
To provide further context, added Table 2 summarizing other allogeneic CAR T cell programs 
in clinical development as well as the following text:
Overall, initial data demonstrate the safety of the allogeneic CAR T cell approach. Compared to 
autologous CD19-directed CAR T cell therapy, the incidence of CRS and neurotoxicity remains 
similar and the events are less severe. In addition, studies of allogeneic CAR T cells 
demonstrate efficacy similar to that seen with autologous CAR T cells.
Section 1.5.2
Table 2
To provide further context, added information regarding the sponsor’s other CAR T cell 
programs in clinical development.
Section 1.5.2
Provided update on clinical data from Study CRSP-ONC-001.
Sections 1.8, 
4.2
Provided a brief information about the addition of new cohorts E and F and added planned 
redosing for Cohort A. Provided additional details regarding possible expansion of cohorts and 
enrollment into Cohort D Subcohorts D1 and D2:
Cohort D (adult B cell ALL) will enroll subjects within the criteria of 2 subcohorts:
D1 will enroll subjects with bone marrow involvement with ≥5% blasts. After 6 subjects are 
treated, the SRC will review the totality of safety data and determine if any further changes are 
needed to the inclusion criteria, specifically around blast count before any subsequent subjects 
are enrolled. 
D2 will enroll subjects with bone marrow MRD-positive (defined as >1 × 10-4 cells detected by 
flow cytometry or PCR) with ≤5% blasts.
Section 4.1
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Dose escalation in Cohort D will be conducted separately from the adult NHL study population 
in Cohorts A, B, C, E, and F. 
Added that throughout dose escalation, once a dose has been cleared in a cohort, the sponsor in 
consultation with the SRC may elect to enroll up to 6 additional subjects at that dose to gather 
additional safety data.
Clarified dose escalation process per cohort and dose level, and that existing CTX110 dose 
rationale applies to Part A (new Section 4.2.1.1) and added specific rationale for Part B (new 
Section 4.2.1.2).
Sections 4.2, 
4.2.1, 4.2.1.1, 
4.2.1.2
Clarified that AEs that have no plausible causal relationship with CTX110 will not be 
considered DLTs.
Section 4.2.2
Updated rationale for CTX110 redosing (Section 4.3.1) and created new sections providing 
overall guidance for redosing (Section 4.3.2), planned redosing in NHL cohorts (Section 4.3.3), 
specific guidance for redosing in Cohorts A, E, and F (Sections 4.3.3.2, 4.3.3.3, respectively), 
and redosing for all cohorts following PD after initial response (Section 4.3.4).
Sections 4.3.1, 
4.3.2, 4.3.3.2, 
4.3.3.3, 4.3.4
Clarified that if a subject experiences severe adverse events related to daratumumab, redosing 
with daratumumab will not be permitted.
Added “After at least 3 subjects are treated at a specific CTX110 dose with daratumumab, the 
sponsor along with the SRC will review the total safety and efficacy data and may decide to 
enroll additional subjects at a specific dose level with a lower dose of daratumumab (8mg/kg).”
Section 5.1, 
Table 14
Clarified that G-CSF may only be administered ≥21 days following CTX110 infusion.
Section 5.4.2
To allow investigators more flexibility, added that in the management of grade 1 CRS in Part A, 
tocilizumab may be considered per investigator’s discretion in consultation with the medical 
monitor.
Corrected description of grade ≥2 CRS as follows:
Subjects who experience grade ≥2 CRS (e.g., hypotension, not responsive to fluids, or hypoxia 
requiring supplemental oxygenation). 
Section 6.2.4
Per a memorandum dated 20 November 2020, added information regarding viral encephalitis 
and lumbar puncture to Sections 6.2.5 and 7.2.11, and created a new section (Section 6.2.5.1) to 
provide more guidance regarding HHV-6 encephalitis diagnosis and management.
