A Single-arm, Open-label Study of Olverembatinib, CD3/CD19 Bispecific T-cell Engager, and Chidamide in Patients With Newly Diagnosed Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia
Phase: PHASE2
Conditions: Acute Lymphoblastic Leukemia, Philadelphia Chromosome, Philadelphia-Positive ALL, Adult ALL, IKZF1 Gene Mutation
Sponsor: Nanfang Hospital, Southern Medical University

A Phase 2, Single-arm, Open-label Study of
Olverembatinib, CD3/CD19 Bispecific T-cell
Engager, and Chidamide in Patients With
Newly
Diagnosed
Philadelphia
Chromosome-positive Acute Lymphoblastic
Leukemia
Date 06.01.2024

1.Background introduction
Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) accounts for
approximately 25% of cases in younger patients and over 40% in older patients diagnosed with
ALL
[1, 2]. TThe presence of the Ph rearrangement gives rise to the BCR-ABL1 fusion gene, which
has been associated with poorer outcomes. A significant feature of Ph+ ALL is the deletion of the
IKZF1 gene (IKZF1del), observed in more than 70% of Ph+ ALL patients
[3, 4]. Ph+ ALL patients with
IKZF1del exhibit poor molecular responses, resistance to therapy, and higher rates of relapse
[5-7].
Before the advent of tyrosine kinase inhibitors (TKIs), the complete response (CR) rate and
prognosis of Ph+ ALL were extremely poor. The combination of chemotherapy with TKIs has
improved the CR rate to 90%, providing more patients with the opportunity to undergo
allogeneic hematopoietic stem cell transplantation (allo-HSCT)
[8-11].
While chemotherapy plus TKIs has improved the complete response (CR) rate in Ph+ ALL, it has
also led to an increase in non-relapse mortality (NRM). The NRM during induction therapy ranges
from 1-3% for children, 10-20% for younger adults, and over 20% for older patients
[12]. TThe
unsatisfactory NRM is attributed to the bone marrow toxicity of multi-drug chemotherapy.
Therefore, there is a need for a low-toxic or even chemo-free regimen. The GIMEMA group has
been a leader in exploring chemo-free treatments for Ph+ ALL since the era of first-generation
(1G) TKIs. The LAL 0201 study reported a 100% CR rate with a chemo-free regimen in 30 patients
older than 60 years. These patients were treated with a TKI, prednisone, and central nervous
system prophylaxis
[13]. The LAL 1205 trial included 55 adult patients with Ph+ ALL, where the
induction therapy comprised the second-generation (2G) TKI dasatinib and prednisone, with
subsequent consolidation therapy decided by investigators. A 100% CR rate was achieved after
induction therapy, and NRM was 0. However, most patients had a positive minimal residual
disease (MRD), and long-term survival was poor. These trials demonstrated that the CR rate and
safety were favorable, and the chemo-free regimen was feasible, but addressing the issues of
poor MRD response and long-term survival is crucial..
The poor long-term survival of Ph+ ALL is often attributed to drug-resistant mutations, including
the T315I mutation, which can be detected in over 75% of relapsed/refractory Ph+ ALL
patients
[14-16]. The emergence of more efficient third-generation (3G) TKIs offers potential
solutions to overcome resistance and improve the complete molecular response (CMR) rate.
Phase 2 trials involving 3G TKIs as monotherapy have shown promising results, with a CMR rate
of 38% and a 1-year overall survival (OS) of 40%
[17]. Combining 3G TKIs with chemotherapy, such
as in the PACE trial, demonstrated a 100% complete response rate and a 5-year OS of 73% in Ph+
ALL patients
[18]. Meta-analyses comparing 3G TKIs with 1/2G TKIs revealed higher CMR and 3-year
OS rates with the use of 3G TKIs.
While the combination of 3G TKIs and chemotherapy may improve long-term survival, the high
non-relapse mortality (NRM) associated with chemotherapy remains a challenge, especially in

older patients. Substituting chemotherapy with immunotherapy, such as blinatumomab, a
CD3/CD19 bispecific T-cell engager (BiTE), has shown promise. Blinatumomab, approved by the
FDA for relapsed/refractory ALL, has demonstrated a 36% complete response rate, an 88% CMR
rate in responders, and a median OS of 9 months as monotherapy
[19, 20]. In relapse/refractory Ph+
ALL, combining blinatumomab with TKIs has shown efficacy, with a CMR rate and 1-year OS of
75% and 73%, respectively
[21]. Inspired by these findings, chemo-free regimens (BiTE+TKI) are
being explored for newly diagnosed Ph+ ALL. The D-ALBA study reported on blinatumomab plus
dasatinib as a chemo-free regimen for newly diagnosed Ph+ ALL
[22]. This study included 63
patients, and after dasatinib induction, 29% achieved CMR. Subsequent blinatumomab
consolidation therapy improved CMR to 60%, with a median OS and disease-free survival (DFS) of
95% and 88%, respectively.
However, long-term survival outcomes with BiTE plus TKI in Ph+ ALL patients were unsatisfactory,
particularly in the IKZF1del subgroup
[23]. In the GIMEMA D-ALBA study, patients with IKZF1del had
the worst prognosis. As IKZF1del is a frequent concomitant mutation in Ph+ ALL, targeting this
mutation may further improve outcomes with a chemo-free regimen. Histone deacetylase (HDAC)
inhibitors, such as chidamide, have shown promise in tumor treatment. Preclinical studies
demonstrated that chidamide can activate transcription of the IKZF1 gene, induce the expression
of ikaros, and inhibit the proliferation of IKZF1del ALL cells. A single-arm trial evaluating
chidamide in Ph-like ALL suggested that chidamide can improve the poor outcomes of IKZF1del
ALL by increasing the expression of ikaros. A post-hoc analysis in the IKZF1del subgroup
demonstrated a 3-year event-free survival (EFS) of 64.8% with chidamide compared to 28.9%
with chemotherapy alone. Multivariate analysis indicated that chidamide can eliminate the poor
outcomes associated with IKZF1del mutation.
These results underscore the potential of TKI combined with BiTE in improving clinical outcomes
in newly diagnosed Ph+ ALL. However, the efficacy of 1/2G TKIs may be insufficient, and the
efficacy of BiTE is inadequate in the IKZF1del subgroup, leading to unsatisfactory long-term
survival. Therefore, the suggestion is that combining 3G TKIs and chidamide with BiTE may
achieve better CMR and long-term survival in Ph+ ALL.

