an Single Center，Single Arm, Phase 3 Study to Evaluate Efficacy and Safety of PD-1 Inhibitor Combined With Azacytidine and HAG Regimen for Patients With Relapsed or Refractory Acute Myeloid Leukemia.
Phase: PHASE3
Conditions: Immunotherapy, Refractory Leukemia, Relapsed Adult AML, Acute Myeloid Leukemia
Sponsor: The First Affiliated Hospital of Soochow University

Study Protocol
PD-1 Inhibitor Combined With Azacytidine and
Homoharringtonine，Cytarabine, G-CSF for Refractory or
Relapsed AML
Vision 1.0
Dec. 20, 2020
ClinicalTrials.gov Identifier:
Principal Investigator
Yue Han, MD, PhD, hanyue@suda.edu.cn; Depei Wu, MD, PhD,
wudepei@suda.edu.cn. Jiangsu Institute of Hematology, The First Affiliated
Hospital of Soochow University, Suzhou 215006, China.

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Protocol version
Issue date
Vision 1.0
Dec. 20, 2020
Vision 1.0 (Dec. 20, 2020)
Applicable Section
Study center:
The First Affiliated Hospital of Soochow University, Suzhou 215006, China;
Protocol Summary
Study center
The First Affiliated Hospital of Soochow University, Suzhou 215006,
China;
Principal Investigator
Yue Han, MD, PhD; Depei Wu, MD, PhD.
Methodology
A prospective, single-arm, single-center, randomized clinical trial.
Primary objective
To assess the efficacy and safety of PD-1 inhibitor combined with
azacytidine and homoharringtonine，cytarabine, G-CSF for refractory
or relapsed AML .
Inclusion criteria
Chinese guidelines for the diagnosis and treatment of relapsed and
refractory acute myeloid leukemia (2017 edition)，excludes acute
promyelocytic leukemia (M3、APL);
Hematopoietic stem cell transplantation ≥3 months, Discontinue
immunosuppressant ≥3 weeks, Patients without graft-versus-host
disease;
Be at least 18 years of age on day of signing informed consent;
Have a performance status of less than or equal to 2 on the
Eastern Cooperative Oncology Group（ECOG）Performance
Scale;
Demonstrate adequate organ function as defined below, all
screening labs should be performed before treatment initiation：
1.
ALT(SGPT) less than or equal to 2.5 × Upper Limit of
Norma（ULN）；
2.
AST (SGOT) less than or equal to 2.5 × ULN；

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3.
Serum total
bilirubin Less than or equal to 2.0 ×
ULN;Note: If total bilirubin >2.0×ULN, subjects with Gilbert syndrome
records are allowed to join the group;
4.
Serum Creatinine ≥30 mL/min
5.
Total white blood cell (WBC) count ≤10,000/µL；Note:
hydroxyurea therapy is allowed to reduce white blood cells to meet this
inclusion criteria.white blood cells should be determined ≥24 hours after
the last hydroxyurea administration. Final hydroxyurea administration
should not ≤3 days prior to the first azacytidine administration.
Exclusion criteria
Patients with chronic myeloid leukemia，AML of other myeloproliferative
disorders Malignant neoplasms with other progression ;
Those who can not control severe infections and other underlying
diseases can not tolerate chemotherapy ;
Patients with cardiac insufficiency：ejection fraction (EF)<30%，New
York Heart Association（NYHA）standards，Cardiac insufficiency II or
above;
Patients with liver and kidney dysfunction：Serum bilirubin (SB)≥2mg/dl，
AST is 2.5 times higher than normal upper limit, serum creatinine (SCr) is
more than 2.5 mg/dl Serious mental illness uncooperative Refusal to join
the study;
Intervention
Azacytidine 75mg/(m2.d) by IV on days 1-7 of every cycle.
Anti-PD-1 mAb 200mg by IV on day 8 of every cycle.
Homoharringtonine(HHT) 2mg/(m2.d) by IV on days 1-6 of every cycle
Cytarabine 10mg/(m2.d) by SC on days 1-7 of every cycle Granulocyte
colony-stimulating factor(G-CSF) 300ug/d by SC on days 1-7 of every
cycle，until absolute neutrophil count(ANC) ＞5X109／L or white blood
cell（WBC）＞20X109／L.
Total number of patients: 30
Total duration of the study: 3 years

