A Biomarker-Directed Phase 2 Trial of SY-1425, a Selective Retinoic Acid Receptor Alpha Agonist, in Adult Patients With Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS)
Phase: PHASE2
Conditions: Acute Myeloid Leukemia, Myelodysplastic Syndrome
Sponsor: Syros Pharmaceuticals

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
Amendment 7 (31 August 2022) 
Confidential 
Page 1 of 141 
STUDY PROTOCOL 
SY-1425-201 
Protocol Title: 
A Biomarker-Directed Phase 2 Trial of SY-1425, a Selective Retinoic 
Acid Receptor Alpha Agonist, in Adult Patients with Acute Myeloid 
Leukemia (AML) or Myelodysplastic Syndrome (MDS) 
Protocol Number: 
SY-1425-201 
Phase:  
2 
Study Drug:  
SY-1425 (tamibarotene), azacitidine, and daratumumab 
IND number:  
129755 
EudraCT number: 2017-000783-14 
Date of Protocol:  
 31 August 2022 (Amendment 7) 
Version History 
Amendment 6: 
29 March 2019 – France only 
Amendment 5: 
25 April 2018 
Amendment 4: 
25 September 2017 – USA Only 
Amendment 3: 
07 July 2017 
Amendment 2: 
20 March 2017 
Amendment 1: 
23 August 2016 
Original:  
18 March 2016 
Sponsor: 
Syros Pharmaceuticals, Inc. 
35 CambridgePark Drive, 4th Floor 
Cambridge, MA 02140 
USA 
Not for Distribution – Do Not Copy 
This study protocol contains confidential information and is the proprietary property of Syros 
Pharmaceuticals, Inc. The protocol is for use by the Principal Investigator and his/her designated 
representatives participating in this investigational trial. This protocol may not be copied or made 
available for review by an unauthorized person or firm without the prior written authorization of 
Syros Pharmaceuticals. 
NCT #: NCT02807558

PROTOCOL SY-1425-201 
 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022) 
 Confidential  
Page 2 of 141 
INVESTIGATOR PROTOCOL APPROVAL 
 
I agree to the terms of this study protocol. I will conduct the study according to the procedures 
specified herein, and according to principles of Good Clinical Practice and local regulations and 
requirements. 
 
Institution/Clinic:  ___________________________________________ 
 
Principal Investigator 
 
Print Name:  ______________________________________ 
 
Signature:  
______________________________________ 
 
Date (mm/dd/yyyy):    ______________________________ 
 
 

PROTOCOL SY-1425-201 
 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022) 
 Confidential  
Page 4 of 141 
CONTACT INFORMATION 
 
Sponsor:  
Syros Pharmaceuticals, Inc. 
35 CambridgePark Drive, 4th Floor 
Cambridge, MA 02140 
USA 
 
 

PROTOCOL SY-1425-201 
 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022) 
 Confidential  
Page 5 of 141 
PROTOCOL SYNOPSIS 
Study Title: 
A Biomarker-Directed Phase 2 Trial of SY-1425, a Selective Retinoic Acid Receptor Alpha 
Agonist, in Adult Patients with Acute Myeloid Leukemia (AML) or  
Myelodysplastic Syndrome (MDS) 
Protocol Number: 
SY-1425-201 
Phase: 
2 
Name of Study Drugs: 
SY-1425, azacitidine, and daratumumab 
Study Population: 
• Relapsed and/or refractory non-acute promyelocytic leukemia (APL) acute myeloid 
leukemia (AML) patients who have failed to achieve a complete remission (CR) or 
partial remission (PR) following standard induction therapy, or have relapsed after 
any duration of CR or PR  
• Relapsed and/or refractory higher-risk Myelodysplastic Syndrome (MDS) 
(High/Very High Risk, as defined by the Revised International Prognostic Scoring 
System [IPSS-R]) patients that have failed to achieve a CR or PR, or any 
hematologic improvement (HI, per International Working Group [IWG] 2006 
criteria) after standard therapy with hypomethylating agents (eg, azacitidine, 
decitabine), or have relapsed after any duration of CR, PR, or HI  
• Newly diagnosed, treatment-naïve non-APL AML patients who, at the time of study 
entry, are unlikely to tolerate standard intensive chemotherapy due to age, 
performance status, or comorbidities. (Referred to as Newly Diagnosed Unfit AML) 
• Transfusion dependent lower-risk MDS patients without the del 5q abnormality who 
are refractory to erythropoietin treatment or unlikely to respond to erythropoietin 
(EPO) treatment (EPO >500). (Referred to as Transfusion Dependent Lower-Risk 
MDS). Lower-risk MDS: Very Low/Low/Intermediate Risk, as defined by IPSS-R. 
Red blood cell (RBC) transfusion dependent anemia defined as no 8 consecutive 
weeks without RBC transfusions within the 16 weeks prior to study entry, or ≥4 
RBC transfusions within the 8 weeks prior to study entry. 

PROTOCOL SY-1425-201 
 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022) 
 Confidential  
Page 6 of 141 
Number of Patients: 
Approximately 162 response evaluable patients will be enrolled into 6 arms:  
• Arm 1 (n = ~ 25 biomarker positive patients): Relapsed and/or refractory non-APL 
AML patients and relapsed and/or refractory higher-risk MDS patients. 
• Arm 2A (n = ~ 25 biomarker positive patients) and Arm 2B (n = ~ 50 patients; ~ 25 
biomarker positive and ~ 25 biomarker negative): Newly diagnosed, treatment-naïve 
non-APL AML patients who, at the time of study entry, are unlikely to tolerate 
standard intensive chemotherapy due to age, performance status, or comorbidities. 
Arm assignment is determined by Investigator choice of treatment. 
− Patients in Arm 2A will receive SY-1425 as a single agent   
− Patients in Arm 2B will receive SY-1425 in combination with azacitidine 
• Arm 3 (n = ~ 25 biomarker positive patients): Transfusion dependent lower-risk 
MDS patients without the del 5q abnormality who are refractory to erythropoietin 
treatment or unlikely to respond to erythropoietin treatment (EPO > 500 mU/mL). 
• Arm 4 (n = ~ 12 biomarker positive patients): Relapsed and/or refractory non-APL 
AML patients, relapsed and/or refractory higher-risk MDS patients.   
• Arm 5 (n = ~ 25 biomarker positive patients): Relapsed and/or refractory non-APL 
AML patients who will receive SY-1425 in combination with azacitidine.  
Biomarker positive patients are defined as patients positive for the RARA super-enhancer 
associated biomarker and/or the IRF8 biomarker. Arms 1, 2A, 2B, 3, and 5 will include 
approximately 20 patients who are positive for the RARA super-enhancer associated biomarker.  
There is no minimum requirement for RARA super-enhancer associated biomarker patients in 
Arm 4. 
Study Objectives: 
Primary Objectives  
• Characterize the clinical activity of SY-1425 in biomarker positive patients by the 
overall response rate (ORR) in patients in Arms 1, 2A, 2B, and 5, and by the 
transfusion independence rate (TIR) in patients in Arm 3  
• Characterize the safety and tolerability of the combination of SY-1425 and 
daratumumab in Arm 4 
Secondary Objectives 
• Characterize the clinical activity of SY-1425 in patients positive for the RARA super-
enhancer associated biomarker by the ORR in Arms 1, 2A, 2B, and 5, and by TIR in 
Arm 3 

PROTOCOL SY-1425-201 
 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022) 
 Confidential  
Page 7 of 141 
• Characterize the clinical activity of SY-1425 in patients positive for the IRF8 
biomarker and negative for the RARA super-enhancer associated biomarker by the 
ORR in Arms 1, 2A, 2B, and 5, and by TIR in Arm 3 
• Characterize the clinical activity of the combination of SY-1425 and azacitidine by 
the ORR in patients in Arm 2B  
• Characterize the clinical activity of the combination of SY-1425 and daratumumab 
by ORR in Arm 4  
• Characterize the clinical activity by patients in Arms 1, 2A, 2B, 3, 4, and 5, based on 
event-free survival (EFS), relapse-free survival (RFS), duration of response (DOR), 
overall survival (OS), hematologic improvement (HI) 
• For all patients, evaluate the requirement for supportive measures secondary to 
cytopenias 
• Characterize the safety and tolerability of SY-1425 as a single agent in Arms 1, 2A, 
and 3, in combination with azacitidine in Arms 2B and 5. 
• Characterize the pharmacokinetics (PK) of SY-1425 after single and multiple doses 
Exploratory Objectives  
• Assess factors associated with the ORR, including but not limited to arm and diagnosis, 
prior treatment, RARA super-enhancer associated biomarker and/or IRF8 biomarker 
status, dehydrogenase/reductase (SDR family) member 3 (DHRS3) induction, myeloid 
differentiation, induction of CD38 expression and other potential predictors of success 
including genotype and mutation status 
• Evaluate changes in Health-Related Quality of Life (HRQOL)  
• Establish PK/PD relationships based on PD markers in leukemic cells from repeat 
peripheral blood samples 
• Characterize the PK of daratumumab in combination with SY-1425 
• Characterize the relationship between SY-1425 activity and baseline tumor biomarker 
levels, and levels over time (RARα mRNA or IRF8 mRNA) 
• Characterize clinical activity of SY-1425 administered as a single agent and in 
combination with azacitidine or daratumumab by time-to-response  
• Characterize expression of myeloid differentiation markers, including CD38, over time 
• Explore the potential role of additional gene or protein alterations (e.g. expression or 
mutation) in sensitivity and/or resistance to SY-1425 using multiplex platform(s)  
Study Design:  
This is a Phase 2, multi-center, open-label study exploring the activity of SY-1425 in patients 
with relapsed or refractory non-APL AML, or higher-risk MDS, newly diagnosed 
treatment-naïve patients with non-APL AML, who are unlikely to tolerate standard intensive 

PROTOCOL SY-1425-201 
 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022) 
 Confidential  
Page 8 of 141 
chemotherapy at the time of study entry, and patients with transfusion dependent, lower-risk 
MDS. All patients must be evaluated for the RARA super-enhancer associated biomarker or the 
associated IRF8 biomarker at the time of the study screening evaluation, as determined in 
peripheral blood using an investigational assay. Patients will accrue to each of the six arms 
based on diagnosis (AML, MDS), prior treatment (relapsed/refractory, newly diagnosed 
treatment-naïve unfit AML patients), risk group (higher-risk MDS, lower-risk MDS transfusion 
dependent), and Investigator choice of treatment (SY-1425 single agent, or in combination with 
azacitidine or daratumumab). SY-1425 will be administered at 6 mg/m2/day orally (PO) in two 
divided doses, which corresponds to the dose approved in Japan for use of tamibarotene in 
patients with relapsed/refractory APL. SY-1425 will be given on a 28-day treatment cycle.  
• Arms 1, 2A, and 3: SY-1425 will be administered as a single agent and dosing will be 
continuous. 
• Arms 2B and 5: Azacitidine will be administered at 75 mg/m2 (intravenously or 
subcutaneously) on Days 1 through 7, daily, of a 28-day cycle. SY-1425 will be 
administered at 6 mg/m2/day PO in two divided doses on Days 8 through 28 of a 28-day 
cycle. 
• Arm 4: SY-1425 will be administered at 6 mg/m2/day PO in two divided doses on a 28-
day treatment cycle. Dosing will be continuous, beginning with a 7-day lead-in, and then 
administered on a 28-day treatment cycle. Daratumumab will be administered at a dose 
of 16 mg/kg starting on Cycle 1 Day 1 weekly for 8 weeks (8 doses total), followed by 
dosing every 2 weeks for 16 weeks (8 doses total), followed by dosing every 4 weeks 
until progression or intolerance. 
The dose of SY-1425 may be increased due to unsatisfactory response as early as C2D1 and 
again at C3D1 in consultation with the Sponsor. SY-1425 doses may be increased for AML and 
higher-risk MDS patients to 9 mg/m2/day if a CR/CRi is not achieved at the C2D1 response 
assessment. The dose may be increased one additional dose level to 12 mg/m2/day if a CR/CRi 
is not achieved at the C3D1 response assessment. Doses may be increased for lower-risk MDS 
patients to 9 mg/m2/day at C2D1 if the patient has not reduced their transfusion requirements by 
50% after 4 weeks (C2D1). The dose may be increased one level to either 9 or 12 mg/m2/day 
after Week 8 (C3D1) for lower-risk MDS patients who have not achieved transfusion 
independence but who have achieved a minor erythroid response.  
Patients will be treated with single agent SY-1425, or SY-1425 in combination with azacitidine 
or daratumumab to determine activity, to establish the safety profile of SY-1425 in patients with 
AML and MDS, to explore the hypothesis that patients with the RARA super-enhancer 
associated biomarker or the associated IRF8 biomarker at baseline are responsive to single 
agent SY-1425 or SY-1425 in combination, to establish the pharmacokinetic/ 
pharmacodynamic (PK/PD) relationships, and to evaluate the relationship between the activity 
of single agent SY-1425 or SY-1425 in combination, and baseline level of RARA and IRF8 
biomarkers.  
In AML and higher-risk MDS patients, response will be measured by changes from baseline in 
peripheral blood counts and bone marrow aspirates. Bone marrow aspirates will be collected to 
measure response on Day 1 of Cycles 2, 3 (if CR/CRi was not achieved on C2D1), and 4, 

PROTOCOL SY-1425-201 
 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022) 
 Confidential  
Page 9 of 141 
followed by every third cycle, with additional bone marrow aspirates analyzed as clinically 
indicated based upon changes in peripheral blood counts, or when it is needed to establish either 
CR or disease progression. Bone marrow aspirate pathology slides (smears) used to assess 
response should be retained at the sites for up to 5 years or until Sponsor approval to discard 
samples is provided, whichever is sooner, to support the potential for future analyses. 
In lower-risk MDS patients, response will be measured by changes from baseline in transfusion 
requirements and peripheral blood counts, which will be evaluated at each study visit. 
Patients may continue to receive study treatment until experiencing unacceptable toxicity, 
disease progression/relapse, decision to pursue post-remission therapy other than SY-1425 
single agent, or SY-1425 in combination with azacitidine or daratumumab, or the Investigator 
determines it is in the best interest of the patient to discontinue treatment. Newly diagnosed 
AML patients enrolled in Arm 2A who achieve a CR/CRi or PR while on SY-1425 single agent 
treatment and then relapse, or who fail to achieve a CR/CRi or PR after completing at least 4 
cycles of SY-1425 single agent treatment, are eligible to receive SY-1425 in combination with 
azacitidine.  
Lower-risk MDS patients will be withdrawn from the study at week 24 if they do not have at 
least a minor erythroid response defined as either a 50% decrease in transfusion requirements or 
a 50% improvement in hemoglobin concentration per the response criteria, defined as a 
hemoglobin increase ≥ 0.75g/dL. Lower-risk MDS patients who in the opinion of the 
Investigator are receiving clinical benefit, but do not meet the minor erythroid response criteria 
can remain on study with Sponsor approval. Lower-risk MDS patients who continue past week 
24 will continue to receive treatment until erythroid relapse (loss of erythroid response), disease 
progression, or unacceptable toxicity. 
An end of treatment (EoT) visit will be conducted for all AML and higher-risk MDS patients 
within 30 days of the last dose of study drug, but prior to the start of any subsequent therapies to 
monitor for safety and resolution of adverse events (AEs). For lower-risk MDS patients, the 
EoT visit will also be the end of study visit which will be conducted 30 days after the last dose 
of study drug. All AML and higher-risk MDS patients will be followed every 3 months for 
survival for up to 2 years and patients who are withdrawn prior to relapse will also follow-up 
for event free survival (EFS). 
However, following implementation of Amendment 7, assessments will be performed per 
institutional standard of care for patients enrolled in Arm 2B or Arm 5. Aside from serious 
adverse event (SAE), adverse event of special interest, and Pregnancy and Birth Event 
collection (via the pharmacovigilance safety database) for patients still receiving study drug in 
Arm 5, the study procedures and data collection outlined in Table 3 will be considered as 
guidance and will no longer be required for the study or entered into the electronic data capture 
system. Patients in Arm 5 may continue to receive study drug until experiencing unacceptable 
toxicity, disease progression/relapse, decision to pursue post-remission therapy other than 
SY-1425 in combination with azacitidine, or the Investigator determines it is in the best interest 
of the patient to discontinue treatment.  

PROTOCOL SY-1425-201 
 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022) 
 Confidential  
Page 10 of 141 
Inclusion Criteria: 
1. Patients must be at least 18 years of age. 
2. Patients must have: 
a. Relapsed and/or refractory non-APL AML that has failed to achieve a CR or PR 
following standard induction therapy, or has relapsed after any duration of CR or PR  
i. Patients must have measurable disease with bone marrow blasts ≥5% at 
screening. 
b. Relapsed and/or refractory higher-risk MDS (High / Very High Risk, as defined by 
the Revised International Prognostic Scoring System (IPSS-R)) patients that have 
failed to achieve a CR or PR, or any HI (per IWG 2006 criteria) after standard 
therapy with hypomethylating agents (eg, azacitidine, decitabine), or have relapsed 
after any duration of CR or PR or HI  
i. Patients must have measurable disease with bone marrow blasts >5% at 
screening. 
c. Newly diagnosed, treatment-naïve non-APL AML in patients who, at the time of 
study entry are unlikely to tolerate standard intensive chemotherapy due to age, 
performance status, or comorbidities based on at least one of the following criteria 
(Ferrara et al, 2013):  
i. Age ≥ 75-years-old 
ii. Eastern Cooperative Oncology Group (ECOG) Performance Status of 3 
iii. Cardiac history of congestive heart failure (CHF) or documented ejection 
fraction (EF) ≤ 50% 
iv. Pulmonary disease with DLCO ≤ 65% or FEVI ≤ 65% 
v. Creatinine clearance ≥ 30 mL/min to < 45 mL/min 
vi. Hepatic impairment with total bilirubin > 1.5 to ≤ 3.0 x upper limit of 
normal (ULN) 
vii. Any other comorbidity that the Investigator judges to be incompatible 
with intensive chemotherapy, and reviewed and approved by the Sponsor 
prior to enrollment 
d. Transfusion dependent lower-risk MDS without the del 5q abnormality, in patients 
refractory to erythropoietin treatment or unlikely to respond to EPO treatment (EPO 
>500).  
i. 
Lower-risk MDS: Very Low /Low / Intermediate Risk, as defined by 
IPSS-R.  
ii. 
Red blood cell (RBC) transfusion dependent anemia defined as no 
8 consecutive weeks without RBC transfusions within the 16 weeks 
prior to study entry, or ≥4 RBC transfusions within the 8 weeks prior to 
study entry.  

PROTOCOL SY-1425-201 
 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022) 
 Confidential  
Page 11 of 141 
iii. 
Refractory to or ineligible for ESAs is defined as RBC-Transfusion 
Dependence despite ESA treatment of ≥40,000 units/week recombinant 
human erythropoietin for 8 weeks or an equivalent dose of darbepoetin 
(150 g/week) or serum EPO level >500 mU/mL in patients not 
previously treated with ESAs. 
3. Patients must be evaluated for the RARA super-enhancer associated biomarker or IRF8 
biomarker as measured by RT-qPCR with a centralized test of peripheral blood at the 
time of study screening.   
a. Patients in arms 1, 2A, 3, 4, and 5 must be positive for the biomarker as defined by a 
predetermined cutoff to be eligible for enrollment.   
4. Must be amenable to serial bone marrow aspirates and peripheral blood sampling during 
the study. 
5. ECOG Performance Status (PS) of 0, 1 or 2. For newly diagnosed AML patients < 75 
years of age, ECOG 0 to 3; for ≥ 75 years of age, ECOG 0 to 2. 
6. Adequate organ function as defined by: 
a. Total bilirubin ≤ 1.5 x the upper limit of normal (ULN), unless suspected to have 
Gilbert’s disease. For newly diagnosed AML patients < 75 years of age, total 
bilirubin ≤ 3.0 x ULN; for ≥ 75 years of age, total bilirubin ≤ 1.5 x ULN. 
b. ALT and AST ≤ 3 x ULN or ≤ 5 x ULN if documented liver infiltration with 
leukemia cells. 
c. Serum creatinine ≤ 2.0 x ULN or calculated creatinine clearance ≥ 45 mL/min based 
on the Cockroft-Gault GFR estimation. For newly diagnosed AML patients < 75 
years of age, creatinine clearance ≥ 30 mL/min; for ≥ 75 years of age, creatinine 
clearance ≥ 45 mL/min. 
7. Discontinued use of chemotherapy, radiation therapy, or growth factors for at least 
2 weeks prior to first study treatment, with the exception of hydroxyurea. 
8. No investigational agents within 2 weeks prior to first study treatment. 
9. No strong inducers of CYP3A4 (see Appendix 5) within 2 weeks prior to first study 
treatment.  
10. Resolved acute effects of any prior AML/MDS therapy to baseline or ≤ Grade 1 CTCAE 
severity. 
11. Serum/urine pregnancy test (for females of childbearing potential) that is negative at 
screening and immediately prior to initiation of treatment (first dose). 
12. Willingness and ability to comply with the scheduled study visits, treatment plans, 
laboratory tests and other procedures.  
13. Fully-executed, signed and dated Institutional Review Board (IRB) or Independent 
Ethics Committee (IEC) approved informed consent document. 

PROTOCOL SY-1425-201 
 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022) 
 Confidential  
Page 12 of 141 
Exclusion Criteria: 
1. APL (M3 subtype of AML) or patients with a t(9:22) cytogenetic translocation. 
2. Hyperleukocytosis (leukocytes ≥ 25 x 109/L) at study entry. These patients may be 
treated with hydroxyurea according to routine practice, and enroll in the study when the 
leukocyte count falls below 25 x 109/L. 
3. Patients known to be refractory to platelet or packed red cell transfusions per 
Institutional Guidelines, or a patient who refuses blood product support. 
4. Prior treatment with ATRA or systemic retinoid for the treatment of hematologic 
malignancy. 
5. Arm 4 only – Prior or concurrent exposure to daratumumab or other CD38 therapies  
6. Arm 4 only – Subject has either of the following: 
a. Known chronic obstructive pulmonary disease (COPD) with a forced expiratory 
volume in 1 second (FEV1) <50% of predicted normal. Note that FEV1 testing is 
required for subjects suspected of having COPD and subjects must be excluded if 
FEV1 is <50% of predicted normal. 
b. Known moderate or severe persistent asthma within the past 2 years (see 
Appendix 8), or uncontrolled asthma of any classification. Note that subjects who 
currently have controlled intermittent asthma or controlled mild persistent asthma 
are allowed to participate in the study. 
7. Patients with other active malignancy (not including basal cell carcinoma, non-
melanoma skin cancer, cervical carcinoma in situ, localized prostate cancer treated with 
hormone therapy). Patients with history of other cancers should be free of disease for at 
least 2 years.  
8. Patients with hypertriglyceridemia defined as >1000 mg/dL (CTCAE v4.03 Grade 4).  
9. Any clinically significant cardiac disease including one of the following currently or in 
the previous 6 months: myocardial infarction, unstable cardiac function due to unstable 
angina or congestive heart failure, congenital long QT syndrome, torsades de pointes or 
clinically-significant ventricular arrhythmias.  
10. QTc interval >480 msec based on triplicate ECG readings using the Fridericia (QTcF), 
with the exception of patients with Right Bundle Branch Block or Left Bundle Branch 
Block. 
11. Patients with an active, life-threatening or clinically-significant uncontrolled systemic 
infection. 
12. Patients with known active uncontrolled central nervous system (CNS) leukemia. 
13. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome 
(AIDS) related illness or hepatitis B or hepatitis C infection. 

PROTOCOL SY-1425-201 
 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022) 
 Confidential  
Page 13 of 141 
a. Arm 4 only: Patients with resolved infection (ie, patients who are HBsAg negative 
but positive for antiHBs or antiHBc) must also be screened using PCR measurement 
of HBV DNA levels. Patients who are PCR positive for HBV will be excluded. 
b. Arm 4 only: Patients with serologic findings suggestive of HBV vaccination 
(antiHBs positivity as the only serologic marker) AND a known history of prior 
HBV vaccination do not need to be tested for HBV DNA by PCR. 
14. Known malabsorption syndrome or other condition that may impair absorption of study 
medication (eg, gastrectomy). 
15. Major surgery within 4 weeks prior to starting study treatment. 
16. Patients taking Vitamin A supplements (>10,000 IU/d) unless discontinued prior to first 
dose of study drug, or having hypervitaminosis A. 
17. Concurrent treatment with any investigational or approved oncology agents (unless 
specified in the protocol, such as hydroxyurea) or herbal preparations. 
18. Arm 4 only: Known allergies, hypersensitivity, or intolerance to mannitol, 
corticosteroids, monoclonal antibodies or human proteins, or their excipients, or known 
sensitivity to mammalian-derived products. 
19. Arm 4 only: Vaccination with live attenuated vaccines within 4 weeks of first study 
drug administration. 
20. Current illicit drug or alcohol abuse. 
21. Other severe acute or chronic medical condition such as refractory congestive heart 
failure, pulmonary disease associated with dyspnea at rest or requiring oxygen therapy, 
kidney dialysis, liver cirrhosis (Child B or C), or psychiatric condition or laboratory 
abnormality that may increase the risk to the patient associated with study participation 
or investigational product administration or which may interfere with the interpretation 
of study results or, in the judgment of the Investigator, would make the patient 
inappropriate for entry into this study. 
22. Pregnant females; breastfeeding females; and males and females of childbearing 
potential not willing to use two highly effective methods of birth control, one being 
barrier method. Intrauterine devices and birth control pills are not barrier methods, but 
are highly effective especially when combined with a barrier method (eg, latex condom 
or a diaphragm or cervical cap) while taking study drug (SY-1425, azacitidine and 
daratumumab) and continuing contraception use for at least 90 days after the last dose of 
study drug. Men/women should not donate sperm or ova during this timeframe. 
a. Non-childbearing potential is defined as menopausal for at least 2 years or 
documented oophorectomy. 
Study Endpoints: 
Primary Endpoints 
• ORR for biomarker positive patients with AML or higher-risk MDS (Arms 1, 2A, 
2B, 5) 

PROTOCOL SY-1425-201 
 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022) 
 Confidential  
Page 14 of 141 
• TIR for patients with lower-risk MDS (Arm 3) 
• Safety and tolerability of SY-1425 in combination with daratumumab assessed by 
the type and frequency of AEs and SAEs using National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE) v 4.03, as well as 
changes in clinically significant clinical laboratory values, electrocardiogram (ECG) 
parameters and vital sign measurement (Arm 4) 
Secondary Endpoints  
• ORR for AML or higher-risk MDS patients positive for the RARA super-enhancer 
associated biomarker (Arms 1, 2A, 2B, and 5) 
• TIR for lower-risk MDS patients positive for the RARA super-enhancer associated 
biomarker (Arm 3) 
• Response rate (ORR + TIR) for patients positive for the IRF8 biomarker and 
negative for the RARA super-enhancer associated biomarker treated with SY-1425 as 
a single agent (Arms 1, 2A, and 3)  
• ORR for AML or higher-risk MDS patients positive for the IRF8 biomarker and 
negative for the RARA super-enhancer associated biomarker (Arms 1, 2A, 2B, and 5) 
• TIR for lower-risk MDS patients positive for the IRF8 biomarker and negative for 
the RARA super-enhancer associated biomarker (Arm 3) 
• ORR for AML patients who are treated with SY-1425 in combination with 
azacitidine (Arm 2B) 
• ORR for AML or higher-risk MDS patients treated with SY-1425 in combination 
with daratumumab (Arm 4) 
• Clinical activity as measured by EFS, RFS, DOR, OS, and HI in Arms 1, 2A, 2B, 4, 
and 5 
• Clinical activity as measured by DOR and HI in Arm 3 
• Proportion of patients requiring supportive measures secondary to cytopenias, as 
measured by changes in transfusion rates, incidence and duration of growth factor 
support and antibiotics use, and number of hospitalizations associated with febrile 
neutropenia and/or thrombocytopenic bleeding 
• Characterize the safety and tolerability of SY-1425 as a single agent and in 
combination with azacitidine by assessing the type and frequency of AEs and SAEs 
using National Cancer Institute (NCI) Common Terminology Criteria for Adverse 
Events (CTCAE) v 4.03, as well as changes in clinically significant clinical 
laboratory values, electrocardiogram (ECG) parameters and vital sign measurements 
(Arms 1, 2A, 2B, 3, and 5) 
• PK parameters of SY-1425, as single agent and in combination with azacitidine or 
daratumumab, after single and multiple doses by performing PK analysis to define 

PROTOCOL SY-1425-201 
 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022) 
 Confidential  
Page 15 of 141 
time to maximum concentration (tmax), Cmax, minimum plasma concentration (Cmin), 
AUC, total body clearance (CL/F) and half-life (t1/2), where the data permits 
Exploratory Endpoints  
• Sensitivity analyses to the primary endpoint to predict ORR or TIR across all 
patients by arm, diagnosis type, prior therapy, RARA super-enhancer associated 
biomarker and/or IRF8 biomarker status; DHRS3 induction, peripheral blood 
myeloid differentiation markers, induction of CD38 expression, genotype and 
mutation status 
• Changes in Health-Related Quality of Life (HRQOL)  
− AML/higher-risk MDS patients (Arms 1, 2A, 2B, 4, and 5): Functional 
Assessment of Cancer Therapy-Leukemia (FACT-Leu) questionnaire 
− Lower-risk MDS patients (Arm 3): Functional Assessment of Cancer Therapy-
Anemia (FACT-An) questionnaire 
• Establish PK/PD relationships by performing analysis of PD biomarkers (DHRS3 
and myeloid differentiation markers) in leukemic cells from repeat peripheral blood 
samples and assessing any changes over time 
• PK parameters for daratumumab in combination with SY-1425, including maximum 
concentration (Cmax) and minimum concentration (Cmin; trough concentration)  
• Characterize the relationship between SY-1425 activity and baseline expression, and 
expression over time of messenger RNA (mRNA) expression of RAR and IRF8 
biomarkers by correlating baseline biomarker mRNA expression levels of RARα 
and IRF8 with ORR, EFS, RFS, DOR, OS, and HI Rate 
• Estimate of median time-to-response  
• Evaluate changes in expression of myeloid differentiation markers, including CD38, 
over time 
• Analysis of additional genes or proteins using multiplex platforms  
Statistical Methods: 
For each of Arms 1, 2A, 2B (biomarker positive subset), 3 and 5, an exact 2-sided 90% 
confidence interval will be calculated for the ORR (Arms 1, 2A, 2B, 5) or TIR (Arm 3). 
Success for Arms 1, 2A and 3 (n=25 each) is achieved if the lower bound of the confidence 
interval excludes 5%. Assuming a 25% response rate for SY-1425 as a single agent, the power 
for each of these arms of this study is 90.4%. Arm 2B has two subgroups defined by biomarker 
status (n=25 each). Success for the biomarker positive subgroup in Arm 2B is achieved if the 
lower bound of the confidence interval excludes 20%. Assuming a 45% response rate for the 
combination of SY-1425 and azacitidine in biomarker positive patients, the power for this 
subgroup of Arm 2B of the study is 86.6%. Success for Arm 5 (n=25) is achieved if the lower 
bound of the confidence interval excludes 10%. Assuming a 30% response rate for the 

PROTOCOL SY-1425-201 
 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022) 
 Confidential  
Page 16 of 141 
combination of SY-1425 and azacitidine in relapsed and/or refractory biomarker-positive AML 
patients, the power for Arm 5 of this study is 80.7%. 
Success for the entire Arm 2B population is achieved if the lower bound of the confidence 
interval excludes 20%.  Assuming a 38% response rate for the combination of SY-1425 and 
azacitidine in the entire Arm 2B population, the power for the secondary endpoint of Arm 2B of 
the study is 84.6%. 
The primary endpoint of Arm 4 is safety and tolerability of SY-1425 in combination with 
daratumumab. The sample size is not based on any hypothesis testing but is appropriate for 
studies of this type with a primary focus on safety. 
No adjustment for multiple hypothesis testing across arms will be made. 
ORR is defined as: 
• AML: ORR as determined by the investigator based on the rate of CR/CRi/CRh. 
MLFS, and PR, per the revised IWG AML criteria (Cheson et al, 2003, 
Bloomfield  et al, 2018). 
• Higher-risk MDS: ORR as determined by the Investigator per the revised IWG AML 
criteria (Cheson et al, 2003) or modified IWG MDS criteria (Cheson et al, 2006). 
Response is based on the rate of CR/CRi, PR, and HI. CR includes marrow CR. 
TIR is defined as: 
• Lower-risk MDS: TIR, defined as the proportion of patients who achieve transfusion 
independence defined as 8 consecutive weeks of RBC transfusion independence. 
Clinical activity of SY-1425, as single agent and in combination with azacitidine or 
daratumumab, as measured by EFS, RFS, DOR, OS, and HI in AML and higher-risk MDS 
patients. 
• EFS: defined as time from first treatment until date of documentation of disease 
relapse following CR/CRi, or death, whichever occurs first. If the patient does not 
achieve a CR, EFS is defined as the point of progression or death, whichever occurs 
first. 
• RFS: defined as time from first objective documentation of CR/CRi (including 
CRh/MLFS for AML patients) or PR until the date of first objective documentation 
of disease relapse or death due to any cause, whichever occurs first.  
• DOR: defined as time from first date of response (CR/CRi [including CRh/MLFS 
for AML patients]), PR, or HI for MDS patients - if best response) until date of 
relapse.  
• OS: defined as time from first treatment until death from any cause. 
• HI Rate: defined according to the modified IWG response criteria for MDS  
(Cheson et al, 2006) as the proportion of patient with a response (lasting at least 
8 weeks) after first treatment. 

PROTOCOL SY-1425-201 
 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022) 
 Confidential  
Page 17 of 141 
Clinical activity of SY-1425 as measured by DOR and HI in transfusion dependent lower-risk 
MDS patients. 
• DOR is defined as the time from first date of response (HI or transfusion 
independence) until date of relapse. 
• HI is defined according to the modified IWG response criteria for MDS  
(Cheson et al, 2006) as response (lasting at least 8 weeks) after first treatment. 