2.Objectives of the trial
2.1 Primary objective
We aim to explore the efficacy and safety of ABC regimen. The primary endpoint is the complete
molecular remission （CMR）at 3 months in adult Ph+ ALL.
2.2 Secondary objectives
To explore

The 5-year overall survival

The 5-year event-free survival

Number of grade >3 adverse events

IKZF1del subgroup analysis

IKZF1plus/CD20 subgroup analysis
3.Inclusion and exclusion criteria
3.1Inclusion criteria

Signed written informed consent.

Newly diagnosed adult B-precursor Ph+ ALL patients.

Age greater or equal to18 years.

ECOG Performance Status 0 or 1.

Ineligible for allo-HSCT.

Renal and hepatic function as defined below:

AST (GOT), ALT (GPT), and AP <2 x upper limit of normal (ULN).

Creatinine clearance equal or greater than 50 mL/min.

Pancreatic function as defined below:

Serum amylase less or equal to 1.5 x ULN

Serum lipase less or equal to1.5 x ULN.

Normal cardiac function.

Negative HIV test, negative HBV DNA and HCV RNA.

Negative pregnancy test in women of childbearing potential.

3.2Exclusion criteria

History of receiving systemic chemotherapy or CAR-T therapy for ALL.

Impaired cardiac function, including any one of the following:

LVEF <45% as determined by MUGA scan or echocardiogram.

Complete left bundle branch block.

Use of a cardiac pacemaker.

ST depression of >1mm in 2 or more leads and/or T wave inversions in 2 or more
contiguous leads.

Congenital long QT syndrome.

History of or presence of significant ventricular or atrial arrhythmia.

Clinically significant resting bradycardia (<50 beats per minute).

QTc >450 msec on screening ECG (using the QTcF formula).

Right bundle branch block plus left anterior hemiblock, bifascicular block.

Myocardial infarction within 3 months prior to starting olverembatinib.

Angina pectoris.

Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the
absorption of olverembatinib or chidamide (e.g., ulcerative diseases, uncontrolled nausea,
vomiting, diarrhea, malabsorption syndrome, or small bowel resection).

History of or current autoimmune disease.

History of or current relevant CNS pathology.

Presence of CNS leukemia.

History of or current autoimmune disease.

History of other malignancies.

Presence active infection.

Nursing women or women of childbearing potential not willing to use an effective form of
contraception during participation in the study and at least 3 months thereafter or male
patients not willing to ensure effective contraception during participation in the study and at
least three months thereafter.
4.Study design
4.1General design
Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) is now a relatively
favorable-risk leukemia with the development of potent BCR::ABL1 tyrosine kinase inhibitors
(TKIs). Achievement of an early and deep complete molecular remission (CMR) is an important

end point in Ph+ ALL and identifies patients who may not need allogeneic hematopoietic stem
cell
transplantation (allo-HSCT).
The
chemotherapy-free
D-ALBA
trial of dasatinib
and
blinatumomab was safe and effective in patients with newly diagnosed Ph-positive ALL and
resulted in an estimated 3-year OS rate of 80% (NEJM 2020, 2022). To further improve the
outcomes, the potent third-generation TKIs, ponatinib and olverembatinib (ASH 2023, abs 1504),
were added to chemotherapy or immunotherapy, resulted in an overall CMR rate of 84%-90%, a
5-year survival rate of 73%, most patients did not undergo allo-HSCT.
Of note, IKZF1plus subgroup still stands for high-risk for Ph+ALL and exhibit poor outcome even in
TKI plus blinatumomab, which indicate IKZF1del confers resistance to immunotherapy. our
previous study found that HDACi tucidinostat/chidamide could restore the expression and
functionality of IKZF1 in IKZF1del samples, including increased expression of CD19 and reduced
focal adhesion (Blood (2021) 138 (Supplement 1): 514.).
ABC study is a phase 2, single-arm, open-label study of Olverembatinib, CD3/CD19 Bispecific
T-cell
Engager,
and
Chidamide
in
patients
with
newly
diagnosed
Philadelphia
Chromosome-positive acute lymphoblastic leukemia (Ph+ALL).
This study combined third
generation TKI (Olverembatinib), histone deacetylase inhibitors (Chidamide) and CD3/CD19
bispecific T-cell engager (Blinatumomab) as first line regimen (ABC regimen) for Ph+ ALL. We aim
to explore the efficacy and safety of ABC regimen. The primary endpoint is the complete
molecular remission （CMR ）
at 3 months, secondary endpoints are overall survival (OS),
event-free survival (EFS), adverse event (AE), IKZF1del, IKZF1plus, IKZF1lpus/CD20 subgroup
EFS/OS.
The ABC regimen include pre-phase, induction, consolidation and maintenance treatment.
Phase One.Induction Consolidation, for 1 year.
1.1 Pretreatment ×1 cycle. Prednisone，1mg/kg/d, from day 1 to 14;
1.2 Induction Therapy × 1 cycle. A: OlverembAtinib (at a dose of 40 mg Qod), from day 8 to 42.
B: Blinatumomab (at a dose of 28 μg per day), from day 15 to 28. C: Chidamide (at a dose of 10
mg Qod), from day 9 to 41.
1.3 Consolidation Block
×
5 cycles. A: Olverembatinib (at a dose of 40 mg Qod) was
administered from day 1 to 42. B: Blinatumomab (at a dose of 28 μg perday) was administered
from day 1 to 14. C: Chidamide (at a dose of 10 mg Qod) was administered from day 14 to 41.
Phase Two. Maintenance Therapy, for 3 years.
2.1 A: Olverembatinib (at a dose of 40 mg Qod) was administered from day 1 to 42.
C: Chidamide (at a dose of 10 mg Qod) was administered from day 14 to 41.
Phase Three. Follow-up, for 5 years.
CNS prophylaxis will be carried out with medicated lumbar punctures (MTX 15 mg,
Methylprednisolone 20 mg): the first CNS prophylaxis will be administered during the prephase.
The 2-6 times prophylaxis will be administered during induction therapy, subsequently, CNS
prophylaxis will be administered at the end of each cycle of consolidation treatment.