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Background
Acute myeloid leukemia (AML) is one of the most common
hematological malignancies, a malignant, clonal disease with poor
prognosis.The rate of complete remission (CR) was 60%-90% in patients with
first induction chemotherapy,10%~40% became refractory. 70% of AML
patients who received the first CR maybe relapsed in the first year after the
CR1.The 5 years total survival (OS) rate of refractory or relapsed AML (RR-
AML) was 5%~10%, and the CR rate was not more than 30% in
general2.there is still no unified treatment regimen for RR-AML , according to
Chinese guidelines for diagnosis and treatment (2017 Edition)3 and United
States National Integrated Cancer Network (NCCN)2019 edition AML clinical
practice guidelines standard4, they still emphasize individualized treatment
and salvage chemotherapy.Therefore, how to treat refractory or relapsed
acute myeloid leukemia is still an urgent clinical problem.
Many studies have shown that epigenetic changes such as DNA
methylation are common in AML and play an important role in the
transformation of myelodysplastic syndrome (MDS) to AML. Demethylation
drugs have become the first-line treatment of AML drugs.The azacytidine is a
5- azide analogues, which has dual mechanism of demethylation and
integrates into DNA and RNA to produce antitumor activity, approved by
Europe in 2008 and China in 2018 for treatment of AML with 20%~30% bone
marrow blast cells5-6.Chinese guidelines for the diagnosis and treatment of
relapsed and refractory acute myeloid leukemia (version 2017) 3
recommended demethylation drugs for patients with poor tolerance and
unsuitable for strong chemotherapy regimens.
Demethylation drugs have been reported to increase the sensitivity of
CAG、HAG and other chemotherapy regimens, thereby improving clinical
efficacy7-8.Homoharringtonine is a cell cycle specific alkaloid. There are
clinical studies showing that the CR rate of the homoharringtonine combined

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with CAG regimen is higher than the CAG regimen for RR-AML9.Based on
this study, azacytidine combined with HAG regimen was used to treat
refractory and relapsed patients.
Ørskov AD 10 found that MDS patients treated with demethylated drugs
(HMAs) lead to the demethylation of programmed death receptor 1(PD-1)
promoter in T cells.And then the expression of PD-1 increased in T cell
surface, and the combination of tumor cell surface PD-L1 hindered the anti-
tumor immune response.Therefore, this immune checkpoint upregulation also
provides strong evidence for the use of PD-1 or PD-L1 pathway inhibitors to
overcome tumor immune resistance. In a phase II clinical trial, PD-1 inhibitor
nivolumab combined with azacytidine treated 70 patients with recurrent AML11,
regimen：Azacytidine 75 mg/m2,d1-7;nivolumab3mg/kg,d1,d14;4-5w
treatment. The total response rate was 33%, patients treated with HMAs for
the first time was 58%, other patients was 22%. 11% incidence of immune-
related side effects at level 3-4.The median overall survival of all patients was
6.3 months, According to the institutional experience of MD Anderson Cancer
Center, it has advantages over azacytidine-based chemotherapy.
To improve the prognosis and survival of RR-AML patients, we propose
to conduct a prospective study to explore the efficacy and safety of PD-1
inhibitor combined with azacytidine and HAG regimen in the treatment of RR-
AML, and to study its related mechanisms.

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Reference
1.
Thol F, Schlenk RF, Heuser M, Ganser A. How I treat refractory and early
relapsed acute myeloid leukemia. Blood. 2015 Jul 16;126(3):319-27. doi:
10.1182/blood-2014-10-551911. Epub 2015 Apr 7. Review.
PubMed
ID: 25852056
2.
Price SL, Lancet JE, George TJ, Wetzstein GA, List AF, Ho VQ,
Fernandez HF, Pinilla-Ibarz J, Kharfan-Dabaja MA, Komrokji RS. Salvage
chemotherapy regimens for acute myeloid leukemia: Is one better? Efficacy
comparison between CLAG and MEC regimens. Leuk Res. 2011
Mar;35(3):301-4. doi: 10.1016/j.leukres.2010.09.002. Epub 2010 Nov
24.
PubMed ID: 21109304
3.
Tallman MS, Wang ES, Altman JK, Appelbaum FR, Bhatt VR, Bixby D,
Coutre SE, De Lima M, Fathi AT, Fiorella M, Foran JM, Hall AC, Jacoby M,
Lancet J, LeBlanc TW, Mannis G, Marcucci G, Martin MG, Mims A, O'Donnell
MR, Olin R, Peker D, Perl A, Pollyea DA, Pratz K, Prebet T, Ravandi F,
Shami PJ, Stone RM, Strickland SA, Wieduwilt M, Gregory KM; OCN,
Hammond L, Ogba N. Acute Myeloid Leukemia, Version 3.2019, NCCN
Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2019 Jun
1;17(6):721-749. doi: 10.6004/jnccn.2019.0028.
PubMed ID: 31200351
4.
Christman JK. 5-Azacytidine and 5-aza-2'-deoxycytidine as inhibitors of
DNA methylation: mechanistic studies and their implications for cancer
therapy. Oncogene. 2002 Aug 12;21(35):5483-95. Review.
PubMed
ID: 12154409
5.
Keating GM. Azacitidine: a review of its use in higher-risk myelodysplastic
syndromes/acute myeloid leukaemia. Drugs. 2009;69(17):2501-18. doi:
10.2165/11202840-000000000-00000. Review.
PubMed ID: 19911860
6.
Gao S, Li Z, Fu JH, Hu XH, Xu Y, Jin ZM, Tang XW, Han Y, Chen SN,
Sun AN, Wu DP, Qiu HY. Decitabine in the Treatment of Acute Myeloid
Leukemia and Myelodysplastic Syndromes, Which Combined with Complex
Karyotype Respectively. Asian Pac J Cancer Prev. 2015;16(15):6627-
32.
PubMed ID: 26434886
7.
Ørskov AD, Treppendahl MB, Skovbo A, Holm MS, Friis LS, Hokland M,
Grønbæk K. Hypomethylation and up-regulation of PD-1 in T cells by
azacytidine in MDS/AML patients: A rationale for combined targeting of PD-1
and DNA methylation. Oncotarget. 2015 Apr 20;6(11):9612-26.
PubMed
ID: 25823822
8.
Daver N, Garcia-Manero G, Basu S, Boddu PC, Alfayez M, Cortes JE,
Konopleva M, Ravandi-Kashani F, Jabbour E, Kadia T, Nogueras-Gonzalez