PROTOCOL SY-1425-201 
 
 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022) 
 
 
Confidential   
 
 
 
 
 
 
 
 
 
 
 
Page 18 of 141 
Figure 1: 
Study Schematic 
 
 
Abbreviations: AML = acute myeloid leukemia; MDS = Myelodysplastic Syndrome. 
NOTE: Each of Arms 1, 2A, 2B, 3, and 5 will include approximately 20 patients who are positive of the RARA super-enhancer associated biomarker 

PROTOCOL SY-1425-201 
 
 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022) 
 
 
Confidential   
 
 
 
 
 
 
 
 
 
 
 
Page 19 of 141 
Table 1: Schedule of Events (Arms 1, 2A, and 3) 
 
Screening 
(a) 
Cycle 1 
Cycles 2-4 
Cycles 
5+ (b) 
Post Dose 
Adjustment 
Visit (c) 
End of 
Treatment 
(EoT) (d) 
Post- treatment 
Follow-up 
(AML & HR 
MDS Only) 
Study Day (D/d) 
Within 30 
days of 
dosing 
D1 
D8 
(±1d) 
D15 
(±1d)  
D22 
(±1d) 
D1 
(±2d) 
D15 
(±2d) 
D1 
(±2d) 
Within 8-15 
days of dose 
adjustment 
Within 30 
days of last 
dose (d) 
Every 3 mo. post 
EoT 
(±14 d) (e) 
Baseline Documentation – All Patients 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Eligibility Review 
X 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
Weight (f) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECOG Performance 
Status 
X 
X 
 
 
 
X 
 
X 
 
X 
 
Physical Exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Safety Labs/Measurements – All Patients 
Hematology (g) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Serum Chemistries (g) 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
Coagulation (g) 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
Triglycerides and Total 
Cholesterol (g) 
X 
X 
 
X 
 
X 
 
X 
X 
X 
 
Urinalysis (g) 
X 
X 
 
 
 
 
 
 
 
X 
 
Pregnancy Test (h) 
X 
X 
 
 
 
X 
 
X 
 
X 
 
Triplicate ECG (i) 
X 
X 
 
X 
 
X 
 
 
 
X 
 

PROTOCOL SY-1425-201 
 
 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022) 
 
 
Confidential   
 
 
 
 
 
 
 
 
 
 
 
Page 20 of 141 
Table 1: Schedule of Events (Arms 1, 2A, and 3) 
 
Screening 
(a) 
Cycle 1 
Cycles 2-4 
Cycles 
5+ (b) 
Post Dose 
Adjustment 
Visit (c) 
End of 
Treatment 
(EoT) (d) 
Post- treatment 
Follow-up 
(AML & HR 
MDS Only) 
Study Day (D/d) 
Within 30 
days of 
dosing 
D1 
D8 
(±1d) 
D15 
(±1d)  
D22 
(±1d) 
D1 
(±2d) 
D15 
(±2d) 
D1 
(±2d) 
Within 8-15 
days of dose 
adjustment 
Within 30 
days of last 
dose (d) 
Every 3 mo. post 
EoT 
(±14 d) (e) 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Clinical Assessments – All Patients 
Adverse Event 
Monitoring (j) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Prior/Concomitant 
Medication Review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Red Blood Cell and 
Platelet Transfusions 
Recorded (k) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Dosing Compliance/ 
Diary Review 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Study Treatment 
SY-1425 
 
Continuous Dosing 
X 
 
 
Clinical Assessments – AML & Higher-Risk MDS Patients Only 
HRQOL (FACT-Leu) 
X 
X 
 
 
 
C4 only 
 
 
 
X 
 
Subsequent Therapies (l) 
 
 
 
 
 
 
 
 
 
 
X 
EFS and Overall Survival 
Follow-Up 
 
 
 
 
 
 
 
 
 
X 
X 
Clinical Assessments – Lower-Risk MDS Patients Only 
HRQOL (FACT-An) 
X 
X 
 
 
 
C4 only 
 
 
 
X 
 

PROTOCOL SY-1425-201 
 
 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022) 
 
 
Confidential   
 
 
 
 
 
 
 
 
 
 
 
Page 21 of 141 
Table 1: Schedule of Events (Arms 1, 2A, and 3) 
 
Screening 
(a) 
Cycle 1 
Cycles 2-4 
Cycles 
5+ (b) 
Post Dose 
Adjustment 
Visit (c) 
End of 
Treatment 
(EoT) (d) 
Post- treatment 
Follow-up 
(AML & HR 
MDS Only) 
Study Day (D/d) 
Within 30 
days of 
dosing 
D1 
D8 
(±1d) 
D15 
(±1d)  
D22 
(±1d) 
D1 
(±2d) 
D15 
(±2d) 
D1 
(±2d) 
Within 8-15 
days of dose 
adjustment 
Within 30 
days of last 
dose (d) 
Every 3 mo. post 
EoT 
(±14 d) (e) 
EPO Levels (m) 
X 
 
 
 
 
 
 
 
 
 
 
Specialty Lab Assessments – All Patients 
Peripheral blood RARA 
Super-Enhancer 
Associated Biomarker 
Assessment and IRF8 
biomarker (n) 
X 
 
 
 
 
 
 
 
 
 
 
ChIP-Sequencing (o) 
X 
 
 
 
 
 
 
 
 
 
 
Blood sample for 
biomarker research (p) 
X 
 
 
 
 
 
 
 
 
 
 
Pharmacokinetics (q) 
 
X 
 
X 
 
X 
 
 
X 
 
 
Blood Sample for ADME 
PGx (r) 
 
X 
 
 
 
 
 
 
 
 
 
Blood Sample for 
Pharmacodynamics (s) 
 
X 
 
X 
 
 
 
 
 
X 
 
Peripheral Blood for 
CD38 & Myeloid Marker 
Immunophenotyping (t) 
 
X 
X 
X 
 
X 
 
Every 3rd 
Cycle 
 
X 
 
Blood Sample for 
Resistance Mechanism 
 
 
 
 
 
 
 
 
 
X 
 
Cytogenetics and 
Mutational Analysis (u) 
X 
 
 
 
 
 
 
 
 
X 
 

PROTOCOL SY-1425-201 
 
 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022) 
 
 
Confidential   
 
 
 
 
 
 
 
 
 
 
 
Page 22 of 141 
Table 1: Schedule of Events (Arms 1, 2A, and 3) 
 
Screening 
(a) 
Cycle 1 
Cycles 2-4 
Cycles 
5+ (b) 
Post Dose 
Adjustment 
Visit (c) 
End of 
Treatment 
(EoT) (d) 
Post- treatment 
Follow-up 
(AML & HR 
MDS Only) 
Study Day (D/d) 
Within 30 
days of 
dosing 
D1 
D8 
(±1d) 
D15 
(±1d)  
D22 
(±1d) 
D1 
(±2d) 
D15 
(±2d) 
D1 
(±2d) 
Within 8-15 
days of dose 
adjustment 
Within 30 
days of last 
dose (d) 
Every 3 mo. post 
EoT 
(±14 d) (e) 
Specialty Lab Assessments – AML& Higher-Risk MDS Patients Only 
Bone Marrow Aspirate 
for Eligibility  
X 
 
 
 
 
 
 
 
 
 
 
Bone Marrow Aspirate 
for Response  
Assessment (v) 
 
 
 
 
 
X 
 
Every 3rd 
Cycle 
 
X 
 
Immunophenotyping (w) 
X 
 
 
 
 
X 
 
Every 3rd 
Cycle 
 
 
 
Abbreviations: ADME = absorption, distribution, metabolism, and excretion; AML = acute myeloid leukemia; BSA = body surface area; ChIP = chromatin immunoprecipitation; 
CR = complete remission; CRi = complete remission, morphologic, with incomplete blood count recovery; D/d = day(s); ECOG = Eastern Cooperative Oncology Group; EoT = 
end of treatment; ECG = electrocardiogram; EFS = event-free survival; EPO = erythropoietin; FACT-An = Factual Assessment of Cancer Therapy-Anemia; FACT-Leu = Factual 
Assessment of Cancer Therapy-Leukemia; HRQOL = Health Related Quality of Life; IRF8 = Interferon Regulatory Factor 8; MDS = Myelodysplastic Syndrome; PD = 
pharmacodynamic; PGx = pharmacogenomics; PK = pharmacokinetic; RARA = retinoic acid receptor alpha; SAE = serious adverse event. 
 
(a) Screening assessments must be performed within 30 days of study drug administration. Screening assessments may also occur on Day 1 prior to dosing. 
(b) Cycle 5 schedule should be followed for all subsequent cycles. 
(c) If a patient has an SY-1425 dose modification (decrease or increase) to a new dose level (as defined in Section 8.4), a dose adjustment visit must be performed within 8-15 
days of the dose adjustment. This visit can be combined with another scheduled visit if it is scheduled to occur within that window.  
(d) An EoT visit for AML and Higher-Risk MDS patients should occur within 30 days of the last dose of study drug, but prior to any subsequent therapies. For Lower-Risk MDS 
patients the EoT visit will also be the end of study visit and should occur 30 days after the last dose of study drug (+/- 5 days). 
(e) AML and Higher-Risk MDS patients will enter post-treatment follow-up. Visits should occur every 3 months post EoT for response assessment and overall survival. These 
visits may be conducted by phone. Follow-up visit window is +/- 14 days. 
(f) Weight will be measured at each visit. Weight will be used to calculate BSA to determine dosing requirements. BSA used for dosing calculations should be updated if the 
weight changes more than 15%. 
(g) Safety laboratory assessments are outlined in Section 7.2 of the protocol and will be performed locally. 
(h) A pregnancy test (urine or serum) must be completed for women of child bearing potential during screening, on Day 1 of each cycle visit, and at EoT.  
(i) ECG on Cycle 1 Day 1 must be performed prior to dosing. All other ECGs can be taken at any time during the study visit. All ECGs will be done as triplicate 12-lead ECGs. 
(j) SAEs will be captured from the time of signing of the Informed Consent Form through 30 days after last dose of study drug, and non-serious AEs from the time of first dose 
of study drug through 30 days after last dose of study drug.  

PROTOCOL SY-1425-201 
 
 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022) 
 
 
Confidential   
 
 
 
 
 
 
 
 
 
 
 
Page 23 of 141 
(k) All transfusions received by the patient from 16 weeks prior to enrollment until the EoT visit will be recorded. 
(l) Subsequent therapies will be recorded for 3 months after the last dose of study drug. 
(m) Low-risk MDS patients in Arm 3 only. 
(n) Peripheral blood sample will be sent to a central lab for assessment of RARA super-enhancer associated biomarker and IRF8 biomarker at screening to confirm eligibility. 
Other associated RARA pathway genes will also be analyzed. 
(o) All patients will have a peripheral blood sample collected at screening for ChIP-sequencing analysis to be performed at a central lab (assuming sufficient material is available 
at time of sample processing). 
(p) For U.S. only: All patients will have a whole blood sample collected at screening (same collection time as the biomarker assessment) for additional biomarker research. 
(q) All patients will have PK sampling on Day 1 of Cycle 1 at 2-4 hours, and 5-8 hours post dose, and on Day 15 of Cycle 1 and Day 1 of Cycles 2, 3, and 4 at two time points at 
least two hours apart. A subset of approximately 15 patients, sufficient to obtain PK evaluable results from at least 10 patients, will have more intensive sampling [pre-dose 
(0h), and 0.5, 1, 2, 4, 6, 8 hours post-dose] on Day 1 and Day 15 of Cycle 1, and will have sparse sampling on Day 1 of Cycles 2, 3, and 4 at two time points at least 2 hours 
apart. If a patient’s SY-1425 dose is modified to a different dose level (see Section 8.4) during the course of the study, PK sampling should occur within 8-15 days of the dose 
adjustment following the same schedule as Cycle 1 Day 1 (either intensive or sparse depending on which PK sampling schedule originally enrolled under). 
(r) Absorption, distribution, metabolism, excretion PGx sample to be taken pre-dose. 
(s) Peripheral blood will be collected in all patients on Day 1 of Cycle 1 pre-dose and 5-8 hours post-dose, on Day 15 of Cycle 1, and at EoT visit to determine changes in RNA 
including dehydrogenase/reductase (SDR family) member 3 (DHRS3). This sample should be collected in the same procedural timeframe as the corresponding PK sample.  
(t) Peripheral blood collected for central analysis of CD38 and myeloid marker immunophenotyping on Days 1 (pre-dose), 8 and 15 of Cycle 1; Day 1 of Cycles 2, 3, 4, followed 
by every third cycle (7, 10, 13, etc); and EoT. Collected only for patients enrolled under Amendment 4 or a subsequent protocol amendment. 
(u) Cytogenetics and mutational analysis will be performed at screening and at the EoT visit. Cytogenetics and mutational analyses will be performed locally. These analyses are 
performed on bone marrow for AML and Higher-Risk MDS patients, and on peripheral blood for Lower-Risk MDS patients. 
(v) Bone marrow aspirates will be collected to assess response in AML and Higher-Risk MDS patients on Day 1 of Cycles 2, 3, 4, followed by every third cycle (7, 10, 13, etc.), 
and as clinically indicated. If a patient achieved a CR/CRi at Cycle 2 Day 1, the Cycle 3 Day 1 bone marrow aspirate is not required. A bone marrow aspirate should be 
collected to confirm relapse which will be recorded as an end of treatment sample and will be used for cytogenetics assessment. For patients enrolled in Arm 2A, an 
unscheduled bone marrow aspirate may be required to support eligibility to receive treatment with SY-1425 in combination with azacitidine after relapse/unsatisfactory 
response with single agent SY-1425. 
(w) Bone marrow aspirate samples will be collected for immunophenotyping to measure myeloid differentiation markers and will be analyzed locally at screening and when 
aspirates are performed to assess response [see footnote (v), above]. Immunophenotyping may also be performed when clinically indicated on peripheral blood to measure 
myeloid differentiation markers. 
 
 

PROTOCOL SY-1425-201 
 
 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022) 
 
 
Confidential   
 
 
 
 
 
 
 
 
 
 
 
Page 24 of 141 
 
Table 2: Schedule of Assessment (Central Laboratory Sampling) (Arms 1, 2A, and 3) 
Study Visit 
Biomarker 
& ChIP 
Sequencing 
Samples  
Pharmacokinetic Sampling – Choose 
Appropriate Schedule Below Based Upon 
Enrollment 
ADME 
PGx 
Sample  
Pharmacodynamics  
Sample  
CD38 & Myeloid 
Marker 
Immunophenotyping (a) 
Resistance 
Mechanism 
Non-Intensive 
Pharmacokinetics 
Sample  
Intensive 
Pharmacokinetics Cohort 
Sample  
Screening 
3 blood 
samples 
collected any 
time during 
visit (b) 
 
 
 
 
 
 
Cycle 1 Day 1 (c) 
 
• 2-4 hours post-
dose 
• 5-8 hours post-
dose 
• pre-dose (0h) (c) 
• 0.5 hours post-dose (± 
15 mins) 
• 1 hour post-dose (± 15 
mins) 
• 2 hours post-dose  
(± 15 mins) 
• 4 hours post-dose 
(± 30 mins) 
• 6 hours post-dose  
(±30 mins) 
• 8 hours post-dose  
(±30 mins) 
• Pre-
dose (c) 
• Pre-dose (c) 
• 5-8 hours post 
dose 
• Collected any time 
during visit (d) 
 
Cycle 1 Day 8 
 
 
 
 
 
• Collected any time 
during visit (d) 
 

PROTOCOL SY-1425-201 
 
 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022) 
 
 
Confidential   
 
 
 
 
 
 
 
 
 
 
 
Page 25 of 141 
 
Table 2: Schedule of Assessment (Central Laboratory Sampling) (Arms 1, 2A, and 3) 
Study Visit 
Biomarker 
& ChIP 
Sequencing 
Samples  
Pharmacokinetic Sampling – Choose 
Appropriate Schedule Below Based Upon 
Enrollment 
ADME 
PGx 
Sample  
Pharmacodynamics  
Sample  
CD38 & Myeloid 
Marker 
Immunophenotyping (a) 
Resistance 
Mechanism 
Non-Intensive 
Pharmacokinetics 
Sample  
Intensive 
Pharmacokinetics Cohort 
Sample  
Cycle 1 Day 15 (c) 
 
• 2 post-dose 
samples at least 
2 hours apart 
 
• pre-dose (0h) (c) 
• 0.5 hours post-dose (± 
15 mins) 
• 1 hour post-dose (± 15 
mins) 
• 2 hours post-dose  
(± 15 mins) 
• 4 hours post-dose  
(± 30 mins) 
• 6 hours post-dose 
(± 30 mins) 
• 8 hours post-dose  
(± 30 mins) 
 
• A postdose 
sample to be 
collected at any 
time point during 
the visit 
• Collected any time 
during visit (d) 
 
Cycle 2 Day 1 
 
• 2 post-dose 
samples at least 
2 hours apart 
• 2 post-dose samples at 
least 2 hours apart 
 
 
• Collected any time 
during visit (d) 
 
Cycle 3 Day 1 
 
• 2 post-dose 
samples at least 
2 hours apart 
• 2 post-dose samples at 
least 2 hours apart 
 
 
• Collected any time 
during visit (d) 
 
Cycle 4 Day 1 
 
• 2 post-dose 
samples at least 
2 hours apart 
• 2 post-dose samples at 
least 2 hours apart 
 
 
• Collected any time 
during visit (d) 
 
Cycle 7 Day 1 and 
every 3rd cycle 
thereafter 
 
 
 
 
 
• Collected any time 
during visit (d) 
 

PROTOCOL SY-1425-201 
 
 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022) 
 
 
Confidential   
 
 
 
 
 
 
 
 
 
 
 
Page 26 of 141 
 
Table 2: Schedule of Assessment (Central Laboratory Sampling) (Arms 1, 2A, and 3) 
Study Visit 
Biomarker 
& ChIP 
Sequencing 
Samples  
Pharmacokinetic Sampling – Choose 
Appropriate Schedule Below Based Upon 
Enrollment 
ADME 
PGx 
Sample  
Pharmacodynamics  
Sample  
CD38 & Myeloid 
Marker 
Immunophenotyping (a) 
Resistance 
Mechanism 
Non-Intensive 
Pharmacokinetics 
Sample  
Intensive 
Pharmacokinetics Cohort 
Sample  
Within 8-15 days 
of a dose 
adjustment (c) 
 
• 2 post-dose 
samples at least 
2 hours apart 
• pre-dose (0h) (c) 
• 0.5 hours post-dose (± 
15 mins) 
• 1 hour post-dose (± 15 
mins) 
• 2 hours post-dose  
(± 15 mins) 
• 4 hours post-dose 
(± 30 mins) 
• 6 hours post-dose  
(± 30 mins) 
• 8 hours post-dose  
(± 30 mins) 
 
 
 
 
End of Treatment 
 
 
 
 
• 1 sample collected 
any time during 
visit 
• Collected any time 
during visit (d) 
• Collected 
any time 
during 
visit 
Abbreviations: ChIP = chromatin immunoprecipitation; mins = minutes; 0h = zero hour; PGx = pharmacogenomics 
(a) Collected only for patients enrolled under Amendment 4 or a subsequent protocol amendment. 
(b) For patients screened in France, only 2 samples will be collected. 
(c) For Cycle 1 Day 1 for all patients, and Cycle 1 Day 15 and post-dose adjustment visits for patients in the intensive PK cohort, the morning dose of SY-1425 must be 
administered in clinic to allow for collection of the pre-dose (0 hour) samples. 
(d) Refer to the Lab Manual for details on number of collection tubes 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
 
Amendment 7 (31 August 2022) 
Confidential  
Page 27 of 141 
Table 3: Schedule of Events (Arms 2B, and 5, and Patients in Arm 2A who receive SY-1425 in Combination with 
Azacitidine After Relapse/Unsatisfactory Response with Single Agent SY-1425) 
 
Screening 
(a) 
Cycle 1 
28 days 
Cycles 2-4 
cycle = 28 days 
Cycles 5+ (b) 
cycle = 28 days 
Post Dose 
Adjustment 
Visit (c) 
End of 
Treatment 
(EoT) (d) 
Post- 
Treatment 
Follow-up 
(e) 
Study Day (D/d) 
Within 30 
days of 
dosing 
D1 
D2-7 
D8 
(±1d) 
D15 
(±1d) 
D22 
(±1d) 
D1 
(±2d) 
D2-7 
D8 
(±2d) 
D15 
(±2d) 
D1 
(±2d) 
D2-7 
(±2d) 
Within 8-15 days 
from dose 
adjustment 
Within 30 days 
of last dose (d) 
Every 3 
months post 
EoT (±14 days) 
Baseline Documentation  
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Review 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight (f) 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
 
ECOG Status 
X 
X 
 
 
 
 
X 
 
 
 
X 
 
 
X 
 
Physical Exam 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
 
Safety Labs/Measurements  
Hematology (g) 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
 
Serum Chemistries (g) 
X 
X 
 
X 
X 
X 
X 
 
 
 
X 
 
X 
X 
 
Coagulation (g) 
X 
X 
 
X 
 
 
X 
 
X 
 
X 
 
 
X 
 
Triglycerides & Total 
Cholesterol (g) 
X 
X 
 
 
X 
 
X 
 
 
 
X 
 
X 
X 
 
Urinalysis (g) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Pregnancy Test (h) 
X 
X 
 
 
 
 
X 
 
 
 
X 
 
 
X 
 
Triplicate ECG (i) 
X 
 
 
X 
 
X 
 
 
X 
 
 
 
 
X 
 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
 
Amendment 7 (31 August 2022) 
Confidential  
Page 28 of 141 
 
Table 3: Schedule of Events (Arms 2B, and 5, and Patients in Arm 2A who receive SY-1425 in Combination with Azacitidine 
After Relapse/Unsatisfactory Response with Single Agent SY-1425) 
 
Screening 
(a) 
Cycle 1 
28 days 
Cycles 2-4 
cycle = 28 days 
Cycles 5+ (b) 
cycle = 28 days 
Post Dose 
Adjustment 
Visit (c) 
End of 
Treatment 
(EoT) (d) 
Post- 
Treatment 
Follow-up 
(e) 
Study Day (D/d) 
Within 30 
days of 
dosing 
D1 
D2-7 
D8 
(±1d) 
D15 
(±1d) 
D22 
(±1d) 
D1 
(±2d) 
D2-7 
D8 
(±2d) 
D15 
(±2d) 
D1 
(±2d) 
D2-7 
(±2d) 
Within 8-15 
days from dose 
adjustment 
Within 30 days 
of last dose (d) 
Every 3 
months post 
EoT 
(±14 days) 
 
Clinical Assessments  
AE Monitoring (j) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Prior/Concomitant 
Medication Review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
RBC & Platelet 
Transfusions Recorded 
(k) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Dosing Compliance/ 
Diary Review 
 
 
 
X 
X 
X 
X 
 
X 
X 
X 
 
X 
X 
 
HRQOL (FACT-Leu) 
X 
X 
 
 
 
 
C4 
only 
 
 
 
 
 
 
X 
 
Subsequent Therapies (l) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
EFS and Overall 
Survival Follow-Up 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Study Treatments 
SY-1425 
 
 
 
Continuous dosing, Days 8-28 of each Cycle 
 
 
Azacitidine 
 
X 
X 
(m) 
 
 
 
X 
X 
(m) 
 
 
X 
X (m) 
 
 
 
 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
 
Amendment 7 (31 August 2022) 
Confidential  
Page 29 of 141 
Table 3: Schedule of Events (Arms 2B, and 5, and Patients in Arm 2A who receive SY-1425 in Combination with 
Azacitidine After Relapse/Unsatisfactory Response with Single Agent SY-1425) 
 
Screening 
(a) 
Cycle 1 
28 days 
Cycles 2-4 
cycle = 28 days 
Cycles 5+ (b) 
cycle = 28 days 
Post Dose 
Adjustment 
Visit (c) 
End of 
Treatment 
(EoT) (d) 
Post- 
Treatment 
Follow-up 
(e) 
Study Day (D/d) 
Within 30 
days of 
dosing 
D1 
D2-7 
D8 
(±1d) 
D15 
(±1d) 
D22 
(±1d) 
D1 
(±2d) 
D2-7 
D8 
(±2d) 
D15 
(±2d) 
D1 
(±2d) 
D2-7 
(±2d) 
Within 8-15 
days from dose 
adjustment 
Within 30 
days of last 
dose (d) 
Every 3 
months post 
EoT 
(±14 days) 
Specialty Laboratory Assessments  
Peripheral blood (RARA 
Super-Enhancer Assoc. 
& IRF8 Assessment) (n) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Molecular analysis (o) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood sample for 
biomarker research (p) 
X 
 
 
 
 
 
C2 
only 
 
 
 
 
 
 
X 
 
Pharmacokinetics (q) 
 
 
 
X 
 
X 
 
 
X 
 
 
 
X 
 
 
Blood Sample for 
ADME PGx (r) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood Sample for 
Pharmacodynamics (s) 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
X 
 
Blood Sample for 
Resistance Mechanism 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Cytogenetics and 
Mutational Analysis (t) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Bone Marrow Aspirate 
for Eligibility  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bone Marrow Aspirate 
for Response 
Assessment (u) 
 
 
 
 
 
 
X 
 
 
 
Every 3rd 
Cycle 
 
 
X 
 
MRD (v, w) 
X 
 
 
 
 
 
X 
 
 
 
Every 3rd 
Cycle 
 
 
 
 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
 
Amendment 7 (31 August 2022) 
Confidential  
Page 30 of 141 
Abbreviations: ADME = absorption, distribution, metabolism, excretion; AE = adverse event; AESI = adverse event of special interest; BSA = body surface area; CR = complete 
remission; CRi = complete remission, morphologic, with incomplete blood count recovery; D/d = day(s); ECOG = Eastern Cooperative Oncology Group; ECG = 
electrocardiogram; EFS = event-free survival; EoT = end of treatment; HRQOL = Health Related Quality of Life; IRF8 = Interferon Regulatory Factor 8; PD = pharmacodynamic; 
PGx = pharmacogenomics; PK = pharmacokinetic; RBC = red blood cell; RARA = retinoic acid receptor alpha; SAE = serious adverse event. 
(a) Screening assessments must be performed within 30 days of study drug administration, and may occur on Day 1 prior to dosing. Screening assessments are not required for 
patients in Arm 2A who receive SY-1425 in combination with azacitidine after relapse/unsatisfactory response with single agent SY-1425. 
(b) Cycle 5 schedule should be followed for all subsequent cycles. Following implementation of Amendment 7, assessments will be performed per institutional standard of 
care for patients enrolled in Arm 5. Aside from SAE, AESI, and Pregnancy and Birth Event collection (via the pharmacovigilance safety database) for patients still 
receiving study drug in Arm 5, the study procedures and data collection outlined in Table 3 will be considered as guidance and will no longer be required for the 
study or entered into the electronic data capture system. 
(c) If a patient has an SY-1425 dose modification (decrease or increase) to a new dose level (as defined in Section 8.4), a dose adjustment visit must be performed within 8-15 
days of the dose adjustment. This visit can be combined with another scheduled visit if it is scheduled to occur within that window. 
(d) An EoT visit should occur within 30 days of the last dose of study drug and prior to any subsequent therapies. 
(e) Patients will enter post-treatment follow-up. Visits should occur every 3 months post EoT for response assessment and overall survival. These visits may be conducted by 
phone. Follow-up visit window is ±14 days. Following implementation of Amendment 7, no further collection of post-treatment follow-up data will occur for patients 
enrolled in Arm 2B or Arm 5; patient follow-up should continue per institutional standard of care. 
(f) Weight will be used to calculate BSA to determine dosing requirements. BSA used for dosing calculations should be updated if the weight changes more than 15%. 
(g) Safety laboratory assessments are outlined in Section 7.2 and will be performed locally. 
(h) A pregnancy test (urine or serum) must be performed for women of childbearing potential during screening, on Day 1 of each cycle, and at EoT. 
(i) ECG on Cycle 1 Day 8 must be performed prior to dosing. All other ECGs can be taken at any time during the study visit. All ECGs will be done as triplicate 12-lead ECGs. 
(j) SAEs will be captured from the time of signing of the informed consent through 30 days after last dose of any study drug, and non-serious AEs from the time of first dose of 
any study drug through 30 days after last dose of any study drug. Following implementation of Amendment 7, see footnote (b) for safety event collection instructions for 
patients still receiving study drug in Arm 5. 
(k) All transfusions received by the patient from 16 weeks prior to enrolment until the EoT visit will be recorded. 
(l) Subsequent therapies will be recorded for 3 months after the last dose of study drug or until implementation of Amendment 7 for patients enrolled in Arm 2B or Arm 5. 
(m) If dosing on Days 6 and 7 is not possible due to logistical limitations, these doses may be delayed to Days 8 and 9. 
(n) Peripheral blood samples will be sent to a central lab for assessment of RARA super-enhancer associated biomarker and IRF8 biomarker at screening. Other associated RARA 
pathway genes will also be analyzed. 
(o) All patients will have peripheral blood sample collected at screening for biomarker sequencing analysis to be performed at a central lab (assuming sufficient material is 
available at time of sample processing). 
(p) For U.S. only: All patients will have a whole blood sample collected at screening (same collection time as the biomarker assessment) for additional biomarker research. 
(q) All patients will have PK sampling on Day 8 of Cycle 1 at 2-4 hours and at 5-8 hours post-dose. PK sampling also on Day 22 of Cycle 1, and on Day 8 of Cycles 2, 3, and 4 at 
two time points at least 2 hours apart. If a patient's SY-1425 dose is modified to a different dose level (see Section 8.4) during the course of the study, PK sampling should 
occur within 8-15 days of dose adjustment following the same schedule as Cycle 1 Day 8. PK sampling is not required for patients in Arm 2A who receive SY-1425 in 
combination with azacitidine after relapse/unsatisfactory response with single agent SY-1425. 
(r) Absorption, distribution, metabolism, excretion PGx sample to be taken Cycle 1 Day 1 pre-dose. PGx sample is not required for patients in Arm 2A who receive SY-1425 in 
combination with azacitidine after relapse/unsatisfactory response with single agent SY-1425. 
(s) Peripheral blood will be collected in patients in Arms 2A and 2B on Day 1 of Cycle 1 pre-dose, on Day 8 of Cycle 1 pre-dose and 5 to 8 hours post-dose, on Day 22 of 
Cycle 1, and at EoT visit to determine changes in RNA including dehydrogenase/reductase (SDR family) member 3 (DHRS3). This sample should be collected in the same 
procedural timeframe as the corresponding PK sample. PD sampling is not required for patients in Arm 2A who receive SY-1425 in combination with azacitidine after 
relapse/unsatisfactory response with single agent SY-1425. 
(t) Cytogenetics and mutational analysis will be performed at screening and at the EoT visit. Cytogenetics and mutational analyses will be performed locally. 
(u) Bone marrow aspirates will be collected to assess morphologic response and minimal residual disease on Day 1 of Cycles 2, 3, 4, followed by every third cycle (7, 10, 13, 
etc.), and as clinically indicated. If a patient achieved a CR/CRi at Cycle 2 Day 1, the Cycle 3 Day 1 bone marrow aspirate is not required. A bone marrow aspirate should be 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
 
Amendment 7 (31 August 2022) 
Confidential  
Page 31 of 141 
collected to confirm relapse which will be recorded as an end of treatment sample and will be used for cytogenetics assessment. Bone marrow aspirate smears should be 
archived for potential future analysis. 
(v) Baseline assessment of immunophenotype by multiparameter flow cytometry  
(w) MRD should be measured when a patient has responded with a CR, per local practice. 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
 
Amendment 7 (31 August 2022) 
Confidential  
Page 32 of 141 
Table 4: Schedule of Assessment (Central Laboratory Sampling) (Arms 2B and 5) 
Study Visit 
Biomarker & 
Sequencing 
Pharmacokinetics Sample  
ADME PGx  
Pharmacodynamics  
(Arm 2B Only) 
Resistance Mechanism  
Screening 
blood samples 
collected any time 
during visit (a) 
 
 
 
 
Cycle 1 Day 1 
 
 
• Pre-dose 
• Pre-dose 
 
Cycle 1 Day 8 (b) 
 
• 2 post-dose samples at 
least 2 hours apart 
 
• Pre-dose (b) 
• 5-8 hours post dose 
 
Cycle 1 Day 22 
 
• 2 post-dose samples at 
least 2 hours apart 
 
• A post-dose sample to be 
collected at any time 
point during the visit 
 
Cycle 2 Day 1 
blood samples 
collected any time 
during visit 
 
 
 
 
Cycle 2 Day 8 
 
• 2 post-dose samples at 
least 2 hours apart 
 
 
 
Cycle 3 Day 8 
 
• 2 post-dose samples at 
least 2 hours apart 
 
 
 
Cycle 4 Day 8 
 
• 2 post-dose samples at 
least 2 hours apart 
 
 
 
Within 8-15 days of a 
dose adjustment 
 
• 2 post-dose samples at 
least 2 hours apart 
 
 
 
End of Treatment (c) 
blood samples 
collected any time 
during visit 
 
 
• Collected any time 
during visit 
• Collected any time 
during visit 
Abbreviations: ADME = absorption, distribution, metabolism, and excretion; PGx = pharmacogenomics. 
(a) For patients screened in France, only 2 samples will be collected. 
(b) For Cycle 1 Day 8, the morning dose of SY-1425 must be administered in clinic to allow for collection of the pre-dose (0 hour) sample. 
(c) Following implantation of Amendment 7, an End of Treatment Visit and the associated assessments will not be required for patients enrolled in Arm 5. 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
 
Amendment 7 (31 August 2022) 
Confidential  
Page 33 of 141 
Table 5: Schedule of Events (Arm 4) 
 
Screening 
(a) 
SY-1425 
Lead-In 
D -7 to -1 
Cycle 1 
Cycle 2 
Cycles 3-6 
Cycles 
7+ (b) 
Post Dose 
Adjustment 
Visit (c) 
End of 
Treatment 
(EoT) (d) 
Post- 
treatment 
Follow-up 
Study Day (D/d) 
Within 30 
days of 
dosing 
D -7 
D -4 
D1  
D8 
(±1d) 
D15 
(±1d)  
D22 
(±1d) 
D1 
(±1d) 
D8 
(±1d) 
D15 
(±1d) 
D22 
(±1d) 
D1 
(±2d) 
D15 
(±2d) 
D1 
(±2d) 
Within 8-15 
days of dose 
adjustment 
Within 30 
days of last 
dose (d) 
Every 3 
mo. post 
EoT 
(±14 d) (e) 
Baseline Documentation 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Eligibility Review 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight (f) 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
ECOG 
Performance 
Status 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
Physical Exam 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Safety Labs/Measurements 
Hematology (g) 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Serum Chemistries 
(g) 
X 
X 
 
X 
X 
X 
X 
X 
 
 
 
X 
 
X 
X 
X 
 
Coagulation (g) 
X 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
Triglycerides and 
Total Cholesterol 
(g) 
X 
X 
 
 
 
X 
 
X 
 
 
 
X 
 
X 
X 
X 
 
Urinalysis (g) 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
 
Amendment 7 (31 August 2022) 
Confidential  
Page 34 of 141 
Table 5: Schedule of Events (Arm 4) 
 
Screening 
(a) 
SY-1425 
Lead-In 
D -7 to -1 
Cycle 1 
Cycle 2 
Cycles 3-6 
Cycles 
7+ (b) 
Post Dose 
Adjustment 
Visit (c) 
End of 
Treatment 
(EoT) (d) 
Post- 
treatment 
Follow-up 
Study Day (D/d) 
Within 30 
days of 
dosing 
D -7 
D -4 
D1  
D8 
(±1d) 
D15 
(±1d)  
D22 
(±1d) 
D1 
(±1d) 
D8 
(±1d) 
D15 
(±1d) 
D22 
(±1d) 
D1 
(±2d) 
D15 
(±2d) 
D1 
(±2d) 
Within 8-15 
days of dose 
adjustment 
Within 30 
days of last 
dose (d) 
Every 3 
mo. post 
EoT 
(±14 d) (e) 
Pregnancy Test (h) 
X 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
Pulmonary 
Function Testing 
(i) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood Group and 
Type Assessment, 
and Indirect 
Antiglobulin Test 
(IAT) (j) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Triplicate ECG (k) 
X 
X 
X 
 