Sections 6.2.5, 
6.2.5.1, 7.2.11
Consolidated criteria and guidance for management of ICANS by moving ICE Assessment table 
from Section 7.2.12 to Section.
Sections 
6.2.5.1, 7.2.12
Provided additional guidance for managing hypogammaglobulinemia:
IV gammaglobulin will be administered for clinically significant hypogammaglobulinemia 
(systemic infections, <400 mg/dL) according to institutional standard of care. 
Section 6.2.6
Added further guidance for managing HLH:
If [CRP and ferritin] laboratory values further support a diagnosis of HLH, CD25 blood levels 
should be determined in conjunction with a bone marrow biopsy and aspirate, if safe to conduct, 
for further confirmation. Where feasible, excess bone marrow samples should be sent to a 
central laboratory. Details of sample preparation and shipment are contained in the Laboratory 
Manual.
Also added the following assessments and clarifications if HLH is suspected:
Check for soluble CD25 and triglycerides
If possible, perform bone marrow biopsy to assess for hemophagocytosis. 
Section 6.2.7
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Change and Rationale 
Affected 
Section(s)
Given the overlap with CRS, subjects should also be managed per CRS treatment guidance in
Table 7 for Part A and Table 9 for Part B. Anakinra may also be considered following 
discussion with the medical monitor.
Added further guidance for managing cytopenias. Specified that for subjects experiencing grade 
≥3 neutropenia, thrombocytopenia, or anemia that has not resolved within 28 days of CTX110 
infusion, a complete blood count with differential must be performed weekly until resolution to 
grade ≤2. Also added that antimicrobial and antifungal prophylaxis should be considered for any 
subject with prolonged neutropenia or on high doses of steroids.
Table 14
Section 6.2.8
Created a new section (Section 6.2.11) regarding special consideration during the COVID-19 
pandemic.
Section 6.2.11
Removed visit window of ±2d from D2 visit and decreased visit window for D3 visit from ±2d 
to ±1d.
Table 14
Added PRO assessments to D1, D28, M9, M18, M30, M42, and M54 visits for gathering more 
frequent and meaningful data in alignment with CTX110 dosing subsequent scheduled visits.
Table 14, 
Table 15
Clarified that the CT scan used for disease response/assessment should be with IV contrast.
Table 14
Section 7.2.15
Removed CTX110 PK sample collection from M9, M15, and M18 visits that may not be 
necessary for PK analysis.
Table 14
Removed Sections 7.3.3
and 7.3.7 
(CTX110) Immunophenotyping) as well as corresponding line items for these assessments in 
Schedule of Assessments, and blood sample collection for these assessments will now occur on 
an “as needed” basis as part of
Table 14, 
Table 15
Sections 7.3.5, 
7.3.5.1
Clarified that
analysis should be a
Table 14, 
Table 15, 
Table 17
To reflect redosing option, revised timeframes for AE collection as follows:
Collect all AEs from informed consent to Month 3 visit 3 months after each CTX110 infusion; 
all SAEs and AESIs after Month 3 visit from 3 months after last CTX110 infusion through to 
Table 14, 
Table 15, 
Sections 8.7, 
10.6.2
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Affected 
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Month 60 24; and CTX110-related AESIs and CTX110-related SAEs, and new malignancies 
from After Month 24 to Month 60, or after a subject starts receives a new 
Collect SAEs resulting in death regardless of relationship to CTX110 from Month 24 to Month 
60 visit.
Cross referenced Table 20 tabulating AE collection by study time period in Section 10.6.2.
Clarified that aspirate in addition to bone marrow biopsy should be collected to confirm CR as 
part of disease evaluation and may also be collected at time of relapse.
Table 14
Section 7.2.16
Specified that in subjects experiencing signs or symptoms of CRS or neurotoxicity, additional 
blood samples for CTX110 PK analysis should be drawn per the scheduled outlined in the 
laboratory manual.