4.2Primary endpoint
Complete molecular response (CMR) at 3 months.
4.3Secondary endpoint

5-year overall survival rate

5-year event-free survival rate

Number of grade >3 adverse events

IKZF1del subgroup analysis

IKZF1plus/CD20 subgroup analysis
5.Toxicity management
5.1 Toxicity of BiTE
While BiTE has demonstrated improved clinical outcomes, its associated toxicity should not be
underestimated. Currently, the toxicity reactions of BiTE in treating hematologic malignancies can
be categorized as follows:
5.1.1Cytokine Release Syndrome (CRS)
CRS is a common occurrence in cell therapy. In early BiTE phase II trials, two patients with a high
tumor burden developed grade 4 CRS. Subsequently, dexamethasone and cyclophosphamide
were employed for pre-treatment in patients with a high tumor burden, resulting in no further
occurrences of
≥grade 3 CRS
[19]. In subsequent Phase II and III trials, dexamethasone
pre-treatment was applied to patients with blast cells exceeding 50% in the bone marrow and
15,000/µL in peripheral blood or elevated lactate dehydrogenase (LDH) levels
[24]. Life-threatening
CRS has been reported in patients undergoing BiTE therapy, typically manifesting within 2 days of
infusion initiation. The median time for CRS regression is 5 days (in cases of regression). CRS
symptoms
include
fever,
headache,
nausea,
fatigue,
hypotension,
elevated
alanine
aminotransferase (ALT), elevated aspartate aminotransferase (AST), elevated total bilirubin, and
disseminated intravascular coagulation (DIC).
CRS involves a systemic inflammatory response mediated by elevated levels of cytokines and
inflammatory factors such as IL-2, IL-6, IL-8, IL-10, TNF- α , and INF- γ . Clinical studies have
observed increased IL-10, IL-6, and IFN- γ
levels during the first cycle of BiTE therapy
[25].

Elevated IL-6 and IL-10 levels may be associated with the occurrence of CRS after BiTE therapy,
potentially linked to hemophagocytic syndrome (HPS) or macrophage activation syndrome
(MAS)
[26].
Early identification of CRS is crucial. During the induction treatment phase with Blinatumomab, a
low dose of 9µg/day for the first 7 days and pre-treatment with dexamethasone are
recommended as prophylaxis for CRS. All patients receive dexamethasone prophylaxis when
initiating BiTE infusion, increasing the dose, or interrupting for more than 4 hours. Tocilizumab,
an IL-6 receptor antagonist, has revolutionized CRS treatment since its successful use by Maude
SL et al. Tocilizumab effectively alleviates CRS symptoms without interfering with the proliferation
and survival of CAR-T cells in vivo. Currently, Tocilizumab is the first-line treatment for severe CRS,
with a recommended FDA-approved dosage of 8mg/kg administered intravenously over one hour.
If the initial administration does not improve CRS symptoms, it can be repeated within the next
24-72 hours
[27-29].
（1）Cytokine Release Syndrome，CRS：
Table 1. CRS Grading System：
Grade 1
Symptoms are not life threatening and require symptomatic
treatment only (fever, nausea, fatigue, headache, myalgias,
malaise)
Grade 2
Symptoms require and respond to moderate intervention:
Oxygen requirement <40% FiO2;
Hypotension responsive to IV fluids or low dose of one
vasopressor;
Grade 2 organ toxicity
Grade 3
Symptoms require and respond to aggressive intervention:
Oxygen requirement ≥40% FiO2;
Hypotension requiring high dose or multiple vasopressors;
Grade 3 organ toxicity or grade 4 transaminitis
Grade 4
Life-threatening symptoms:
Requirement for ventilator support;
Grade 4 organ toxicity (excluding transaminitis);
Grade 5
Death.
Based on the NCI Common Terminology Criteria for Adverse Events (CTCAE) version;
Patients suspected of severe CRS (grade 3-4) should be closely monitored, and transferred to the
intensive care unit if necessary. Immunosuppressants should be given for treatment, and the
preferred choice is the IL-6 receptor blocker, Tocilizumab. Mild CRS can be treated with
glucocorticoids.