 
 
 
X 
 
 
 
C3 & 
C4 
only 
 
 
 
X 
 
Vital Signs (l) 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Clinical Assessments 
Adverse Event 
Monitoring (m) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Prior/Concomitant 
Medication 
Review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Red Blood Cell 
and Platelet 
Transfusions (n) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Dosing 
Compliance/ 
Diary Review 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
 
Amendment 7 (31 August 2022) 
Confidential  
Page 35 of 141 
Table 5: Schedule of Events (Arm 4) 
 
Screening 
(a) 
SY-1425 
Lead-In 
D -7 to -1 
Cycle 1 
Cycle 2 
Cycles 3-6 
Cycles 
7+ (b) 
Post Dose 
Adjustment 
Visit (c) 
End of 
Treatment 
(EoT) (d) 
Post- 
treatment 
Follow-up 
Study Day (D/d) 
Within 30 
days of 
dosing 
D -7 
D -4 
D1  
D8 
(±1d) 
D15 
(±1d)  
D22 
(±1d) 
D1 
(±1d) 
D8 
(±1d) 
D15 
(±1d) 
D22 
(±1d) 
D1 
(±2d) 
D15 
(±2d) 
D1 
(±2d) 
Within 8-15 
days of dose 
adjustment 
Within 30 
days of last 
dose (d) 
Every 3 
mo. post 
EoT 
(±14 d) (e) 
HRQOL (FACT-
Leu) 
X 
 
 
X 
 
 
 
 
 
 
 
C4 
only 
 
 
 
X 
 
Subsequent 
Therapies (o) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
EFS and Overall 
Survival Follow-
Up 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
Study Treatment 
SY-1425 
 
Continuous Dosing 
X 
 
 
Pre-infusion 
Medications (p) 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Daratumumab 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Post-infusion 
Medications (q) 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Specialty Lab Assessments 
Peripheral blood 
RARA Super-
Enhancer 
Associated 
Biomarker 
Assessment and 
IRF8 biomarker (r) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
 
Amendment 7 (31 August 2022) 
Confidential  
Page 36 of 141 
Table 5: Schedule of Events (Arm 4) 
 
Screening 
(a) 
SY-1425 
Lead-In 
D -7 to -1 
Cycle 1 
Cycle 2 
Cycles 3-6 
Cycles 
7+ (b) 
Post Dose 
Adjustment 
Visit (c) 
End of 
Treatment 
(EoT) (d) 
Post- 
treatment 
Follow-up 
Study Day (D/d) 
Within 30 
days of 
dosing 
D -7 
D -4 
D1  
D8 
(±1d) 
D15 
(±1d)  
D22 
(±1d) 
D1 
(±1d) 
D8 
(±1d) 
D15 
(±1d) 
D22 
(±1d) 
D1 
(±2d) 
D15 
(±2d) 
D1 
(±2d) 
Within 8-15 
days of dose 
adjustment 
Within 30 
days of last 
dose (d) 
Every 3 
mo. post 
EoT 
(±14 d) (e) 
Blood sample for 
biomarker research 
(s) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SY-1425 
Pharmacokinetics 
(t) 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Daratumumab 
Pharmacokinetics 
(u) 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Blood Sample for 
ADME PGx (v) 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood Sample for 
Pharmacodynamic
s (w) 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
Peripheral Blood 
for CD38 & 
Myeloid Marker 
Immunophenotypi
ng (x) 
 
X 
X 
X 
X 
X 
 
X 
 
 
 
C3 & 
C4 
only 
 
Every 
3rd 
Cycle 
 
X 
 
Blood Sample for 
Resistance 
Mechanism 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Cytogenetics and 
Mutational 
Analysis (y) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
 
Amendment 7 (31 August 2022) 
Confidential  
Page 37 of 141 
Table 5: Schedule of Events (Arm 4) 
 
Screening 
(a) 
SY-1425 
Lead-In 
D -7 to -1 
Cycle 1 
Cycle 2 
Cycles 3-6 
Cycles 
7+ (b) 
Post Dose 
Adjustment 
Visit (c) 
End of 
Treatment 
(EoT) (d) 
Post- 
treatment 
Follow-up 
Study Day (D/d) 
Within 30 
days of 
dosing 
D -7 
D -4 
D1  
D8 
(±1d) 
D15 
(±1d)  
D22 
(±1d) 
D1 
(±1d) 
D8 
(±1d) 
D15 
(±1d) 
D22 
(±1d) 
D1 
(±2d) 
D15 
(±2d) 
D1 
(±2d) 
Within 8-15 
days of dose 
adjustment 
Within 30 
days of last 
dose (d) 
Every 3 
mo. post 
EoT 
(±14 d) (e) 
Bone Marrow 
Aspirate for 
Eligibility  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Bone Marrow 
Aspirate for 
Response  
Assessment (z) 
 
 
 
 
 
 
 
X 
 
 
 
C3 & 
C4 
only 
 
Every 
3rd 
Cycle 
 
X 
 
Immunophenotypi
ng (aa) 
X 
 
 
 
 
 
 
X 
 
 
 
C3 & 
C4 
only 
 
Every 
3rd 
Cycle 
 
 
 
Abbreviations: ADME = absorption, distribution, metabolism, and excretion; AML = acute myeloid leukemia; BSA = body surface area; CR = complete remission; CRi = 
complete remission, morphologic, with incomplete blood count recovery; D/d = day(s); ECOG = Eastern Cooperative Oncology Group; EoT = end of treatment; ECG = 
electrocardiogram; EFS = event-free survival; EPO = erythropoietin; FACT-Leu = Factual Assessment of Cancer Therapy-Leukemia; HRQOL = Health Related Quality of Life; 
IRF8 = Interferon Regulatory Factor 8; MDS = Myelodysplastic Syndrome; PD = pharmacodynamic; PGx = pharmacogenomics; PK = pharmacokinetic; RARA = retinoic acid 
receptor alpha; SAE = serious adverse event. 
 
(a) Screening assessments must be performed within 30 days of study drug administration. Screening assessments may also occur on Day -7 prior to dosing. 
(b) Cycle 7 schedule should be followed for all subsequent cycles. 
(c) If a patient has an SY-1425 dose modification (decrease or increase) to a new dose level (as defined in Section 8.4), a dose adjustment visit must be performed within 8-15 
days of the dose adjustment. This visit can be combined with another scheduled visit if it is scheduled to occur within that window.  
(d) An EoT visit should occur within 30 days of the last dose of study drug, but prior to any subsequent therapies.  
(e) Patients will enter post-treatment follow-up. Visits should occur every 3 months post EoT for response assessment and overall survival. These visits may be conducted by 
phone. Follow-up visit window is +/- 14 days. 
(f) Weight will be used to calculate BSA to determine dosing requirements. BSA used for SY-1425 dosing calculations should be updated if the weight changes more than 15%. 
Daratumumab dose will be calculated based on the patient’s weight at Cycle 1 Day 1 rounded to the nearest kilogram. The dose of daratumumab will remain constant 
throughout the study unless the patient’s weight changes more than 10%. 
(g) Safety laboratory assessments are outlined in Section 7.2 of the protocol and will be performed locally. Based on emerging safety information for daratumumab, patients 
enrolled into Arm 4 prior to the Syros administrative letter dated 26 December 2018 who had been receiving daratumumab for less than 6 months as of that date, an HBV 
serology test should be performed at the next scheduled visit. Patients with resolved infection (ie, patients who are HBsAg negative but positive for antiHBs or antiHBc) 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
 
Amendment 7 (31 August 2022) 
Confidential  
Page 38 of 141 
should also have HBV DNA PCR test performed. The Sponsor should be consulted to determine the clinical management of patients who are either seropositive for HBV 
(defined by a positive test for HBsAg) or PCR positive for HBV.  
(h) A pregnancy test (urine or serum) must be completed for women of child bearing potential during screening, on Day -7 (pre-dose), on Day 1 of each cycle visit, and at EoT.  
(i) For patients with COPD, FEV1 should be measured. Symptom and disease directed exams should be performed as clinically indicated during the treatment phase. 
(j) ABO, Rh and IAT will be assessed. A wallet card with the patient’s blood type and IAT will be provided to patients. 
(k) ECG on Day -7 must be performed prior to dosing. All other ECGs can be taken at any time during the study visit. All ECGs will be done as triplicate 12-lead ECGs. 
(l) Vital signs (blood pressure, temperature, pulse) measured in sitting position. On Cycle 1 Day 1: before the start of daratumumab infusion; at 0.5, 1, 1.5, 2, 3.5 hours after the 
start of the infusion; at the end of the infusion; 0.5 and 1 hour after the end of the infusion. For all other infusions, vital signs will be measured before infusion starts and at the 
end of the infusion. 
(m) SAEs will be captured from the time of signing of the Informed Consent Form through 30 days after last dose of any study drug, and non-serious AEs from the time of first 
dose of any study drug through 30 days after last dose of any study drug.  
(n) All transfusions received by the patient from 16 weeks prior to enrollment until the EoT visit will be recorded. 
(o) Subsequent therapies will be recorded for 3 months after the last dose of study drug. 
(p) Administer pre-infusion medications approximately 1 to 3 hours before daratumumab infusion. One hour prior to infusion is preferred, however, PO pre-infusion medications 
may be administered within 3 hours before the infusion. Includes acetaminophen (650-1000 mg), antihistamine (diphenhydramine 25-50 mg, or equivalent), 
methylprednisolone (100 mg or equivalent for the first 2 doses, and 60 mg for all subsequent doses in the absence of infusion related reactions in the first 2 doses), and a 
leukotriene inhibitor (bronchospasm prophylaxis is optional with first dose on Cycle 1 Day 1 only for patients considered at risk for bronchospasm). See Section 8.2.3.2.1. 
(q) All subjects will receive oral methylprednisolone (20 mg or equivalent) on the 2 days following all daratumumab infusions (beginning the day after the infusion). In the 
absence of infusion related AEs after the first 3 infusions, post-infusion corticosteroids should be administered per investigator discretion. Post-infusion medications may also 
include antihistamine (diphenhydramine 25-50 mg, or equivalent), leukotriene inhibitor, short-acting β2 adrenergic receptor agonist (e.g. salbutamol aerosol), and control 
medications for lung disease (e.g. inhaled corticosteroids ± long-acting β2 adrenergic receptor agonists for patients with asthma; long-acting bronchodilators such as 
tiotropium or salmeterol ± inhaled corticosteroids for patients with COPD). See Section 8.2.3.2.2. 
(r) Peripheral blood sample will be sent to a central lab for assessment of RARA super-enhancer associated biomarker and IRF8 biomarker at screening to confirm eligibility. 
Other associated RARA pathway genes will also be analyzed. 
(s) All patients will have a whole blood sample collected at screening (same collection time as the biomarker assessment) for additional biomarker research. 
(t) SY-1425 PK: All patients will have PK sampling pre-dose (0h), and 0.5, 1, 2, 4, 6, 8 hours post-dose on Days -7 and -4. If a patient’s SY-1425 dose is modified to a different 
dose level (see Section 8.4) during the course of the study, PK sampling should occur within 8-15 days of the dose adjustment following the same schedule as Day -7. 
(u) Daratumumab PK: All patients will have PK sampling on Cycle 1 Day 1 prior to infusion (0h) and prior to the end of infusion (5-10 mins before end of infusion), and on 
Cycle 1 Day 8 prior to infusion (0h). 
(v) Absorption, distribution, metabolism, excretion PGx sample to be taken pre-dose. 
(w) Peripheral blood will be collected in all patients on Day -7 pre-dose and 5-8 hours post-dose, on Day 8 of Cycle 1, and at EoT visit to determine changes in RNA including 
dehydrogenase/reductase (SDR family) member 3 (DHRS3). This sample should be collected in the same procedural timeframe as the corresponding PK sample.  
(x) Peripheral blood collected for central analysis of CD38 and myeloid marker immunophenotyping on Days -7 (pre-dose) and -4; Days 1, 8 and 15 of Cycle 1; Day 1 of Cycles 
2, 3, 4, followed by every third cycle (7, 10, 13, etc); and EoT. For timepoints on days on which daratumumab is administered, collection is performed prior to daratumumab 
dosing. 
(y) Cytogenetics and mutational analysis will be performed at screening and at the EoT visit. Cytogenetics and mutational analyses will be performed locally.  
(z) Bone marrow aspirates will be collected to assess response on Day 1 of Cycles 2, 3, 4, followed by every third cycle (7, 10, 13, etc.), and as clinically indicated. If a patient 
achieved a CR/CRi at Cycle 2 Day 1, the Cycle 3 Day 1 bone marrow aspirate is not required. A bone marrow aspirate should be collected to confirm relapse which will be 
recorded as an end of treatment sample and will be used for cytogenetics assessment 
(aa) Bone marrow aspirate samples will be collected for immunophenotyping to measure myeloid differentiation markers and will be analyzed centrally at screening and when 
aspirates are performed to assess response [see footnote (y), above]. Immunophenotyping may also be performed locally when clinically indicated on peripheral blood and/or 
bone marrow aspirate to measure myeloid differentiation markers. 
 
 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
 
Amendment 7 (31 August 2022) 
Confidential  
Page 39 of 141 
Table 6: Schedule of Assessment (Central Laboratory Sampling) (Arm 4) 
 
Study Visit 
Biomarker 
Samples  
Pharmacokinetic Sampling 
ADME PGx 
Sample  
Pharmacodynamics  
Sample  
CD38 & Myeloid 
Marker 
Immunophenotyping 
Resistance 
Mechanism 
Immunophenotyping 
(Bone Marrow 
Aspirate) 
SY-1425 PK 
Daratumumab PK 
Screening 
2 blood samples 
collected any time 
during visit (a) 
 
 
 
 
 
 
Within 30 days of 
dosing 
SY-1425 
Lead-In 
Day -7 (b) 
 
• pre-dose (0h) (b) 
• 0.5 hours post-
dose (± 15 mins) 
• 1 hour post-dose 
(± 15 mins) 
• 2 hours post-dose  
(± 15 mins) 
• 4 hours post-dose 
(± 30 mins) 
• 6 hours post-dose  
(±30 mins) 
• 8 hours post-dose  
(±30 mins) (c) 
 
• Pre-dose (b) 
• Pre-dose (b) 
• 5-8 hours post 
dose 
• Collected pre-dose 
(b), (d) 
 
 
SY-1425 
Lead-In 
Day -4 (b) 
 
• pre-dose (0h) (b) 
• 0.5 hours post-
dose (± 15 mins) 
• 1 hour post-dose 
(± 15 mins) 
• 2 hours post-dose  
(± 15 mins) 
• 4 hours post-dose 
(± 30 mins) 
• 6 hours post-dose  
(±30 mins) 
• 8 hours post-dose  
(±30 mins) (c) 
 
 
 
• Collected any time 
during visit (d) 
 
 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
 
Amendment 7 (31 August 2022) 
Confidential  
Page 40 of 141 
Table 6: Schedule of Assessment (Central Laboratory Sampling) (Arm 4) 
 
Study Visit 
Biomarker 
Samples  
Pharmacokinetic Sampling 
ADME PGx 
Sample  
Pharmacodynamics  
Sample  
CD38 & Myeloid 
Marker 
Immunophenotyping 
Resistance 
Mechanism 
Immunophenotyping 
(Bone Marrow 
Aspirate) 
SY-1425 PK 
Daratumumab PK 
Cycle 1 
Day 1 
 
 
• Prior to 
daratumumab 
infusion (0h) 
• Prior to the end 
of daratumumab 
infusion (5-10 
mins before end 
of infusion) 
 
 
• Collected prior to 
daratumumab 
dosing (d) 
 
 
Cycle 1 
Day 8 
 
 
• Prior to 
daratumumab 
infusion (0h) 
 
• A post-dose 
sample to be 
collected at any 
time point during 
the visit 
• Collected prior to 
daratumumab 
dosing (d) 
 
 
Cycle 1 
Day 15 
 
 
 
 
 
• Collected prior to 
daratumumab 
dosing (d) 
 
 
Cycle 2 
Day 1 
 
 
 
 
 
• Collected prior to 
daratumumab 
dosing (d) 
 
Bone marrow aspirate 
sample collected 
Cycle 3 
Day 1 
 
 
 
 
 
• Collected prior to 
daratumumab 
dosing (d) 
 
Bone marrow aspirate 
sample collected 
Cycle 4 
Day 1 
 
 
 
 
 
• Collected prior to 
daratumumab 
dosing (d) 
 
Bone marrow aspirate 
sample collected 
Cycle 7 
Day 1 and 
every 3rd 
cycle 
thereafter 
 
 
 
 
 
• Collected prior to 
daratumumab 
dosing (d) 
 
Bone marrow aspirate 
sample collected 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
 
Amendment 7 (31 August 2022) 
Confidential  
Page 41 of 141 
Table 6: Schedule of Assessment (Central Laboratory Sampling) (Arm 4) 
 
Study Visit 
Biomarker 
Samples  
Pharmacokinetic Sampling 
ADME PGx 
Sample  
Pharmacodynamics  
Sample  
CD38 & Myeloid 
Marker 
Immunophenotyping 
Resistance 
Mechanism 
Immunophenotyping 
(Bone Marrow 
Aspirate) 
SY-1425 PK 
Daratumumab PK 
Within 8-
15 days of 
a dose 
adjustment 
(b) 
 
• pre-dose (0h) (b) 
• 0.5 hours post-
dose (± 15 mins) 
• 1 hour post-dose 
(± 15 mins) 
• 2 hours post-dose  
(± 15 mins) 
• 4 hours post-dose 
(± 30 mins) 
• 6 hours post-dose  
(± 30 mins) 
• 8 hours post-dose  
(± 30 mins) (c) 
 
 
 
 
 
 
End of 
Treatment 
 
 
 
 
• 1 sample 
collected any time 
during visit 
• Collected any time 
during visit (d) 
• 1 sample 
collected 
any time 
during 
visit 
 
Abbreviations: mins = minutes; 0h = zero hour; PGx = pharmacogenomics 
(a) For patients screened in France, only 2 samples will be collected. 
(b) For Days -7 and -4, and post-dose adjustment visits, the morning dose of SY-1425 must be administered in clinic to allow for collection of the pre-dose (0 hour) samples. 
(c) Collection of the 8 hour post-dose samples may be omitted due to logistical issues and patient hardship when necessary. 
(d) Refer to Lab Manual for details on number of collection tubes 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 42 of 141 
TABLE OF CONTENTS 
SPONSOR PROTOCOL APPROVAL ...........................................................................................3 
CONTACT INFORMATION ..........................................................................................................4 
PROTOCOL SYNOPSIS ................................................................................................................5 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................50 
1. 
BACKGROUND ........................................................................................................53 
1.1. 
Acute Myeloid Leukemia and Myelodysplastic Syndrome ........................................53 
1.2. 
SY-1425 ......................................................................................................................53 
1.2.1. 
Preclinical Data ...........................................................................................................54 
1.2.1.1. 
Mechanism of Action .................................................................................................54 
1.2.1.2. 
Safety Pharmacology, Toxicology, and Pharmacokinetic Studies .............................54 
1.2.2. 
Clinical Experience .....................................................................................................56 
1.3. 
Azacitidine ..................................................................................................................59 
1.3.1. 
Rationale for Combination of SY-1425 and Azacitidine ...........................................59 
1.4. 
Daratumumab .............................................................................................................60 
1.4.1. 
Rationale for Combination of SY-1425 and Daratumumab .......................................61 
1.5. 
Study Rationale ...........................................................................................................61 
2. 
OBJECTIVES .............................................................................................................63 
2.1. 
Primary .......................................................................................................................63 
2.2. 
Secondary ...................................................................................................................63 
2.3. 
Exploratory .................................................................................................................63 
3. 
STUDY ENDPOINTS ................................................................................................65 
3.1. 
Primary .......................................................................................................................65 
3.2. 
Secondary ...................................................................................................................65 
3.3. 
Exploratory Endpoints ................................................................................................66 
4. 
STUDY DESIGN .......................................................................................................67 
5. 
STUDY POPULATION .............................................................................................70 
5.1. 
Number of Patients .....................................................................................................70 
5.2. 
Duration of Study .......................................................................................................70 
5.3. 
Inclusion Criteria ........................................................................................................71 
5.4. 
Exclusion Criteria .......................................................................................................73 
6. 
STUDY CONDUCT ...................................................................................................76 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 43 of 141 
6.1. 
General Instructions ....................................................................................................76 
6.2. 
Study Procedures by Time Point ................................................................................76 
6.3. 
Premature Discontinuation .........................................................................................76 
7. 
DESCRIPTION OF STUDY PROCEDURES ...........................................................78 
7.1. 
Baseline Documentation .............................................................................................78 
7.1.1. 
Informed Consent .......................................................................................................78 
7.1.2. 
Eligibility Review .......................................................................................................78 
7.1.3. 
Medical History ..........................................................................................................78 
7.1.4. 
Demographics .............................................................................................................78 
7.1.5. 
Height .........................................................................................................................78 
7.1.6. 
Weight .........................................................................................................................78 
7.1.7. 
ECOG Performance Status .........................................................................................78 
7.1.8. 
Physical Examination .................................................................................................78 
7.2. 
Safety and Laboratory Assessments ...........................................................................79 
7.2.1. 
Hematology .................................................................................................................79 
7.2.2. 
Serum Chemistries ......................................................................................................79 
7.2.3. 
Coagulation .................................................................................................................79 
7.2.4. 
Triglycerides and Total Cholesterol ...........................................................................79 
7.2.5. 
Urinalysis ....................................................................................................................79 
7.2.6. 
Pregnancy Test ............................................................................................................79 
7.2.7. 
Electrocardiograms .....................................................................................................79 
7.2.8. 
Vital Signs ..................................................................................................................80 
7.2.9. 
Pulmonary Function Testing (Arm 4 Only)................................................................80 
7.2.10. 
Blood Group and Type Assessment, and Indirect Antiglobulin Test (Arm 4 
Only) ...........................................................................................................................80 
7.3. 
Clinical Assessments ..................................................................................................81 
7.3.1. 
Adverse Event Monitoring .........................................................................................81 
7.3.2. 
Prior, Concomitant, and Subsequent Medication Review ..........................................81 
7.3.3. 
Blood Product Transfusions .......................................................................................81 
7.3.4. 
Erythropoietin Levels – Lower-Risk MDS Patients Only ..........................................81 
7.3.5. 
Dosing Compliance/Diary Review .............................................................................81 
7.3.6. 
Health Related Quality of Life ...................................................................................81 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 44 of 141 
7.3.7. 
Event Free Survival and Overall Survival - AML and Higher-Risk MDS 
Patients Only ...............................................................................................................82 
7.4. 
Specialty Laboratory Assessments .............................................................................82 
7.4.1. 
RARα and IRF8 biomarker assessments ....................................................................82 
7.4.2. 
Development of Future Companion Diagnostic .........................................................82 
7.4.3. 
Identification of Additional Biomarkers of Response to SY-1425 ............................82 
7.4.4. 
Identification of Resistance Mechanisms for SY-1425 ..............................................82 
7.4.5. 
Bone Marrow Sample Collection - AML and Higher-Risk MDS Patients 
Only ............................................................................................................................82 
7.4.5.1. 
Bone Marrow Aspirate for Response Assessment (AML and Higher-Risk 
MDS Patients Only) ....................................................................................................83 
7.4.5.2. 
Immunophenotyping (AML and Higher-Risk MDS Patients Only) ..........................83 
7.4.5.3. 
CD38 and Myeloid Marker Immunophenotyping (Central Analysis) ........................83 
7.4.6. 
Pharmacokinetics ........................................................................................................84 
7.4.7. 
ADME Pharmacogenomics ........................................................................................84 
7.4.8. 
Pharmacodynamics .....................................................................................................85 
7.4.9. 
Additional Exploratory Biomarker Analysis ..............................................................85 
7.5. 
Amendment 7 Study Procedure Changes ...................................................................85 
8. 
STUDY DRUG MANAGEMENT .............................................................................87 
8.1. 
Allocation to Treatment ..............................................................................................87 
8.2. 
Study Drug Administration.........................................................................................87 
8.2.1. 
SY-1425 ......................................................................................................................87 
8.2.2. 
Azacitidine ..................................................................................................................88 
8.2.3. 
Daratumumab .............................................................................................................88 
8.2.3.1. 
Daratumumab Preparation ..........................................................................................88 
8.2.3.2. 
Daratumumab Administration ....................................................................................88 
8.3. 
Reference/Control Therapy ........................................................................................91 
8.4. 
Recommended Dose Modifications ............................................................................91 
8.4.1. 
SY-1425 Guidelines ....................................................................................................91 
8.4.1.1. 
Dose Increases ............................................................................................................91 
8.4.1.2. 
Dose Reductions .........................................................................................................92 
8.4.1.3. 
Non-Hematologic Adverse Events .............................................................................92 
8.4.1.4. 
Hematologic Adverse Events: ....................................................................................93 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 45 of 141 
8.4.1.5. 
Discontinuation of Therapy Due to Treatment-Related Toxicity ...............................93 
8.4.1.6. 
Alternative Dosing Regimens .....................................................................................93 
8.4.2. 
Azacitidine Guidelines ................................................................................................93 
8.4.2.1. 
Dose Adjustments Based on Hematology Laboratory Values ...................................93 
8.4.2.2. 
Dose Adjustments Based on Serum Electrolytes and Renal Toxicity ........................94 
8.4.3. 
Dose Delay Guidelines for Patients Receiving SY-1425 in Combination with 
Azacitidine ..................................................................................................................94 
8.4.4. 
Daratumumab Guidelines ...........................................................................................95 
8.4.4.1. 
Daratumumab Cycle Delay .........................................................................................95 
8.4.4.2. 
Daratumumab Interruption or Missed Doses ..............................................................96 
8.4.4.3. 
Dose Delay Guidelines for Patients Receiving SY-1425 in Combination with 
Daratumumab .............................................................................................................96 
8.5. 
Study Drug Dosing Compliance .................................................................................96 
8.5.1. 
SY-1425 ......................................................................................................................96 
8.5.2. 
Azacitidine ..................................................................................................................97 
8.5.3. 
Daratumumab .............................................................................................................97 
8.6. 
Study Drug Storage and Drug Accountability ............................................................97 
8.6.1. 
SY-1425 ......................................................................................................................97 
8.6.2. 
Azacitidine ..................................................................................................................97 
8.6.3. 
Daratumumab .............................................................................................................97 
8.7. 
Concomitant Medications ...........................................................................................98 
8.7.1. 
Cytotoxic or Investigational Therapy .........................................................................98 
8.7.2. 
Other Agents Targeting CD38 (Arm 4 Only) .............................................................98 
8.7.3. 
Oral Hydroxyurea .......................................................................................................98 
8.7.4. 
Antibacterial, Antifungal, and Antiviral .....................................................................98 
8.7.5. 
Hematopoietic Growth Factors ...................................................................................98 
8.7.6. 
Platelet Transfusions ...................................................................................................98 
8.7.7. 
Red Blood Cell Transfusions ......................................................................................99 
8.7.8. 
Moderate and Strong Inhibitors and Strong Inducers of CYP3A4 .............................99 
8.7.9. 
Antifibrinolytic ...........................................................................................................99 
8.7.10. 
Retinoic Acid Syndrome .............................................................................................99 
8.7.11. 
Multivitamin and Supplements ...................................................................................99 
8.7.12. 
Antacids and Proton pump inhibitors .........................................................................99 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 46 of 141 
8.8. 
Description of SY-1425 ............................................................................................100 
8.8.1. 
Drug Substance .........................................................................................................100 
8.8.2. 
Drug product .............................................................................................................100 
8.8.3. 
Drug Product Precautions .........................................................................................101 
8.9. 
Description of Azacitidine ........................................................................................101 
8.10. 
Description of Daratumumab ...................................................................................101 
9. 
ADVERSE EVENTS................................................................................................102 
9.1. 
Definition of an Adverse Event ................................................................................102 
9.2. 
Definition of a Serious Adverse Event .....................................................................102 
9.3. 
Procedures for Eliciting, Recording, and Reporting Adverse Events ......................103 
9.3.1. 
Eliciting and Recording Adverse Events ..................................................................103 
9.3.2. 
Adverse Event Relationship Assessment ..................................................................103 
9.3.3. 
Adverse Event Severity Assessment ........................................................................104 
9.4. 
Specific Instructions for Recording Adverse Events on the eCRF ...........................104 
9.4.1. 
Diagnosis Versus Signs and Symptoms ...................................................................104 
9.4.2. 
Adverse Events Occurring Due to Other Events ......................................................104 
9.4.3. 
Persistent of Recurrent Adverse Events ...................................................................105 
9.4.4. 
Disease Under Study .................................................................................................105 
9.4.5. 
New Cancers .............................................................................................................105 
9.5. 
Reporting of Serious Adverse Events .......................................................................105 
9.6. 
Reporting of Adverse Events of Special Interest ......................................................106 
9.7. 
Pregnancy and Birth Events Procedures ...................................................................106 
9.8. 
Overdose ...................................................................................................................107 
9.9. 
Clinical Laboratory Changes ....................................................................................107 
9.10. 
Reporting of Serious Adverse Events to Institutional Review Boards/Ethics 
Committees ...............................................................................................................108 
9.11. 
Reporting of Serious Adverse Events to Regulatory Authorities .............................108 
10. 
STATISTICS ............................................................................................................109 
10.1. 
General Procedures ...................................................................................................109 
10.2. 
Analysis Populations ................................................................................................109 
10.3. 
Determination of Sample Size ..................................................................................109 
10.4. 
Statistical Analysis ....................................................................................................110 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 47 of 141 
10.4.1. 
Demographic and Baseline Characteristics ..............................................................110 
10.4.2. 
Analysis of Efficacy .................................................................................................110 
10.4.2.1. 
Primary Endpoints ....................................................................................................110 
10.4.3. 
Secondary Endpoints ................................................................................................111 
10.4.4. 
Exploratory Endpoints ..............................................................................................112 
10.4.5. 
Analysis of Safety .....................................................................................................113 
10.4.5.1. 
Adverse Events .........................................................................................................113 
10.4.5.2. 
Laboratory Determination ........................................................................................113 
10.4.5.3. 
Other Safety Data .....................................................................................................113 
10.5. 
Interim Analysis ........................................................................................................114 
10.6. 
Pharmacokinetics ......................................................................................................114 
10.7. 
Pharmacodynamics ...................................................................................................114 
11. 
ETHICS AND RESPONSIBILITIES .......................................................................115 
11.1. 
Good Clinical Practice ..............................................................................................115 
11.2. 
Ethical Conduct of the Study ....................................................................................115 
11.3. 
Informed Consent .....................................................................................................115 
11.4. 
Records Management ...............................................................................................115 
11.5. 
Source Documentation ..............................................................................................116 
11.6. 
Study Drug Accountability .......................................................................................116 
11.7. 
Auditing and Monitoring ..........................................................................................116 
11.8. 
Study Report and Publications..................................................................................116 
11.9. 
Study Discontinuation ..............................................................................................116 
11.10. 
Confidentiality ..........................................................................................................117 
12. 
REFERENCES .........................................................................................................118 
13. 
APPENDICES ..........................................................................................................121 
APPENDIX 1. NAMES OF STUDY PERSONNEL................................................................122 
APPENDIX 2. ECOG PERFORMANCE STATUS.................................................................123 
APPENDIX 3. CRITERIA FOR DETERMINATION OF MDS IPSS-R RISK 
CATEGORY .............................................................................................................124 
APPENDIX 4. IWG RESPONSE CRITERIA TABLE FOR AML, MDS AND 
HEMATOLOGIC IMPROVEMENT .......................................................................125 
APPENDIX 5. CYP3A INHIBITORS/INDUCERS .................................................................129 
APPENDIX 6. FACT-AN QOL................................................................................................130 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 48 of 141 
APPENDIX 7. FACT-LEU QOL..............................................................................................133 
APPENDIX 8. ASTHMA GUIDELINES ................................................................................136 
APPENDIX 9. THE FAMILY OF ANTIHISTIMINE MEDICATIONS ................................140 
APPENDIX 10. CONVERSION TABLE FOR GLUCOCORTICOID DOSE ........................141 
 
 
 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 49 of 141 
LIST OF TABLES 
Table 1: 
Schedule of Events (Arms 1, 2A, and 3) ....................................................................19 
Table 2: 
Schedule of Assessment (Central Laboratory Sampling) (Arms 1, 2A, and 3) ..........24 
Table 3: 
Schedule of Events (Arms 2B, and 5, and Patients in Arm 2A who receive 
SY-1425 in Combination with Azacitidine After Relapse/Unsatisfactory 
Response with Single Agent SY-1425) ......................................................................27 
Table 4: 
Schedule of Assessment (Central Laboratory Sampling) (Arms 2B and 5) ...............32 
Table 5: Schedule of Events (Arm 4) ............................................................................................33 
Table 6: Schedule of Assessment (Central Laboratory Sampling) (Arm 4) ..................................39 
Table 7: List of Clinical APL Studies with Tamibarotene (SY-1425) ..........................................57 
Table 8: Daratumumab Infusion Rates ..........................................................................................89 
Table 9: Dose Increases of SY-1425 .............................................................................................91 
Table 10: Dose Reductions of SY-1425 ........................................................................................92 
Table 11: Azacitidine Dose Adjustments Based on Nadir Counts ................................................94 
Table 12: Azacitidine Dose Adjustments Based on Nadir Counts and Cellularity .......................94 
Table 13: Daratumumab Administration Schedule........................................................................96 
 
LIST OF FIGURES 
Figure 1: 
Study Schematic .........................................................................................................18 
Figure 2: 
Chemical Structure ...................................................................................................100 
 