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GM, Ning J, Pemmaraju N, DiNardo CD, Andreeff M, Pierce SA, Gordon T,
Kornblau SM, Flores W, Alhamal Z, Bueso-Ramos C, Jorgensen JL, Patel KP,
Blando J, Allison JP, Sharma P, Kantarjian H. Efficacy, Safety, and
Biomarkers of Response to Azacitidine and Nivolumab in
Relapsed/Refractory Acute Myeloid Leukemia: A Nonrandomized, Open-
Label, Phase II Study. Cancer Discov. 2019 Mar;9(3):370-383. doi:
10.1158/2159-8290.CD-18-0774. Epub 2018 Nov 8.
PubMed ID: 30409776
9.
Ivanoff S, Gruson B, Chantepie SP, Lemasle E, Merlusca L, Harrivel V,
Charbonnier A, Votte P, Royer B, Marolleau JP. 5-Azacytidine treatment for
relapsed or refractory acute myeloid leukemia after intensive chemotherapy.
Am J Hematol. 2013 Jul;88(7):601-5. doi: 10.1002/ajh.23464. Epub 2013 May
30.
PubMed ID: 23619977
10. Itzykson R, Thépot S, Berthon C, Delaunay J, Bouscary D, Cluzeau T,
Turlure P, Prébet T, Dartigeas C, Marolleau JP, Recher C, Plantier I,
Stamatoullas A, Devidas A, Taksin AL, Guièze R, Caillot D, Vey N, Adès L,
Ifrah N, Dombret H, Fenaux P, Gardin C. Azacitidine for the treatment of
relapsed and refractory AML in older patients. Leuk Res. 2015 Feb;39(2):124-
30. doi: 10.1016/j.leukres.2014.11.009. Epub 2014 Nov 24.
PubMed
ID: 25524177
11. Santini V, Ossenkoppele GJ. Hypomethylating agents in the treatment of
acute myeloid leukemia: A guide to optimal use. Crit Rev Oncol Hematol.
2019 Aug;140:1-7. doi: 10.1016/j.critrevonc.2019.05.013. Epub 2019 May 25.
Review.
PubMed ID: 31153036

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Rationale of this study
Acute myeloid leukemia (AML) is one of the most common hematological
malignancies, a malignant, clonal disease with poor prognosis.there is
still no unified treatment regimen for RR-AML.
Demethylation drugs have been reported to increase the sensitivity of CAG、
HAG and other chemotherapy regimens, thereby improving clinical efficacy.
HMAs lead to the demethylation of programmed death receptor 1(PD-1)
promoter in T cells.And then the expression of PD-1 increased in T cell surface,
Therefore, this provides strong evidence for the use of PD-1 or PD-L1 pathway
inhibitors to overcome tumor immune resistance.
Study objectives
Primary objective and primary endpoint
Primary objective:
This study aims to validate the efficacy and safety of PD-1 inhibitor
combined with azacytidine and homoharringtonine，cytarabine, G-CSF for
refractory or relapsed AML
Primary endpoint:
Number of Participants (Responders) achieving CR+CRi+PR after the eighth cycle
treatments.
Secondary objectives and secondary endpoints:
Number of Participants (Responders) Achieving Overall Response Rate(ORR) After the
Eighth Cycle Treatments;time from randomization to death from any cause;The time
between the beginning of the group and the occurrence of any event, including death,
progression of the disease, chemotherapy regimen, conversion to chemotherapy, addition
of other treatment, occurrence of fatal or intolerable side effects, etc;Time between the
beginning of randomization and the progression (in any way) of tumorigenesis or (for any
reason) death
Research design