5.1.2Neurotoxicity
In clinical trials involving ALL patients treated with BiTE, approximately 65% experienced central
nervous system (CNS) toxicity, with CNS adverse events of grade 3 or higher accounting for 7-14%.
Neurological events, such as headache and tremor, were the most common, occurring within the
first two weeks of BiTE therapy. Specifically, around 13% of patients encountered severe CNS
toxicity (grade 3 or higher), including encephalopathy, tics, speech disorders, consciousness
disorders, confusion, disorientation, coordination disorders, and balance issues
[30, 31]. The grading
principles refer to the appendix.
The precise mechanism of neurotoxicity induced by BiTE remains unclear. Retrospective studies
suggest associations between neurotoxicity and a history of more than two previous salvage
treatments or neurological diseases. However, baseline IL-6 levels or tumor burden do not seem
linked to the severity of neurotoxicity
[32]. Potential mechanisms may involve the disruption of the
blood-brain barrier due to treatment or disease, along with the release of cytokines after binding
to CD19-positive cells in the CNS.
For CNS events of grade 3 or lower, most studies recommend suspending Blinatumomab
treatment and waiting for recovery. In cases of neurotoxic events of grade 4 or higher, BiTE
therapy is discontinued. When facing grade 3 toxicity, it is advisable to discontinue BiTE until
achieving grade 1 for three consecutive days. After this recovery period, Blinatumomab
treatment at 9 µg/day can be reinstated. If CNS toxicity escalates during this phase, permanent
discontinuation of Blinatumomab is recommended. In the absence of CNS adverse reactions, the
dose can be restored to 28 µg/day after seven days. If grade 3 CNS toxicity persists for over one
week or if there is more than one seizure episode, discontinuation of medication is also
recommended.
Steroids remain pivotal in the treatment of neurotoxicity and can be used for severe symptoms
such as encephalopathy or aphasia. Supportive treatment, including antiepileptic drugs for
seizures,
should
be
considered
as
needed.
One
study
demonstrated
the
concurrent
administration of levetiracetam (500mg, bid) during Blinatumomab administration to prevent
neurotoxicity
[22].
（2）Neurotoxicity：
Table2 Immune effector Cell-Associated Neurotoxicity Syndrome（ICANS）grading
system.
Neurotoxicity
Domain
Grade 1
Grade 2
Grade 3
Grade 4
ICE Score*
7-9
3-6
0-2
0 (patient is
unarousable and
unable to
perform ICE)
Depressed level
Awakens
Awakens
Awakens only
Patient is

of
consciousness**
spontaneously
to voice
to tactile
stimulus
unarousable or
requires vigorous
or repetitive
tactile stimuli to
arouse. Stupor or
coma
Seizure
N/A
N/A
Any clinical
seizure focal or
generalized
that resolves
rapidly; or
Non-convulsive
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
findings***
N/A
N/A
N/A
Deep focal motor
weakness such as
hemiparesis or
paraparesis
Raised ICP /
Cerebral edema
N/A
N/A
Focal/local
edema on
neuroimaging
Diffuse cerebral
edema on
neuroimaging;
Decerebrate or
decorticate
posturing; or
Cranial nerve VI
palsy; or
Papilledema; or
Cushing’s triad
ICANS grade is determined by the most severe event (ICE score, level of consciousness, seizure,
motor finds, raised ICP/cerebral edema) not attributable to any other cause.
*A patient with an ICE score of 0 may be classified as having Grade 3 ICANS if the patient is awake
with global aphasia. But a patient with an ICE score of 0 may be classified as having Grade 4
ICANS if the patient is unarousable.
**Depressed level of consciousness should be attributable to no other cause (e.g. no sedating
medication)
***Tremors and myoclonus associated with immune effector cell therapies may be graded
according to CTCAE v5.0 but they do not influence ICANS grading.
Table3
ICE Grading System
ICE Grading System

Orientation: Orientation to year, month, city, hospital: 4 points
Naming: Name 3 objects (e.g., point to clock, pen, button): 3 points
Following 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 (e.g., The national flag of China is a
five-star red flag): 1 point
Attention: Count backwards from 100 by ten: 1 point
Score 10: No impairment
Score 7-9: Grade 1 ICANS
Score 3-6: Grade 2 ICANS
Score 0-2: Grade 3 ICANS
5.1.2.1 Management recommendations for status epilepticus
Non Convulsive Status Epilepticus, NCSE
• Assess airway, respiration, and circulation, and check blood sugar.
• Control epilepsy with lorazepam 0.5mg IV, and if necessary, increase by 0.5mg every 5 minutes
until a total of 2mg is used.
• Levetiracetam 500mg IV to maintain dose.
• If the epilepsy persists, transfer to ICU for monitoring, with phenobarbital 60mg IV.
• After remission of NCSE, maintain the following dosage: lorazepam 0.5mg q8h IV; Levetiracetam
1000 mg q12h IV; Phenobarbital 30mg q12h IV.
Non Convulsive Status Epilepticus, NCSE
• Evaluate airway, respiration and circulation and check blood glucose.
• Transfer to ICU care.
• Lorazepam 2mg IV, if uncontrolled, additional 2mg IV for seizure control, total dosage 4mg.
• Levetiracetam 500mg IV push to maintain dose.
• If persistent seizures cannot be controlled, add phenobarbital 15 mg/kg.
• Maintain the following doses after remission of convulsive status epilepticus maintenance
status: lorazepam 0.5 mg q8h IV 3 times daily; levetiracetam 1000 mg q12h IV; phenobarbital 30
mg q12h IV.
• If seizures are difficult to control, continuous EEG monitoring should be performed.
All drug doses are for adults.