 
 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 50 of 141 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Definition 
ADME 
Absorption, Distribution, Metabolism, and Excretion  
AE 
Adverse Event 
AESI 
Adverse Events of Special Interest 
ALT 
Alanine Aminotransferase 
AML 
Acute Myeloid Leukemia  
ANC 
Absolute Neutrophil Count 
APL 
Acute Promyelocytic Leukemia 
AST 
Aspartate Aminotransferase 
ATO 
Arsenic Trioxide 
ATRA 
All-Trans Retinoic Acid  
AUC 
Area Under the Curve 
ChIP 
Chromatin Immunoprecipitation 
CL/F 
Total Body Clearance from Plasma 
Cmax 
Maximum Plasma Concentration 
Cmin 
Minimum Plasma Concentration 
CNS 
Central nervous system 
COPD 
Chronic Obstructive Pulmonary Disease 
CR 
Complete Remission; Complete Response 
CRF 
Case Report Form 
CRi 
CR, morphologic, with incomplete blood count recovery  
CRO 
Contract Research Organization 
CTCAE 
Common Terminology Criteria for Adverse Events 
DHRS3 
Dehydrogenase/reductase (SDR family) member 3 
DOR 
Duration of Response 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EDC 
Electronic data capture (system) 
EFS 
Event-Free Survival 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 51 of 141 
Abbreviation 
Definition 
EoT 
End of Treatment  
EPO 
Erythropoietin 
EU 
European Union 
FACT-An 
Factual Assessment of Cancer Therapy-Anemia 
FACT-Leu 
Factual Assessment of Cancer Therapy-Leukemia 
FEV1 
Forced Expiratory Volume in 1 Second 
GCP 
Good Clinical Practice 
HBV 
Hepatitis B Virus 
HCC 
Hepatocellular Carcinoma 
HI 
Hematologic Improvement 
HIV 
Human immunodeficiency virus  
HRQOL 
Health Related Quality of Life 
IAT 
Indirect Antiglobulin Test 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IRF8 
Interferon Regulatory Factor 8 
IRB 
Institutional Review Board 
IPSS-R 
Revised International Prognostic Scoring System 
IRR 
Infusion Related Reaction 
IWG 
International Working Group 
MDS 
Myelodysplastic Syndrome  
MedDRA 
Medical Dictionary for Regulatory Activities 
MPD 
Myeloproliferative Disease 
MRD 
Minimal Residual Disease 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for 
Adverse Events 
ORR 
Overall Response Rate 
OS 
Overall Survival 
PD 
Pharmacodynamic 
PDX 
Patient Derived Xenograft 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 52 of 141 
Abbreviation 
Definition 
PK 
Pharmacokinetic 
po/PO 
By Mouth, Orally 
PR 
Partial remission 
RARα 
Retinoic Acid Receptor Alpha 
RBC 
Red Blood Cell 
RFS 
Relapse-free Survival 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SE 
Super-enhancers 
t1/2 
Half-life 
tmax 
Time to Maximum Concentration 
ULN 
Upper Limit of Normal 
US 
United States 
WBC 
White Blood Cell 
 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 53 of 141 
1. 
BACKGROUND 
1.1. 
Acute Myeloid Leukemia and Myelodysplastic Syndrome  
Acute Myeloid Leukemia (AML) is the most common leukemia in adults (Ferrara and Schiffer, 
2013) with an estimate of 20,830 new cases (4 new cases per 100,000) diagnosed in the United 
States (US) in 2015 (SEER data, 2016). Current treatment paradigms in younger patients  
(< 60 years) include induction regimens of standard cytotoxic chemotherapy (cytarabine and an 
anthracycline) and consolidation with additional chemotherapy and/or hematopoietic stem cell 
transplantation. While complete remission (CR) may be achieved initially in over 80% of 
patients, the 5-year overall survival is 35% to 40%. In older patients with AML (≥ 60 years), 
where the objectives of treatment are more commonly palliative, the use of hypomethylating 
agents may extend survival, but cure rates are very low. The estimated number of AML deaths in 
the US in 2015 was 10,460 with the percent of overall patients surviving 5 years reported at 
25.9% (SEER data, 2016).  
Myelodysplastic syndrome (MDS) is a heterogeneous hematopoietic disease commonly 
associated with bone marrow failure, peripheral blood cytopenias and associated complications 
of anemia, infection or hemorrhage, and progression to AML. The incidence of MDS is similar 
to that of AML, and is estimated at approximately 5 per 100,000, representing the most 
commonly diagnosed myeloid neoplasm in the US and Europe (Cogle et al, 2014). While MDS 
is generally a more indolent disease, early on lower-risk MDS patients commonly experience 
cytopenias with associated complications of anemia, infections, and/or bleeding. The prognosis 
of patients with later stage MDS is poor, and associated with low overall survival, similar to 
AML. Currently available therapies for MDS in the US include hypomethylating agents and 
lenalidomide which may limit the clinical impact of MDS. However, there remains unmet 
medical need for new agents that can extend survival and improve quality of life in patients with 
MDS (DeZern, 2015). 
1.2. 
SY-1425 
SY-1425 (tamibarotene) is an orally available, synthetic retinoid approved in Japan (Amnolake® 
Tablets) since April 2005 for the treatment of relapsed or refractory Acute Promyelocytic 
Leukemia (APL) whose disease is characterized by the presence of the t(15;17) translocation or 
expression of the PML-RARα gene. Tamibarotene was designed to be a more potent and 
selective retinoic acid receptor alpha (RARα) agonist with significantly improved in vivo 
pharmacologic properties compared to all-trans retinoic acid (ATRA), a component of the 
current first-line treatment of APL in the US. In vitro, tamibarotene is approximately 10-fold 
more potent than ATRA. It has a lower affinity for cellular retinoic acid binding protein, the 
overexpression of which is associated with resistance to ATRA, and is not subject to the 
predominant route of retinoid metabolism by Cyp26A1. These two features likely contribute to 
the sustained plasma levels of tamibarotene with repeated dosing. Furthermore, tamibarotene is a 
selective RAR agonist, whereas ATRA is a non-selective agonist of RAR,  and , and can 
isomerize in vivo to bind Retinoid X and peroxisome proliferator-activated receptors. This 
selectivity may provide SY-1425 a distinct and favorable safety, tolerability and efficacy profile. 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 54 of 141 
1.2.1. 
Preclinical Data 
1.2.1.1. 
Mechanism of Action 
SY-1425 is a potent and selective small molecule agonist of the RARα. Retinoic acid receptors 
are transcription factors that act as transcriptional repressors in the unbound state and as 
transcriptional activators when bound by an agonist ligand. As previously described in the 
context of APL with the t(15;17) PML-RARα translocation, RARα agonist binding relieves 
pathogenic repression of myeloid differentiation, enabling normalization of myelopoiesis and 
terminal differentiation of tumor cells. 
Super-enhancers (SEs) have recently been identified as exceptionally large clustered enhancer 
regions in the human genome, which are densely occupied by transcription factors, cofactors and 
chromatin regulators. They have been implicated in directing gene expression programs that 
define cell identity and also regulate oncogenes important in the pathogenesis of cancer. Syros 
has used genome wide profiling of AML patient samples to identify a SE at the RARA gene locus 
regulating expression of the RARA gene in a subset of non-APL AML primary patient samples. 
This SE leads to upregulation of RARα mRNA levels and defines a novel subset of AML that 
Syros found to be uniquely responsive to SY-1425 in vitro and in vivo. In non-APL AML cell 
lines, SY-1425 inhibited the proliferation of cells containing the RARA SE and high RARα 
transcript levels, but not in those without. Furthermore, in these sensitive cell lines genes 
consistent with promotion of differentiation were upregulated in response to SY-1425, similar to 
the RARα agonist response in APL. In patient-derived xenograft (PDX) models, tumor growth 
was inhibited and survival prolonged in those containing high levels of RARα mRNA expression 
but not in PDX models whose tumor cells contained low levels of RARα mRNA. These PDX 
models with high levels of RARα mRNA also demonstrated an increase in differentiated cell 
number and diversity, with a reduction of blasts in both peripheral blood and bone marrow with 
SY-1425 treatment. A similar correlation was made with the SE strength and mRNA levels of 
Interferon Regulatory Factor 8 (IRF8) which is a downstream nuclear effector of the interferon 
pathway known to have cross talk with RARα signaling.  
These studies indicate that RARα mRNA levels and mRNA levels for other RARα pathway-
associated genes, such as IRF8, may be potential biomarkers for response to SY-1425. Analysis 
of a public mRNA expression data set derived from MDS patient samples further indicates that 
similar to AML, MDS contains a subpopulation of patients with significantly elevated mRNA for 
RARα. Moreover, SE analysis has confirmed that MDS patient cells contain a RARA SE of 
comparable magnitude to those in AML, thus extending the potential for SY-1425 therapeutic 
use to MDS. 
These data lead to the hypothesis that the presence of a SE at the RARA gene and concomitant 
high levels of RARα mRNA expression (along with the RARα pathway associated gene IRF8) in 
AML and MDS patients predicts for response to SY-1425 treatment.  
1.2.1.2. 
Safety Pharmacology, Toxicology, and Pharmacokinetic Studies 
The nonclinical safety assessment indicated that the activity and toxicity profile of tamibarotene 
is qualitatively similar to other retinoids, a class for which there is extensive nonclinical and 
clinical experience. No novel toxicities have been identified for tamibarotene. In addition, the 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 55 of 141 
hematopoietic effects noted with tamibarotene appear to be less than those observed with other 
retinoids suggesting that tamibarotene may be better tolerated. 
A battery of safety pharmacology studies was conducted for the evaluation of the potential 
effects of tamibarotene on the nervous, respiratory, cardiovascular, renal and gastrointestinal 
systems in mice, rats and/or dogs. No major pharmacologic effects were identified in the safety 
pharmacology studies. 
In single dose studies with tamibarotene, the maximum tolerated nonlethal dose was 200 mg/kg 
and ≥100 mg/kg in the rat and dog, respectively. The LD50 in the rat was calculated to be 
~342 mg/kg. 
A series of genotoxicity studies were conducted with tamibarotene. Tamibarotene was negative 
for mutagenicity in a bacterial revertant mutation assay and negative for clastogenicity in an in 
vivo mouse micronucleus assay. Tamibarotene was positive for clastogenicity in a Chinese 
Hamster Lung cell assay at the highest concentration tested (86 μg/mL) without S9 activation but 
negative in the presence of S9 metabolic activation. 
Repeat oral dose toxicity studies have been conducted for up to 26 and 39 weeks in rats and 
dogs, respectively, at doses up to 0.4 mg/kg/day. The duration of the chronic toxicity studies is 
sufficient to support the proposed duration of dosing in the Phase 2 clinical trial. The spectrum of 
toxicities observed with tamibarotene are similar to other retinoids. Test article-related effects 
were noted in bone, testes, vaginal and uterine epithelium, gastrointestinal tract, skin and 
mucocutaneous junctions. Clinical pathology alterations included effect on white blood cell 
(WBC) differential (increased neutrophils), serum proteins and liver enzymes. Similar findings 
have been described in humans, supporting the appropriateness of rat and dog for the evaluation 
of tamibarotene. As anticipated with retinoids, tamibarotene exhibited reproductive toxicity 
including teratogenicity.  
The pharmacokinetic profile of tamibarotene, including absorption, distribution, metabolism, and 
excretion, has been evaluated primarily in rats and dogs following single and repeat dose oral 
and/or IV studies in which radiolabeled drug was administered. Pharmacokinetics in rats and 
dogs suggest that absorption following oral administration is relatively rapid in both species with 
time of maximum concentration (tmax) in the 1-2 hour range. The oral absorption in male rat was 
estimated as 67%. Plasma radioactivity levels at maximum plasma concentration (Cmax), area 
under the curve (AUC) and 24 hours after dosing suggested accumulation from Day 1 to Day 7 
of dosing. Whole body autoradiography studies in rats showed peak tissue radioactivity 
concentrations were observed within 1 hour post-dose for the majority of tissues and decreased 
over the 168 hours post-dose. The greatest concentration of radioactivity at 1 hour after dosing 
was observed in the liver, which was approximately 12 times higher than in the plasma. Levels 
of radioactivity in the adrenals, small intestine, kidney, duodenum, stomach, esophagus, 
Harderian gland, and brown fat were approximately 1.4 to 4.3 times higher than the levels in the 
plasma. Placental transfer of tamibarotene-related material was observed in pregnant rats with 
fetal liver showing the highest level of radioactivity.  
Protein binding was extensive in the rat, dog, and human plasma with binding ≥ 98.7%. Protein 
binding appeared to be independent of concentration and was also determined to be reversible. 
Tamibarotene was predominantly bound to serum albumin in the dog and human plasma with 
lesser amounts bound to γ-globulins (dog and human) and human α1-acid glycoprotein.  

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 56 of 141 
The in vitro studies suggest that there was a low to negligible potential for drug-drug interactions 
based on protein-binding characteristics.  
In vitro metabolism studies of tamibarotene conducted with human liver microsomes 
demonstrated extensive metabolism of the parent compound and the generation of two major 
metabolites, M-3 (6-hydroxy-tamibarotene) and M-4 (7-hydroxy-tamibarotene). The data also 
suggest that tamibarotene is unlikely to alter the pharmacokinetic (PK) profile of concomitantly 
administered drugs that are metabolized by CYP enzymes, but that the PK profile of 
tamibarotene may be altered by CYP3A4 inhibitors and inducers. 
The predominant moiety in the plasma of rats and dogs was the parent compound. There are 
potentially two major metabolic pathways in the rat. For the first potential major pathway, 
tamibarotene undergoes 6- or 7-hydroxylation to yield the related hydroxy-tamibarotene (M-3 or 
M-4). The hydroxylated tamibarotene is subsequently converted to oxo-tamibarotene (M-5 or 
M-7). For the second potential major pathway, tamibarotene undergoes hydrolysis of the 
carboxamide bond to yield tetrahydro-tetramethyl-naphthylamine and terephthalic acid. Taurine 
conjugates of tamibarotene, M-3, and M-4 (M-6, M-1, and M-2, respectively) are also formed. 
Excretion patterns following oral administration of radiolabeled tamibarotene were comparable 
for rats and dogs, with the primary route of excretion in the feces and the majority of the 
radioactive dose being excreted within the first 24 hours after dosing. Data generated in bile 
duct-cannulated rats dosed intraduodenally with bile from treated rats indicated that tamibarotene 
and its metabolites underwent extensive enterohepatic recirculation. Lacteal secretion of 
tamibarotene-related material was observed in rat with milk:plasma ratios of between 13- and 
94-fold. Unchanged tamibarotene was the major drug-related component in milk, with small 
amounts of M-6 and tetrahydro-tetramethyl-naphthylamine also detected.  
1.2.2. 
Clinical Experience 
Table 7: List of Clinical APL Studies with Tamibarotene (SY-1425) lists the previous oncology 
clinical studies of tamibarotene in patients with APL; all have been completed.  
 
 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 57 of 141 
Table 7: List of Clinical APL Studies with Tamibarotene (SY-1425) 
Study 
Identifier 
Indication 
Dose/regimen 
Design 
Patients Enrolled (N) 
Tobita et al. 
(1997) 
APL, relapsed 
after ATRA 
6 mg/m2/day induction 
for up to 8 weeks 
P2 efficacy and 
safety, open-label 
single arm 
25 (24 evaluable) 
TOS-80T-003 
Study (2002) 
APL (relapsed 
and treatment 
naïve) 
6 mg/m2/day induction 
for up to 8 weeks 
Ph2 PK, efficacy, 
and safety, open-
label single arm 
42 (41 safety-evaluable, 
39 efficacy-evaluable) 
Shinagawa et 
al. (2014) 
APL in remission 
after consolidation 
(Maintenance) 
6 mg/m2/day for 14 
days every 3 months for 
2 years 
Ph3 randomized 
controlled vs ATRA 
347, including 
134 randomize to 
maintenance with 
tamibarotene 
Sanford et al. 
(2015) 
APL relapsed 
after ATRA and 
ATO 
6 mg/m2/day induction 
and for up to six cycles 
of consolidation (every 
other month) for 1 year. 
Ph2 efficacy and 
safety, single arm, 
open-label 
14 
Wang et al. 
(2015) 
Relapsed APL 
6 mg/m²/day 
Ph3 randomized 
open-label, 
tamibarotene/ATO 
vs ATRA/ATO 
71, including 35 treated 
with tamibarotene 
 
In Japan, the recommended dose of tamibarotene for the treatment of patients with 
relapsed/refractory APL is 6 mg/m2/day administered as divided doses after breakfast and dinner. 
Approximately 1400 patients were treated with tamibarotene in clinical trials and in the post 
marketing approval setting. The Japanese approval is based on data from two Phase 2 studies, the 
Koseisho study (Tobita et al, 1997) and the TOS-80T-003 study (Amnolake® label). In the two 
Phase 2 clinical studies conducted with tamibarotene, 63 efficacy evaluable APL patients, who 
were either naïve to treatment (5 patients) or who had relapsed following a complete response 
with ATRA (58 patients), received tamibarotene (6 mg/m2/day; range 3 to 12 mg/m2/day) for up 
to 8 weeks. Overall, 60% of patients had a complete response to treatment. The TOS-80T-003 
study enrolled 42 Japanese patients with APL. Of 39 efficacy evaluable patients, 5 individuals 
were APL-treatment naïve and 34 had been treated previously with ATRA. Tamibarotene was 
also administered orally (PO) at a dose of 6 mg/m2/day for eight weeks (range; 3 to 
12 mg/m2/day). The overall complete response rate in these patients was 61.5%. In patients who 
were in first relapse following ATRA therapy, the complete response rate was 81%, compared to 
those in second or more relapse who had a 31% complete response rate. Most of the adverse 
events (AEs) seen were mild and typical of this class of drugs and the incidence of AEs was 
similar across the dose range tested. AEs included dry skin, skin rash, headache, bone pain, fever 
and elevated blood tests for cholesterol, lipids (triglycerides), liver function enzymes and WBC 
counts. Retinoic Acid Syndrome was reported in three patients (7.3%). Thus, tamibarotene was 
shown to be safe, well tolerated and efficacious in the Japanese population with 
relapsed/refractory APL. 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 58 of 141 
In the US, tamibarotene activity was evaluated by another sponsor in patients with relapsed or 
refractory APL following treatment with ATRA and arsenic trioxide (ATO). A Phase 2 trial was 
conducted at eight clinical sites in the US, Italy and Spain. A total of 14 patients, 12 of whom 
relapsed following ATRA and ATO and 2 of whom were refractory to ATRA and ATO and 
other chemotherapeutic agents, received treatment with tamibarotene (Sanford et al, 2015). 
Patients were dosed 6 mg/m2 daily for 56 days for induction then every other month as 
consolidation therapy for 1 year. The overall response rate (ORR) was 64% (n=9), the rate of 
complete cytogenetic response was 43% (n=6) and the rate of complete molecular response was 
21% (n=3). After induction, 5 (36%) patients achieved a CR, 4 (29%) achieved a CR with 
incomplete recovery of counts (CRi) and 5 (36%) had resistant disease. Six (43%) patients who 
achieved a CR (n = 3) or CRi (n = 3) achieved a complete cytogenetic response at a median time 
of 43 d after starting treatment (range 28–120 d). Seven of the 9 responders relapsed after a 
median of 4.6 months (range 1.6-26.8 months). The median event-free survival (EFS) was 
3.5 months and the median overall survival was 9.5 months. Adverse events reported in greater 
than 20% of the patients included rash, infection, headache, diarrhea, neutropenia, insomnia, 
oropharyngeal pain, dry skin and syncope. All of these events were Grade 1 or 2 except for 
neutropenia (Grade 2-4). The overall response rate of CR + CRi was 64% (9/14) in this APL 
study and was consistent with that observed in the Japanese Phase 2 studies. It is also notable 
that these patients were more heavily pre-treated (median of two prior remissions and failure of 
both ATRA and ATO).  
In China, a recent report (Wang et al, 2015) describes a phase 3, randomized, open-label, 
parallel-group, active-controlled, multicenter, study of 56 days treatment duration evaluating the 
efficacy and safety of 6 mg/m2/day tamibarotene versus 25 mg/m2/day ATRA, each in 
combination with ATO (0.15 mg/kg/day) in patients with relapsed APL. Patients were randomly 
assigned to ATRA + ATO (n=35) or tamibarotene + ATO (n=35). The CR rate was significantly 
higher in the tamibarotene + ATO group (80% vs. 54%; P = 0.022). The number who showed 
complete molecular remission was also significantly higher in the tamibarotene + ATO group 
(23% versus 3%), demonstrating a higher quality of remissions. The most commonly-reported 
adverse reactions included hypertriglyceridemia, hypercholesterolemia, rash, and elevation of 
alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, in both groups. 
The tolerability observed in the study group was considered to be similar between groups. The 
only adverse finding reported to show an appreciable intergroup difference was leukocytosis, 
which occurred at a significantly lower frequency in the tamibarotene + ATO group than in the 
ATRA + ATO group, suggesting a reduced risk of RAS. 
Tamibarotene was studied in APL maintenance therapy in comparison to ATRA (Shinagawa et 
al, 2014). Newly diagnosed APL patients in molecular remission at the end of consolidation 
therapy (n = 269 of 347 enrolled) were randomized to receive either tamibarotene (n = 134) at 
6 mg/m2 or ATRA (n = 135) at 45 mg/m2 daily for 14 days every 3 months for 2 years. The 
relapse-free survival (RFS) rate was similar between treatments at 4 years (91% tamibarotene 
and 84% ATRA [p=0.095]). An analysis of patients with a high-risk of relapse (initial WBC 
≥ 10.0 x 109/L) revealed a significant difference in RFS in favor of tamibarotene (87% 
tamibarotene versus 58% ATRA [p = 0.028]). Both treatments were generally well-tolerated, 
with most AEs considered mild or moderate. The most common drug-related events of grade 2 or 
greater in both arms were dyslipidemia, rash, increased AST/ALT and headache. Of these, 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 59 of 141 
dyslipidemia and skin rash were more common in the tamibarotene arm. Discontinuations due to 
AE occurred in seven patients in the tamibarotene arm (skin rash in 5 patients; liver dysfunction, 
elevated triglycerides in 1 patient each) and four patients in the ATRA arm (nausea, headache, 
liver dysfunction and elevated triglycerides in 1 patient each). Overall, AEs seen with 
tamibarotene during extended maintenance therapy were similar to those reported in the previous 
Japanese APL registration studies. 
Additional clinical trials have explored the activity of tamibarotene as single-agent treatment in 
advanced hepatocellular carcinoma (HCC) and in combination with paclitaxel/carboplatin in 
non-small cell lung cancer. Tamibarotene was studied in an open-label study in HCC (Kanai et 
al, 2014). Thirty-six patients enrolled and 31 received tamibarotene 8 or 12 mg/day. One patient 
achieved a partial response and seven achieved stable disease; disease control rate was 32%. 
Adverse events were experienced by all patients and were generally mild and consistent with 
those reported in other studies. Fourteen (14) of 31 patients (45%) experienced AEs considered 
drug-related and of grade 3-4. These AEs included increases in cholesterol, -GTP, AST or 
alkaline phosphatase, decrease in leukocytes, platelets or hemoglobin, thrombosis and rash. 
Serious adverse events (SAEs) included thrombosis of a limb (2 patients), pulmonary artery 
(2 patients) or portal vein (one patient). One patient died of interstitial lung disease. 
Tamibarotene was also studied in a Phase 2b clinical trial in patients with Stage IIIB (with 
pleural effusion) or Stage IV non-small cell lung cancer. Patients were treated with up to 6 cycles 
of paclitaxel plus carboplatin, plus either tamibarotene (6 mg/m2/day) or placebo, followed by 
continuous treatment with either tamibarotene or placebo. The trial enrolled 145 non-small cell 
lung cancer patients. The study was terminated after a planned interim futility analysis, based on 
127 efficacy evaluable patients with a median follow-up of 7.7 months, showed that the primary 
efficacy endpoint (improvement in PFS) would not be met. There were 38 deaths, including 
19 due to disease progression (10 on the experimental arm, 9 on the control arm), 8 due toxicity 
(6 experimental, 2, control), and 11 with unknown causes (6 experimental, 5 control). The AE 
profile in 136 safety evaluable patients (73, tamibarotene + paclitaxel and carboplatin arm, 
63 placebo + paclitaxel and carboplatin arm) showed a similar overall incidence of AEs 
(86.2% tamibarotene arm vs. 87.3% placebo arm). A higher incidence of ≥Grade 3 SAEs 
including thromboembolic events (6.9% vs. 1.6%) was reported in the tamibarotene vs. placebo 
arms, respectively. In general, the safety profile was consistent with the AE profile demonstrated 
in APL with single agent tamibarotene. 
1.3. 
Azacitidine 
Azacitidine is a pyrimidine analogue that exerts antineoplastic effects on abnormal 
hematopoietic bone marrow cells through multiple mechanisms including DNA 
hypomethylation. Cytotoxicity may also result from incorporation into DNA and RNA, with 
inhibition of DNA, RNA and protein synthesis. Azacitidine is approved in the US and European 
Union (EU) for MDS. Azacitidine is also approved for use in AML in the EU, and is widely 
accepted as standard of care for treatment of AML in the US. 
1.3.1. 
Rationale for Combination of SY-1425 and Azacitidine 
Azacitidine is an azanucleotide analog that is used in the treatment of myeloid malignancies 
(Derissen et al, 2013). As a hypomethylating agent, azacitidine works by inhibiting DNMT1 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 60 of 141 
leading to depletion of methyl-cytosine in the DNA of the tumor cells (Derissen et al, 2006; 
Voso et al, 2014; Stresemann et al, 2008). Hypomethylation leads to the re-expression of genes 
associated with differentiation and growth arrest, contributing to its antineoplastic therapeutic 
effects. The RAR, encoded by the RARA gene, is a nuclear hormone receptor that acts as a 
transcriptional repressor when unbound by a ligand and as a gene activator when bound by an 
agonist (Niederreither and Dollé, 2008). While RARα is present in many tissues, it is especially 
important in the normal maturation of myeloid cells (Kastner et al, 2001). The tumor cells from 
the novel subset of AML defined by an RARA SE, leading to upregulated RARα expression, or 
high IRF8 expression are uniquely responsive to the RARα agonist, SY-1425. SY-1425 binds to 
RARα, and reprograms the tumor cells to express genes associated with myeloid differentiation 
and anti-proliferative responses. The loss of methyl-cytosine residues induced by azacitidine 
primes the tumor cells for reprogramming by SY-1425 thereby enhancing gene activation by 
SY-1425, which switches RARα from a repressive state to an activating state. Thus, the two 
agents may work cooperatively to promote terminal differentiation and decrease proliferation of 
the AML tumor cells, with the potential for increased clinical benefit. 
In cell line models, the combination of azacitidine and SY-1425 showed synergistic anti-
proliferative effects on the cells where a more than additive reduction in tumor cell growth was 
observed over a range of concentrations of each drug. Following up on this finding, SY-1425 and 
azacitidine were administered to a disseminated patient derived xenograft mouse model of 
RARA-high AML. Indeed, the combination demonstrated superior efficacy at reducing tumor 
burden, achieving deeper and prolonged CR, based on bone marrow and peripheral tumor cell 
reduction, as compared to the single agents. Mechanistic studies in AML cell line models have 
revealed that while azacitidine had moderate suppressive or activating effects on a broad set of 
genes, the addition of SY-1425 resulted in very strong and specific induction of RARα target 
genes. Furthermore, since both agents work with DNA interacting targets, it was hypothesized 
that the source of cell killing potentially originated from DNA damage. Indeed, the combination 
of SY-1425 with azacitidine or decitabine in cell line models resulted in emergent induction of 
DNA damage as detected by PARP cleavage and phosphorylation of H2A.X 
As of 29 October 2018, SY-1425, in combination with azacitidine, in biomarker positive newly 
diagnosed unfit AML patients showed evidence of clinical activity with a high response rate and 
a rapid onset of responses. ORR was 63% (5/8) and the CR/CRi rate was 50% (4/8) with the 
majority of initial responses at C2D1. In biomarker-negative patients the ORR was 17% (1/6), 
with 1 CR observed; while these data were less mature, they preliminarily support the use of the 
RARA pathway activation biomarker(s) for patient selection.  SY-1425 + azacitidine was 
generally well tolerated with no evidence for increased toxicities of the combination 
(Cook  et al, 2018). 
1.4. 
Daratumumab 
Daratumumab is a human IgG1ĸ monoclonal antibody (mAb) that binds with high affinity to a 
unique epitope on CD38. It is a targeted immunotherapy that attacks tumor cells that overexpress 
CD38, a transmembrane glycoprotein, in a variety of hematological malignancies. Daratumumab 
induces lysis of CD38-expressing tumor cells by a wide spectrum of mechanisms including 
complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity 
(ADCC), and antibody-dependent cellular phagocytosis (ADCP), through activation of 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 61 of 141 
complement proteins, natural killer (NK) cells, and macrophages, respectively (de Weers et al, 
2011; Overdijk et al, 2015). Daratumumab is approved in the United States and European Union 
for use in multiple myeloma. 
1.4.1. 
Rationale for Combination of SY-1425 and Daratumumab 
CD38 expression in AML is considered to be generally low (CD38lo), but moderate in 
expression in a subset of patients (CD38dim) (Keyhani et al, 2000). CD38 induction in response 
to SY-1425 was observed by mRNA and FACS in RARA-high and IRF8-high cell line models 
of AML.  In addition, AML patient samples showed similar rates of CD38 induction in response 
to ex vivo treatment with SY-1425 by FACS. Furthermore, ex vivo functional assays of normal 
human natural killer (NK) cell mediated killing of RARA-high AML cell lines showed that only 
the combination of SY-1425 and daratumumab, but neither agent on their own, could induce 
robust apoptosis of the AML cells and interferon gamma secretion of NK cells (indicative of NK 
cell activation.  
The kinetics of induction showed that maximal levels of CD38 were achieved within 24 to 72 
hours of SY-1425 ex vivo exposure.  This provided a potential rationale to explore combination 
with a compound known to target CD38 and already approved in another hematology indication.   
1.5. 
Study Rationale 
Knowledge of underlying AML biology has increased significantly in the past two decades, with 
a focus on underlying cytogenetic and molecular aberrations (Grimwade et al, 2016), and 
dysregulated epigenetic mechanisms being associated with the pathogenesis of the disease 
(Wouters and Delwel, 2016). A recent approach to investigate transcriptional control of genes 
important in cancer identified an important role for the SE. SEs are exceptionally large clustered 
enhancer regions in the human genome, densely occupied by transcription factors, cofactors and 
chromatin regulators. They have been implicated in directing gene expression programs that 
define cell identity and also regulate oncogenes important in the pathogenesis of cancer (Hnisz et 
al, 2013). Syros’ scientists have studied SEs and their contributions to the pathogenesis of AML, 
and identified a SE controlling the RARA gene locus in a subset of non-APL AML primary 
patient samples. They also found upregulation of RARα mRNA expression is associated with the 
SE at the RARA gene locus. This excess RAR expression allows the tumor to suppress 
differentiation by favoring the gene repression function of RARα in the absence of a concomitant 
increase of natural ligand. Upregulation of this RARA repressive circuit creates a de novo 
susceptibility for the tumor, by increasing sensitivity to SY-1425 a potent and selective RARα 
agonist. It was demonstrated that increased RARα mRNA expression correlated with increased 
sensitivity to SY-1425 in vitro and predicted response to SY-1425 in PDX models of AML. The 
mechanism of RAR-mediated differentiation block in the tumor and consequent response to 
SY-1425 is similar to that described with retinoids in APL, based on the presence of a specific 
pathogenic fusion gene, PML-RARA. These data, therefore, define a novel subset of AML, 
distinct from APL, that Syros found to be uniquely responsive to SY-1425 in vitro and in vivo. 
Furthermore, the existence of the SE at the RARA gene locus and upregulation of RARα mRNA 
expression has also been identified in a subset of patients with MDS. Since RARα mRNA and 
RARA SE strength are highly correlated, RARα mRNA levels and mRNA levels for pathway-

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 62 of 141 
associated transcriptional complex partner genes, such as IRF8, can be used to quantify a 
biomarker in patients with AML and MDS for response to SY-1425. 
The broad objectives of this clinical study conducted by Syros are to evaluate SY-1425 as single 
agent and in combination with azacitidine or daratumumab in patients with AML and MDS who 
are selected based on the presence of the RARA super-enhancer associated biomarker or IRF8 
biomarker.  
  