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Type of study
This is a prospective, single-arm, single-center randomized clinical trial.
Experimental diagram
The overall design of the study is shown in Figure 1.
refractory or relapsed AML
Eligibility for
enroll
END
NO
YES
AZA+PD-1 inhibitor+HAG
CR/CRi+PR+HI
NR
assessment after two cycles
AZA+PD-1 inhibitor,
2 cycles
Continuation or
withdrawal
CR/CRi
PR+HI+NR
AZA+PD-1 inhibitor
to the end

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Figure 1. The flow chart of the overall study design
Dosage and administration
Treatment:
Azacytidine 75mg/(m2.d) by IV on days 1-7 of every cycle;
PD-1 inhibitor 200mg by IV on day 8 of every cycle;
Homoharringtonine(HHT) 2mg/(m2.d) by IV on days 1-6 of every cycle
Cytarabine 10mg/(m2.d) by SC on days 1-7 of every cycle Granulocyte
colony-stimulating factor(G-CSF) 300ug/d by SC on days 1-7 of every
cycle，until absolute neutrophil count(ANC) ＞5X109／L or white blood
cell（WBC）＞20X109／L.

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Study process
Screening phase (3 days)
Inclusion /Exclusion Criteria
Demographic data: age, sex, nationality, address, spouse's characteristics,
contact information.
Physical examination: height, body weight, blood pressure, body
temperature, heart rate, body surface area, respiratory and cardiovascular
system examination, nervous system examination, Eastern Cooperative
Oncology Group (ECOG) score, etc.
Laboratory examination:
Blood analysis: blood routine test, blood biochemistry
BM examination: marrow morphology examination, Flow cytology,etc.
Treatment period (28 days)
Drugs will be given based on the protocol;
Blood routine test and blood biochemistry are performed once a day and
once a week, respectively;
T Cellular Subjects and PD-1 are performed before AZA;
Important vital signs are recorded;
Adverse events will be recorded and managed according to this protocol.
Termination phase
Demographic data: age, sex, nationality, address, spouse's characteristics,
contact information.
General information: past history, allergic history, previous disease and
status.

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Physical examination: height, body weight, blood pressure, body
temperature, heart rate, body surface area, respiratory and cardiovascular
system examination, nervous system examination, ECOG score, etc.
Laboratory examination:
Blood analysis: blood routine test, blood biochemistry,
T Cellular Subjects and PD-1 are performed ;
Bone marrow examination: marrow morphology examination, flow
cytology.
Follow-up phase (6 months)
Routine blood examination will be repeated once every 1 month;
The changes of other complications;
Survival will be long-term recorded until death.
Response evaluation
Response: According to the 2020 NCCN guidelines.
Safety evaluations
Safety and tolerability are assessed throughout the study.

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Safety endpoints
White blood cell count, hemoglobin, liver function, renal function.
Clinical symptoms:
Newly occurred symptoms during the study period: fever, nausea, cough,
somnolence, depression, constipation, diarrhea, petechia, edema, pharyngitis,
pulmonary edema, atrial fibrillation, tachycardia, mycobacterium avium
complex infectious, hyperglycemia，neutropenia, anemia.
Laboratory examination
Blood routine test, blood biochemistry, virological testing, electrocardiogram,
etc.
Adverse event
Definition and record of an adverse event
Adverse events are defined as any harmful medical manifestations occurring
in a person who participates in a biomedical research whether this
manifestation is related to the research or the product used in the research.
An adverse effect may be any unfavourable or unexpected sign (including
abnormal laboratory results), any symptom or temporary disorder associated
with the use of the product, with or without relation to the product.
The clinically significant abnormality must be reported as an adverse event
(AE) in the eCRF, and AE is supposed to record the time of occurrence, the
stage of severity, the duration of time, measures and outcomes.
Classification of adverse event severity
Every case report is performed by the grade of severity about drug adverse
reactions：
Mild: usually transient symptoms unaffecting the daily life;