5.1.2.2 Recommendations for the management of increased
intracranial pressure
Optic papilla edema* grade 1 or 2 accompanied by cerebrospinal fluid
pressure (CSF) <20 mmHg without hydrocephalus
• Acetazolamide 1000 mg IV followed by 250-1000 mg IV q12h (adjust drug dosage based on
renal function and acid-base balance, monitor 1-2 times daily)
Optic papilla edema* grade 3,4 or 5 accompanied by any imaging
evidence of cerebral edema, or cerebrospinal fluid pressure (CSF) ≥20
mmHg
• CRES grade 4 recommends the use of high-dose glucocorticoids such as : methylprednisolone
1g / day.
• Raise the head of the bed by 30 degrees.
• Arterial carbon dioxide (PaCO2) is brought to 28-30 mmHg by hyperventilation, and this state is
maintained for no more than 24h.
• Hypertonic therapy: use of mannitol (20 g/dl solution) or hypertonic saline (3% or 23.4%, as
indicated below)
- Mannitol: initial dose 0.5-1g/kg; maintenance dose 0.25-1g/kg q6h while monitoring
metabolism and serum osmolality every 6h, if serum osmolality ≥320 mOsm/kg or osmotic
pressure difference ≥40, discontinue mannitol.
- Hypertonic saline: the initial dose of 3 % hypertonic saline 250ml; the rate is maintained at
50-75 ml/h while electrolytes are monitored every 4 h. The infusion is discontinued if the serum
sodium level is ≥155 mEq/l.
- For impending brain herniation: give 30 ml of 23.4% hypertonic saline initially; repeat after 15
minutes if needed.
• If the patient has ommaya reservoir, the cerebrospinal fluid drainage pressure is less than 20
mmHg.
• Neurology and anesthesiology consultations are invited in case of EEG bursts of inhibitory
electrical activity.
• Metabolic analysis is performed every 6h and head CT scans are performed daily, while the
doses of the above drugs are adjusted to prevent recurrent cerebral edema, renal failure,
electrolyte abnormalities, hypovolemia and hypotension.
All drug doses are for adult subjects;

5.1.3 Hypoglobulinemia
In a Phase II study, immunoglobulin levels were monitored for a long period in 6 MRD+ ALL
patients. The levels of immunoglobulin G (IgG) in all responders decreased to the lowest point of
baseline by 29%, and no IgG decrease was observed in one unresponsive patient
[33]. The TOWER
study
reported
that
6%
of
patients
receiving
Blinatumomab
treatment
developed
hypoglobulinemia, while among patients receiving chemotherapy, this proportion was 1%
[24]. BiTE
activated T cells not only attack tumor cells, but also normal tissues expressing the same antigen,
causing damage to normal tissues, which is known as the "on-target/off-tumor" toxic reaction. B
cell deficiency is a typical on-target/off-tumor toxicity response in BiTE treatment of B cell
malignancies, which can be effectively treated through immunoglobulin replacement therapy.
In addition, many studies have reported neutropenia, although its rate are lower than those in
the chemotherapy group. The incidence of various infections, including bloodstream infections,
catheter-related infections, fungal infections, and bacterial sepsis, is as high as 25%. Therefore,
the need for immunoglobulin replacement therapy and antibiotics prophylaxis can be considered.
6.Evaluation
6.1 Efficacy evaluation
The primary endpoint of this study is the complete molecular remission rate ( CMR ) at 3 months
of treatment. The secondary endpoints are 5-year overall survival ( OS ) and event-free survival
( EFS ).
6.2 Safety evaluation
All patients who have received at least one drug treatment in this study will be included in the
safety analysis. All data will be analyzed based on the actual treatment received, and variables for
safety analysis include AEs, clinical laboratory tests, examination results, and physical
examination results.

7.Safety monitoring, reporting and medical
treatment
7.1 Definition of Adverse Event (AE)
An AE is any untoward medical occurrence in a clinical study subject administered a medicinal
(investigational or non-investigational) product. An AE does not necessarily have a causal
relationship with the treatment. An AE may therefore be any unfavorable and unintended sign
(including an abnormal finding), symptom, or disease temporally associated with the use of a
medicinal (investigational or noninvestigational) product, whether or not related to that
medicinal
(investigational
or
non-investigational)
product.
(Definition
per
International
Conference on Harmonisation [ICH]). This includes any occurrence that is new in onset or
aggravated in severity or frequency from the baseline condition, or abnormal results of
diagnostic procedures, including laboratory test abnormalities.
7.2 Adverse reaction
An adverse reaction is defined as a response to a medicinal product which is noxious and
unintended. Response in this context means that a causal relationship between a medicinal
product and an AE is at least a reasonable possibility (see Annex IV, ICH-E2A Guideline). Note: The
sponsor collects AEs starting with the signing of the ICF (refer to Section Adverse Events, for time
of last AE recording).
7.3 Serious adverse event (SAE)
A SAE based on ICH and EU guidelines on pharmacovigilance for Medicinal Products for Human
Use is any untoward medical occurrence that at any dose:

Results in death

Is life-threatening (the subject was at risk of death at the time of the event. It does not refer
to an event that hypothetically might have caused death if it were more severe)

Requires inpatient hospitalization or prolongation of existing hospitalization

Results in persistent or significant disability/incapacity

Is a congenital anomaly/birth defect

Is a suspected transmission of any infectious agent via a medicinal product

Is medically important*
*Medical and scientific judgment should be exercised in deciding whether expedited reporting is
also appropriate in other situations, such as important medical events that may not be
immediately life threatening or result in death or hospitalization but may jeopardize the subject
or may require intervention to prevent one of the other outcomes listed in the definition above.