 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 63 of 141 
2. 
OBJECTIVES 
2.1. 
Primary 
The primary objectives are: 
• Characterize the clinical activity of SY-1425 in biomarker positive patients by the 
overall response rate (ORR) in patients in Arms 1, 2A, 2B, and 5, and by the 
transfusion independence rate (TIR) in patients in Arm 3  
• Characterize the safety and tolerability of the combination of SY-1425 and 
daratumumab in Arm 4 
2.2. 
Secondary 
The secondary objectives are: 
• Characterize the clinical activity of SY-1425 in patients positive for the RARA super-
enhancer associated biomarker by the ORR in Arms 1, 2A, 2B, and 5, and by TIR in 
Arm 3 
• Characterize the clinical activity of SY-1425 in patients positive for the IRF8 
biomarker and negative for the RARA super-enhancer associated biomarker by the 
ORR in Arms 1, 2A, 2B, and 5, and by TIR in Arm 3 
• Characterize the clinical activity of the combination of SY-1425 and azacitidine by 
the ORR in patient in Arm 2B 
• Characterize the clinical activity of the combination of SY-1425 and daratumumab by 
ORR in Arm 4 
• Characterize the clinical activity by patients in Arms 1, 2A, 2B, 3, 4, and 5, based on 
event-free survival (EFS), relapse-free survival (RFS), duration of response (DOR), 
overall survival (OS), hematologic improvement (HI) 
• For all patients, evaluate the requirement for supportive measures secondary to 
cytopenias 
• Characterize the safety and tolerability of SY-1425 as a single agent in Arms 1, 2A 
and 3, in combination with azacitidine in Arms 2B and 5. 
• Characterize the PK of SY-1425 after single and multiple doses 
2.3. 
Exploratory 
The exploratory objectives are: 
• Assess factors associated with the ORR, including but not limited to arm and 
diagnosis, prior treatment, RARA super-enhancer associated biomarker and/or IRF8 
biomarker status, dehydrogenase/reductase (SDR family) member 3 (DHRS3) 
induction, myeloid differentiation, induction of CD38 expression and other potential 
predictors of success including genotype and mutation status 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 64 of 141 
• Evaluate changes in Health-Related Quality of Life (HRQOL)  
• Establish PK/PD relationships based on PD markers in leukemic cells from repeat 
peripheral blood samples 
• Characterize the PK of daratumumab in combination with SY-1425 
• Characterize the relationship between SY-1425 activity and baseline tumor biomarker 
levels, and levels over time (RARα mRNA or IRF8 mRNA) 
• Characterize clinical activity of SY-1425 administered as a single agent and in 
combination with azacitidine or daratumumab by time-to-response  
• Characterize expression of myeloid differentiation markers, including CD38, over 
time 
• Explore the potential role of additional gene or protein alterations (e.g. expression or 
mutation) in sensitivity and/or resistance to SY-1425 using multiplex platform(s)  

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 65 of 141 
3. 
STUDY ENDPOINTS  
3.1. 
Primary 
• ORR for biomarker positive patients with AML or higher-risk MDS (Arms 1, 2A, 2B, 
and 5) 
• TIR for patients with lower-risk MDS (Arm 3) 
• Safety and tolerability of SY-1425 in combination with daratumumab assessed by the 
type and frequency of AEs and SAEs using National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) v 4.03, as well as changes in 
clinically significant clinical laboratory values, electrocardiogram (ECG) parameters 
and vital sign measurements (Arm 4) 
3.2. 
Secondary 
• ORR for AML or higher-risk MDS patients positive for the RARA super-enhancer 
associated biomarker (Arms 1, 2A, 2B and 5) 
• TIR for lower-risk MDS patients positive for the RARA super-enhancer associated 
biomarker (Arm 3) 
• Response rate (ORR +TIR) for patients positive for the IRF8 biomarker and negative 
for the RARA super-enhancer associated biomarker treated with SY-1425 as a single 
agent (Arms 1, 2A, and 3) 
• ORR for AML or higher-risk MDS patients positive for the IRF8 biomarker and 
negative for the RARA super-enhancer associated biomarker (Arms 1, 2A, 2B, and 5) 
• TIR for lower-risk MDS patients positive for the IRF8 biomarker and negative for the 
RARA super-enhancer associated biomarker (Arm 3) 
• ORR for AML patients who are treated with SY-1425 in combination with azacitidine 
(Arm 2B) 
• ORR for AML or higher-risk MDS patients treated with SY-1425 in combination 
with daratumumab (Arm 4) 
• Clinical activity as measured by EFS, RFS, DOR, OS, and HI in Arms 1, 2A, 2B, 4, 
and 5 
• Clinical activity as measured by DOR and HI in Arm 3 
• Proportion of patients requiring supportive measures secondary to cytopenias, as 
measured by changes in transfusion rates, incidence and duration of growth factor 
support and antibiotics use, and number of hospitalizations associated with febrile 
neutropenia and/or thrombocytopenic bleeding 
• Characterize the safety and tolerability of SY-1425 as a single agent and in 
combination with azacitidine by assessing the type and frequency of AEs and SAEs 
using National Cancer Institute (NCI) Common Terminology Criteria for Adverse 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 66 of 141 
Events (CTCAE) v 4.03, as well as changes in clinically significant clinical 
laboratory values, electrocardiogram (ECG) parameters and vital sign measurements 
(Arms 1, 2A, 2B, 3, and 5) 
• PK parameters of SY-1425, as single agent and in combination with azacitidine or 
daratumumab, after single and multiple doses by performing PK analysis to define 
time to maximum concentration (tmax), Cmax, minimum plasma concentration (Cmin), 
AUC, total body clearance (CL/F) and half-life (t1/2), where the data permits 
3.3. 
Exploratory Endpoints 
• Sensitivity analyses to the primary endpoint to predict ORR or TIR across all patients 
by arm and diagnosis type, prior therapy, RARA super-enhancer associated biomarker 
and/or IRF8 biomarker status; DHRS3 induction, peripheral blood myeloid 
differentiation markers, induction of CD38 expression, genotype and mutation status 
• Changes in Health-Related Quality of Life (HRQOL)  
− AML/higher-risk MDS patients (Arms 1, 2A, 2B, 4, and 5): Functional 
Assessment of Cancer Therapy-Leukemia (FACT-Leu) questionnaire 
− Lower-risk MDS patients (Arm 3): Functional Assessment of Cancer Therapy-
Anemia (FACT-An) questionnaire 
• Establish PK/PD relationships by performing analysis of PD biomarkers (DHRS3 and 
myeloid differentiation markers) in leukemic cells from repeat peripheral blood 
samples and assessing any changes over time 
• PK parameters for daratumumab in combination with SY-1425, including maximum 
concentration (Cmax) and minimum concentration (Cmin; trough concentration) 
• Characterize the relationship between SY-1425 activity and baseline expression, and 
expression over time of messenger RNA (mRNA) expression of RAR and IRF8 
biomarkers by correlating baseline biomarker mRNA expression levels of RARα and 
IRF8 with ORR, EFS, RFS, DOR, OS, and HI Rate 
• Estimate of median time-to-response  
• Evaluate changes in expression of myeloid differentiation markers, including CD38, 
over time 
• Analysis of additional genes or proteins using multiplex platforms 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 67 of 141 
4. 
STUDY DESIGN 
This is a Phase 2, multi-center, open-label study exploring the activity of SY-1425 in patients 
with relapsed or refractory non-APL AML or higher-risk MDS, newly diagnosed treatment-naïve 
patients with non-APL AML who are unlikely to tolerate standard intensive chemotherapy at the 
time of study entry, and patients with transfusion-dependent lower-risk MDS without the del 5q- 
abnormality who are refractory to erythropoietin treatment or unlikely to respond to 
erythropoietin (EPO) treatment (EPO > 500).  
All patients must be evaluated for the RARA super-enhancer associated biomarker or the 
associated IRF8 biomarker at the time of the study screening evaluation, as determined in 
peripheral blood using an investigational assay. Patients will accrue to each of the six arms based 
on diagnosis (AML, MDS), prior treatment (relapsed/refractory, newly diagnosed treatment-
naïve unfit AML patients), risk group (higher-risk MDS, lower-risk MDS transfusion 
dependent), and Investigator choice of treatment (SY-1425 single agent, or in combination with 
azacitidine or daratumumab). SY-1425 will be administered at 6 mg/m2/day orally (PO) in two 
divided doses, which corresponds to the dose approved in Japan for use of tamibarotene in 
patients with relapsed/refractory APL. SY-1425 will be given on a 28-day treatment cycle.  
• Arms 1, 2A, and 3: SY-1425 will be administered as a single agent and dosing will be 
continuous. 
• Arms 2B and 5: Azacitidine will be administered at 75 mg/m2 (intravenously or 
subcutaneously) on Days 1 through 7, daily, of a 28-day cycle. SY-1425 will be 
administered at 6 mg/m2/day PO in two divided doses on Days 8 through 28 of a 28-day 
cycle. 
• Arm 4: SY-1425 will be administered at 6 mg/m2/day PO in two divided doses. Dosing 
will be continuous, beginning with a 7-day lead-in, and then administered on a 28-day 
treatment cycle. Daratumumab will be administered at a dose of 16 mg/kg starting on 
Cycle 1 Day 1 weekly for 8 weeks (8 doses total), followed by dosing every 2 weeks for 
16 weeks (8 doses total), followed by dosing every 4 weeks until progression or 
intolerance.   
The dose of SY-1425 may be increased due to unsatisfactory response as early as C2D1 and 
again at C3D1 in consultation with the Sponsor. SY-1425 doses may be increased for AML and 
higher-risk MDS patients to 9 mg/m2/day if a CR/CRi is not achieved at the C2D1 response 
assessment. The dose may be increased one additional dose level to 12 mg/m2/day if a CR/CRi is 
not achieved at the C3D1 response assessment. Doses may be increased for lower-risk MDS 
patients to 9 mg/m2/day at C2D1 if the patient has not reduced their transfusion requirements by 
50% after 4 weeks (C2D1). The dose may be increased one level to either 9 or 12 mg/m2/day 
after week 8 (C3D1) for lower-risk MDS patients who have not achieved transfusion 
independence but who have achieved a minor erythroid response.  
Patients will be treated with single agent SY-1425, or SY-1425 in combination with azacitidine 
or daratumumab to determine activity, to establish the safety profile of SY-1425 in patients with 
AML and MDS patients, to explore the hypothesis that patients with the RARA super-enhancer 
associated biomarker or the associated IRF8 biomarker at baseline are responsive to single agent 
SY-1425 or SY-1425 in combination, to establish the pharmacokinetic/ pharmacodynamic 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 68 of 141 
(PK/PD) relationships, and to evaluate the relationship between single agent SY-1425 or 
SY-1425 in combination activity and baseline RARA and IRF8 biomarkers.  
In AML and higher-risk MDS patients, response will be measured by changes from baseline in 
peripheral blood counts and bone marrow aspirates. Bone marrow aspirates will be collected to 
measure response on Day 1 of Cycles 2, 3 (if CR/CRi was not achieved on C2D1), and 4, 
followed by every third cycle, with additional bone marrow aspirates analyzed as clinically 
indicated based upon changes in peripheral blood counts, or when it is needed to establish either 
CR or disease progression.  Bone marrow aspirate pathology slides (smears) used to assess 
response should be retained at the site for up to 5 years or until Sponsor approval to discard 
samples is provided, whichever is sooner, to support the potential for future analyses. 
In lower-risk MDS patients, response will be measured by changes from baseline in transfusion 
requirements and peripheral blood counts, which will be evaluated at each study visit. 
Patients may continue to receive study treatment until experiencing unacceptable toxicity, 
disease progression/relapse, decision to pursue post-remission therapy other than SY-1425 single 
agent, or SY-1425 in combination with azacitidine or daratumumab, or the Investigator 
determines it is in the best interest of the patient to discontinue treatment. Newly diagnosed 
AML patients enrolled in Arm 2A who achieve a CR/CRi or PR while on SY-1425 single agent 
treatment and then relapse, or who fail to achieve a CR/CRi or PR after completing at least 4 
cycles of SY-1425 single agent treatment, are eligible to receive SY-1425 in combination with 
azacitidine.  
Lower-risk MDS patients will be withdrawn from the study at week 24 if they do not have at 
least a minor erythroid response defined as either a 50% decrease in transfusion requirements or 
a 50% improvement in hemoglobin concentration per the response criteria, defined as a 
hemoglobin increase ≥ 0.75 g/dL. Lower-risk MDS patients who in the opinion of the 
Investigator are receiving clinical benefit, but do not meet the minor erythroid response criteria 
can remain on study with Sponsor approval. Lower-risk MDS patients who continue past week 
24 will continue to receive treatment until erythroid relapse (loss of erythroid response), disease 
progression, or unacceptable toxicity. 
An end of treatment (EoT) visit will be conducted for all AML and higher-risk MDS patients 
within 30 days of the last dose of study drug, but prior to the start of any subsequent therapies to 
monitor for safety and resolution of adverse events (AEs). For lower-risk MDS patients, the EoT 
visit will also be the end of study visit which will be conducted 30 days after the last dose of 
study drug. All AML and higher-risk MDS patients will be followed every 3 months for survival 
for up to 2 years and patients who are withdrawn prior to relapse will also follow-up for event 
free survival (EFS). 
However, following implementation of Amendment 7, assessments will be performed per 
institutional standard of care for patients enrolled in Arm 2B or Arm 5. Aside from SAE, adverse 
event of special interest (AESI), and Pregnancy and Birth Event collection (via the 
pharmacovigilance safety database) for patients still receiving study drug in Arm 5, the study 
procedures and data collection outlined in Table 3 will be considered as guidance and will no 
longer be required for the study or entered into the electronic data capture system (EDC). 
Patients in Arm 5 may continue to receive study drug until experiencing unacceptable toxicity, 
disease progression/relapse, decision to pursue post-remission therapy other than SY-1425 in 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 69 of 141 
combination with azacitidine, or the Investigator determines it is in the best interest of the patient 
to discontinue treatment.  
 
 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 70 of 141 
5. 
STUDY POPULATION 
5.1. 
Number of Patients 
Approximately 162 response evaluable patients will be enrolled into 6 arms:  
• Arm 1 (n= ~ 25 biomarker positive patients): Relapsed and/or refractory non-APL 
AML patients and relapsed and/or refractory higher-risk MDS patients. 
• Arm 2A (n= ~ 25 biomarker positive patients) and Arm 2B (n= ~ 50 patients;  ~ 25 
biomarker positive and ~ 25 biomarker negative): Newly diagnosed, treatment-naïve 
non-APL AML patients who, at the time of study entry, are unlikely to tolerate 
standard intensive chemotherapy due to age, performance status, or comorbidities. 
Arm assignment is determined by Investigator choice of treatment.  
− Patients in Arm 2A will receive SY-1425 as a single agent.   
− Patients in Arm 2B will receive SY-1425 in combination with azacitidine 
• Arm 3 (n= ~ 25 biomarker positive patients): Transfusion dependent lower-risk MDS 
patients without the del 5q abnormality who are refractory to erythropoietin treatment 
or unlikely to respond to erythropoietin treatment (EPO >500 mU/mL). 
• Arm 4 (n = ~ 12 biomarker positive patients): Relapsed and/or refractory non-APL 
AML patients, relapsed and/or refractory higher-risk MDS patients. 
• Arm 5 (n = ~ 25 biomarker positive patients): Relapsed and/or refractory non-APL 
AML patients who will receive SY-1425 in combination with azacitidine.  
Biomarker positive patients are defined as patients positive for the RARA super-enhancer 
associated biomarker and/or the IRF8 biomarker. Arms 1, 2A, 2B, 3 and 5 will include 
approximately 20 patients who are positive of the RARA super-enhancer associated biomarker. 
There is no minimum requirement for RARA super-enhancer associated biomarker patients in 
Arm 4. 
Response evaluable patients will be defined as study patients receiving at least one complete 
cycle of study treatment, have completed at least one response assessment, and do not have any 
major protocol violations or are withdrawn from the study before completion of Cycle 1 because 
of documented disease progression (see Section 10.2).  
Patients will be enrolled across approximately 20 centers in the US and Europe. A patient is 
considered enrolled upon receipt of first dose of any study drug.  
5.2. 
Duration of Study 
Patients may continue to receive study treatment until experiencing unacceptable toxicity, 
disease progression/relapse, decision to pursue post-remission therapy other than SY-1425 single 
agent, or SY-1425 in combination with azacitidine or daratumumab, or the Investigator 
determines it is in the best interest of the patient to discontinue treatment. Newly diagnosed 
AML patients enrolled in Arm 2A who achieve a CR/CRi or PR while on SY-1425 single agent 
treatment and then relapse, or who fail to achieve a CR/CRi or PR after completing at least 4 
cycles of SY-1425 single agent are eligible to receive SY-1425 in combination with azacitidine.  

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 71 of 141 
Lower-risk MDS patients will be withdrawn from the study at week 24 if they do not have at 
least a minor erythroid response defined as either a 50% decrease in transfusion requirements or 
a 50% improvement in hemoglobin concentration per the response criteria, defined as a 
hemoglobin increase ≥ 0.75g/dL. Lower-risk MDS patients who in the opinion of the 
Investigator are receiving clinical benefit, but don’t meet the minor erythroid criteria can remain 
on study with Sponsor approval. Lower-risk MDS patients who continue past week 24 will 
continue to receive treatment until erythroid relapse, disease progression, or unacceptable 
toxicity. 
An EoT visit will be conducted for all AML and higher-risk MDS patients within 30 days of the 
last dose of study drug, but prior to the start of any subsequent therapies to monitor for safety 
and resolution of AEs. For lower-risk MDS patients, the EoT visit will also be the end of study 
visit which will be conducted 30 days after the last dose of study drug. All AML and higher-risk 
MDS patients will be followed every 3 months for survival for up to 2 years and patients who are 
withdrawn prior to relapse will also follow-up for event free survival.  
However, following implementation of Amendment 7, assessments will be performed per 
institutional standard of care for patients enrolled in Arm 2B or Arm 5. Aside from SAE, AESI, 
and Pregnancy and Birth Event collection (via the pharmacovigilance safety database) for 
patients still receiving study drug in Arm 5, the study procedures and data collection outlined in 
Table 3 will be considered as guidance and will no longer be required for the study or entered 
into the EDC. Patients in Arm 5 may continue to receive study drug until experiencing 
unacceptable toxicity, disease progression/relapse, decision to pursue post-remission therapy 
other than SY-1425 in combination with azacitidine, or the Investigator determines it is in the 
best interest of the patient to discontinue treatment. 
5.3. 
Inclusion Criteria 
1. Patients must be at least 18 years of age. 
2. Patients must have: 
a. Relapsed and/or refractory non-APL AML that has failed to achieve a CR or PR 
following standard induction therapy, or has relapsed after any duration of CR or PR  
i. Patients must have measurable disease with bone marrow blasts ≥5% at screening. 
b. Relapsed and/or refractory higher-risk MDS (High / Very High Risk, as defined by 
the Revised International Prognostic Scoring System (IPSS-R)) patients that have 
failed to achieve a CR or PR, or any HI (per IWG 2006 criteria) after standard 
therapy with hypomethylating agents (eg, azacitidine, decitabine), or have relapsed 
after any duration of CR or PR or HI  
i. Patients must have measurable disease with bone marrow blasts >5% at screening. 
c. Newly diagnosed, treatment-naïve non-APL AML in patients who, at the time of 
study entry are unlikely to tolerate standard intensive chemotherapy due to age, 
performance status, or comorbidities based on at least one of the following criteria 
(Ferrara et al, 2013):  
i. 
Age ≥ 75-years-old 
ii. 
Eastern Cooperative Oncology Group (ECOG) Performance Status of 3 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 72 of 141 
iii. 
Cardiac history of congestive heart failure (CHF) or documented ejection 
fraction (EF) ≤ 50% 
iv. 
Pulmonary disease with DLCO ≤ 65% or FEVI ≤ 65% 
v. 
Creatinine clearance ≥ 30 mL/min to < 45 mL/min 
vi. 
Hepatic impairment with total bilirubin > 1.5 to ≤ 3.0 x upper limit of normal 
(ULN) 
vii. 
Any other comorbidity that the Investigator judges to be incompatible with 
intensive chemotherapy, and reviewed and approved by the Sponsor prior to 
enrollment 
d. Transfusion dependent lower-risk MDS without the del 5q abnormality, in patients 
refractory to erythropoietin treatment or unlikely to respond to EPO treatment (EPO 
>500).  
i. 
Lower-risk MDS: Very Low /Low / Intermediate Risk, as defined by 
IPSS-R.  
ii. 
Red blood cell (RBC) transfusion dependent anemia defined as no 
8 consecutive weeks without RBC transfusions within the 16 weeks 
prior to study entry, or ≥4 RBC transfusions within the 8 weeks prior to 
study entry.  
iii. 
Refractory to or ineligible for ESAs is defined as RBC-Transfusion 
Dependence despite ESA treatment of ≥40,000 units/week recombinant 
human erythropoietin for 8 weeks or an equivalent dose of darbepoetin 
(150 g/week) or serum EPO level >500 mU/mL in patients not 
previously treated with ESAs. 
3. Patients must be evaluated for the RARA super-enhancer associated biomarker or IRF8 
biomarker as measured by RT-qPCR as defined by a predetermined cutoff based on 
centralized testing of peripheral blood at the time of study screening. 
a. Patients in arms 1, 2A, 3, 4, and 5 must be positive for the biomarker to be eligible for 
enrollment.   
4. Must be amenable to serial bone marrow aspirates and peripheral blood sampling during 
the study. 
5. ECOG Performance Status (PS) of 0, 1 or 2. For newly diagnosed AML patients < 75 
years of age, ECOG 0 to 3; for ≥ 75 years of age, ECOG 0 to 2. 
6. Adequate organ function as defined by: 
a. Total bilirubin ≤ 1.5 x the upper limit of normal (ULN), unless suspected to have 
Gilbert’s disease. For newly diagnosed AML patients < 75 years of age, total 
bilirubin ≤ 3.0 x ULN; for ≥ 75 years of age, total bilirubin ≤ 1.5 x ULN. 
b. ALT and AST ≤ 3 x ULN or ≤ 5 x ULN if documented liver infiltration with 
leukemia cells 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 73 of 141 
c. Serum creatinine ≤ 2.0 x ULN or calculated creatinine clearance ≥ 45 mL/min based 
on the Cockroft-Gault GFR estimation. For newly diagnosed AML patients < 75 
years of age, creatinine clearance ≥ 30 mL/min; for ≥ 75 years of age, creatinine 
clearance ≥ 45 mL/min. 
7. Discontinued use of chemotherapy, radiation therapy, or growth factors for at least 
2 weeks prior to first study treatment, with the exception of hydroxyurea. 
8. No investigational agents within 2 weeks prior to first study treatment. 
9. No strong inducers of CYP3A4 (see Appendix 5) within 2 weeks prior to first study 
treatment.  
10. Resolved acute effects of any prior AML/MDS therapy to baseline or ≤ Grade 1 CTCAE 
severity. 
11. Serum/urine pregnancy test (for females of childbearing potential) that is negative at 
screening and immediately prior to initiation of treatment (first dose). 
12. Willingness and ability to comply with the scheduled study visits, treatment plans, 
laboratory tests and other procedures.  
13. Fully-executed, signed and dated Institutional Review Board (IRB) or Independent Ethics 
Committee (IEC) approved informed consent document. 
5.4. 
Exclusion Criteria 
1. APL (M3 subtype of AML) or patients with a t(9:22) cytogenetic translocation. 
2. Hyperleukocytosis (leukocytes ≥25 x 109/L) at study entry. These patients may be treated 
with hydroxyurea according to routine practice, and enroll in the study when the 
leukocyte count falls below 25 x 109/L. 
3. Patients known to be refractory to platelet or packed red cell transfusions per Institutional 
Guidelines, or a patient who refuses blood product support. 
4. Prior treatment with ATRA or systemic retinoid for the treatment of hematologic 
malignancy. 
5. Arm 4 only – Prior or concurrent exposure to daratumumab or other CD38 therapies 
6. Arm 4 only – Subject has either of the following: 
a. Known chronic obstructive pulmonary disease (COPD) with a forced expiratory 
volume in 1 second (FEV1) <50% of predicted normal. Note that FEV1 testing is 
required for subjects suspected of having COPD and subjects must be excluded if 
FEV1 is <50% of predicted normal. 
b. Known moderate or severe persistent asthma within the past 2 years (see 
Appendix 8), or uncontrolled asthma of any classification. Note that subjects who 
currently have controlled intermittent asthma or controlled mild persistent asthma are 
allowed to participate in the study. 
7. Patients with other active malignancy (not including basal cell carcinoma, non-melanoma 
skin cancer, cervical carcinoma in situ, localized prostate cancer treated with hormone 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 74 of 141 
therapy). Patients with history of other cancers should be free of disease for at least 
2 years.  
8. Patients with hypertriglyceridemia defined as >1000 mg/dL (CTCAE v4.03 Grade 4).  
9. Any clinically significant cardiac disease including one of the following currently or in 
the previous 6 months: myocardial infarction, unstable cardiac function due to unstable 
angina or congestive heart failure, congenital long QT syndrome, torsades de pointes or 
clinically-significant ventricular arrhythmias.  
10. QTc interval >480 msec based on triplicate ECG readings using the Fridericia (QTcF), 
with the exception of patients with Right Bundle Branch Block or Left Bundle Branch 
Block. 
11. Patients with an active, life-threatening or clinically-significant uncontrolled systemic 
infection. 
12. Patients with known active uncontrolled central nervous system (CNS) leukemia. 
13. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome 
(AIDS) related illness or hepatitis B or hepatitis C infection. 
a. Arm 4 only: Patients with resolved infection (ie, patients who are HBsAg negative 
but positive for antiHBs or antiHBc) must also be screened using PCR measurement 
of HBV DNA levels. Patients who are PCR positive for HBV will be excluded. 
b. Arm 4 only: Patients with serologic findings suggestive of HBV vaccination 
(antiHBs positivity as the only serologic marker) AND a known history of prior HBV 
vaccination do not need to be tested for HBV DNA by PCR. 
14. Known malabsorption syndrome or other condition that may impair absorption of study 
medication (eg, gastrectomy). 
15. Major surgery within 4 weeks prior to starting study treatment. 
16. Patients taking Vitamin A supplements (>10,000 IU/d) unless discontinued prior to first 
dose of study drug, or having hypervitaminosis A. 
17. Concurrent treatment with any investigational or approved oncology agents (unless 
specified in the protocol, such as hydroxyurea) or herbal preparations. 
18. Arm 4 only: Known allergies, hypersensitivity, or intolerance to mannitol, 
corticosteroids, monoclonal antibodies or human proteins, or their excipients, or known 
sensitivity to mammalian-derived products. 
19. Arm 4 only: Vaccination with live attenuated vaccines within 4 weeks of first study drug 
administration. 
20. Current illicit drug or alcohol abuse. 
21. Other severe acute or chronic medical condition such as refractory congestive heart 
failure, pulmonary disease associated with dyspnea at rest or requiring oxygen therapy, 
kidney dialysis, liver cirrhosis (Child B or C), or psychiatric condition or laboratory 
abnormality that may increase the risk to the patient associated with study participation or 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 75 of 141 
investigational product administration or which may interfere with the interpretation of 
study results or, in the judgment of the Investigator, would make the patient inappropriate 
for entry into this study. 
22. Pregnant females; breastfeeding females; and males and females of childbearing potential 
not willing to use two highly effective methods of birth control, one being barrier 
method. Intrauterine devices and birth control pills are not barrier methods, but are highly 
effective especially when combined with a barrier method (eg, latex condom or a 
diaphragm or cervical cap) while taking study drug (SY-1425, azacitidine and 
daratumumab) and continuing contraception use for at least 90 days after the last dose of 
study drug. Men/women should not donate sperm or ova during this timeframe. 
a. Non-childbearing potential is defined as menopausal for at least 2 years or 
documented oophorectomy. 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 76 of 141 
6. 
STUDY CONDUCT 
6.1. 
General Instructions 
Patient enrollment is defined by when the first dose of study drug has been received by a patient. 
The contact information for Syros and designee(s), the Contract Research Organization (CRO), 
laboratory(s), and any other vendors for this study can be found in the study manual. 
6.2. 
Study Procedures by Time Point 
The study procedure schedule per visit is detailed in the Schedule of Events (Table 1, Table 3 
and Table 5). Additional details may also be found in the study and laboratory manuals.  
6.3. 
Premature Discontinuation 
Patients can withdraw from study anytime at their request or they can be withdrawn by the 
Investigator or Sponsor for reasons of safety or compliance with study procedures.  
Patients may be withdrawn from treatment if they are experiencing unacceptable toxicity or 
adverse event, disease progression, decision to pursue post-remission therapy other than 
SY-1425 single agent, or SY-1425 in combination with azacitidine or daratumumab, or if the 
Investigator determines it is in the best interest of the patient to discontinue treatment. Newly 
diagnosed AML patients enrolled in Arm 2A who achieve a CR/CRi or PR while on SY-1425 
single agent treatment and then relapse, or who fail to achieve a CR/CRi or PR after completing 
at least 4 cycles of SY-1425 single agent are eligible to receive SY-1425 in combination with 
azacitidine. Patients may be replaced if they are not response evaluable (eg, withdraw from study 
prior to first response assessment, see Section 10.2). 
Lower-risk MDS patients will be withdrawn from the study at week 24 if they do not have at 
least a minor erythroid response defined as either a 50% decrease in transfusion requirements or 
a 50% improvement in hemoglobin concentration per the response criteria, defined as a 
hemoglobin increase ≥ 0.75g/dL. Lower-risk MDS patients who in the opinion of the 
Investigator are receiving clinical benefit, but don’t meet the minor erythroid criteria can remain 
on study with Sponsor approval. Lower-risk MDS patients who continue past week 24 will 
continue to receive treatment until erythroid relapse, disease progression, or unacceptable 
toxicity.  
An EoT visit will be conducted for all AML and higher-risk MDS patients within 30 days of the 
last dose of study drug, but prior to the start of any subsequent therapies to monitor for safety 
and resolution of AEs. For lower-risk MDS patients, the EoT visit will also be the end of study 
visit which will be conducted 30 days after the last dose of study drug. All AML and higher-risk 
MDS patients will be followed every three months for survival for up to 2 years and patients who 
are withdrawn prior to relapse will also follow-up for EFS.  
However, following implementation of Amendment 7, assessments will be performed per 
institutional standard of care for patients enrolled in Arm 2B or Arm 5. Aside from SAE, AESI, 
and Pregnancy and Birth Event collection (via the pharmacovigilance safety database) for 
patients still receiving study drug in Arm 5, the study procedures and data collection outlined in 
Table 3 will be considered as guidance and will no longer be required for the study or entered 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 77 of 141 
into the EDC. Patients in Arm 5 may continue to receive study drug until experiencing 
unacceptable toxicity, disease progression/relapse, decision to pursue post-remission therapy 
other than SY-1425 in combination with azacitidine, or the Investigator determines it is in the 
best interest of the patient to discontinue treatment. 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 78 of 141 
7. 
DESCRIPTION OF STUDY PROCEDURES 
Following implementation of Amendment 7, assessments will be performed per institutional 
standard of care for patients enrolled in Arm 2B or Arm 5. Aside from SAE, AESI, and 
Pregnancy and Birth Event collection (via the pharmacovigilance safety database) for patients 
still receiving study drug in Arm 5, the study procedures and data collection outlined in Section 7 
will be considered as guidance and will no longer be required for the study or entered into the 
EDC. See Section 7.5 for additional details. 
7.1. 
Baseline Documentation 
7.1.1. 
Informed Consent 
All patients must provide written informed consent prior to any study-specific procedures being 
performed. 
7.1.2. 
Eligibility Review 
A review of all eligibility criteria will be performed on or before Cycle 1 Day 1 (Arms 1, 2A, 2B, 
3, and 5) or Day -7 of the SY-1425 Lead-In (Arm 4), before enrolling a patient on the study. 
7.1.3. 
Medical History 
A complete medical history will be performed for each patient during the screening period. The 
history will include all prior therapies and patient’s disease history. Concomitant therapies must 
also be recorded as outlined in Section 7.3.2. 
7.1.4. 
Demographics 
Date of birth, ethnicity, sex, and race will be recorded during the screening period.  
7.1.5. 
Height 
Height will be measured at screening only. 
7.1.6. 
Weight 
Weight will be measured as per the schedule of events. Weight will be used to calculate body 
surface area (BSA) dosing requirements. BSA used for SY-1425 dosing calculations should be 
updated if the weight changes more than 15%. For Arm 4, the dose of daratumumab should be 
recalculated if the patient’s weight changes by more than 10%. 
7.1.7. 
ECOG Performance Status 
Eastern Cooperative Oncology Group (ECOG) Performance Status (Oken et al, 1982) will be 
assessed during screening and Day 1 of each cycle and at EoT visit. 
7.1.8. 
Physical Examination 
Patients will have a physical exam as per the schedule of events. This exam will be completed 
according to standard of care guidelines 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 79 of 141 
7.2. 
Safety and Laboratory Assessments 
Laboratory assessments will be drawn at the time points outlined in the schedule of events. 
7.2.1. 
Hematology 
Hemoglobin, platelets, WBC (leukocyte count including differential), neutrophils (absolute 
neutrophil count, [ANC] calculated from the leukocyte count and WBC differential count), 
lymphocytes, monocytes, eosinophils, basophils, and circulating blast counts will be captured 
according to the schedule of events. 
7.2.2. 
Serum Chemistries 
Sodium, potassium, chloride, bicarbonate (CO2), blood urea nitrogen (BUN), creatinine, glucose, 
calcium, phosphorus, magnesium, uric acid, total protein, albumin, lactate dehydrogenase 
(LDH), alkaline phosphatase, total bilirubin, direct bilirubin, indirect bilirubin, AST, ALT, 
amylase, and lipase will be captured according to the schedule of events. 
7.2.3. 
Coagulation 
Prothrombin time (PT), international normalized ratio (INR), and activated partial prothrombin 
time (aPTT) will be captured according to the schedule of events. 
7.2.4. 
Triglycerides and Total Cholesterol 
Triglycerides and total cholesterol will be captured according to the schedule of events. 
7.2.5. 
Urinalysis 
Microscopic urinalysis including pH, specific gravity, protein, red and white blood cells, 
leukocyte esterase, and nitrate will be captured according to the schedule of events. 
7.2.6. 
Pregnancy Test 
Females of childbearing potential must have a negative serum or urine pregnancy test prior to 
starting study drug treatment and on Day 1 of each cycle and at EoT visit. For Arm 4, pregnancy 
testing will also be done pre-dose on Day -7 of the SY-1425 Lead-In. 
7.2.7. 
Electrocardiograms 
Triplicate 12-lead ECGs will be performed for all patients during screening and at EoT.  
Patients enrolled in Arms 1, 2A and 3 will have also have triplicate ECGs performed on Cycle 1 
Day 1 (pre-dose), Cycle 1 Day 15, Cycle 2 Day 1, Cycle 3 Day 1, and Cycle 4 Day 1. 
Patients enrolled in Arms 2B and 5 will have also have triplicate ECGs performed on Cycle 1 
Day 8 (pre-dose), Cycle 1 Day 22, Cycle 2 Day 8, Cycle 3 Day 8 and Cycle 4 Day 8.  
Patients enrolled in Arm 4 will also have triplicate ECGs performed on Day -7 (pre-dose) and 
Day -4 of the SY-1425 Lead-In, Cycle 2 Day 1, Cycle 3 Day 1, and Cycle 4 Day 1. 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 80 of 141 
7.2.8. 
Vital Signs 
Vital signs will include blood pressure, body temperature, and heart rate. See schedule of events 
for time points. 
Patients enrolled in Arm 4 will have vital signs monitored extensively on Cycle 1 Day 1 before, 
during (at 0.5, 1, 1.5, 2, 3.5 hours after the start of the infusion), and after (at the end of the 
infusion, and 0.5 and 1 hour after the end of the infusion) the first infusion of daratumumab. For 
all other infusions, vital signs will be measured before the start of the infusion and at the end of 
the infusion. 
7.2.9. 
Pulmonary Function Testing (Arm 4 Only) 
Patients enrolled in Arm 4 will have pulmonary function testing (PFT) performed at screening. 
For patients with COPD, FEV1 should be measured. Symptom and disease directed exams 
should be performed as clinically indicated during the treatment phase.  
7.2.10. 
Blood Group and Type Assessment, and Indirect Antiglobulin Test (Arm 4 
Only) 
Blood Type, Rh, and Indirect Antiglobulin Test (IAT) should be done before the first dose of 
daratumumab. Subject RBC phenotyping (standard or extended) is an alternative option to the 
IAT test, if locally required.  Either method must be completed prior to first daratumumab 
infusion. 
Daratumumab interferes with the IAT, which is a routine pre-transfusion test performed to 
identify a patient’s antibodies to minor antigens so that suitable donor blood can be given for 
transfusion.   Daratumumab does not interfere with ABO/RhD typing.  CD38 is expressed at 
very low levels on erythrocytes.  Daratumumab binds to the CD38 on erythrocytes, which results 
in a positive IAT (Indirect Antiglobulin Test).   This positive result masks the detection of 
antibodies to minor antigens and may prevent or delay blood banks from issuing donor blood for 
transfusion.  This effect occurs during daratumumab treatment and for up to 6 months after 
treatment ends.  Subjects will receive a patient identification wallet card for the study that 
includes the blood profile (ABO, Rh, and IAT or phenotyping) determined before the first 
infusion of daratumumab along with information on the IAT interference for healthcare 
providers/blood banks.  Subjects are to carry this card throughout the treatment period and for at 
least 6 months after treatment ends.  Blood banks can eliminate the daratumumab IAT 
interference with IAT by treating reagent RBCs with dithiothreitol (DTT) (Chapuy et al, 2015; 
Chapuy et al, 2016). 
Possible methods for blood banks to provide safe RBCs for transfusion to subjects receiving 
daratumumab include: 
a) Providing ABO/RhD compatible, phenotypically (standard or extended phenotyping) or 
genotypically matched units 
b) Providing ABO/RhD compatible, K-negative units after ruling out or identifying 
alloantibodies using DTT-treated reagent RBCs 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 81 of 141 
Uncrossmatched, ABO/RhD compatible RBC units should be administered if transfusion is 
needed emergently as per local blood bank practice. 
Despite daratumumab binding to CD38 on erythrocytes, no indication of clinically significant 
hemolysis has been observed in daratumumab studies. 
7.3. 
Clinical Assessments 
7.3.1. 
Adverse Event Monitoring 
Assessment of AEs, both serious and non-serious, will be monitored throughout the study. SAEs 
will be captured from the time of signing of the Informed Consent Form (ICF) through 30 days 
after last dose of any study drug, and non-serious AEs from the time of first dose of any study 
drug through 30 days after last dose of any study drug. AEs information will include the type, 
severity, timing, seriousness, and relatedness. All AEs will be recorded in the electronic case 
report form (eCRF). Refer to Section 9 for more details. 
7.3.2. 
Prior, Concomitant, and Subsequent Medication Review 
Prior AML and MDS related and all concomitant medications will be recorded from screening 
until EoT. All subsequent therapies for disease under study will be recorded for AML and 
higher-risk MDS patients until 3 months after the last dose of study drug. See Section 8.7 for 
more details. 
7.3.3. 
Blood Product Transfusions 
All transfusions (pRBCs, platelets, number of units, days of administration) will be recorded 
from 16 weeks prior to enrollment until the EoT visit. 
7.3.4. 
Erythropoietin Levels – Lower-Risk MDS Patients Only 
Lower-risk MDS patients capture EPO levels at screening. 
7.3.5. 
Dosing Compliance/Diary Review 
All patients will be instructed to maintain a dosing diary that records the time and number of SY-
1425 tablets taken for each dosing interval in the study. This diary will be reviewed at each study 
visit for compliance. 
7.3.6. 
Health Related Quality of Life 
Patient reported health related quality of life (HRQOL) will be evaluated at screening, Cycle 1 
Day 1, Cycle 4 Day 1, and at EoT to determine the impact of SY-1425 treatment. AML and 
Higher-Risk MDS patients will be evaluated using the Factual Assessment of Cancer Therapy-
Leukemia (FACT-Leu) questionnaire (Appendix 7). Lower-Risk MDS patients will be evaluated 
using the Factual Assessment of Cancer Therapy-Anemia (FACT-An) questionnaire 
(Appendix 6). The FACT-Leu and FACT-An questionnaires are to be self-administered by the 
patient. The questionnaires should be completed by the patient prior to other clinical assessments 
being performed and should be reviewed by the site for completeness. If any questions were 
incomplete, the site should encourage the patient to complete any missing questions.   