Table 14
Section 7.3.1
Specified that in subjects experiencing signs or symptoms of CRS or ICANS, additional 
samples should be drawn per the schedule outlined in the laboratory manual.
Table 14
Section 7.3.2
Added tumor biopsy upon suspected PD to confirm disease progression.
Table 15
Added sample collection for assessment of cell-free DNA upon disease progression.
Table 15
Removed sample collection for
assessment from M30, M42, and M54 
visits.
Table 15
Clarified that certain assessments for visits after Day 8 may be performed as in-home or 
alternate-site visits, including assessments for hospital utilization, changes in health and/or 
changes in medications, body system assessment, vital signs, weight, PRO questionnaire 
distribution, and blood sample collections for local and central laboratory assessments.
Table 14, 
Table 15
Added schedule of unique assessments for planned redosing for Cohort E (Table 16)
Table 16
To reflect added cohorts, clarified parameters for subject replacement as follows:
During Part B, subjects who withdraw from the study before receiving LD chemotherapy in 
Cohorts A, B, D, E, or F, or before daratumumab in Cohort C may be replaced.
Section 7.1.4
To reflect added cohorts, clarified timing of pregnancy tests as follows:
… and a serum or urine pregnancy test within 72 hours of beginning LD chemotherapy (Cohorts 
A, B, and D, E, and F), daratumumab (Cohort C), or second dose of CTX110 (Cohort E 
redosing), including the redosing schedule for respective cohorts.
Section 7.2.5
Table 17
Removed requirement for additional cardiac assessments during grade 3 or 4 CRS to provide 
investigators with increased flexibility in patient management.
Section 7.2.7
To reflect added cohorts, clarified timing of ECGs as follows:
12-lead ECGs will be obtained during screening, prior to daratumumab infusion (Cohort C 
only), prior to LD chemotherapy on the first day of treatment (Cohorts A, B, D, E, and F), prior 
to CTX110 administration on Day 1 (all cohorts), and on Day 28.
Section 7.2.8
Added EQ-5D-5L questionnaire to assess PROs in all cohorts, and FACT-Leu questionnaire to 
assess PROs in Cohort D.
Section 7.2.13
To reflect redosing option, added that data on hospitalization will be collected during the first 2 
months after each CTX110 infusion.
Section 7.2.14
Allowed additional imaging at Month 2 is per investigator discretion for subjects in Cohort E to 
provide investigators with increased flexibility in patient management.
Section 7.2.15
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In addition to bone marrow biopsy for NHL, included aspirate sampling to maintain consistency 
with Laboratory Manual.
Section 7.2.16
Specified that for subjects with adult B cell ALL, bone marrow and aspirate may be assessed for 
MRD by molecular approaches such as PCR in addition to multicolor flow cytometry.
Section 7.2.18
Specified that instead of 
 
Table 17
Provided more detailed information regarding hospitalizations that qualify as an AE or SAE.
Original:
Interventions for pretreatment conditions (such as elective surgery) or medical procedures that 
were planned before study participation are not considered AEs. Hospitalization for study 
treatment infusions or precautionary measures per institutional policy are not considered AEs.
Replaced with:
Elective or preplanned treatment or medical/surgical procedures (scheduled prior to the subject 
being enrolled into the study) for a documented pre-existing condition that did not worsen from 
baseline is not considered an AE (serious or nonserious). However, an untoward medical event 
occurring during the prescheduled elective procedure or routinely scheduled treatment should be 
recorded as an AE or SAE.
Section 8.1
Provided clarification regarding abnormal laboratory results that qualify as an AE.
Only abnormal laboratory results considered by the investigator to be clinically significant 
should be reported as AEs (e.g., an abnormal laboratory finding associated with clinical 
symptoms, prolonged duration, that requires additional monitoring and/or medical intervention). 