These should usually be considered serious
7.4 Special reporting situations
Safety events of interest on a sponsor study drug that may require expedited reporting and/or
safety evaluation include, but are not limited to:

Overdose of a sponsor study drug

Suspected abuse/misuse of a sponsor study drug

Inadvertent or accidental exposure to a sponsor study drug

Medication error involving a sponsor product (with or without subject/patient exposure to
the sponsor study drug, eg, name confusion)
Special reporting situations should be recorded in the CRF. Any special reporting situation that
meets the criteria of a SAE should be recorded on the SAE form.
7.5
Reporting procedures
7.5.1 All adverse events
All AEs and special reporting situations, whether serious or non-serious, will be reported from
the time a signed and dated ICF is obtained until completion of the subject's last study-related
procedure (which may include contact for follow-up of safety). Serious AEs, including those
spontaneously reported to the investigator within 30 days after the last dose of study drug, must
be reported. All events that meet the definition of a SAE will also be reported as SAE, regardless
of whether they are protocol-specific assessments. All AEs, regardless of seriousness, severity, or
presumed relationship to study drug, must be recorded using medical terminology in the source
document and the CRF. Whenever possible, diagnoses should be given when signs and symptoms
are due to a common etiology (eg, cough, runny nose, sneezing, sore throat, and head congestion
should be reported as "upper respiratory infection"). Investigators must record in the CRF their
opinion concerning the relationship of the AEs to study therapy. All measures required for AE
management must be recorded in the source document. The sponsor assumes responsibility for
appropriate reporting of AEs to the regulatory authorities.
7.5.2 Serious adverse events
All SAEs occurring during the study must be reported to PI within 24 hours of their knowledge of
the event. All SAEs that have not resolved by the end of the study, or that have not resolved upon
discontinuation of the subject's participation in the study, must be followed until any of the
following occurs:

The event resolves.

The event stabilizes.

The event returns to baseline, if a baseline value/status is available.

The event can be attributed to agents other than the study drug or to factors unrelated to
study conduct.


It becomes unlikely that any additional information can be obtained (subject or health care
practitioner refusal to provide additional information, lost to follow-up after demonstration
of due diligence with follow-up efforts).
Suspected transmission of an infectious agent by a medicinal product will be reported as a SAE.
Any event requiring hospitalization (or prolongation of hospitalization) that occurs during the
course of a subject's participation in a study must be reported as a SAE, except hospitalizations
for the following:

Hospitalizations not intended to treat an acute illness or AE (eg, social reasons such as
pending placement in long-term care facility).

Surgery or procedure planned before entry into the study (must be documented in the CRF).
Note: Hospitalizations that were planned before the signing of the ICF, and where the
underlying condition for which the hospitalization was planned has not worsened, will not
be considered SAEs. Any AE that results in a prolongation of the originally planned
hospitalization is to be reported as a new SAE.

Disease progression should not be recorded as an AE or SAE; instead, signs and symptoms of
clinical sequelae resulting from disease progression/lack of efficacy will be reported if they
fulfill the SAE definition.

A standard procedure for protocol therapy administration will not be reported as a SAE.

Hospitalization or prolonged hospitalization for a complication of therapy administration will
be reported as a SAE.

The
administration of blood
or
platelet transfusion.
Hospitalization or
prolonged
hospitalization for a complication of such transfusion remains a reportable SAE.

A procedure for protocol/disease-related investigations (eg, surgery, scans, endoscopy,
sampling for laboratory tests, bone marrow sampling, pharmacokinetic or biomarker blood
sampling). Hospitalization or prolonged hospitalization for a complication of such
procedures remains a reportable SAE.

Prolonged hospitalization for technical, practical, or social reasons in the absence of an AE.

A procedure planned before entry into the study (must be documented in the CRF).
Prolonged hospitalization for a complication considered to be at least possibly related to the
study drug remains a reportable SAE.
7.5.3 Pregnancy
All initial reports of pregnancy must be reported to PI within 24 hours of their knowledge of the
event. Abnormal pregnancy outcomes (eg, spontaneous abortion, stillbirth and congenital
anomaly) are considered serious adverse events and must be reported as a SAE. Any subject who
becomes pregnant during the study must discontinue further study treatment. Because the effect
of the study drug on sperm is unknown, pregnancies in partners of male subjects included in the
study will be reported by the study-site personnel within 24 hours of their knowledge of the
event. Follow-up information regarding the outcome of the pregnancy and any postnatal
sequelae in the infant will be required.

8.Trial termination / suspension criteria
8.1 Suspension criteria:

Serious safety issues arise in the test;

The research unit requests a suspension;

There are major errors in the trial protocol during the trial that made it difficult to evaluate
the safety and efficacy of the treatment;

The administrative department requests the suspension
8.2 Termination criteria:
All subjects can withdraw from the study at any stage of the trial, regardless of whether a reason
is provided. Subjects who withdraw from the study will not be discriminated against or retaliated
against for doing so, and their medical entitlements will not be affected. If the researcher
accidentally enroll the subjects who do not meet the inclusion criteria, the subjects should
immediately withdraw from the study after discovery, and inform the research unit or its
representative in time, and re-enroll the subjects as a substitute. In the absence of exceptional
circumstances, according to the judgment of the researcher, if the subject continues to
participate in the study, there will be a safety hazard that seriously threatens life and the subject
should be notified in time to withdraw from the study. In addition, subjects may withdraw from
discontinuation of treatment or from this study under the following conditions:

During the course of the trial, if a subject develops an intolerable AE or a clinically significant
laboratory outlier, at the discretion of the investigator, the subject may choose to withdraw
from the study and appropriate measures shall be taken with respect to him/her. At this
time the investigator should report to the research unit or its designee;

Subjects are reluctant to continue to participate in this study;

Subjects with poor compliance should withdraw from the study when they have a serious
impact on the safety and efficacy data analysis of the experiment;

Subjects should be withdrawn from this study when the investigator or research unit
discontinues this study for any reason;
If the subjects withdraw from the study after receiving BiTE treatment, they need to complete
the inspection items required to withdraw from the visit in the visit flow chart.
9.Data management
9.1 Data management

Researchers must ensure that the data is true, complete and accurate;

Any corrections to the test record should be made only by underlining, marginal notation of
the changed data, justification, signature and date by the investigator, and not by erasing or
overwriting the original record;

Laboratory examination items are complete.