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 82 of 141 
7.3.7. 
Event Free Survival and Overall Survival - AML and Higher-Risk MDS Patients 
Only 
All AML and higher-risk MDS patients will be followed for survival for up to 2 years and 
patients who are withdrawn prior to relapse will also follow-up for event free survival.  
7.4. 
Specialty Laboratory Assessments 
7.4.1. 
RARα and IRF8 biomarker assessments 
This study will be evaluating patients with AML and MDS for the presence of a biomarker based 
on the expression levels of RARα mRNA or IRF8 mRNA in peripheral blood mononuclear cells. 
The analysis will be determined based on peripheral blood collected during the screening 
procedures. Both biomarkers will be assessed as “biomarker positive” based on exceeding a 
predetermined cutoff using an investigational test, conducted at a central Clinical Laboratory 
Improvement Amendments (CLIA) registered laboratory.  
7.4.2. 
Development of Future Companion Diagnostic 
Peripheral blood samples collected from all screened patients may also be used to develop a 
future companion diagnostic for RARα and IRF8. 
7.4.3. 
Identification of Additional Biomarkers of Response to SY-1425 
In addition to evaluation of RAR mRNA and IRF8 mRNA, other mRNA levels for other RARα 
pathway associated genes such as CTNNB1 will also be explored. 
Furthermore, chromatin immunoprecipitation (ChIP)-sequencing, RNA sequencing and DNA 
sequencing will be undertaken in patients where material is available. ChIP-sequencing will be 
used to evaluate the correlation between SE strength for RARA, IRF8, other super-enhancers in 
the malignant cells, and RNA expression levels of genes controlled by those SEs. RNA and 
DNA sequencing will be used to identify additional molecular alterations potentially associated 
with response to SY-1425. 
7.4.4. 
Identification of Resistance Mechanisms for SY-1425 
Resistance to ATRA in APL has been linked to both adaptive hypercatabolic response, resulting 
in reduction of effective ATRA exposure, and through mutations in the RARα ligand binding 
domain reducing the agonist potential of retinoids (Gallagher, 2002). RNA and DNA sequencing 
will be used in a blood sample collected at EoT to identify potential molecular alterations 
associated with resistance to treatment with SY-1425. 
7.4.5. 
Bone Marrow Sample Collection - AML and Higher-Risk MDS Patients Only 
Patients will have bone marrow aspirates collected during screening and on Day 1 of Cycles 2, 3 
(if CR/CRi was not achieved on C2D1), and 4 with additional aspirates collected every third 
cycle starting with C7D1, and as clinically indicated based upon changes in peripheral blood 
counts, or when it is needed to establish either CR or disease progression. The sample collected 
upon relapse will represent the end of treatment collection.  
Bone marrow aspirate samples will be analyzed locally at the clinical site to: 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 83 of 141 
• Assess disease using the response criteria as outlined in Appendix 4. 
• Analyze cytogenetics to determine karyotype (and IPSS-R score at screening) and 
disease response assessments 
• Determine blast count  
• Mutational analysis as routinely done by the clinical site (at screening and relapse) 
• Immunophenotyping to measure myeloid differentiation markers as routinely done by 
the clinical site 
− Note:  Patients enrolled in Arm 4 will have bone marrow aspirate analyzed for 
immunophenotyping at a central laboratory.  Local analyses may also be 
performed if clinically indicated. 
• MRD assessment per local practice in those patients who have achieved a CR 
7.4.5.1. 
Bone Marrow Aspirate for Response Assessment (AML and Higher-Risk MDS 
Patients Only) 
Assessment of disease will be determined using the response criteria as outlined in Appendix 4. 
Response will be measured by changes from baseline in peripheral blood counts and bone 
marrow aspirate. Bone marrow aspirates will be collected to measure response on Day 1 of 
Cycles 2, 3 (if CR/CRi was not achieved on C2D1), and 4, followed by every third cycle 
beginning on C7D1, with additional bone marrow aspirates analyzed as clinically indicated 
based on changes in peripheral blood counts, or when it is needed to establish either CR or 
disease progression.  
7.4.5.2. 
Immunophenotyping (AML and Higher-Risk MDS Patients Only) 
Bone marrow aspirate samples obtained at the time of screening, when bone marrow aspirates 
are collected to assess response, and upon relapse to be analyzed using local laboratories for 
changes in the expression of myeloid differentiation markers (eg, CD11b, CD13, CD15, CD33) 
as routinely done by the clinical site. Note:  Patients enrolled in Arm 4 will have bone marrow 
aspirate analyzed for immunophenotyping at a central laboratory.  Local analyses may also be 
performed if clinically indicated.  Immunophenotyping may also be performed when clinically 
indicated on peripheral blood to measure myeloid differentiation markers. 
7.4.5.3. 
CD38 and Myeloid Marker Immunophenotyping (Central Analysis) 
Patients enrolled in Arms 1, 2A and 3 under Amendment 4 or a subsequent protocol amendment 
will have peripheral blood collected for central analysis of CD38 and myeloid marker 
immunophenotyping on Days 1 (pre-dose), 8 and 15 of Cycle 1; Day 1 of Cycles 2, 3, 4, 
followed by every third cycle beginning at Cycle 7 Day 1; and at EoT. 
Patients enrolled in Arm 4 will have peripheral blood collected for central analysis of CD38 and 
myeloid marker immunophenotyping on Days -7 (pre-dose) and -4 of the SY-1425 Lead-In; 
Days 1, 8 and 15 of Cycle 1; Day 1 of Cycles 2, 3, 4, followed by every third cycle beginning at 
Cycle 7 Day 1; and at EoT. For timepoints on days on which daratumumab is administered, 
collection is performed prior to daratumumab dosing. 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 84 of 141 
7.4.6. 
Pharmacokinetics 
Blood samples will be taken to determine SY-1425 plasma concentrations. The time of dosing 
and sample collection, including hour and minutes, must be recorded. Details regarding the 
preparation, handling, and shipping of samples can be found in the study manual.  
Patients enrolled in Arms 1, 2A and 3 will have sparse PK sampling on Day 1 of Cycle 1 at 
2-4 hours, and 5-8 hours post dose, and on Day 15 of Cycle 1 and Day 1 of Cycles 2, 3, and 4 at 
two time points at least 2 hours apart.  
A subset of approximately 15 patients enrolled in Arms 1, 2A and 3, sufficient to obtain PK 
evaluable results from at least 10 patients, will have more intensive sampling [pre-dose (0 hour), 
and 0.5, 1, 2, 4, 6, 8 hours post-dose] on Day 1 and Day 15 of Cycle 1, and will have sparse 
sampling on Day 1 of Cycles 2, 3, and 4 at two time points at least 2 hours apart. 
For patients in Arm 2A who receive SY-1425 in combination with azacitidine after 
relapse/unsatisfactory response with single agent SY-1425, PK sampling is not required once 
initiating combination treatment. 
Patients enrolled in Arms 2B and 5 will have sparse PK sampling on Day 8 of Cycle 1 at 2-4 
hours and at 5-8 hours post-dose. PK sampling will also occur on Day 22 of Cycle 1, and on Day 
8 of Cycles 2, 3 and 4 at two post-dose time points at least 2 hours apart. 
Patients enrolled in Arm 4 will have SY-1425 PK sampling [pre-dose (0 hour), and 0.5, 1, 2, 4, 
6, 8 hours post-dose] on Day -7 and Day -4 of the SY-1425 Lead-In. Patients enrolled in Arm 4 
will also have daratumumab PK sampling on Cycle 1 Day 1 prior to infusion (0h) and prior to 
the end of infusion (5-10 minutes before end of infusion), and on Cycle 1 Day 8 prior to infusion 
(0h). 
If a patient’s SY-1425 dose is modified (increased or decreased) during the course of the study, 
PK sampling should occur within 8 to 15 days of the dose adjustment. Patients in the sparse PK 
sampling will have two samples taken at least 2 hours apart. Patients in the intensive PK 
sampling schedule will have more intensive sampling (pre-dose [0 hour], and 0.5, 1, 2, 4, 6 and 8 
hours post-dose).  
7.4.7. 
ADME Pharmacogenomics 
A peripheral blood sample will be obtained on Cycle 1 Day 1 pre-dose (Arms 1, 2A, 2B, 3, 
and 5) or pre-dose on Day -7 of the SY-1425 Lead-In (Arm 4) and analyzed centrally for all 
patients to evaluate if absorption, distribution, metabolism, and excretion (ADME) genes 
contribute to inter-patient differences in the exposure of SY-1425.  
For patients in Arm 2A who receive SY-1425 in combination with azacitidine after 
relapse/unsatisfactory response with single agent SY-1425, a pharmacogenomics sample is not 
required. 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 85 of 141 
7.4.8. 
Pharmacodynamics 
Peripheral blood will be collected and analyzed centrally in all patients. Patients enrolled in 
Arms 1, 2A and 3 will have sampling on Cycle 1 Day 1 (pre-dose (0 hour), and between 
5-8 hours post dose), Day 15, and EoT visit for RNA analysis.  
For patients in Arm 2A who receive SY-1425 in combination with azacitidine after 
relapse/unsatisfactory response with single agent SY-1425, PD sampling is not required once 
initiating the combination treatment.  
Patients enrolled in Arm 2B will have sampling on Cycle 1 Day 1 (pre-dose), Cycle 1 Day 8 
(pre-dose (0 hour), and between 5-8 hours post dose), Day 22, and EoT visit. 
Patients enrolled in Arm 4 will have sampling on Day -7 of the SY-1425 Lead-In (pre-dose 
(0 hour), and between 5-8 hours post dose), Cycle 1 Day 8, and EoT visit. 
DHRS3 (SDR family), a metabolic enzyme that is an important component of cellular 
maintenance of retinol homeostasis, will be included in the RNA analysis. The expression of this 
gene is tightly controlled in response to retinoic acid abundance. DHRS3 gene expression is most 
strongly induced by SY-1425 in AML cells harboring the RARA super-enhancer. However, there 
is also a significant upregulation in peripheral blood mononuclear cells, which may act as 
surrogate tissue for measuring SY-1425 response. 
7.4.9. 
Additional Exploratory Biomarker Analysis 
Any research blood sample remaining will be preserved and used to perform additional 
exploratory analysis focusing on furthering knowledge on either AML/MDS cancer or the 
compound SY-1425. 
7.5. 
Amendment 7 Study Procedure Changes 
Following implementation of Amendment 7, only the following study assessments will be 
required for patients in Arm 5 who are still receiving study drug: 
• SAE collection (see Section 9.5 for reporting) is required for Amendment 7 
• AESI collection (see Section 9.6) is required for Amendment 7 
• Pregnancy and Birth Event collection (see Section 9.7 for reporting) is required for 
Amendment 7 
Aside from SAE, AESI, and Pregnancy and Birth Event collection (via the pharmacovigilance 
safety database) for patients receiving study drug in Arm 5, the study procedures and data 
collection outlined in Table 3 will be considered as guidance only and will no longer be required 
for the study or collected in the EDC. 
Rather than following the SoA (Table 3) for Arm 5 patients, approximately every 3 months the 
Investigator or designee will provide an update to the sponsor regarding the status of the patient 
and whether or not the patient continues to receive benefit from the study drug. Patients in Arm 5 
may continue to receive study drug until experiencing unacceptable toxicity, disease 
progression/relapse, decision to pursue post-remission therapy other than SY-1425 in 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 86 of 141 
combination with azacitidine, or the Investigator determines it is in the best interest of the patient 
to discontinue treatment (see Section 8.2.1).  
In addition, no further collection of post-treatment follow-up data will occur for patients enrolled 
in Arm 2B or Arm 5; patient follow-up should continue per institutional standard of care. 
See Section 8.5.1 for updated requirements regarding SY-1425 dosing compliance and 
Section 8.6.1 regarding SY-1425 drug accountability. 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 87 of 141 
8. 
STUDY DRUG MANAGEMENT 
8.1. 
Allocation to Treatment 
All protocol specific requirements must be completed and documented prior to study drug 
administration. Following determination that the patient meets all eligibility criteria, the 
Investigator or designee will enroll the patient according to procedures described in the study 
manual. Patients enrolled in Arms 1, 2A and 3 will receive SY-1425 as a monotherapy. Patients 
enrolled in Arms 2B and 5 will receive SY-1425 in combination with azacitidine. Newly 
diagnosed AML patients enrolled in Arm 2A who achieve a CR/CRi or PR while on SY-1425 
single agent treatment and then relapse, or who fail to achieve a CR/CRi or PR after completing 
at least 4 cycles of SY-1425 single agent treatment are eligible to receive SY-1425 in 
combination with azacitidine. Patients enrolled in Arm 4 will receive SY-1425 in combination 
with daratumumab. 
8.2. 
Study Drug Administration 
8.2.1. 
SY-1425 
SY-1425 will be supplied as 2 mg tablets. Each patient will receive 6 mg/m2/day PO divided into 
two doses.  
The dose of SY-1425 may be increased due to unsatisfactory response as early as C2D1 and 
again at C3D1 in consultation with the Sponsor. SY-1425 doses may be increased for AML and 
higher-risk MDS patients to 9 mg/m2/day if a CR/CRi is not achieved at the C2D1 response 
assessment. The dose may be increased one additional dose level to 12 mg/m2/day if a CR/CRi is 
not achieved at the C3D1 response assessment. Doses may be increased for lower-risk MDS 
patients to 9 mg/m2/day at C2D1 if the patient has not reduced their transfusion requirements by 
50% after 4 weeks (C2D1). The dose may be increased one level to either 9 or 12 mg/m2/day 
after week 8 (C3D1) for lower-risk MDS patients who have not achieved transfusion 
independence but who have achieved a minor erythroid response.  
Calculated doses will be rounded up to the nearest even number. For doses of 10 mg/day or 
14 mg/day, for which the number of tablets daily is uneven (5 or 7 tablets), then the larger 
number (3 or 4 tablets, respectively) should be taken in the morning. Patients will be instructed 
to take the dose with a glass of water after their morning and evening meal. Tablets should not be 
crushed, broken or split. If a tablet is damaged (broken, crushed, split, etc.), the patient should 
record the information in the diary and bring the damaged tablet to the next study visit. Dosing 
should not be repeated if a patient vomits. A dose missed by greater than 4 hours should be 
skipped. SY-1425 will be given on a 28-day treatment cycle. For patients enrolled in Arms 1, 
2A, 3 and 4, dosing will be continuous. For patients enrolled in Arms 2B and 5, SY-1425 will be 
administered on Days 8 through 28 of a 28-day cycle. 
Patients may continue to receive study treatment until experiencing unacceptable toxicity, 
disease progression/relapse, decision to pursue post-remission therapy other than SY-1425 or the 
Investigator determines it is in the best interest of the patient to discontinue treatment. Newly 
diagnosed AML patients enrolled in Arm 2A who achieve a CR/CRi or PR while on SY-1425 
single agent treatment and then relapse, or who fail to achieve a CR/CRi or PR after completing 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 88 of 141 
at least 4 cycles of SY-1425 single agent treatment are eligible to receive SY-1425 in 
combination with azacitidine. 
Lower-risk MDS patients will be withdrawn from the study at week 24 if they do not have at 
least a minor erythroid response defined as either a 50% decrease in transfusion requirements or 
a 50% improvement in hemoglobin concentration per the response criteria, defined as a 
hemoglobin increase ≥ 0.75g/dL. Lower-risk MDS patients who in the opinion of the 
Investigator are receiving clinical benefit, but do not meet the minor erythroid response criteria 
can remain on study with Sponsor approval. Lower-risk MDS patients who continue past week 
24 will continue to receive treatment until erythroid relapse, disease progression, or unacceptable 
toxicity. 
Following implementation of Amendment 7, patients in Arm 5 may continue to receive study 
drug until experiencing unacceptable toxicity, disease progression/relapse, decision to pursue 
post-remission therapy other than SY-1425 in combination with azacitidine, or the Investigator 
determines it is in the best interest of the patient to discontinue treatment.  
8.2.2. 
Azacitidine 
Azacitidine is commercially available as lyophilized powder in 100 mg single-dose vials. Each 
patient enrolled in Arms 2B and 5 will receive 75 mg/m2 (intravenously or subcutaneously) on 
Days 1 through 7, daily of a 28-day cycle.  
8.2.3. 
Daratumumab 
Daratumumab supplied for IV infusion in this study is a colorless to yellow liquid and sterile 
concentrate of 20 mg/mL as a liquid vial. Each patient enrolled in Arm 4 will receive 
daratumumab 16 mg/kg starting on Cycle 1 Day 1 weekly for 8 weeks (8 doses total), followed 
by dosing every 2 weeks for 16 weeks (8 doses total), followed by dosing every 4 weeks until 
progression or intolerance. 
8.2.3.1. 
Daratumumab Preparation 
Infusion solution will be prepared as a 1,000-mL (first dose) or 500-mL (second and subsequent 
doses) dilution of daratumumab in sterile, pyrogen-free 0.9% NaCl. Preparation of infusion bags 
should be done on the day of the planned infusion. Daratumumab must be administered as an 
IV infusion given through a well-functioning IV catheter by using an infusion pump. The study 
drug must be filtered by using an inline filter (0.2 μM) during the infusion.  
8.2.3.2. 
Daratumumab Administration 
Daratumumab (16 mg/kg) will be administered as an IV infusion. Each subject’s dose will be 
calculated based on the subject’s weight at Cycle 1 Day 1 rounded to the nearest kilogram. The 
dose of daratumumab will remain constant throughout the study, unless the subject’s weight 
changes more than 10% from Cycle 1 Day 1. All infusions will be planned as outpatient visits. 
Subjects will receive pre-infusion medications and post-infusion medications as detailed in the 
protocol (Sections 8.2.3.2.1 and 8.2.3.2.2 respectively). 
The dilution volumes, initial infusion rates, and increment for the first, second, and subsequent 
doses are provided in Table 8. The first infusion, with a volume of 1,000 mL, takes 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 89 of 141 
approximately 8 hours; the second and subsequent infusions, with volumes of 500 mL, take 
approximately 4 hours. The maximum infusion rate for all infusions is 200 mL/hour. 
Table 8: Daratumumab Infusion Rates 
 
Dilution 
Volume 
Initial Infusion 
Rate (first 
hour) 
Incremental 
Increases in 
Infusion Ratea 
Maximum 
Infusion Rate 
First infusion 
1000 mL 
50 mL/hour 
50 mL/hour every 
hour 
200 mL/hour 
Second infusionb 
500 mL 
50 mL/hour 
50 mL/hour every 
hour 
200 mL/hour 
Subsequent 
infusionsc 
500 mL 
100 mL/hour 
50 mL/hour every 
hour 
200 mL/hour 
a. Consider titration of the infusion rate only in the absence of infusion reactions. 
b. Dilution volume of 500 mL should be used only if there were no Grade 1 (mild) or greater 
infusion reactions during the first 3 hours of the first infusion. Otherwise, continue to use a 
dilution volume of 1000 mL. 
c. Use a modified initial rate for subsequent infusions (ie, third infusion onwards) only if 
there were no Grade 1 (mild) or greater infusion reactions during a final infusion rate of 
≥100 mL/hr in the first two infusions. Otherwise, continue to use instructions for the 
second infusion. 
As noted in Table 5, vital signs should be monitored extensively on Cycle 1 Day 1 before, 
during, and after the first infusion of daratumumab. For all other infusions, vital signs should be 
measured before the start of the infusion and at the end of the infusion. If a subject experiences 
any significant medical event, then the investigator should assess whether the subject should stay 
overnight for observation. If the subject has not experienced a significant medical event but is 
hospitalized overnight only for observation, then the hospitalization should not be reported as a 
serious adverse event. 
8.2.3.2.1. Daratumumab Pre-Infusion Medications 
In an effort to prevent infusion related reactions, all subject will receive the following medications 
1 to 3 hours prior to each study drug administration (1 hour prior to study drug administration is 
preferred): 
• An antipyretic: paracetamol (acetaminophen) 650-1000 mg IV or PO 
• An antihistamine: diphenhydramine 25-50 mg IV or PO, or equivalent. Avoid IV use of 
promethazine. (see Appendix 9 for list of antihistamines that may be used) 
• A corticosteroid: methylprednisolone 100 mg IV or PO or equivalent for the first 2 doses and 
60 mg for all subsequent doses (in the absence of IRR adverse events in the first 2 doses). 
Substitutions for methylprednisolone are allowed (refer to Appendix 10).  
• A Leukotriene Inhibitor (optional) on Cycle 1 Day 1: montelukast 10 mg PO, or equivalent. 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 90 of 141 
If necessary, all PO pre-infusion medications may be administered outside of the clinic on the 
day of the infusion, provided they are taken within 3 hours before the infusion 
8.2.3.2.2. Daratumumab Post-Infusion Medications 
In an effort to prevent delayed infusion-related reactions, all subjects will receive long- or 
intermediate-acting corticosteroids orally (20 mg methylprednisolone or equivalent in 
accordance with local standards) on the 2 days following all daratumumab infusions (beginning 
the day after the infusion). 
In the absence of infusion-related AEs after the first 3 infusions, post-infusion corticosteroids 
should be administered per investigator discretion. 
For subjects with a higher risk of respiratory complications (eg, subjects with mild asthma or 
subjects with COPD who have an FEV1 <80% at screening or developed FEV1 <80% during the 
study without any medical history) the following post-infusion medications should be considered: 
• Antihistamine (diphenhydramine or equivalent)  
• Leukotriene inhibitor (montelukast or equivalent) 
• Short-acting β2 adrenergic receptor agonist such as salbutamol aerosol  
• Control medications for lung disease (eg, inhaled corticosteroids ± long-acting β2 adrenergic 
receptor agonists for subjects with asthma; long-acting bronchodilators such as tiotropium or 
salmeterol ± inhaled corticosteroids for subjects with COPD) 
In addition, these at-risk subjects may be hospitalized for monitoring for up to 2 nights after an 
infusion. If subjects are hospitalized, then their spirometry test (FEV1) should be performed before 
discharge. If these subjects are not hospitalized, then a follow-up telephone call should be made to 
monitor their condition within 48 hours after all infusions. If the subject has not experienced a 
significant medical event but is hospitalized overnight only for observation, then the 
hospitalization should not be reported as a serious adverse event. Investigators may prescribe 
bronchodilators, H1-antihistamines, and corticosteroids that are deemed necessary to provide 
adequate supportive care in the event a bronchospasm occurs after subjects are released from the 
hospital/clinic. If an at-risk subject experiences no major infusion-related reactions, then these 
post-infusion medications may be waived after 4 doses at the investigator’s discretion.  
Any post-infusion medication will be administered after the infusion has completed. 
8.2.3.2.3. Management of Daratumumab Infusion-Related Reactions (IRR) 
Subjects should be carefully observed during daratumumab infusions. Trained study staff at the 
clinic should be prepared to intervene in case of any infusion reactions, and resources necessary 
for resuscitation must be available. Attention to staffing should be considered when multiple 
subjects will be dosed at the same time. 
For infusion reactions of any grade/severity, immediately interrupt the daratumumab infusion 
and manage symptoms. Management of infusion reactions may further require reduction in the 
rate of infusion, or treatment discontinuation of daratumumab. 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 91 of 141 
8.2.3.2.3.1. Daratumumab Infusion-Related Reactions of Grade 1 or Grade 2 
If the investigator assesses a Grade 1-2 IRR adverse event to be related to administration of study 
drug, then the daratumumab infusion should be paused. Once IRR symptoms resolve and the 
subject's condition is stable, the daratumumab infusion may be restarted at the investigator's 
discretion. Upon restart of daratumumab infusion, the infusion rate should be half of that 
employed before the interruption. If the patient does not experience any further IRR symptoms, 
infusion rate escalation may resume at increments and intervals as clinically appropriate up to the 
maximum rate of 200 mL/hour (Table 8). 
If the subject experiences a Grade 2 or higher event of laryngeal edema, or a Grade 2 or higher 
event of bronchospasm that does not respond to systemic therapy and does not resolve within 
6 hours from onset, then the subject must be withdrawn from daratumumab treatment. 
8.2.3.2.3.2. Daratumumab Infusion-Related Reactions of Grade 3 or Higher 
For IRR adverse events that are Grade 4, the daratumumab infusion must be stopped and the 
subject withdrawn from daratumumab treatment.  
For IRR adverse events that are Grade 3, the daratumumab infusion must be stopped and the 
subject must be observed carefully. Once reaction symptoms resolve, consider restarting the 
infusion at no more than half the rate at which the reaction occurred. If the subject does not 
experience additional symptoms, resume infusion rate escalation at increments and intervals as 
outlined in Table 8. If the intensity of the adverse event returns to Grade 3 after restart of the 
daratumumab infusion, then the procedure described in this section should be repeated, or the 
subject may be withdrawn from treatment. Should the intensity of the adverse event increase to 
Grade 3 for a third time, then the subject must be withdrawn from daratumumab treatment. 
8.3. 
Reference/Control Therapy 
All patients will receive open label SY-1425 single agent, or SY-1425 in combination with 
azacitidine or daratumumab. 
8.4. 
Recommended Dose Modifications 
8.4.1. 
SY-1425 Guidelines 
SY-1425 dosing may be modified due to unsatisfactory response or toxicity as described below. 
8.4.1.1. 
Dose Increases 
Table 9: Dose Increases of SY-1425 
Dose Level 
SY-1425 Dose 
Initial Dose: Level 0 
6 mg/m2/day 
Dose Increase: Level +1 
9 mg/m2/day 
Dose Increase: Level +2 
12 mg/m2/day 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 92 of 141 
The dose of SY-1425 may be increased due to unsatisfactory response as early as C2D1 and 
again at C3D1 in consultation with the Sponsor. 
AML and Higher-Risk MDS patients: Doses may be increased for AML and higher-risk MDS 
patients to Dose Increase Level +1 if a CR/CRi is not achieved at the C2D1 response assessment. 
The dose may be increased by one dose level (to Dose Increase Level +1, or +2 for those who 
already had a prior dose level increase) if a CR/CRi is not achieved at the C3D1 response 
assessment. If in the opinion of the Investigator, a dose increase is not recommended as outlined 
above, the case should be discussed with the Sponsor for approval.  
Lower-Risk MDS patients: Doses may be increased for lower-risk MDS patients at C2D1 to 
Dose Increase Level +1 if the patient has not reduced their transfusion requirements by 50% after 
4 weeks. The dose may be increased by one dose level (to Dose Increase Level +1, or +2 for 
those who already had a prior dose level increase) after week 8 (C3D1) for lower-risk MDS 
patients who have not achieved transfusion independence but have achieved a minor erythroid 
response.  
If a patient has an SY-1425 dose increase, a dose adjustment visit must be performed within 8 to 
15 days of the dose adjustment to capture safety assessments and PK data. This visit can be 
combined with another scheduled visit if it is scheduled to occur within that window.  
8.4.1.2. 
Dose Reductions 
Table 10: Dose Reductions of SY-1425 
Dose Level 
SY-1425 Dose 
Initial Dose: Level 0 
6 mg/m2/day 
Dose Reduction: Level -1 
4.5 mg/m2/day 
Dose Reduction: Level -2 
3.0 mg/m2/day 
Dose reductions may be recommended to optimize management of patients with adverse events 
as outlined in Section 8.4.1.3 and 8.4.1.4. If a patient has an SY-1425 dose reduction, a dose 
adjustment visit must be performed within 8 to 15 days of the dose adjustment to capture safety 
assessments and PK data. This visit can be combined with another scheduled visit if it is 
scheduled to occur within that window. 
Note: For patients who previously dose escalated as outlined in Section 8.4.1.1, dose reductions 
should be one dose level at a time. For example, a patient at 12 mg/ m2/day should be reduced to 
9 mg/m2/day, and a patient at 9 mg/m2/day should be reduced to 6 mg/m2/day for their initial 
dose reduction. 
8.4.1.3. 
Non-Hematologic Adverse Events  
SY-1425 doses will be withheld for patients experiencing: 
• Non-hematologic AEs of ≥ Grade 3 and deemed related to SY-1425, or  
• Laboratory abnormalities that are ≥ Grade 3 and deemed related to SY-1425 
[ie, unrelated to the underlying hematologic malignancy, complications of the 
malignancy (eg, infection and bleeding), and unrelated to concurrent medications, 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 93 of 141 
with the exception of asymptomatic hypertriglyceridemia, or hypercholesterolemia 
which should only be held if AE severity reaches Grade 4] 
SY-1425 treatment may resume at the Initial Dose Level once the event has resolved to 
≤ Grade 1 or baseline. The Investigator may choose to reduce the dose by 1 level based on the 
AE severity, time to resolution, and clinical judgment. 
For recurrence of the same AE responsible for a dose interruption in patients on the Initial Dose 
Level, SY-1425 may be resumed, but the dose must be reduced by one Dose Reduction Level. 
An additional dose reduction for recurrence of the same AE may be taken if needed. 
Dosing may be increased to a prior dose level if the AE remains ≤ Grade 1 or at baseline for 
28 days. 
8.4.1.4. 
Hematologic Adverse Events:  
It is not anticipated that SY-1425 dose modifications would be needed for hematologic events 
(ie, cytopenias, complications associated with cytopenias including infection, bleeding). 
However, if in the opinion of the Investigator, a dose modification is clinically indicated, the 
dose may be reduced by one dose level, following the guidance for non-hematologic AEs. 
Based upon the mechanism of action of SY-1425, which may promote myeloid cell 
differentiation, early signs of WBC increases are anticipated and may not represent progression 
of disease. 
8.4.1.5. 
Discontinuation of Therapy Due to Treatment-Related Toxicity 
Study treatment should not be resumed in the case of the following treatment-related events: 
• Cardiac event (Grade 4 arrhythmia or heart failure) 
• ≥ 56-day (2 cycle) dose delay due to a treatment-related adverse event  
8.4.1.6. 
Alternative Dosing Regimens 
Continuous daily dosing in 28-day (4 week) cycles will be initially evaluated. Alternative dosing 
regimens may be explored with Sponsor approval, should it be deemed necessary to manage 
chronic toxicities. 
8.4.2. 
Azacitidine Guidelines 
Azacitidine dosing may be modified if no beneficial effect is seen or due to toxicity as per the 
below guidelines (VIDAZA Prescribing Information 2016). Local guidelines and best practices 
may also be followed for azacitidine dose adjustments due to toxicity, as applicable (VIDAZA 
Summary of Product Characteristics 2016). 
8.4.2.1. 
Dose Adjustments Based on Hematology Laboratory Values 
For patients with baseline (start of treatment) WBC ≥ 3.0 x 109/L, ANC ≥ 1.5 x 109/L, and 
platelets ≥ 75.0 x 109/L, adjust the dose as follows, based on nadir counts for any given cycle as 
described in Table 11. 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 94 of 141 
Table 11: Azacitidine Dose Adjustments Based on Nadir Counts 
Nadir Counts 
% Dose in the Next Course 
Absolute Neutrophil Count 
(x109/L) 
Platelets (x109/L) 
<0.5 
<25.0 
50% 
0.5-1.5 
25.0-50.0 
67% 
>1.5 
>50.0 
100% 
For patients whose baseline counts are WBC < 3.0 x 109/L, ANC < 1.5 x 109/L, or platelets 
< 75.0 x 109/L, base dose adjustments on nadir counts and bone marrow biopsy cellularity at the 
time of the nadir as noted in Table 12, unless there is clear improvement in differentiation 
(percentage of mature granulocytes is higher and ANC is higher than at onset of that course) at 
the time of the next cycle, in which case continue the current dose. 
Table 12: Azacitidine Dose Adjustments Based on Nadir Counts and Cellularity 
White Blood Cell or 
Platelet Nadir 
% decrease in counts 
from baseline 
Bone Marrow Biopsy Cellularity at Time of Nadir (%) 
30-60 
15-30 
<15 
% Dose in the Next Course 
50-75 
100 
50 
33 
>75 
75 
50 
33 
 
If a nadir as defined in the table above has occurred, give the next course 28 days after the start 
of the preceding course, provided that both the WBC and the platelet counts are >25% above the 
nadir and rising. If a >25% increase above the nadir is not seen by day 28, reassess counts every 
7 days. If a 25% increase is not seen by Day 42, reduce the scheduled dose by 50%. 
8.4.2.2. 
Dose Adjustments Based on Serum Electrolytes and Renal Toxicity 
If unexplained reductions in serum bicarbonate levels to <20 mEq/L occur, reduce the dosage by 
50% for the next course. Similarly, if unexplained elevations of blood urea nitrogen or serum 
creatinine occur, delay the next cycle until values return to normal or baseline and reduce the 
dose by 50% for the next course. If recovery to normal or baseline has not occurred by Day 42, 
please consult Sponsor on how to proceed for the next course. 
8.4.3. 
Dose Delay Guidelines for Patients Receiving SY-1425 in Combination with 
Azacitidine 
If criteria for SY-1425 dose hold are met, azacitidine dosing may continue unless criteria for 
hold are also met. If discontinuation of SY-1425 is required per criteria in Section 8.4.1.5, then 
the patient should be discontinued from all study drug and have an end of treatment visit 
performed. 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 95 of 141 
If criteria for azacitidine dose hold are met, SY-1425 dosing may continue unless criteria for 
hold are also met. Day 1 of the next treatment cycle is delayed until azacitidine dosing may 
resume. 
8.4.4. 
Daratumumab Guidelines 
Dose modification of daratumumab is not permitted. Dose delay is the primary method for 
managing daratumumab-related toxicities. 
8.4.4.1. 
Daratumumab Cycle Delay 
On the first day of each new treatment cycle and before each daratumumab dose, the subject will 
be evaluated by the treating physician for possible toxicities that may have occurred after the 
previous dose(s). Toxicities are to be assessed according to NCI CTCAE, Version 4.03. Dose 
modifications or delays will be made based on the toxicity experienced during the previous cycle 
of therapy or newly encountered on Day 1 of a cycle. 
 