Whenever possible, these should be reported as a clinical diagnosis rather than the abnormal 
parameter itself (i.e., neutropenia vs neutrophil count decreased). Abnormal laboratory results 
without clinical significance (based on the investigator’s judgement) are should not required to
be recorded as AEs. However, abnormal laboratory findings that result in new or worsening 
clinical sequelae, require therapy, or adjustment in current therapy are considered AEs and 
should be graded and reported per CTCAE version 5.0. Where applicable, clinical sequelae (not
the laboratory abnormality) are to be recorded as the AE.
Section 8.1
Provided guidance regarding classification of AEs and hospitalizations as SAEs:
The AE is considered by the investigator to be a Other important/significant medical events. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, they 
may jeopardize the patient or subject and may require medical or surgical intervention to 
prevent one of the outcomes listed in this definition. 
Hospitalization for study treatment infusions, or planned hospitalizations following CTX110 
infusion, are not considered SAEs. Furthermore, hospitalizations for observation or 
prolongation of hospitalization for observation alone should not be reported as an SAE unless 
they are associated with a medically significant event that meets other SAE criteria as assessed 
by the investigator.
Section 8.2
Clarified that if the relationship between the SAE and the investigational product is determined 
to be "possible," a rationale for the assessment must be provided by the reporting investigator.
Section 8.5
Updated the time period for adverse event collection to align with the planned and optional 
redosings. Also clarified that if a subject starts a new 
after the Month 3 study 
visit, only CTX110-related SAEs and CTX110-related AESIs, and new malignancies will be 
reported. 
Section 8.7
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Affected 
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Clarified that events that are clearly consistent with the expected progression of disease under 
study should be considered as anticipated and not subject to expedited reporting. Progression 
should be recorded in the eCRF, but the sponsor will not report those events in an expedited 
manner to the regulatory authorities.
Section 8.8
Updated definition of end of study as follows: 
The end of the study is defined the time at which the last subject completes the Month 60 visit
and enrolls in the long-term follow-up study, is considered lost to follow-up, withdraws consent, 
or dies.
Section 9.3
Added that duration of clinical benefit (DOCB) will be calculated as the time between the first 
objective response and the disease progression or death.
Section 10.2.2
To reflect option of repeat dosing, updated definition of DLT evaluable set to: All subjects who 
receive CTX110 and complete the DLT evaluation period or discontinue early after 
experiencing a DLT. For Cohorts A, B, C, D, and F, the DLT evaluation period will begin with 
first CTX110 infusion and last for 28 days. For Cohort E, the DLT evaluation period will last 
for 28 days after the second infusion, for a total of approximately 7 weeks (21 days from initial 
infusion + 28 days from second infusion). The DES will be used for determination of the
recommended Part B dose
Updated the FAS to include all subjects who received CTX110 infusion.
Section 10.3
To reflect option of repeat dosing, clarified that the DSMB will review safety data twice a year 
until the last treated subject in Part B is at least 2 years after-treatment last CTX110 infusion.
Section 10.5.2
Updated definition of TEAE.
Original:
AEs observed after the start of LD chemotherapy (Cohorts A, B, and D) or after the start of 
daratumumab (Cohort C). 
Revised:
AEs that start or worsen on or after the initial CTX110 infusion.
Added reference to Table 20 in Section 8.7 for AE collection by study time period description 
and deleted this description from Section 10.6.2 for precision and accuracy.
Section 10.6.2 
Deleted a country-specific text for hospitalization for 14 days after CTX110 infusion from this 
version of the protocol and moved to a country-specific version.
Section 14.4
Appendix D
Updated summary of changes and protocol history.
Sections 
14.9.1, 14.9.4
Appendix H
Minor editorial and formatting changes were made as applicable.
14.7.4.
Summary of Changes to Protocol CRSP-ONC-001 V4.0, Amendment 3 (Global 
or Rest of the World)
Protocol CRSP-ONC-001 Version 4.0, 17 June 2020 was created by amending Version 3.0, 10 
February 2020. Key changes made in this version of the protocol are summarized below.