9.2 Data recording
The data about the subjects on the case report form should be recorded by means of a subject
code, and the subjects should be identified only by the subject code or their initials.
9.3 Completion and transfer of case reports
The case report form is completed by the investigator and must be completed for each enrolled
case. The completed case report form is reviewed by the Clinical Research Associate and the first
copy is transferred to the data manager for data entry and management.
9.4 Data Entry and Modification
Professional data management unit is responsible for data entry and management. The data
management software was implemented to compile the data entry program for data entry and
management. In order to ensure the accuracy of the data, double entry and proofreading should
be carried out by two data administrators independently.
For the questions in the case report form, the data managers will have the Data Rating
Questionnaire(DRQ) and send questions to the researchers through the clinical monitors. The
researchers should answer and return as soon as possible. The data managers will modify,
confirm and input the data according to the researchers' answers, and can send DRQ again if
necessary.
9.5 Data Audit and locking
The main researchers, data administrators and statistical analysts confirm the statistical analysis
population, lock the database after solving all data questions, and sign the audit report at the
same time.
10.Statistical considerations
10.1
Sample size
This study is designed to evaluate the activity of Olverembatinib, Chidamide plus Blinatumomab
in adult Ph+ ALL, in terms of percentage of patients who achieve a CMR at 3 months. The
estimated ORR rate of ABC regimen in the treatment of Ph+ALL is about 95%. ; this percentage
was estimated on the basis of a pilot study. The number of patients required to demonstrate this
hypothesis with a power of 90% and a Type I error probability of 5%, and considering a 10%
drop-out, is 67
10.2 Analysis
Response achievement will be evaluated in terms of percentage of successful responses over all

eligible and evaluable patients enrolled in the study (following an Intention-To-Treat principle). All
AEs will be tabulated. All reported toxicities will be correlated with clinical outcome. Patients’
characteristics will be summarized by means of cross-tabulations for categorical variables or by
means of quantiles for continuous variables. In univariate analysis non-parametric tests will be
performed for comparisons between groups (Chi-Squared and Fisher Exact test in case of
categorical variables or response rate, Mann-Whitney and Kruskal-Wallis test in case of
continuous variables) and logistic regression will be performed in multivariate analysis to assess
the effect of clinical and biologic factors on CMR rate. OS will be defined as the time from
treatment start to death from any cause. DFS will be defined as the time from the achievement of
CHR to relapse, death, or date of last follow-up for patients alive in first CHR. CMR duration will
be defined as the time form the achievement of CMR to molecular relapse, death or date of last
follow-up for patients alive in first CMR. The OS, DFS and duration of CMR probabilities will be
estimated using the Kaplan-Meier method. CIR will be calculated from the achievement of CHR to
relapse or date of last follow-up for patients alive in first CHR, using the cumulative incidence
method and considering death in CHR as competing risk. Subgroups comparisons will be
performed for descriptive purposes. Differences in terms of OS, DFS duration of CMR will be
evaluated by means of Log-Rank test in univariate analysis and by means of the Cox regression
model in multivariate analysis, after assessment of proportionality of hazards. CIR will be
estimated by cumulative incidence curves using the proper non-parametric method. The Gray
test will be applied for significance tests on cumulative incidence curves. Median follow-up time
will be estimated by reversing the codes for the censoring indicator in a Kaplan-Meier analysis.
Confidence intervals will be calculated at 95% level and forest plots wil be used to summarize
differences among subgroups. All analysis will be performed using the SPSS software.
10.3 Safety analyses
Analysis of safety data will be conducted on the safety population, which includes all subjects
who receive at least 1 dose of study medication. This population will be used for all safety
analyses and all analyses of treatment compliance and exposure. All data will be analyzed
according to the treatment subjects actually received. The safety variables to be analyzed include
AEs, clinical laboratory tests (hematology and chemistry), physical examination results, ECGs, and
deaths. Safety variables will be tabulated by descriptive statistics (n, mean, median, standard
deviation, minimum, and maximum; or n and percent). No formal statistical testing is planned.
11.Study management
11.1 GCP
Regulatory organization and implementation of GCP:
1)Both drug registration applicants and researchers should adopt standard operating procedures
to implement the quality control and quality assurance system of clinical trials.
2)The original data must meet the GCP requirements of our country.
3)The laboratory test results must be accurate and reliable.
4)The observations and findings used was verified to ensure the reliability of the data.