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Moderate: symptoms probably affecting the daily life;
Severe: symptoms seriously affecting the daily life.
Relevance
Definite relevance: The adverse event is clearly related to the
investigational agent. For example, an event that follows a reasonable
temporal sequence from administration of the study intervention abides by
a known or expected response pattern to the suspected intervention, which
improves by stoppage and reappears through repeated exposures, but is
unable to be reasonably explained by the known characteristics of the
subject’s clinical state;
Possible relevance: An adverse event that follows a reasonable temporal
sequence from administration of the study intervention abides by a known
or expected response pattern to the suspected intervention, which can be
easily induced by various other factors;
Irrelevance: The adverse event is clearly uncorrelated with the research
agent or procedure. For example, there exists another plausible cause,
and/or a clinically plausible temporal sequence is inconsistent with the
onset of the event and the study intervention and/or a causal relationship is
considered biologically implausible.
Serious adverse event:
A serious adverse event (SAE) event is defined as the event with one of the
following consequences:
Death;
Life-threatening condition;
Hospitalization or extension of hospitalization;
Temporary or permanent disability;
Congenital anomaly or malformation;

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Important medical events: although the event caused by the drug which
may endanger the subjects may not be life-threatening and result in death
or require hospitalization, medical or surgical intervention requires to be
taken to prevent one of the outcomes based on the appropriate medical
judgment.
Definition of an unexpected adverse event:
An unexpected adverse event of the product is defined as the event with the
nature, severity or course non-corresponding to the product information
mentioned in the summary when it is authorized or in the investigator's
brochure when it is not authorized.
Expected adverse events:
Due to myelosuppression
Neutropenia related infections, fever;
Bleeding: ecchymosis, petechial, haematemesis, hemoptysis, melena,
hematuresis, etc;
Weary, somnolence, pale, etc (due to anemia);
Due to other non-hematological toxicity
Liver dysfunction;
Renal dysfunction;
Related to the haematological disease
Death
Relapse of any kind
Related to drug allergy
Erythra, edema, pruritus, swelling, etc.
Procedures of all adverse event
Investigators must immediately take necessarily measures at once to protect
subjects’ safety, when serious adverse events occur. Furthermore, all adverse

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events should be followed up and investigated, and detailed records are
supposed to be made and signed.
All serious and non-serious AEs and special situation will be reported from the
signature to completion of the subject’s last study-related procedure (which
may include the follow-up contact for safety). SAEs must be reported using
the Serious Adverse Event Form. The sponsor will evaluate any safety
information that is spontaneously reported by an investigator beyond the time
frame specified in the protocol.
All AEs, regardless of the severity or presumed relationship with the study
treatment, must be recorded in the source document and eCRF using medical
terminology. Whenever possible, diagnosis should be made when signs and
symptoms are caused by the common etiology. Investigators must record
their opinions on the relationship between AEs and the study treatment in the
eCRF. All measures required for (serious) AEs must be recorded in the
source document and reported according to sponsor instructions.
Monitoring committee
A safety committee comprised of 3 persons independent of the trial will be
organized and will meet to check the safety related to the study treatment
during the study. In terms of the overall mortality of each arm and serious
adverse events, review will be performed by the independent safety
committee. The committee is responsible for
haemovigilance/pharmacovigilance of the study and acts as an additional
warning sign against haemovigilance/pharmacovigilance of the study.
Contact
Yue Han (Email: hanyue@suda.edu.cn), Depei Wu (wudepei@suda.edu.cn),
The First Affiliated Hospital of Soochow University, Suzhou 215006, China.
Statistical methods

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Statistical analysis will be done by the sponsor or under the authority of the
sponsor. A general description of the statistical methods to be used to analyze
the efficacy and safety data is outlined below. Baseline for all analyses will be
the day of randomization unless otherwise specified.
Sample size estimation
We used the formula of sample size estimate when comparing the
independent rates two groups.
α=0.05, bilateral test
Statistical analysis
Kaplan- Meier method was performed to estimate the 1-year survival rate
Procedures
All initial PQCs must be reported to the sponsor by the investigational staff
within 24 hours after being made aware of the event.
If the defect is combined with an SAE, the investigational staff must report the
PQC to the sponsor according to the SAE reporting timelines. A sample of the
suspected product should be maintained for further investigation if requested
by the sponsor.
Ethical statement
Ethical principles
The study should be carried out in accordance with Helsinki declaration
proposed by World Medical Association and subsequent amendments and
approved by the Independent Ethics Committee (IEC) before implementation.
AZA
CR/CRi
PD-1+AZA+HAG
CR/CRi
Testing
effectiv
eness
18%
38.5 %
80 %