Change and Rationale
Affected Section(s)
Added the following language to align the Synopsis and Body of the protocol.
Protocol Synopsis
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“Dose escalation will be performed using a standard 3+3 design in which 3 to 6 
subjects will be enrolled at each dose level depending on the occurrence of dose-
limiting toxicity (DLT), as defined in the protocol. The SRC will review available data 
when the DLT observation period ends for the last subject enrolled in each cohort. The 
SRC will be responsible for making dose escalation decisions based on review of all 
available safety pharmacokinetic data. For cases in which dose escalation is permitted, 
the SRC may alternatively decide to enroll an additional 3 subjects at the current dose 
level. Based on ongoing assessment of benefit and risk, the SRC may stop dose 
escalation before a maximum tolerated dose (MTD) is determined.”
Updated the total CAR+ T cell dose to be administered in Dose Level 4 of Part A to 6 
×108 since a full log increase between Dose Levels 3 and 4 was considered 
unattainable by the SRC and sponsor. 
Original
“1x109”
Protocol Synopsis,
Table 4 
Added guidelines for de-escalation to 4.5x108 total CAR+ T cell dose to ensure patient 
safety in the higher dose escalation dose levels:
“Data from DL3 will be evaluated by the SRC to determine whether dose escalation 
will continue with DL4. If 1 of 3 subjects in DL4 experiences a DLT, the SRC and 
sponsor may expand to treat 3 more subjects at DL4 or de-escalate to a lower dose 
level consisting of 4.5x108 CAR+ T cells.”
Protocol Synopsis,
Section 4.2
Clarified that the grading and management of CRS will use the Lee et al.,014 criteria in 
Part A and the American Society for Transplantation and Cellular Therapy (ASTCT) 
criteria (Lee et al.,2019) in Part B. 
At the time of the original protocol version (V1.0), the well-known Lee et al., 2014 
CRS grading criteria was applied. However, this has been updated to the ASTCT 
criteria (Lee et al., 2019), which has become the worldwide standard for CRS grading. 
Therefore, the sponsor plans to use the ASTCT criteria during Part B (cohort 
expansion) of the trial. The sponsor will continue to use both published CRS grading 
criteria (Lee et al., 2014, Lee et al., 2019) for future reporting of CRS.
Added the following tables for the grading and management of CRS in Part B:
Table 8:  Grading of CRS According to the ASTCT Consensus Criteria (Lee et al., 
2019) – Part B
Table 9:  CRS Grading and Management Guidance – Part B
Protocol Synopsis,
Section 4.2.2,
Section 6.2.4,
Section 6.2.7,
Section 10.2.3,
Section 10.6.2
Added that this study will allow for one-time redosing of subjects (NHL) with CTX110 
based on the investigator’s decision in consultation with CRISPR Therapeutics medical 
monitor. To be considered for redosing, subjects must have either 1) achieved a PR or 
CR after CTX110 infusion and subsequently progressed or relapsed within 12 months 
of the initial CTX110 infusion, or 2) remain in PR (but not CR) at the Month 3 visit. 
The earliest time at which a subject could be redosed is ≥2 months after the initial 
CTX110 infusion. Added the redosing criteria and Stage 1 screening assessment that 
must be repeated for redosing
Added that all other visits (starting with Stage 2) should be performed as per the 
Schedule of Assessments (Table 14) consistent with their initial dosing. Subjects in the 
dose escalation cohort (A, B, or C) who undergo redosing with CTX110 will receive 
the same lymphodepletion regimen (Stage 2) as (a) identical to that previously 
received, or (b) subsequently cleared during dose escalation. Subjects in the expansion 
cohort will be redosed with the recommended Part B dose.