5)Established a complete study organization and clarified the responsibilities of personnel at all
levels.
6)The main researchers were responsible for total quality control and carried out the duties of
personnel at all levels.
7)The main researchers were responsible for designing the study scheme, informed consent form,
and implemented it with the consent of the drug registration applicant. After the end of the study,
the main researchers wrote the summary report of the study.
8)The designated researcher was responsible for formulating the test implementation rules and
SOP used in the trial.
9)All participants was organized by the trial team before the study, and all the participants must
be trained by GCP.
10)Doctors and nurses participating in the trial should strictly abide by the provisions of the
scheme, proceed in accordance with the procedures, and were not allowed to change them at
will.
11) The designated statistician was responsible for the overall statistical processing of the data.
11.2 Privacy protection
All the data of the participants during the study were entered into the computer for confidential
storage and analysis, and if necessary, the relevant institutions may audit the records to confirm
the authenticity, accuracy and completeness of the data, and the data obtained from the study
may also be published in academic journals, but the names of the participants will not be
published and the privacy of the participants will be kept confidential.
We took additional precautions to ensure the confidentiality of documents and prevented the
identification of participants from genetic data. However, under special circumstances, some
people may see a participant 's genetic data and personal identification number. For example, in
the case of medical first aid, the sponsor, his doctor or researcher, may know the participant
identification number and has access to the participant 's genetic data. In addition, relevant
regulators require access to relevant documents.
11.3 Situations during study
1)Protocol amending: if the protocol is to be revised after it has been approved by the Ethics
Committee, a "statement of revision of the protocol" shall be drawn up and signed by the PI. The
protocol can be amended by approving of the PI and the drug registration applicant;
2)the amended protocol must be submitted to the ethics committee before being executed;
3)No one participating in the trial shall violate the protocol. In the event of a violation of the
protocol, it is necessary to write a description and notify the drug registration applicant, who has
the right to decide whether the trial will continue or not;
4)If the participant violates the protocol slightly, the researcher should promptly notify the
applicant for drug registration, discuss together, and deal with the violation and shedding of the
participant; a slight deviation that does not affect the safety of the participant or the integrity of
the trial scheme is called a mild violation.
5)Any adverse events (adverse event, AE) or serious adverse events (severe adverse event,SAE)
that occur during the trial will be reported and dealt with in accordance with the requirements of

the program and SOP.
11.4 Quality control and assurance
11.4.1 Quality assurance
The sponsor or the cooperative unit entrusted by the sponsor to be responsible for all or part of
the responsibilities and tasks related to this study(including CRO, SMO, statistical units, clinical
centers, etc.) should establish their own quality assurance systems, perform their respective
duties, strictly follow the clinical trial plan, and adopt corresponding standard operating
procedures to ensure the implementation of clinical trial quality control and quality assurance
system.
11.4.2 Quality assurance of clinical trial process
Before the start of the clinical trial, the researchers should receive the training of the trial scheme,
so that the researchers can have a well-grounded understanding of the clinical trial scheme and
the specific connotation of each indicator. Quality control personnel should check the basic
conditions of clinical trials to ensure that the conditions of clinical trials can meet the
requirements of the program. In the course of the trial, the researchers should conscientiously
carry out the clinical operation according to the requirements of the institutional SOP and the
trial plan, and record it in a true, timely, complete and standardized manner. The quality control
personnel check the quality of the test process and the corresponding original records. After the
experiment, the research unit collates the corresponding project documents, which are checked
and archived by the quality control personnel. The quality assurance department of the clinical
research unit conducts an enforceable inspection of the trial. When non-conformities are found,
promptly notify the researcher and the person in charge of the unit to make corrections, and
follow up the corrections.
11.4.3 Responsibilities of sponsor
The sponsor is responsible for initiating, applying for, organizing and providing funds for this
clinical trial. The sponsor submitted the application for clinical trial to the China Food and Drug
Administration in accordance with the provisions of China's GCP, The measure of Drug
Registration and other legal documents, and may also entrust contract research organizations
(CRO) to carry out some work and tasks in clinical trials.
The sponsor selected the institutions and researchers of the clinical trial and recognizes their
qualifications and conditions to ensure the completion of the trial.
When the sponsor provided experimental drugs to researchers, the management system and
recording system of experimental drugs were established.
11.4.4 Responsibilities of the researchers
The clinical study is conducted in accordance with the moral, ethical and scientific principles as
well as program design and regulation set out in the Helsinki Declaration and China's GCP.
The researchers are responsible for making medical decisions related to clinical trials to ensure

that participant s are treated in time when they develop AE during the trial. Researchers are
aware of the procedures and requirements for reporting SAE, and record and report these events
as required.
Researchers should put the data into eCRF accurately, completely, timely and legally, and accept
the supervision or inspection of sponsors, inspectors, inspectors dispatched by CRO, or drug
supervision and administration departments to ensure the quality of clinical trials.
11.4.5 Publication of research data
The sponsor has exclusive right to the data of this study. Except with the written consent of the
sponsor. With regard to manuscripts and publication, the sponsor has the final say.
12.Ethics
12.1 Ethics committee
Prior to the start of the trial, researchers are required to submit the researcher's manual, trial
scheme, informed consent, CRF and experimental drug test report (based on submission), as well
as any other information given to the participant s, to the ethics committee for approval. Any
changes to the study scheme must be approved by the Ethics Committee.
12.2 Informed consent
Qualified researchers must explain to each participant the nature, purpose, procedures, expected
time, potential risks and benefits, and any discomfort that may arise in the informed consent in
detail. Each participant must know that participation in the trial is voluntary and that he / she can
withdraw from the trial and his / her informed consent at any time without affecting his / her
subsequent treatment or relationship with the therapist.
The informed consent form should be given in a standard format and in non-professional
language as far as possible. Each informed consent must include all of the above and a voluntary
declaration. The informed consent form should be submitted to the Ethics Committee for
approval.
After explaining the basic contents of the trial, and the researchers have been convinced that
each participant who participates in the trial knows about the purpose of the trial, each
participant will be asked to sign his name and date on the informed consent form. Participants
should read and consider their statements before signing and dating, and an informed consent
form should be obtained and kept after signing. The participants were not allowed to enter the
test if the informed consent form was not signed without informed consent.
12.3 Other
When the participants are unable to participate in informed consent independently, there must
be a reliable fair witness or legal representative present in the whole process of informed
consent. The choice of fair witness or legal representative shall not infringe upon the participant
's right to confidentiality. After the participant 's oral consent, the fair witness or legal
representative should sign and date the informed consent form to prove that the information is

accurate.

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