The study treatment must be held if any of the following criteria below are met, to allow for 
recovery from toxicity, regardless of relationship to daratumumab or SY-1425, unless 
attributable to underlying disease.  For example, cytopenias attributable to AML may not be 
considered toxicities of treatment. 
 
The criteria for a dose delay are: 
 
• Grade 4 hematologic toxicity, except for grade 4 lymphopenia 
• Grade 3 or higher thrombocytopenia 
• Febrile neutropenia 
• Neutropenia with infection, of any grade 
• Grade 3 or higher non-hematologic toxicities with the following exceptions:  
o Grade 3 nausea that responds to antiemetic treatment within 7 days 
o Grade 3 vomiting that responds to antiemetic treatment within 7 days 
o Grade 3 diarrhea that responds to antidiarrheal treatment within 7 days 
o Grade 3 fatigue that was present at baseline or that lasts for <7 days after the last 
administration of daratumumab 
o Grade 3 asthenia that was present at baseline or that lasts for <7 days after the last 
administration of daratumumab 
 
Administration of daratumumab may be restarted upon recovery from toxicity to Grade 2 or 
baseline, with the exception that Grade 2 laryngeal edema or Grade 2 bronchospasm must be 
fully recovered. 
 
If daratumumab administration does not commence within the prespecified window (Table 13) 
of the scheduled administration date, then the dose will be considered a missed dose. 
Administration may resume at the next planned dosing date. A missed dose will not be made up. 
 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 96 of 141 
Table 13: Daratumumab Administration Schedule 
Cycles 
Frequency 
Dose Held 
Dosing Re-start 
1 and 2 
Weekly (q1wk) 
>3 days 
next planned weekly dosing date 
3 to 6 
Biweekly (q2wks) 
>7 days 
next planned biweekly dosing date 
7+ 
Every 4 weeks (q4wks) >14 days 
next planned every 4 weeks dosing 
date 
 
Cycles may be delayed up to 4 weeks (Cycle 1 to Cycle 6) or up to 6 weeks (Cycle 7 and beyond).  
If Day 1 of a cycle is delayed, Day 1 of subsequent cycles should be adjusted accordingly to 
maintain the 28-day cycle duration.  However, if a within-cycle dose is delayed, then the dates of 
the subsequent within-cycle doses should not be adjusted.  Any adverse event deemed to be related 
to daratumumab that requires a dose hold of more than 4 weeks (Cycle 1 to Cycle 6) or more than 
6 weeks (Cycle 7 and beyond) will result in permanent discontinuation of daratumumab.  
Any dose hold of more than 56 days due to unresolved direct daratumumab toxicity will result in 
permanent discontinuation of daratumumab. Any dose hold of more than 28 days and less than 
56 days due to unresolved direct daratumumab toxicity may lead to discontinuation or continued 
daratumumab and requires review by the sponsor. Dose holds of more than 28 days for other 
reasons should be discussed with the sponsor.  
8.4.4.2. 
Daratumumab Interruption or Missed Doses 
A daratumumab dose that is held for more than the permitted time (Table 13) from the per-
protocol administration date for any reason other than toxicities suspected to be related to 
daratumumab should be brought to the attention of the Sponsor at the earliest possible time. 
Subjects whose dose was delayed for more than 4 weeks (Cycle 1 to Cycle 6) or more than 
6 weeks (Cycle 7 and beyond) should have study treatment discontinued, unless, upon 
consultation with the sponsor and the review of safety and efficacy, continuation is agreed upon. 
8.4.4.3. 
Dose Delay Guidelines for Patients Receiving SY-1425 in Combination with 
Daratumumab 
If criteria for SY-1425 dose hold are met, daratumumab dosing may continue unless criteria for 
hold are also met. If discontinuation of SY-1425 is required per criteria in Section 8.4.1.5, then 
the patient should be discontinued from all study drug and have an end of treatment visit 
performed 
If criteria for daratumumab dose hold are met, SY-1425 dosing may continue unless criteria for 
hold are also met. Day 1 of the next treatment cycle is delayed until daratumumab dosing may 
resume. 
8.5. 
Study Drug Dosing Compliance 
8.5.1. 
SY-1425 
Patients will maintain diaries to include the date and time each dose of SY-1425 is taken 
including hour and minute. Patients are required to return the carton or bottle(s) and unused 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 97 of 141 
study medications at each study visit. If a tablet is damaged (broken, crushed, split, etc.), the 
patient should record the information in the diary and bring the damaged tablet to the next study 
visit. The diaries and study drug materials will be used to complete a compliance assessment and 
drug accountability. The number of tablets returned by the patient at the end of a cycle will be 
counted, documented, and recorded as part of drug accountability requirements. Following 
implementation of Amendment 7, Arm 5 patients who are still receiving study drug will no 
longer be required to maintain a diary to document SY-1425 compliance. 
8.5.2. 
Azacitidine 
Azacitidine will be administered via intravenous or subcutaneous injection as described in the 
prescribing information under the supervision of the study site staff. 
8.5.3. 
Daratumumab 
Daratumumab will be administered via intravenous infusion as described in the prescribing 
information under the supervision of the study site staff. 
8.6. 
Study Drug Storage and Drug Accountability 
8.6.1. 
SY-1425 
Until dispensed to the patients, the study drug will be stored in a securely locked area, accessible 
to authorized personnel only. Tablets should be stored at room temperature (15°C to 30°C) and 
should not be removed from the blister strips or bottles until immediately before administration. 
The Investigator is responsible for SY-1425 accountability throughout the study. Accurate 
records of all SY-1425, received, dispensed from and returned to the study site are to be 
maintained by the study site. SY-1425 accountability will be monitored throughout the study. 
SY-1425 will be disposed of according to applicable regulations and Syros instruction. 
Following implementation of Amendment 7, SY-1425 accountability will be communicated to 
the Sponsor approximately every 3 months. 
Refer to the study-specific pharmacy manual for complete details for SY-1425. 
8.6.2. 
Azacitidine 
Unreconstituted vials should be stored at room temperature (15°C to 30°C). Refer the azacitidine 
package insert for complete details, as applicable (VIDAZA Prescribing Information 2016; 
VIDAZA Summary of Product Characteristics 2016). 
8.6.3. 
Daratumumab 
Daratumumab must be stored in the original carton in a refrigerator at controlled temperatures 
ranging from 2°C to 8°C until it is removed for dose preparation. Daratumumab must not be 
utilized after the expiry date printed on the label. Daratumumab must be protected from light and 
must not be frozen. Daratumumab does not contain preservatives; therefore, any unused portion 
remaining in the vial must be discarded. Refer to the study-specific pharmacy manual for 
complete details for daratumumab. 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 98 of 141 
8.7. 
Concomitant Medications 
Every concomitant medication and blood product required by the patient within 30 days prior to 
study drug administration or at any time during the course of the study are considered 
concomitant medications and must be documented.  
8.7.1. 
Cytotoxic or Investigational Therapy 
No concomitant cytotoxic or investigational therapy is allowed during the study.  
8.7.2. 
Other Agents Targeting CD38 (Arm 4 Only) 
The use of other agents that target CD38 is not allowed during the study. 
8.7.3. 
Oral Hydroxyurea 
If required for control of a patient’s peripheral blast count, oral hydroxyurea may be 
administered up through the first 14 days of treatment with SY-1425. Treatment beyond 14 days 
will require approval from the study Sponsor. 
8.7.4. 
Antibacterial, Antifungal, and Antiviral 
The use of prophylactic antibacterial, antifungal, and antiviral agents is recommended to be used 
as clinically indicated according to each institution’s guidelines. 
For patients enrolled in Arm 4, pneumocystis carinii/jirovecii pneumonia (PCP) prophylaxis 
should be considered, as per institutional guidelines. 
For patients enrolled in Arm 4, prophylaxis for herpes zoster reactivation is recommended during 
the Treatment Phase, as per institutional guidelines and continue for 3 months following 
treatment. Initiate antiviral prophylaxis to prevent herpes zoster reactivation within 1 week after 
starting study treatment and continue for 3 months following study treatment. Acceptable 
antiviral therapy includes acyclovir (eg, 400 mg given orally 3 times a day, or 800 mg given 
orally 2 times a day or per institutional standards), famcyclovir (eg, 125 mg given orally, twice a 
day or per institutional standards), or valacyclovir (eg, 500 mg given orally, twice a day or per 
institutional standards), initiated within 1 week after the start of study drug. 
8.7.5. 
Hematopoietic Growth Factors 
Hematopoietic growth factors should not be given prophylactically unless confirmation of 
aplasia at the first treatment assessment by bone marrow aspirate or in specific clinical 
conditions in accordance with American Society of Clinical Oncology (ASCO) guidelines. 
8.7.6. 
Platelet Transfusions 
Administration of platelet transfusions may be utilized throughout the study as clinically 
indicated.  

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 99 of 141 
8.7.7. 
Red Blood Cell Transfusions 
Administration of RBC transfusions may be utilized throughout the study as clinically indicated 
and should be administered according to institutional guidelines.  
8.7.8. 
Moderate and Strong Inhibitors and Strong Inducers of CYP3A4 
CYP3A4 is not a major enzyme involved in the clearance of SY-1425, and therefore, CYP3A4 
inhibitors and also inducers should not have a clinically significant impact on SY-1425 plasma 
PK exposure (see IB for more information). Administration of CYP3A4 inhibitors and inducers 
may be utilized throughout the study as clinically indicated. 
8.7.9. 
Antifibrinolytic 
Investigators should also be advised of the potential for thrombosis observed when drugs similar 
to SY-1425 (e.g., ATRA/tretinoin) have been combined with an antifibrinolytic. Antifibrinolytic 
medicines should be used with caution while on study drug. 
8.7.10. 
Retinoic Acid Syndrome 
Patients should be carefully monitored for the development of RAS. High-dose dexamethasone 
(i.e., 10 mg/m2 IV twice daily), and supportive measures (e.g., diuretics, dialysis, mechanical 
ventilation) as needed, should be implemented at the earliest suspicion of RAS. Glucocorticoid 
therapy should continue until complete disappearance of symptoms and then tapered. SY-1425 
therapy should be temporarily discontinued until RAS is considered controlled and ≤ Grade 2.  
8.7.11. 
Multivitamin and Supplements 
Vitamin A supplements (≥10,000 IU/d) are not allowed while on study treatment. 
8.7.12. 
Antacids and Proton pump inhibitors 
Antacids, H2-receptor antagonists: such as cimetidine, and Proton pump inhibitors (PPIs), such 
as omeprazole, should be used with caution while on study treatment.  
 
 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 100 of 141 
8.8. 
Description of SY-1425 
8.8.1. 
Drug Substance 
 
INN: 
Tamibarotene 
Company code: 
SY-1425 
Alternative names: 
SY-1425, INNO-507; Am-80; OP-01, TOS-80T; TM-
411; AMNOLAKE® Tablets (trade name in Japan); 4-
[(5,5,8,8-tetramethyl-6,7-dihydronaphthalen-2-
yl)carbamoyl]benzoic acid; N-(5,6,7,8-tetrahydro-
5,5,8,8-tetramethyl-2-naphthyl)terephthalamic acid p-
[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-
naphthyl)carbamoyl]benzoic acid; 4-[(1,1,4,4-
tetramethyltetralin-6-yl)carbamoyl]benzoic acid 
Chemical name: 
4-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-
yl)carbamoyl]benzoic acid 
Chem. Abst. Registry Number: 94497-51-5 
Formula:  
C22H25NO3 
Molecular weight: 
351.4 g/mol 
Physical appearance 
White crystals or crystalline powder 
Figure 2: Chemical Structure  
 
 
8.8.2. 
Drug product 
SY-1425 is supplied as white, uncoated tablets containing lactose, starch, hydroxypropyl 
cellulose and magnesium stearate and 2 mg of SY-1425. Tablets are packaged in either child-

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 101 of 141 
proof aluminum blister strips or white round 30 cc HDPE bottles with 28 mm child-resistant 
caps. Each blister strip contains 10 tablets, with 5 blister strips contained in a sealed carton, 
which is labeled in accordance with applicable requirements. Each bottle contains 100 tablets, 
and includes a 1 gram desiccant canister and cotton coil. 
8.8.3. 
Drug Product Precautions 
It is possible that SY-1425 drug substance may contain a small amount of sodium hydrosulfite. 
In accordance with Federal regulations, the following warning is provided: 
Contains sodium hydrosulfite, a sulfite that may cause allergic-type reactions including 
anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain 
susceptible people. The overall prevalence of sulfite sensitivity in the general population is 
unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in non-
asthmatic people. 
SY-1425 is teratogenic; therefore, it should not be administered to women who are pregnant. 
Tamibarotene has been reported to cause abnormalities in spermatogenesis in animal 
experiments using rats and dogs. Patients who are fertile must agree to use 2 highly effective 
methods of birth control, one being barrier method. Intrauterine devices and birth control pills 
are not barrier methods, but are highly effective especially when combined with a barrier method 
(eg, latex condom or a diaphragm or cervical cap) while taking investigational product 
(SY-1425) and continuing contraception use for at least 90 days after the last dose of study drug 
for men and 6 months for women. Men/women should not donate sperm or ova during this 
timeframe. 
8.9. 
Description of Azacitidine 
 For information regarding azacitidine drug substance, drug product, storage, and warnings and 
precautions, please refer to the azacitidine package insert, as applicable (VIDAZA Prescribing 
Information 2016; VIDAZA Summary of Product Characteristics 2016). 
8.10. 
Description of Daratumumab 
Daratumumab supplied for IV infusion in this study is a colorless to yellow liquid and sterile 
concentrate of 20 mg/mL as a liquid vial. The study agent should be essentially free of visible 
particulate matter at the time of dosage preparation and drug product administration. 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 102 of 141 
9. 
ADVERSE EVENTS 
9.1. 
Definition of an Adverse Event 
An AE is any untoward medical occurrence in a patient or clinical investigation patient 
associated with the use of a drug or with study participation, whether or not considered related to 
study drug. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of an investigational 
product, whether or not related to the investigational product. An AE can arise from any use of 
the drug, and from any route of administration, formulation or dose, including an overdose.  
Medical conditions present prior to screening, as well as ongoing changes in laboratory 
values/conditions that are being treated at baseline, will be captured as medical history unless the 
frequency, severity or character of the condition worsens during the trial (after first dose of any 
study drug) for which the condition would then be captured as an AE. 
9.2. 
Definition of a Serious Adverse Event 
An SAE is any AE that meets any of the following criteria: 
• Death 
• Life-threatening 
• Inpatient hospitalization or prolongation of existing hospitalization, except for: 
− Elective or pre-planned treatment for a pre-existing condition that is unrelated to 
the indication under study and has not worsened since signing the ICF (as 
documented as medical history on the eCRF), or 
− Scheduled therapy for the target disease of the study, including admissions for 
transfusion support or convenience, or for observation only following 
daratumumab administration in the absence of a significant medical event 
o Any untoward occurrence during an elective or pre-planned treatment, or 
scheduled therapy for target disease must be reported as an AE/SAE. In 
general, hospitalization signifies that the patient has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the 
physician's office or outpatient setting. When in doubt as to whether 
'hospitalization' occurred or was necessary, the AE should be considered 
serious 
• Persistent or significant disability/incapacity 
• Congenital anomaly/birth defect in the offspring of a patient who received SY-1425 
• Important medical events, defined as an AE that may not result in death, be life-
threatening, or require hospitalization, may be considered an SAE when, based upon 
appropriate medical judgment, they may jeopardize the patient and may require 
medical or surgical intervention to prevent one of the outcomes listed in this 
definition. Examples of such events include intensive treatment in an emergency 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 103 of 141 
room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in inpatient hospitalization, and development of drug dependency or drug 
abuse. 
9.3. 
Procedures for Eliciting, Recording, and Reporting Adverse Events 
9.3.1. 
Eliciting and Recording Adverse Events 
Patients will be instructed to report all AEs and will be asked a general health status question at 
each study visit. All AEs occurring in treated patients will be recorded in the eCRF from the time 
of first dose of any study drug until 30 days after the last dose of any study drug in the eCRF. 
However, following implementation of Amendment 7, recording of AEs in the eCRF will no 
longer be required for Arm 5 patients receiving study drug. Only SAEs, AESI, and Pregnancy 
and Birth Events will continue to be reported via the pharmacovigilance safety database. 
All SAEs occurring from the signing of ICF through 30 days post last dose of any study drug 
will be processed as outlined in Section 9.5. An SAE will be followed until it is either resolved, 
has returned to baseline, or is determined to be a stable or chronic condition.  
At each required visit during the trial, all AEs that have occurred since the previous visit must be 
reviewed. The Investigator, or appropriate designee, must determine if the AE is serious or 
non-serious.  
9.3.2. 
Adverse Event Relationship Assessment 
The Investigator is required to provide an assessment of relationship of AEs and SAEs to study 
drug. A number of factors should be considered in making this assessment including: 1) the 
temporal relationship of the event to the administration of study drug; 2) whether an alternative 
etiology has been identified; and/or 3) biological plausibility. The following guidelines should be 
used by Investigators to assess the relationship of an AE to the administration of the study drug.  
 “Not Related” assessment 
• None: The event is related to an etiology other than study drug administration (the 
alternative etiology must be documented in the patient’s medical record). 
• Remote: The event is unlikely to be related to study drug and likely to be related to 
factors other than study drug. 
“Related” assessment 
• Possible: There is an association between the event and the administration of study 
drug, and there is a plausible mechanism for the event to be related to study drug; but 
there may also be alternative etiologies, such as characteristics of the patient’s clinical 
status or underlying disease. 
• Probable: There is an association between the event and the administration of study 
drug, there is a plausible mechanism for the event to be related to study drug, and the 
event could not be reasonably explained by known characteristics of the patient’s 
clinical status or an alternative etiology is not apparent. 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 104 of 141 
• Definite: There is an association between the event and the administration of study 
drug, there is a plausible mechanism for the event to be related to study drug, and 
causes other than study drug have been ruled out and/or the event re-appeared on 
re-exposure to study drug. 
9.3.3. 
Adverse Event Severity Assessment 
The severity of the AE will be assessed according to the NCI CTCAE v4.03, effective date 
14 June 2010 as well as changes in clinically significant clinical laboratory values, ECG 
parameters and vital sign measurements. Toxicities that are not specified in NCI CTCAE v4.03 
will be defined as follows:  
• Grade 1: The AE is noticeable to the patient, it does not require discontinuation or 
reduction of the dose of study drug, but may require additional therapy. 
• Grade 2: The AE interferes with the patient’s daily activities; it does not require 
discontinuation of study drug, but may require additional therapy. 
• Grade 3: The AE is intolerable and necessitates discontinuing or reducing the dose of 
study drug or additional therapy. 
• Grade 4: The patient is at immediate risk of death from the AE. 
• Grade 5: The AE is fatal. 
9.4. 
Specific Instructions for Recording Adverse Events on the eCRF 
Following implementation of Amendment 7, recording of AEs (serious and nonserious) in the 
eCRF will no longer be required for Arm 5 patients receiving study drug; the eCRF instructions 
described in Section 9.4 are no longer applicable for these patients. Only SAEs (see Section 9.5), 
AESI (see Section 9.6), and Pregnancy and Birth Events (see Section 9.7) will continue to be 
reported via the pharmacovigilance safety database. 
9.4.1. 
Diagnosis Versus Signs and Symptoms 
If a diagnosis is known at the time of reporting, then the diagnosis should be recorded in the 
eCRF rather than the individual signs and symptoms (eg, record myocardial infarction rather 
than chest pain, shortness of breath); however, if a constellation of signs and/or symptoms cannot 
be medically characterized as a single diagnosis or syndrome, at the time of reporting, each 
individual event should be recorded as an AE on the eCRF. If a diagnosis is subsequently 
established, it should be reported as follow-up and should replace the applicable individual signs 
and/or symptoms as the event term on the eCRF. 
9.4.2. 
Adverse Events Occurring Due to Other Events 
In general, AEs occurring secondary to other events should be identified by their primary cause. 
For example, if severe vomiting is known to result in dehydration, it is sufficient to record only 
vomiting as the AE on the eCRF; however, clinically significant AEs occurring secondary to an 
initiating event should be recorded as independent events on the eCRF. For example, if severe 
vomiting leads to acute renal failure, both events should be recorded on the eCRF. 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 105 of 141 
9.4.3. 
Persistent of Recurrent Adverse Events 
A persistent AE is one that extends continuously, without resolution or change in severity, 
between patient evaluation timepoints. Such events should only be recorded once on the AE 
eCRF. If a persistent AE becomes more severe or lessens in severity, it should be recorded as a 
new AE on the eCRF.  
A recurrent AE is one that occurs and resolves between patient evaluation timepoints, and 
subsequently recurs. All recurrent AEs should be recorded as new events on the AE eCRF. 
9.4.4. 
Disease Under Study 
Progression of the underlying disease, including death from progression of the underlying 
disease, is considered an efficacy outcome parameter and should not be captured as an AE/SAE. 
Documentation of the progression of disease must be obtained and recorded in the eCRF. 
9.4.5. 
New Cancers 
The development of a new primary cancer should be regarded as an AE and will generally meet 
at least one of the serious criteria (See Section 9.2). New primary cancers are those that are not 
the primary reason for the administration of study drug treatment and have developed after the 
patient has received at least one dose of study drug upon enrollment in the study. They do not 
include metastases of the original cancer, or diagnosis of AML in a patient previously diagnosed 
with MDS.  
Symptoms of metastasis or the metastasis itself should not be reported as an AE/SAE, as they are 
considered to be disease progression. 
9.5. 
Reporting of Serious Adverse Events 
All SAEs must be reported to Syros or designee (contact information provided below) within 
24 hours after the Investigator’s first knowledge of the event, even if the experience does not 
appear to be related to study drug, from the time of signing ICF through 30 days after the last 
dose of any study drug. This timeframe also applies to additional information that is obtained as 
a part of the follow-up on previously reported SAEs. 
To report an SAE, the site must email, phone, or fax the information to the information listed 
below within 24 hours after becoming aware of the event. 
SAE Reporting Contact Information 
Email 
Fax Number 
SyrosPV@primevigilance.com 
1-855-234-6419 
The initial SAE report must be as complete as possible, including minimally the patient number 
and initials or date of birth, details of the event(s), and an assessment of the causal relationship 
between the event and the investigational drug. Information not available at the time of the initial 
report (eg, an end date for the SAE, or laboratory values received after the report) must be 
documented on a follow-up SAE report form. All follow-up information must be reported using 
the same timelines as the initial report. 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 106 of 141 
If, at any time, after completion of the SAE reporting period (ie, 30 days after last dose of any 
study drug), an Investigator becomes aware of an SAE that is suspected by the Investigator to be 
related to study drug, the event must be reported to the Syros, or designee, as described above. 
Follow-up information may be requested by Syros or designee. 
9.6. 
Reporting of Adverse Events of Special Interest 
AESIs must be reported to Syros, or designee, within 24 hours from first knowledge of the 
event(s) on an SAE Report Form regardless if assessed as non-serious or serious. AESI for the 
study include: 
• Combination of ALT or AST > 3 x ULN and total bilirubin >2 x ULN 
• Triglycerides severity Grade ≥ 3 
• Total cholesterol severity Grade > 3 
• Rash severity Grade ≥ 3 
• Bleeding events with severity Grade ≥ 3  
• Infectious events with severity Grade ≥ 3 
AESIs are to be reported from the first dose of SY-1425 until the EoT visit. As there will be no 
EoT visit for Arm 5 patients still receiving study treatment at the time of implementation of 
Amendment 7, AESIs are to be reported from the first dose of SY-1425 until the last dose of any 
study drug for these patients. 
9.7. 
Pregnancy and Birth Events Procedures 
Pregnancies occurring in patients, or partners of male patients, during the study treatment period 
until 30 days after the patient’s last dose of any study drug are considered immediately 
reportable events. If a pregnancy occurs in a patient, all study drug must be discontinued 
immediately. SY-1425 and azacitidine have both been shown to be teratogenic in animal studies, 
and animal studies have not been conducted to assess the risk with use of daratumumab during 
pregnancy. Therefore pregnant women should be referred to an obstetrician/gynecologist 
experienced in reproductive toxicity for further evaluation and counseling. 
The pregnancy must be reported to Syros, or designee, within 24 hours of the Investigator’s 
knowledge of the pregnancy using the Pregnancy Notification Form using timelines as described 
in Section 9.5. 
The Investigator will follow the pregnant patient until completion of the pregnancy, and must 
notify Syros, or designee, of the outcome within 24 hours of the Investigator’s knowledge of the 
pregnancy outcome. The Investigator will provide this information on the Pregnancy Outcome 
Report Form. This notification includes pregnancies resulting in live, “normal” births. 
If the pregnant patient experiences an SAE, during her pregnancy, or the outcome of the 
pregnancy meets the criteria for immediate classification as an SAE (ie, spontaneous abortion 
[any congenital anomaly detected in an aborted fetus is to be reported], stillbirth, neonatal death, 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 107 of 141 
or congenital anomaly), the Investigator should follow the procedures for reporting SAEs as 
described in Section 9.5. 
All neonatal deaths and congenital anomalies that occur within 30 days of birth (regardless of 
relationship to study drug) should be reported as SAEs. In addition, any infant death or 
congenital anomaly occurring after 30 days that the Investigator suspects is related to the in utero 
exposure to study drug should also be reported to Syros, or designee as described in Section 9.5. 
The Investigator will follow the pregnancy at least until birth or pregnancy termination.  
9.8. 
Overdose 
There has been no experience with acute overdose of tamibarotene in humans. However, 
overdose with other retinoids has been associated with transient headache, facial flushing, 
cheilosis, abdominal pain, dizziness, and ataxia. These symptoms have resolved quickly without 
apparent residual effects. Management of overdose with tamibarotene should focus on 
monitoring target organ function to preserve their viability and prevent complications. 
One case of overdose with azacitidine was reported during clinical trials (VIDAZA Prescribing 
Information 2016; VIDAZA Summary of Product Characteristics 2016). A patient experienced 
diarrhea, nausea, and vomiting after receiving a single intravenous dose of approximately 
290 mg/m2, almost 4 times the recommended starting dose. In the event of overdose, the patient 
should be monitored with appropriate blood count tests and should receive supportive treatment, 
as necessary. There is no known antidote for azacitidine overdose. 
The dose of daratumumab at which severe toxicity occurs is not known. In the event of an 
overdose, monitor patients for any signs or symptoms of adverse effects and provide appropriate 
supportive treatment (DARZALEX Prescribing Information 2017; DARZALEX Summary of 
Product Characteristics 2017). 
9.9. 
Clinical Laboratory Changes 
If an abnormal laboratory value or vital sign is associated with clinical signs and/or symptoms, 
the sign or symptom should be reported as AEs. If the laboratory abnormality is a sign of a 
disease or syndrome, only the diagnosis needs to be recorded on the eCRF and SAE Report 
Form. Following implementation of Amendment 7, recording of AEs (serious and nonserious) in 
the eCRF will no longer be required for Arm 5 patients receiving study drug; the eCRF 
instructions described in Section 9.9 are no longer applicable for these patients. Only SAEs (see 
Section 9.5), AESI (see Section 9.6), and Pregnancy and Birth Events (see Section 9.7) will 
continue to be reported via the pharmacovigilance safety database. 
Abnormal laboratory values will not be reported as AEs unless the laboratory result: 
• Requires a dose adjustment or schedule change to study drug 
• Leads to discontinuation of treatment  
• Requires additional testing or therapeutic intervention  
• Is associated with accompanying signs/symptoms  
• Is considered to be an AE by the Investigator 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 108 of 141 
9.10. 
Reporting of Serious Adverse Events to Institutional Review 
Boards/Ethics Committees 
Syros, or designee, shall notify the Investigator of potential serious risks from clinical trials or 
any other sources, including the following: 
• SAEs assessed by the Investigator and/or Syros as, related to study drug, and assessed 
by Syros as unexpected for study drug, 
• Any findings from other studies that suggest a significant risk in humans exposed to 
the drug, 
• Any findings from animal or in vitro testing that suggests a significant risk to humans 
exposed to the drug, such as mutagenicity, teratogenicity, or carcinogenicity; or report 
of significant organ toxicity at or near the expected human exposure 
The Investigator must comply with the applicable regulatory requirements and timelines related 
to the reporting of SAEs to their IRB or Ethics Committee (EC). Investigators must also submit 
safety information provided by Syros, or designee, to the IRB or EC, according to local 
requirements. 
The Investigator must keep copies of all SAE information, including correspondence with Syros 
and all IRB/EC information on file. 
9.11. 
Reporting of Serious Adverse Events to Regulatory Authorities 
Syros, or designee, shall notify Regulatory Authorities of serious, unexpected adverse reactions 
or other adverse events, per local requirements. Expectedness will be determined using the 
current tamibarotene Investigator Brochure. 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 109 of 141 
10. 
STATISTICS 
10.1. 
General Procedures 
Frequency distributions will be used for categorical variables and appropriate summary statistics 
(ie, mean, median, and range) for quantitative/continuous variables. Each arm (six analysis 
groups) will be reported and analyzed independently, with no adjustment for multiple hypothesis 
testing. Two-sided 90% confidence intervals will be provided for key endpoints, ie, primary and 
secondary endpoints at a minimum. 
Additional details of the analyses will be provided in the statistical analysis plan (SAP). Any 
deviations in the planned analysis as stated in the protocol will be delineated in the SAP. Any 
deviations from the SAP will be reported in the clinical study report. 
10.2. 
Analysis Populations 
Screened: All screened patients (consented) regardless of receipt of the investigational product 
comprise the screened analysis population. This population will be used only for the generation 
of demographics and RARA and IRF8 biomarker results. 
Safety Population: All screened patients who received any amount of study drug (SY-1425 or 
combination treatment) comprise the safety population. This population will be further divided 
by arm as noted in the analysis. 
PK Evaluable: All patients enrolled who receive any amount of SY-1425 and have an adequate 
number of SY-1425 concentration determinations for PK calculations comprise the PK evaluable 
analysis population. 
PD Evaluable: All patients enrolled who receive any amount of SY-1425 and have an adequate 
number of samples for PD determination comprise the PD evaluable analysis population. 
Response Evaluable: The response evaluable analysis population is comprised of all patients 
enrolled who: 
• Complete 1 cycle of SY-1425, and have a follow-up assessment of disease status, and 
do not have any major protocol violations, or 
• Are withdrawn from the study before completion of cycle 1 because of documented 
disease progression 
10.3. 
Determination of Sample Size 
Approximately 162 response-evaluable patients are required (ie, approximately 25 biomarker 
positive patients each in Arms 1, 2A, 3, and 5; approximately 50 patients in Arm 2B (~ 25 
biomarker positive and ~ 25 biomarker negative); and approximately 12 biomarker positive 
patients in Arm 4) and will be analyzed separately with no adjustment for multiple hypothesis 
testing across arms, in part for practical reasons as arms may have very different rates of 
enrollment. This is a fixed design trial.  
For each of Arms 1, 2A, 2B (biomarker positive subset), 3, and 5, an exact 2-sided 90% 
confidence interval will be calculated for ORR or TIR. Success for Arms 1, 2A and 3 (n=25 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 110 of 141 
each) is achieved, if the lower bound of the confidence interval excludes 5%. Assuming a 25% 
response rate for SY-1425 as a single agent, the power for each of these arms of this study is 
90.4%. Arm 2B has two subgroups defined by biomarker status (n=25 each). Success for the 
biomarker positive subgroup in Arm 2B is achieved if the lower bound of the confidence interval 
excludes 20%. Assuming a 45% response rate for the combination of SY-1425 and azacitidine in 
biomarker positive patients, the power for this subgroup of Arm 2B of the study is 86.6%. 
Success for Arm 5 (n=25) is achieved if the lower bound of the confidence interval excludes 
10%. Assuming a 30% response rate for the combination of SY-1425 and azacitidine in relapsed/ 
refractory biomarker-positive AML patients, the power for this arm of the study is 80.7%. 
Therefore, as an example, an ORR or TIR of 4/25 (16%) (90% CI: 5.7 to 33.0%) for Arms 1, 2A, 
and 3 would be considered a success for each of these arms, an ORR of 9/25 (36%) (90% CI: 
20.2 to 54.4%) would be considered a success for the biomarker positive Arm 2B subgroup, and 
an ORR of 6/25 (24%) (90% CI: 11.0 to 42.0%) would be considered a success in Arm 5. No 
adjustment for multiple hypothesis testing across arms will be made.   
Success for the entire Arm 2B population is achieved if the lower bound of the confidence 
interval excludes 20%. Assuming a 38% response rate for the combination of SY-1425 and 
azacitidine in the entire Arm 2B population, the power for secondary endpoint of Arm 2B is 
84.6%.   
The primary endpoint of Arm 4 is safety and tolerability of SY-1425 in combination with 
daratumumab. The sample size of 12 biomarker positive patients is not based on any hypothesis 
testing but is appropriate for studies of this type with a primary focus on safety. 
10.4. 
Statistical Analysis 
10.4.1. 
Demographic and Baseline Characteristics 
The screened analysis population will be summarized by biomarker status, disease type, and 
prior therapy. 
The safety population will be used to summarize demographic and baseline characteristics, in a 
descriptive fashion. Data to be evaluated will include at least age, sex, race, characteristics of 
disease (including baseline biomarkers), and baseline disease severity assessment as well as 
other potential prognostic factors and disease characteristics. 
10.4.2. 
Analysis of Efficacy 
10.4.2.1. Primary Endpoints 
The ORR and TIR by group, specifically, in Arms 1, 2A, 2B (biomarker positive subgroup), 3, 
and 5, are the primary endpoints. 
ORR is defined as: 
• AML: ORR as determined by the Investigator based on the rate of CR/CRi/CRh, 
MLFS, and PR, per the revised IWG AML criteria (Cheson et al, 2003, 
Bloomfield  et al, 2018). 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 111 of 141 
• Higher-risk MDS: ORR as determined by the Investigator per the revised IWG AML 
criteria (Cheson et al, 2003) or modified IWG MDS criteria (Cheson et al, 2006). 
Response is based on the rate of CR/CRi, PR, and HI. CR includes marrow CR. 
TIR is defined as: 
• Lower-risk MDS: The transfusion independence rate (TIR) rate defined as the 
proportion of patients who achieve transfusion independence defined as 8 consecutive 
weeks of RBC transfusion independence. 
The primary endpoint for Arm 4 is to characterize the safety and tolerability of SY-1425 in 
combination with daratumumab by assessing the type and frequency of AEs and SAEs using 
NCI CTCAE v4.03, as well as changes in clinically significant clinical laboratory values, ECG 
parameters and vital sign measurements. 
10.4.3. 
Secondary Endpoints 
Characterize the clinical activity of SY-1425 in patients positive for the RARA super-enhancer 
associated biomarker in Arms 1, 2A, 2B, 3, and 5. Summaries of ORR or TIR will be provided 
for all patients positive for the RARA super-enhancer associated biomarker (including IRF8 
positive and IRF8 negative patients), for double positive patients (including only IRF8 positive 
patients), and for single positive patients (including only IRF8 negative patients), separately. 
• Overall response rate (ORR) for AML or higher-risk MDS patients (Arms 1, 2A, 2B, 
and 5) 
• Transfusion independence rate (TIR) for lower-risk MDS patients (Arm 3) 
Characterize the clinical activity of SY-1425 in patients positive for the IRF8 biomarker and 
negative for the RARA super-enhancer associated biomarker in Arms 1, 2A, 2B, 3, and 5. 
• Response rate (ORR + TIR) for patients treated with SY-1425 as a single agent 
(Arms 1, 2A, and 3) 
• ORR for AML or higher-risk MDS patients (Arms 1, 2A, 2B and 5) 
• TIR for lower-risk MDS patients (Arm 3) 
Characterize the clinical activity of the combination of SY-1425 and azacitidine in patients in 
Arm 2B. 
• Overall response rate (ORR) for AML patients (Arm 2B) 
Characterize the clinical activity of the combination of SY-1425 and daratumumab by ORR in 
Arm 4. 
Characterize the clinical activity of SY-1425 as measured by EFS, RFS, DOR, OS, and HI in 
AML and higher-risk MDS patients. 
• EFS: defined as time from first treatment until date of documentation of disease 
relapse following CR/CRi, or death, whichever occurs first. If the patient does not 
achieve a CR, EFS is defined as the point of progression or death, whichever occurs 
first. 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 112 of 141 
• RFS: defined as time from first objective documentation of CR/CRi (including CRh, 
MLFS for AML patients), or PR until the date of first objective documentation of 
disease relapse or death due to any cause, whichever occurs first.  
• DOR: defined as time from first date of response (CR/CRi [including CRh, MLFS for 
AML patients], PR, or HI for MDS patients - if best response) until date of relapse.  
• OS: defined as time from first treatment until death from any cause. 
• HI Rate: defined according to the modified IWG response criteria for MDS (Cheson 
et al, 2006) as the proportion of patient with a response (lasting at least 8 weeks) after 
first treatment. 
Characterize the clinical activity of SY-1425 as measured by DOR and HI in transfusion 
dependent lower-risk MDS patients. 
• DOR is defined as the time from first date of response (HI or transfusion 
independence) until date of relapse. 
• HI is defined according to the modified IWG response criteria for MDS (Cheson et al, 
2006) as response (lasting at least 8 weeks) after first treatment. 
Time to event data will be assessed using the Kaplan-Meier method. Details on censoring and the 
analysis will be provided in SAP. 
Changes in transfusion rates, incidence and duration of use for growth factor support and 
antibiotics, and number of hospitalizations associated with febrile neutropenia and/or 
thrombocytopenic bleeding will be summarized. 
Characterize the safety and tolerability of SY-1425 as a single agent and in combination with 
azacitidine by assessing the type and frequency of AEs, SAEs using NCI CTCAE v4.03, as well 
as changes in clinically significant clinical laboratory values, ECG parameters and vital sign 
measurements (Arms 1, 2A, 2B, 3, and 5). 
Estimate the PK parameters of SY-1425, as single agent and in combination with azacitidine or 
daratumumab, after single and multiple doses by performing PK analysis to define tmax, Cmax, 
Cmin, AUC, CL/F, and t1/2, where the data permits. 
10.4.4. 
Exploratory Endpoints 
• Sensitivity analyses to the primary endpoint to predict ORR or TIR across all patients 
by arm, prior treatment, and diagnosis type, RARA super-enhancer associated 
biomarker and/or IRF8 biomarker status; DHRS3 induction, peripheral blood myeloid 
differentiation markers, induction of CD38 expression, genotype and mutation status 
• Changes from baseline in Health-Related Quality of Life (HRQOL)  
− AML/higher-risk MDS patients (Arms 1, 2A, 2B, 4, and 5): Functional 
Assessment of Cancer Therapy-Leukemia (FACT-Leu) questionnaire 
− Lower-risk MDS patients (Arm 3): Functional Assessment of Cancer Therapy-
Anemia (FACT-An) questionnaire 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 113 of 141 
• Establish PK/PD relationships by performing analysis of PD biomarkers (DHRS3 and 
myeloid differentiation markers) in leukemic cells from repeat peripheral blood 
samples and assessing any changes over time 
• PK parameters for daratumumab in combination with SY-1425, including maximum 
concentration (Cmax) and minimum concentration (Cmin; trough concentration) 
• Characterize the relationship between SY-1425 activity and baseline messenger RNA 
(mRNA) expression of RAR and IRF8 biomarkers by correlating baseline 
biomarker mRNA expression levels of RARα and IRF8 with ORR, EFS, RFS, DOR, 
OS, and HI Rate 
• Estimate of median time-to-response  
• Evaluate changes in expression of myeloid differentiation markers, including CD38, 
over time 
• Analysis of additional genes or proteins using multiplex platform  
10.4.5. 
Analysis of Safety 
Safety tabulations will include treatment-emergent adverse events (TEAEs), vital signs, ECG, 
laboratory tests, and concomitant medications separately by arm. Severity grade will be defined 
by the NCI-CTCAE v4.03. 
Safety evaluations will be based on the incidence, severity, and type of AEs, and clinically 
significant changes in the patient’s physical examination findings, vital signs and clinical 
laboratory results. Safety variables will be described and presented for the Safety Population. 
Exposure to study drug, dosing compliance, and reasons for discontinuation of study treatment 
will be tabulated.  
10.4.5.1. Adverse Events 
AEs will be coded by system organ class (SOC) and preferred term using the most current 
Medical Dictionary for Regulatory Activities (MedDRA) at the time of study initiation. Severity 
of AEs will be assigned according to NCI-CTCAE (v.4.03). AEs will be summarized by SOC, 
preferred term and severity accordingly. 
 