Protocol Synopsis,
Section 4.3,
Section 4.3.1,
Table 15,
Section 13
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CTX110 for B Cell Malignancies
Version 7.0, 12 September 2022
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Change and Rationale
Affected Section(s)
Provided the rationale for redosing CTX110 in a subsection (Section 4.3.1). Given the 
clinical safety data with CTX110 to date, and the proof of concept demonstrated by 
similar therapies that show redosing of allogeneic CAR T can induce objective 
responses, the sponsor proposes to include redosing in this protocol for subjects that 
meet specific criteria designed to protect subject safety.
Updated the neurotoxicity grading reference to Lee et al.,2019. Lee et al.,2018 referred 
to the article in press.
Original
“Lee et al. 2018”
Replaced ASBMT with ASTCT consensus recommendations. Mentioned that ASTCT 
was formerly known as American Society for Blood and Marrow Transplantation, 
ASBMT.
Section 4.2.2,
Section 6.2.4,
Section 6.2.5,
Section 10.6.2,
Section 13
Removed the sentence “The infusion of each vial should occur within 20 minutes of 
thawing.” since the specifics are covered in the infusion manual.
“CTX110 consists of allogeneic T cells modified with CRISPR-Cas9, 
 
 
The infusion of each vial should 
occur within 20 minutes of thawing. Infusion should preferably occur through a central 
venous catheter. A leukocyte filter must not be used.”
Section 5.3
Added “In addition to treatment guidelines provided in Table 12Table 11, nonsteroidal 
agents (e.g., anakinra, etc.) may be considered for ICANS management after discussion 
with the CRISPR medical monitor (Neill et al., 2020).”
Section 6.2.5
Added the following statement in case of severe cytopenias observed with higher 
cyclophosphamide or daratumumab infusion
“G-CSF administration may be considered earlier but must first be discussed with the 
medical monitor.”
Section 6.2.8
Updated the AE, SAE, and AESI collection guidelines:
“All SAEs and AESIs should be reported for up to 3 months after CTX110 infusion if a 
subject starts a new
before Month 3 study visit. After Month 3 study 
visit if a subject starts a new 
 only SAEs and AESIs related to 
CTX110 will be reported. If a subject does not receive CTX110 therapy after 
enrollment, the AE reporting period ends 30 days after last study-related procedure 
(e.g., biopsy, imaging, LD chemotherapy).
Original
“If a subject begins new
before Month 3 study visit, only SAEs and 
AESIs should be reported for up to 3 months after CTX110 infusion. Only AESIs will 
be reported if a subject begins new
after Month 3 study visit. If a 
subject does not receive CTX110 therapy after enrollment, the AE reporting period 
ends 30 days after last study-related procedure (e.g., biopsy, imaging, LD 
chemotherapy).
…
Deleted the redundant information (Section 8.7) shown in strikethrough. The 
information exists in the updated Table 18
“All SAEs and AESIs, whether or not they are considered related to the investigational 
product, must be reported. SAEs and AESIs must be reported to PrimeVigilance within 
24 hours of the first awareness of the event.”
Table 14, Footnote 12
Section 8.7,
Section 8.8
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CTX110 for B Cell Malignancies
Version 7.0, 12 September 2022
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Page 191 of 194
Change and Rationale
Affected Section(s)
Updated footnote 29 of the Schedule of Assessments to:
Clarify that Day 1 PK samples should be collected prior to CTX110 infusion on 
Day 28 and M2 prior to each daratumumab redosing. 
Added that samples for
assessment will be collected at the 
same specified time as that for the PK sample.
Table 14
Updated the analysis sets to the following:
“Part A (Dose Escalation)
DLT evaluable set (DES): All subjects who receive CTX110 and are followed for at 
least 28 days postinfusion or discontinue early after experiencing a DLT. The DES will 
be used for determination of the recommended Part B dose. 
Part A + Part B (Dose Escalation + Cohort Expansion)
Enrolled set: All subjects enrolled in the study. The Enrolled set will be classified 
according to the assigned dose level of CTX110.