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Information and informed consent
All the patients who agree to participate should be asked to sign the
informed consent form to prove their approval for participation in this study.
The informed consent form must be signed and dated personally by the
patients and investigators.
Before obtaining the informed consent, the investigators must provide
sufficient information to the patients who are potential participants in this
study:
The investigators should orally inform the patients of all the relevant
circumstances of this study;
The information provided to patients must be fully and easily understood by
non-professionals, so that they can make a decision according to their own
willingness based on their full understanding of this study;
Additionally, the patients voluntarily participate in the study, and are free to
quit from the study at any time, without any reasons. The subsequent
treatment of patients is not under the influence of unwilling to participate or
quitting from the study.
All the patients who agree to participate should be asked to sign the
Informed Consent Form (ICF) to prove their approval for participation in this
study. The ICF must be signed and dated personally by the patients and
the investigators;

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The signed ICF will be kept in the Data Center and must be safely kept for
future review at any time throughout the study.
Withdrawal from the study
The main withdrawal criteria are as following:
Changes in the patient’s condition after inclusion, which suggests that the
study protocol is unsuitable for the patient;
Severe complications affecting the implementation of the study treatment;
Patients who are confirmed to require emergency treatment due to other
diseases after inclusion;
Treatment unmated with the study protocol;
Patients who voluntarily quit or discontinue any examination, treatment and
monitoring required by the study for personal reasons at any stage after
inclusion in this study. The PI also has the right to withdraw patients from
the study if he/she feels that the withdrawal is in the best interests of the
patients.
Identity and privacy of patients
After obtaining an ICF, each enrolled patient is assigned a subject number
(allocation number). This number will represent the identity of the patient
during the study and for the retrieving of dedicated clinical research
database;
Throughout the study, several measures will be taken to minimize any
breaches of personal information, including:
Only the PI and co-investigators will be able to link to the research data of
the patients to themselves through the identifiable table after authorization;
Collection, transmission, handling and storage of the study data must
comply with the data protection and privacy regulations.

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Responsibility of independent ethics committee
The responsibilities of independent ethics committee include:
Review of this study;
Evaluate this study to determine if risks to which patients are exposed have
been duly minimized and whether these risks are reasonable compared to
expected benefits;
Check the study protocol and relevant documents (patient information
sheet, ICF, CRF, etc.) submitted by the Research Committee before
beginning of the study;
Provide the written proof of ethical review opinions, the written proof of the
date of the review meeting, the written proof of the members presenting at
the meeting and voting members, the written proof of recording of the
reviewed versions of study protocol, ICF and other related documents, and
if possible, a copy of the minutes, to the Research Committee. The study
can begin only after obtaining the written proof of favorable
opinions/approval of the IEC;
Supervise the legitimacy of the process of informed consent;
Ensure the safety of patients during the research process by examining the
reported safety information. The investigators should report to the IEC on
any therapeutic complications which may affect the safety of patients.
When complications that affect the patient safety occur, the IEC should
inform PI to withdraw patients from the study and use any possible
treatment to cure patients. If the PI decides not to withdraw patients from
the study, he should provide a written proof of explanation to the IEC;
Review the reasonableness of the costs incurred by patients in the course
of the study through a selective check for hospitalization expenses. When
the patient has indications for off-label use of drugs, the IEC will receive the
notice and the description of relevant situation from the investigators. The
IEC should record the relevant records;

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Review the revisions of the study protocol, and any changes must be
approved by the IEC before they are adopted. Unless the change is
necessary to eliminate an immediate hazard to the patients, in which case
the IEC should be informed as soon as possible;
Review the progress of the study annually and the close-out report
submitted by the Research Committee at the end of the trial.
Responsibility of investigator
The responsibilities of investigators are as follows:
Investigators, participated in the clinical trial, should be obtained certificate
for assistant practicing doctor, resigned and attended the training of the
GCP guidelines and the correlation of laws and regulations, possessed
specialty, qualification and ability in clinical trial.
Subjects are adequately recruited by the investigator during required time
according to the clinical trial，and operation capacity and possibility to be
qualified the item should be evaluated by the previous working experience.
Investigators are familiar with clinical trial protocols and execute instruction
strictly according to the protocols and case report form.
In all adverse events, subjects must be taken appropriate therapies and
made a contact with the investigator as soon as possible. Investigators will
take responsibilities of relevant medical decision of clinical trial to ensure
subjects that is taken adequate medical treatment.
Any information on the case report form possesses original data, to ensure
the case history and case report form filled in truly, accurately, completely，
timely, regularly and legally.
Subjects will be illustrated the relevant situation where the clinical trial is
fully consent by Ethics Committee. The informed consent will be acquired
and, during the process, it must meet the specification.