Treated set: All subjects who received any study treatment in the study. The subjects in 
the Treated set will be classified according to the received study treatment.
Full analysis set (FAS): All subjects who received CTX110 infusion and had the 
opportunity to be followed for at least 3 months (i.e., completed at least 3 months 
follow-up or discontinued prior to data cut-off). The subjects in FAS will be classified 
according to the assigned dose level of CTX110. The FAS will be the primary analysis 
set for clinical activity assessment. 
Safety analysis set (SAS): All subjects who received CTX110 infusion. The subjects in 
SAS will be classified according to the received dose level of CTX110. The SAS will 
be the primary analysis set for the characterization of CTX110 safety profile. 
Original
“Part A (Dose Escalation)
DLT evaluable set: All subjects who receive CTX110 and are followed for at least 
28 days postinfusion or withdraw consent after experiencing a DLT
Part A + Part B (Dose Escalation + Cohort Expansion)
Full analysis set (FAS): All subjects who are enrolled and receive CTX110 infusion 
and have baseline and at least 1 post-baseline disease assessment. The subjects in FAS 
will be classified according to the assigned dose level of CTX110. The FAS will be the 
default analysis set for clinical activity assessment. 
Safety analysis set (SAS): All subjects who are enrolled and receive study treatment. 
The subjects in SAS will be classified according to the received study treatment. The 
SAS will be the default set for safety analyses.”
Section 10.3
Separated analyses in Section 10.6.3 into. 2 sections, 1 for Pharmacokinetic and 
Pharmacodynamic Analyses (Section 10.6.3) and another for
to represent information appropriate for respective sections.
Section 10.6.3
Section 10.6.4
Updated summary of changes and protocol history.
Section 14.9 
(Appendix H),
Section 14.9.4
Minor editorial and formatting changes were made throughout as applicable.
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Version 7.0, 12 September 2022
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14.7.5.
Protocol History
Document/Version
Date
Global/Country/Site Specific
Original Protocol/Version 1.0
06 February 2019
Global
Amendment 1/Version 2.0
06 May 2019
Global
Amendment 2/Version 3.0
10 February 2020
Global
Amendment 3/Version 4.0
17 June 2020
Global
Amendment 4/Version 5.0
12 February2021
Global
Amendment 5/Version 6.0
30 July 2021
Global
Amendment 6/Version 7.0
12 September 2022
Global
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CTX110 for B Cell Malignancies
Version 7.0, 12 September 2022
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14.8.
Appendix H: Signature Pages
PROTOCOL APPROVAL SIGNATURE PAGE
Protocol
CRSP-ONC-001
Title
A Phase 1 Dose Escalation and Cohort Expansion Study of the Safety and 
Efficacy of Anti-CD19 Allogeneic CRISPR-Cas9–Engineered T Cells 
(CTX110) in Subjects With Relapsed or Refractory B Cell Malignancies
Date
12 September 2022
Version
7.0
Amendment
6
Reviewed and Approved by:
Medical Monitor
CRISPR Therapeutics AG
Date
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Protocol CRSP-ONC-001
CTX110 for B Cell Malignancies
Version 7.0, 12 September 2022
Confidential 
Page 194 of 194
PROTOCOL ACCEPTANCE FORM
Protocol
CRSP-ONC-001
Title
A Phase 1 Dose Escalation and Cohort Expansion Study of the Safety and 
Efficacy of Anti-CD19 Allogeneic CRISPR-Cas9–Engineered T Cells 
(CTX110) in Subjects With Relapsed or Refractory B Cell Malignancies
Date
12 September 2022
Version
7.0
Amendment:
6
I have carefully read this protocol and agree that it contains all of the necessary information 
required to conduct this study. I agree to conduct this study as described and according to the 
Declaration of Helsinki, International Conference on Harmonisation (ICH) Guidelines for Good 
Clinical Practice (GCP), and all applicable regulatory requirements.
Investigator’s Signature
Date
Name (printed)
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