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Supervision and inspection will be received by supervisor and inspector
assigned by sponsor to ensure the quality of clinical trial.
Any advices and suggestions focused on the study protocols might be
submit to the principal institution of clinical research, and made a
discussion with sponsor and coordination institutions to decide whether
adopting the above advice or suggestions, during the clinical trial executed
by each institutions.
Publications
All the data collected during this study are the property of the study sponsor
and cannot be communicated in any case to a third party without the written
agreement of the investigator.
Any publication or communication (oral or written) will be decided from a
common agreement between the investigators and will respect the
international recommendations: "Uniforms Requirements for Manuscripts
Submitted to Biomedical Journals"
(http://www.cma.ca/publications/mwc/uniform.htm): notably, an authorship
will be proposed to each clinical center participating in the study and to
each member of the steering committee according to his/her actual
participation.
Organization and responsibility
The Research Committee is responsible for developing study protocol, auditing
patient eligibility and guiding interpretation of informed consent. It is also
responsible for collection of complication reports, guiding diagnosis and
treatment
of
complications
and
emergency
intervention
for
serious
complications, as well as approving the content and distribution of all
publications related to the study.

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Appendix
Appendix 1. ECOG score
Appendix 2. NCCN Guidelines Version 2.2020 Acute Myeloid Leukemia
Appendix 3. Patient consent form for study participation

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Appendix 1. ECOG score*
Grade
Performance status
0
Fully active, able to carry on all pre-disease performance without
restriction.
1
Able to move freely and take mild physical activity, such as
housework and office work, but restricted in severe physical activity.
2
Able to move freely and take care of himself, but loss of work
capability; doing activities for more than half of the waking hours.
3
Capable of taking care of himself partially, confined to the bed or chair
for more than half of the waking hours.
4
Completely disabled, unable to take care of himself and totally
confined to the bed or chair.
5
Dead
Notes: ECOG=Eastern Cooperative Oncology Group; * Oken M, Creech R, Tormey D, et al.
Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol.
1982;5:649-655.

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Appendix 2.NCCN Guidelines Version 2.2020 Acute Myeloid Leukemia

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Appendix 3: Patient consent form for study participation
Title: Low-dose decitabine for refractory prolonged isolated
thrombocytopenia after hematopoietic cell transplantation
Investigator OR
institution Name
Study Site
Patient Name
Please tick each box below if you have known the corresponding
statement.
(to be completed by the patient)

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What you should know about a research study
Someone will explain this research study to you.

A research study is something you volunteer for.

Presence or absence of participation in the research study is up to you.

You can choose not to take part in the research study.

You can agree to take part now and later change your mind.

Whatever you decide it will not be held against you.

You can feel free to ask all the questions that you want before you decide .
What is the purpose of this study?
Acute
myeloid
leukemia
(AML)
is
one
of
the
most
commonhematological malignancies, a malignant, clonal disease with poor
prognosis.The rate of complete remission (CR) was 60%-90% in patients
with first induction chemotherapy,10%~40% became refractory. 70% of AML
patients who received the first CR maybe relapsed in the first year after the
CR1.The 5 years total survival (OS) rate of refractory or relapsed AML (RR-
AML) was 5%~10%, and the CR rate was not more than 30% in
general.there is still no unified treatment regimen for RR-AML.The immune
checkpoint inhibitor (ICB) PD-1 can overcome the immune tolerance of
tumor cells. It has advantages over azacytidine-based chemotherapy.
Demethylation drugs have been reported to increase the sensitivity of CAG、HAG
and other chemotherapy regimens, thereby improving clinical efficacy.
To improve the prognosis and survival of RR-AML patients, we propose
to conduct a prospective study to explore the efficacy and safety of PD-1
inhibitor combined with azacytidine and HAG regimen in the treatment of RR-
AML, and to study its related mechanisms.
Why have I been chosen?
We are inviting patients who
Chinese guidelines for the diagnosis and treatment of relapsed and
refractory acute myeloid leukemia (2017 edition)，excludes acute
promyelocytic leukemia (M3、APL);
Hematopoietic stem cell transplantation ≥3 months, Discontinue
immunosuppressant ≥3 weeks, Patients without graft-versus-host
disease;
Do I have to take part?
Participation in the study is entirely voluntary.
You will be given sufficient time to consider whether you want to
participate in the study.
Non-participation in the study will not affect your future care that you

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will receive from your medical and nursing team in our hospital.
If you decide to join the study, you will be asked to sign an informed
consent form.
You are free to withdraw from this research at any time and without
giving a reason. Any of your current medical care and future
treatment in our hospital will not be affected.
What will happen to me if I take part?
All patients who agree to take part and provide a written informed
consent form will be included into this study.
You will be treated with Azacytidine 75mg/(m2.d) by IV on days 1-7 of
every cycle. Anti-PD-1 mAb 200mg by IV on day 8 of every
cycle.Homoharringtonine(HHT) 2mg/(m2.d) by IV on days 1-6 of
every cycle Cytarabine 10mg/(m2.d) by SC on days 1-7 of every cycle
Granulocyte colony-stimulating factor(G-CSF) 300ug/d by SC on days
1-7 of every cycle，until absolute neutrophil count(ANC) ＞5X109／L
or white blood cell（WBC）＞20X109／L.
Your doctors will introduce the detailed treatment procedures to you.
You are free to ask any question about the treatments you may have.
How long will I be in the study
If you participate in this study, you will receive 1 therapy for 4 weeks.
Follow up will continue indefinitely, for as long as 8 months or longer.
You can stop participating at any time. However, if you decide to stop
participating in the study, we encourage you to talk to the researcher
and your regular doctor first.
What are the risks of the study?
Potential adverse event of azacytidine includes:
Myelosuppression:
Neutropenia related infections, fever;
Bleeding: ecchymosis, petechial, haematemesis, hemoptysis, melena,
hematuresis, etc;
Weary, somnolence, pale, etc (due to anemia);
Other non-hematological toxicity:
Liver dysfunction; Renal dysfunction;
Drug allergy
Erythra, edema, pruritus, swelling, etc
Potential adverse event of PD-1 inhibitor includes:
immune-related adverse events (irAEs). Such as rash, pruritus,
diarrhea, pneumonia, liver and kidney function damage, endocrine
dysfunction, etc.
Others:
There also may be other unexpected complications or discomforts
that we cannot predict.

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Your doctors will do their best to prevent complications and to treat
them if occur. You will receive the best medical care available during
and after the study and in the unlikely event of an injury arising from
taking part in this study, you will be provided with the necessary care.
Are there benefits you to taking part in the study?
You’ll get free treatment of 2 cycles PD-1 inhibitor and related test
(e.g., immune function, PD-1/PD-L1 expression, cytokines,
etc).Patients will receive 100 RMB travel subsidy for each follow-
up.Another possible benefit you may experience from this research
includes prolongation of survival time. However, there is no guarantee
that each patient will benefit from the treatment in this research.
Furthermore, the results obtained from this study may be useful in
guiding the treatment for patients with such disease in the future.
What are my responsibilities in this study?
If you choose to take part in this study, you will need to:
Keep your study appointments.
Tell your doctor about:
All medications and supplements you are taking;
Any discomforts or complications you suspect;
Any doctors’ visits or hospital stays outside of this study;
Whether you have been or are currently in another research study.
How will my privacy be protected?
Your health information, such as your response to cancer treatment,
results of study tests, and medicines you took, will be kept by the data
center of this research. This information is strictly confidential.
However, your name and contact information will not be put in the
database. If information from this study is published or presented at
scientific meetings, there will be no personally identifiable information.
What happens if I change my mind during the study?
We would certainly recommend that you continue the study, however,
participation in the study is voluntary and you may stop the
participation at any time that you wish without losing any of your rights
as a patient here. Your treatment at our hospital will not be affected in
any way. The PI of this study also has the right to withdraw patients
from the study if he feels that the withdrawal is in your best interests.
Your follow-up information will still be kept by doctor after you have
stopped participating in the research.
Who is organizing the research?

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The study is organized by the The First Affiliated Hospital of Soochow
University, Suzhou 215006, China.
Whom do I call if I have questions or problems?
For information about your disease and research-related injury, you may
contact:
Name (institution) :
Telephone Number:
For information about this study, you may contact:
Name (institution) :
Telephone Number:
For information about your rights as a research subject, you may
contact: Name (institution) :
Telephone Number:

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Signature page
I have read all the above, asked questions, and received answers
concerning areas I did not understand. I have had the opportunity to take
this consent form home for review or discussion.
I willingly give my consent to participate in this program. Upon signing this
form I will receive a copy. I may also request a copy of the protocol (full
study plan).
Patient
signature
Name
(print)
Date
signed
Investigator (institution) Statement and Signature
to be completed by the person taking consent
I have discussed this clinical research study with the patient and/or his or
her authorized representative using a language that is understandable and
appropriate. I believe that I have fully informed the participant of the nature
of this study and the possible benefits and risks of taking part. I believe the
participant has understood this explanation.
Investigator OR
institution signature
Name
(print)
Date
signed