10.4.5.2. Laboratory Determination 
Actual values and change from baseline values for continuous laboratory data will be 
summarized descriptively. Categorical measurements will be similarly summarized for actual 
values. Laboratory results categorized as outside of the normal range will be summarized in 
worst case shift tables. Clinically significant or not clinically significant criteria may be applied 
for out of range values. 
10.4.5.3. Other Safety Data 
Temperature, vital signs, body weight, physical examination findings, ECG, and concomitant 
medications will be summarized. 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 114 of 141 
10.5. 
Interim Analysis 
There is no formal interim analysis in which alpha-spending is required prior to the single 
planned final analysis for the by Arm primary and secondary endpoints.  
10.6. 
Pharmacokinetics 
Plasma concentration versus time data will be analyzed using non-compartmental methods to 
determine tmax, Cmax, Cmin, AUC, CL/F, and t1/2. Parametric models will be utilized as the data 
permit. 
10.7. 
Pharmacodynamics 
DHRS3 gene expression is most strongly induced by SY-1425 in AML cells harboring the RARA 
super-enhancer or IRF8 biomarker. However, there is also a significant upregulation in 
peripheral blood mononuclear cells (PBMCs), which may act as surrogate tissue for measuring 
SY-1425 response. DHRS3 gene expression which may be induced by SY-1425 in PBMCs will 
be assessed. Relationships between RARA and IRF8 biomarker status, PK parameters, related 
TEAEs, and efficacy outcomes may be assessed as the data permit. 
 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 115 of 141 
11. 
ETHICS AND RESPONSIBILITIES 
11.1. 
Good Clinical Practice 
This study will be conducted in accordance with ICH-GCP and all applicable requirements. 
Periodic monitoring visits will be conducted to ensure compliance to the protocol and all good 
clinical practices. Access to study documents will be provided to Syros, its designees, and the 
regulatory agencies to perform verification that the data being recorded in the CRFs is complete 
and accurate. 
11.2. 
Ethical Conduct of the Study 
The study will be conducted in accordance with all applicable regulatory requirements and 
adhere to the general principles set forth in the Guidelines for GCP (ICH 1996) and the 
Declaration of Helsinki (World Medical Association 1996 & 2008). 
The Investigator is responsible for having the approval of study protocol, investigator brochure, 
informed consent, advertisements (if applicable), any written information to be provided to 
patients, safety updates, and any revisions to the documents by the IRB/IEC. The Investigator is 
responsible for keeping the IRB/IEC apprised of the progress of the study and of any changes 
made to the protocol as deemed appropriate. 
Protocol modifications, except those intended to reduce immediate risk to study patients, may be 
made only by Syros. A protocol change intended to eliminate an apparent immediate hazard to 
patients may be implemented immediately, provided the IRB/IEC is notified within 5 days. 
Any permanent change to the protocol must be handled as a protocol amendment. The written 
amendment must be submitted to the IRB/IEC and the Investigator must await approval before 
implementing the changes. Syros will submit protocol amendments to the appropriate regulatory 
authorities for approval. 
If in the judgment of the IRB/IEC, the Investigator, and/or Syros, the amendment to the protocol 
substantially changes the study design and/or increases the potential risk to the patients and/or 
has an impact on the patient's involvement as a study participant, the currently approved written 
ICF will require similar modification. In such cases, informed consent will be renewed for 
patients enrolled in the study before continued participation. 
11.3. 
Informed Consent 
The Investigator must ensure that each study patient, or guardian/legal representative, is fully 
informed and written informed consent is obtained prior to initiation of any study specific 
activity. A copy of the written informed consent document must be provided to the patient. The 
Investigator is required to maintain the signed informed consent and documentation of the 
process must comply with ICH-GCP and all applicable regulatory requirements. 
11.4. 
Records Management 
The Investigator will keep all study records according to ICH-GCP and applicable regulatory 
requirements. The site is instructed to maintain all documentation and any other documentation 
that is required by law for 5 years after the termination or conclusion of the study or longer 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 116 of 141 
periods as required by regulatory requirements. The Investigator must receive Syros’ written 
permission before destroying any study documentation, even after the records retention period 
has expired. 
If the Investigator is unable to retain the study records for the required time period, Syros must 
be notified to allow the transfer of study records to Syros, another institution, or to a third party 
as appropriate. 
11.5. 
Source Documentation 
The Investigator is required to maintain accurate source documents that record all observations 
for each study patient. eCRFs will be completed for each patient in the study. It is the 
responsibility of the Investigator to ensure the accuracy, timeliness, and completeness of the data 
that is reported in the eCRFs. The source records are typically the patient’s chart and should be 
consistent with the data recorded in the eCRF. The Investigator or designee should complete the 
eCRF as soon as possible after the data is collected. Following implementation of Amendment 7, 
no further eCRFs will be required to be completed for patients enrolled in Arm 2B or Arm 5, 
unless the eCRF data were collected prior to implementation of the amendment. 
11.6. 
Study Drug Accountability 
The Investigator is responsible for study drug accountability throughout the study as per the 
study-specific pharmacy manual. Accurate records of study drug, received, dispensed from and 
returned to the study site are to be maintained by the study site. Study drug accountability will be 
monitored throughout the study. Study drug will be disposed of according to applicable 
regulations and Syros instruction. Following implementation of Amendment 7, SY-1425 
accountability will be communicated to the Sponsor approximately every 3 months. 
11.7. 
Auditing and Monitoring 
During the study, Syros or its designee will conduct periodic monitoring visits to ensure that 
ICH-GCP practices are being adhered to. The monitors will review source documentation to 
confirm that accuracy of the data recorded in the eCRF. The investigator and institution is 
required to allow direct access to the source documentation, eCRFs, and any other study 
documentation to study monitors and any regulatory agencies to confirm the accuracy and 
completeness of the data recorded in the eCRFs. 
11.8. 
Study Report and Publications 
Syros is responsible for preparing and providing the appropriate regulatory authorities with CSRs 
according to the applicable regulatory requirements. 
The publication policy of Syros is discussed in the Investigator's Clinical Trial Agreement. 
11.9. 
Study Discontinuation 
Syros reserves the right to terminate the study, or terminate the study at an investigator’s site at 
any time. The Principal Investigator may terminate the study at his/her site at any time. Should 
this be necessary, Syros or a specified designee will inform the appropriate regulatory authorities 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 117 of 141 
of the termination of the study and the reasons for its termination, and the PI will inform the 
IRB/IEC of the same. In terminating the study, Syros and the Principal Investigator will assure 
that adequate consideration is given to the protection of the patients’ interests. 
11.10. 
Confidentiality 
All information generated in this study is considered highly confidential and must not be 
disclosed to any person or entity not directly involved with the study unless prior written consent 
is gained from Syros. However, authorized regulatory officials, IRB/IEC personnel, Syros and its 
authorized representatives are allowed full access to the records. 
Identification of patients and case report forms (CRFs) shall be made by initials, screening and 
treatment numbers only. If required, the patient's full name may be made known to an authorized 
regulatory agency or other authorized official. 
 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 118 of 141 
12. 
REFERENCES 
Bloomfield CD, Estey E, Pleyer L, Schuh AC, Stein EM, Tallman MS, Wei A; Time to repeal 
and replace response criteria for acute myeloid leukemia? Blood Rev. 2018 Sep;32(5):416-425.  
Chapuy CI, Nicholson RT, Aguad MD, Chapuy B, Laubach JP, Richardson, PG, et al. Resolving 
the daratumumab interference with blood compatibility testing. Transfusion. 2015; 55:1545-
1554. 
Chapuy CI, Aguad MD, Nicholson RT, AuBuchon JP, Cohn CS, Delaney M, et al. International 
validation of a dithiothreitol (DTT)-based method to resolve the daratumumab interference with 
blood compatibility. Transfusion. 2016;56(12):2964-2972.  
Cheson BD, Bennett JM, Kopecky KJ, Büchner T, Willman CL, Estey EH, et al. Revised 
recommendations of the International Working Group in for diagnosis, standardization response 
criteria, treatment outcomes, and reporting standards for therapeutic trials in acute myeloid 
leukemia. J Clin Oncol. 2003;21(24):4642-4649. 
Cheson BD, Greenberg PL, Bennett JM, Lowenberg B, Wijermans PW, Nimer SD, et al. Clinical 
application and proposal for modification of the International Working Group (IWG) response 
criteria in myelodysplasia. Blood. 2006;108(2):419-425. Epub 2006 Apr 11. 
Cogle CR, Iannacone MR, Yu D, Cole AL, Imanirad I, Yan L, et al. High rate of 
myelodysplastic syndrome cases and an improved method of case ascertainment. Leuk Res. 
2014;38(1):71-75. Epub 2013 Nov 5. 
Cook RJ, Moyo TK, Liesveld JL, Rizzieri DA, Stein EM, de Botton S et al; Early Results From a 
Biomarker-Directed Phase 2 Trial of SY-1425 in Combination with Azacitidine or Daratumumab 
in Non-APL Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS). Abstract 
2735, American Society of Hematology, December 2018 
DARZALEX (daratumumab) [Prescribing Information]. Janssen Biotech, Inc, Horsham, PA; 
2017; Available from: https://www.darzalex.com/sites/www.darzalex.com/files/darzalex-
prescribing-information.pdf. Accessed 01 August 2017. 
DARZALEX (daratumumab) [Summary of Product Characteristics]. Janssen-Cilag International 
NV, Beerse, Belgium; 2017; Available from: 
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Product_Information/human/004077/WC500207296.pdf. Accessed 01 August 2017. 
de Weers M, Tai Y-T, van der Veer MS, Bakker JM, Vink T, Jacobs DCH, et al. Daratumumab, 
a Novel Therapeutic Human CD38 Monoclonal Antibody, Induces Killing of Multiple Myeloma 
and Other Hematological Tumors. J Immunol. 2011;186:1840-1848. 
Derissen E J, Beijnen J H, Schellens J H. Concise drug review: azacitidine and decitabine. 
Oncologist. 2013;18(5): 619–624. 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 119 of 141 
DeZern AE. Nine years without a new FDA-approved therapy for MDS: how can we break 
through the impasse? Hematology Am Soc Hematol Educ Program. 2015;2015(1):308-316. 
Döhner, H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Büchner T, et al. Diagnosis and 
management of AML in adults: 2017 ELN recommendations from an international expert panel. 
Blood. 2017;129(4):424-447. Epub 2016 Nov 28. 
FDA.gov [Internet]. Silver Spring (MD): Drug Development and Drug Interactions: 
Classification of Inhibitors. 2014 (updated 2014 Oct 27; cited 08 March 2016]. Available from: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractio
nsLabeling/ucm093664.htm#classInhibit. Accessed 08 February 2017. 
Ferrara F, Schiffer CA. Acute myeloid leukemia in adults. Lancet. 2013;381(9865):484-95. 
Ferrara F, Barosi G, Venditti A, Angelucci E, Gobbi M, Pane F, et al. Consensus-based 
definition of unfitness to intensive and non-intensive chemotherapy in acute myeloid leukemia: a 
project of SIE, SIES and GITMO group on a new tool for therapy decision making. Leukemia. 
2013;27(5):997-999. 
Gallagher RE. Retinoic acid resistance in acute promyelocytic leukemia. Leukemia. 
2002;16(10):1940-1958. 
Greenberg PL, Tuechler H, Schanz J, Sanz G, Garcia-Manero G, Solé F, et al. Revised 
international prognostic scoring system for Myelodysplastic Syndrome, Blood. 
2012;120(12):2454-65. Epub 2012 Jun 27. 
Grimwade D, Ivey A, Huntly BJ. Molecular landscape of acute myeloid leukemia in younger 
adults and its clinical relevance. Blood. 2016;127(1):29-41. Epub 2015 Dec 10. 
Hnisz D, Abraham BJ, Lee TI, Lau A, Saint-André V, Sigova AA, et al. Transcriptional super-
enhancers connected to cell identity and disease. Cell. 2013;155(4):934-947. Epub 2013 Oct 10. 
Kanai F, Obi S, Fujiyama S, Shiina S, Tamai H, Mochizuki H, et al. An open-label phase I/III 
study of tamibarotene in patients with advanced hepatocellular carcinoma. Hepatol Int. 
2014;8(1):94-103. Epub 2013 Jul 25. 
Kastner P, Chan S. Function of RARα during the maturation of neutrophils. Oncogene. 
2001;20:7178–7185. 
Keyhani A, Huh YO, Jendiroba D, Pagliaro L, Cortez J, Pierce S, et al. Increased CD38 
expression is associated with favorable prognosis in adult leukemia. Leu Res. 2000;24(2):153-9. 
Niederreither K, Dollé, P. Retinoic acid in development: towards an integrated view. Nat. Rev. 
Genet. 2008;(7):541–553. Epub 2008 Jun 10. 
Oken MM, Creech RH, Tormey DC, Horton J, DavisTE, McFadden ET, et al. Toxicity and 
response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 
1982;5(6):649-55. 
Overdijk MB, Verploegen S, Bogels M, van Egmond M, van Bueren JJL, Mutis T, et al. 
Antibody-mediated phagocytosis contributes to the anti-tumor activity of the therapeutic 
antibody daratumumab in lymphoma and multiple myeloma. mAbs. 2015;7(2):311-21. 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 120 of 141 
Sanford D, Lo-Coco F, Sanz MA, Di Bona E, Coutre S, Altman JK, et al. Tamibarotene in 
patients with acute promyelocytic leukaemia relapsing after treatment with all-trans retinoic acid 
and arsenic trioxide. Br J Haematology. 2015;171(4):471-477. Epub 2015 Jul 24. 
Shinagawa K, Yanada M, Sakura T, Ueda Y, Sawa M, Miyatake M, et al. Tamibarotene as 
maintenance therapy for acute promyelocytic leukemia: results from a randomized controlled 
trial. J Clin Oncol. 2014;32(33):3729-35; Epub 2014 Sep 22. 
Stresemann C, Bokelmann, I, Mahlknecht U, Lyko, F. Azacytidine causes complex DNA 
methylation responses in myeloid leukemia. Mol. Cancer Ther. 2008;7:2998–3005. 
Tobita T, Takeshita A, Kitamura K, Ohnishi K, Yanagi M, Hiraoka A, et al. Treatment with a 
new synthetic retinoid, Am80, of acute promyelocytic leukemia relapsed from complete 
remission induced by all-trans retinoic acid. Blood. 1997;90(3): 967-73. 
VIDAZA (azacitidine for injection), for subcutaneous or intravenous use [Prescribing 
Information]. Celgene Corporation, Summit, NJ; 2016; Available from: 
http://www.celgene.com/content/uploads/vidaza-pi.pdf. Accessed 08 February 2017. 
VIDAZA (azacitidine for injection), for subcutaneous use [Summary of Product Characteristics]. 
Celgene Europe Ltd, Stockley Park, Uxbridge, UK; 2016; Available from: 
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-
_Product_Information/human/000978/WC500050239.pdf. Accessed 08 February 2017. 
Voso M T, Santini V, Fabiani E, Fianchi L, Criscuolo M, Falconi G, et al. Why methylation is 
not a marker predictive of response to hypomethylating agents. Haematologica. 
2014;99(4):613-619. 
Wang J, Mi Y, Jiang B, Chen X, Ji C, Li Y, et al. Tamibarotene compared to all-trans retinoic 
acid (ATRA) as add-on to arsenic trioxide (ATO) in subjects with relapsed acute promyelocytic 
leukemia (APL) ASH poster, December 2015 (220).  
Wouters BJ, Delwel R. Epigenetics and approaches to targeted epigenetic therapy in acute 
myeloid leukemia. Blood. 2016;127(1):42-52; Epub 2015 Dec 10. 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 121 of 141 
13. 
APPENDICES 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 122 of 141 
APPENDIX 1. NAMES OF STUDY PERSONNEL 
Contact information can be found in the study manual provided to the site. 
 
 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 123 of 141 
APPENDIX 2. ECOG PERFORMANCE STATUS 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease performance without 
restriction. 
1 
Symptoms but ambulatory. Restricted in physically strenuous activity, but ambulatory 
and able to carry out work of a light or sedentary nature (eg, light housework, office 
work) 
2 
In bed <50% of the time. 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 
In bed >50% of time. Capable of only limited selfcare, confined to bed or chair more 
than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self care. Totally confined 
to bed or chair. 
5 
Dead 
As published in Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. 
Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol. 
1982;5(6):649-55. 
 
 
 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 124 of 141 
APPENDIX 3. CRITERIA FOR DETERMINATION OF MDS IPSS-R 
RISK CATEGORY 
MDS Cytogenetic Scoring System (IPSS-R) 
Cytogenetic prognostic 
subgroups 
Cytogenetic abnormalities 
Very good 
-Y, del(11q) 
Good 
Normal, del(5q), del(12p), del(20q), double including del(5q) 
Intermediate 
del(7q), +8, +19, i(17q), any other single or double independent clones 
Poor 
-7, inv(3)/t(3q)/del(3q), double including -7/del(7q),        Complex: 3 
abnormalities 
Very poor 
Complex: >3 abnormalities 
MDS Prognostic Score Values (IPSS-R) 
 
Score Value 
Prognostic variable 
0 
0.5 
1 
1.5 
2 
3 
4 
Cytogenetics 
Very 
Good 
- 
Good 
– 
Inter-
mediate 
Poor 
Very 
Poor 
Marrow blasts (%) 
≤2 
- 
>2 - < 5 
- 
5-10 
>10 
- 
Hemoglobin (g/dL) 
≥10 
- 
8 - < 10 
< 8 
- 
- 
- 
Platelet Count (x 109/L) 
≥100 
50 - <100 
<50 
- 
- 
- 
- 
Absolute Neutrophil 
Count (x 109/L) 
≥0.8 
<0.8 
- 
- 
- 
- 
- 
MDS IPSS-R Prognostic Risk Category and Risk Score (Sum of Prognostic Score Values) 
Risk Category 
Overall Risk Score 
Very Low  
≤1.5 
Low  
>1.5-3 
Intermediate 
>3-4.5 
High 
>4.5-6 
Very High 
>6 
Greenberg PL, Tuechler H, Schanz J, Sanz G, Garcia-Manero G, Solé F, et al. Revised international prognostic 
scoring system for myelodysplastic syndromes. Blood. 2012;120(12):2454-65. Epub 2012 Jun 27. 
 
 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 125 of 141 
APPENDIX 4. IWG RESPONSE CRITERIA TABLE FOR AML, MDS 
AND HEMATOLOGIC IMPROVEMENT 
Response Criteria for Acute Myeloid Leukemia 
Hematologic Responses to Treatment 
Response Criteria 
Neutrophils  
per (L) 
Platelets 
per (L) 
Bone Marrow Blasts (%) 
Complete Response (CR) 
1,000 
100,000 
<5 with spicules, no Auer rods  
Cytogenetic CR (CRc)  
1,000 
100,000 
<5, cytogenetics - normal 
Molecular CR (CRm)  
1,000 
100,000 
<5, molecular - negative  
CR, with incomplete blood count 
recovery (CRi) 
<1,000  
 -or 
<100,000 
<5, either neutrophils or 
platelets not recovered 
CR with partial hematologic 
recovery (CRh) 
>500 
>50,000 
<5, with partial recovery of 
peripheral counts 
MLFS 
NA 
NA 
<5, with no hematologic 
recovery required 
Partial Remission (PR) 
1,000 
100,000 
50% decrease from baseline, 
with decrease to 5-25 
Partial Remission with incomplete 
blood count recovery (PRi) 
<1,000  
 -or- 
<100,000 
50% decrease from baseline, 
with decrease to 5-25 
Minor Response 
NA 
NA 
25% decrease from baseline 
Stable Disease 
NA 
NA 
Blasts stable 25% 
There is no minimum requirement for bone marrow cellularity or hemoglobin concentration for response criteria 
Cheson BD, Bennett JM, Kopecky KJ, Büchner T, Willman CL, Estey EH, etc. Revised recommendations of the 
International Working Group for diagnosis, standardization of response criteria, treatment outcomes, and reporting 
standards for therapeutic trials in acute myeloid leukemia. J Clin Oncol. 2003;21(24):4642-9. 
Bloomfield CD, Estey E, Pleyer L, Schuh AC, Stein EM, Tallman MS, Wei A; Time to repeal and replace response 
criteria for acute myeloid leukemia? Blood Rev. 2018 Sep;32(5):416-425.  
 
 
 
 
 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 126 of 141 
Treatment Failure 
Category 
Definition 
Comment 
Progressive Disease (PD) 
Evidence for an increase in bone marrow blast 
percentage and/or increase of absolute blast 
counts in the blood: 
• >50% increase in marrow blasts over 
baseline (a minimum 15% point increase is 
required in cases with <30% blasts at 
baseline; or persistent marrow blast 
percentage of >70% over at least 3 months; 
without at least a 100% improvement in 
absolute neutrophil count (ANC) to an 
absolute level [>0.5 x 109/L (500/ìL), 
and/or platelet count to >50 x 109/L 
(50,000/ìL) non-transfused]; or 
• >50% increase in peripheral blasts (WBC x 
% blasts) to >25 x 109/L (>25,000/ìl) (in 
the absence of differentiation syndrome) a; 
or 
• New extramedullary disease 
In general, at least 2 cycles of treatment 
should be administered. 
 
Blast increases should be observed in 2 
consecutive marrow assessments at least 4 
weeks apart; the date of progression should 
then be defined as of the first observation 
date. 
 
“Progressive disease” is usually 
accompanied by a decline in ANC and 
platelets and increased transfusion 
requirement and decline in performance 
status or increase in symptoms. 
a Differentiation syndrome, ie, a transient increase in the percentage of bone marrow blasts and an absolute increase 
in blood blasts, may be observed with targeted therapies; in this setting, an increase in blasts may not necessarily 
indicate progressive disease. 
 
Döhner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Büchner H, et al. Diagnosis and management of 
AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129(4):424-447. 
 
 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 127 of 141 
Response Criteria and Progression Definitions for Myelodysplasia 
Response 
Criteria 
Peripheral Blood 
Bone Marrow 
Blasts (BMB) (%) 
Other 
Hgb  
(g/dL) 
Neutrophils  
per (L) 
Platelets 
per (L) 
Blasts 
(%) 
 
 
Complete 
Remission 
(CR) 
11 
1.0 x 109  
100 x 109 
0 
5 
Normal maturation of all cell lines, 
note if has persistent dysplasia 
Partial 
Remission 
(PR) 
 
 
 
 
Decreased by 
50% from 
baseline, but >5% 
All CR criteria if abnormal before 
treatment except BMB 
Marrow CR 
(mCR) 
If hematologic improvement (HI) response, 
note in addition to Marrow CR 
decreased by 
50% from 
baseline, and 5% 
 
Stable Disease 
 
 
 
 
 
Failure to achieve PR & no 
evidence of progression for >8 wks 
Failure 
 
 
 
 
 
Death, or disease progression: 
worsening cytopenia, increase in % 
BM blasts, progression to a more 
advanced MDS FAB subtype 
Relapse after 
CR or PR 
 
 
 
 
 
At least one of the following: 
Return to pre-treatment BMB % 
Decrement of 50% from 
maximum remission/response  
levels in granulocytes or platelets 
Reduction in Hgb 1.5g/dL or 
transfusion dependence 
Cytogenetic Response 
Complete 
Partial 
Evaluation 
Disappearance of chromosomal abnormality with no appearance of new ones 
50% reduction of chromosomal abnormality 
Disease Progression, patients with: 
<5% bone marrow blasts 
5-10% bone marrow blasts 
10-20% bone marrow blasts 
20-30% bone marrow blasts 
 
 
For all categories 
Evaluation Criteria: 
50% increase to >5% bone marrow blasts 
50% increase to >10% bone marrow blasts 
50% increase to >20% bone marrow blasts 
50% increase to >30% bone marrow blasts 
 
At least 50% decrease from maximum remission/response in granulocytes or platelets 
or Reduction in Hgb by 2 g/dL 
or Transfusion dependence 
Cheson BD, Greenberg PL, Bennett JM, Lowenberg B, Wijermans PW, Nimer SD, et al. Clinical application and 
proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood. 
2006 Jul 15;108(2):419-25. Epub 2006 Apr 11. 
 
 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 128 of 141 
Response Criteria for Hematologic Improvement (HI) for Myelodysplasia 
Hematologic Improvement* 
Response Criteria (response lasting 8 weeks) 
Erythroid response (pre-treatment <11g/dL) 
 
 
Hgb increase by 1.5 g/dL 
Relevant reduction of units of RBC transfusions by an absolute 
number of at least 4 RBC transfusions/8 weeks as compared to 
the pretreatment transfusion number in the previous 8 weeks 
(only RBC transfusions given for Hb 9 g/dL pretreatment will 
count in the RBC transfusion evaluation). 
Platelet Response (pretreatment <100 x109/L) 
Absolute increase of 30 x109/L if starting with >20 x 109/L 
platelets 
Increase from <20 x 109/L to >20 x109/L and by at least 100% 
Neutrophil Response (pretreatment <1 x 109/L) 
At least a 100% increase and an absolute increase >0.5 x109/L 
Progression or relapse after HI in the absence of another 
explanation 
At least one of the following: 
At least 50% decrease from maximum response levels in 
granulocytes or platelets; 
Reduction in Hgb by 1.5g/dL; 
Transfusion dependence. 
Cheson BD, Greenberg PL, Bennett JM, Lowenberg B, Wijermans PW, Nimer SD, et al. Clinical application and 
proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood. 
2006;108(2):419-425. Epub 2006 Apr 11. 
 
 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 129 of 141 
APPENDIX 5. CYP3A INHIBITORS/INDUCERS 
Strong Inhibitors  
(≥5-fold increase in AUC or > 
80% decrease in CL) 
Moderate inhibitors  
(≥ 2 but < 5-fold increase in 
AUC or 50-80% decrease in 
CL) 
Strong Inducers 
(≥ 80% decrease in AUC) 
boceprevir 
clarithromycin 
conivaptan 
grapefruit juice 
indinavir 
itraconazole 
ketoconazole 
lopinavir/ritonavir 
mibefradil 
nefazodone 
nelfinavir 
posaconazole 
ritonavir  
saquinavir 
telaprevir 
telithromycin 
voriconazole 
amprenavir 
aprepitant, 
atazanavir 
ciprofloxacin 
darunavir/ritonavir 
diltiazem 
erythromycin 
fluconazole 
fosamprenavir 
grapefruit juice 
imatinib 
verapamil 
avasimibe 
carbamazepine 
phenytoin 
rifampin 
St. John’s wort 
 
FDA.gov [Internet]. Silver Spring (MD): Drug Development and Drug Interactions: 
Classification of Inhibitors. 2014 (updated 2014 Oct 27; cited 2016 March 8]. Available from: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractio
nsLabeling/ucm093664.htm#classInhibit. 
 
 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 130 of 141 
APPENDIX 6. FACT-AN QOL 
Below is a list of statements that other people with your illness have said are important. Please circle or 
mark one number per line to indicate your response as it applies to the past 7 days. 
 
 
PHYSICAL WELL-BEING 
 
Not at 
all 
A little 
bit 
Some-what 
Quite a 
bit 
Very 
much 
 
GP1 
I have a lack of energy 
0 
1 
2 
3 
4 
GP2 
I have nausea 
0 
1 
2 
3 
4 
GP3 
Because of my physical condition, I have trouble 
meeting the needs of my family 
 
0 
 
1 
 
2 
 
3 
 
4 
GP4 
I have pain 
0 
1 
2 
3 
4 
GP5 
I am bothered by side effects of treatment 
0 
1 
2 
3 
4 
GP6 
I feel ill 
0 
1 
2 
3 
4 
GP7 
I am forced to spend time in bed 
0 
1 
2 
3 
4 
 
 
SOCIAL/FAMILY WELL-BEING 
 
Not at 
all 
A little 
bit 
Some-what 
Quite a 
bit 
Very 
much 
 
GS1 
I feel close to my friends 
0 
1 
2 
3 
4 
GS2 
I get emotional support from my family 
0 
1 
2 
3 
4 
GS3 
I get support from my friends 
0 
1 
2 
3 
4 
GS4 
My family has accepted my illness 
0 
1 
2 
3 
4 
GS5 
I am satisfied with family communication about 
my illness 
 
0 
 
1 
 
2 
 
3 
 
4 
GS6 
I feel close to my partner (or the person who is my 
main support) 
 
0 
 
1 
 
2 
 
3 
 
4 
Q1 
Regardless of your current level of sexual activity, please 
answer the following question. If you prefer not to 
answer it, please mark this box           and go to the next 
section. 
 
 
 
 
 
GS7 
I am satisfied with my sex life 
0 
1 
2 
3 
4 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 131 of 141 
Please circle or mark one number per line to indicate your response as it applies to the past 7 days. 
 
 
EMOTIONAL WELL-BEING 
Not at 
all 
A little 
bit 
Some-what 
Quite 
a bit 
Very 
much 
 
GE1 
I feel sad 
0 
1 
2 
3 
4 
GE2 
I am satisfied with how I am coping with my illness 
0 
1 
2 
3 
4 
GE3 
I am losing hope in the fight against my illness 
0 
1 
2 
3 
4 
GE4 
I feel nervous 
0 
1 
2 
3 
4 
GE5 
I worry about dying 
0 
1 
2 
3 
4 
GE6 
I worry that my condition will get worse 
0 
1 
2 
3 
4 
 
 
 
 
FUNCTIONAL WELL-BEING 
 
Not at 
all 
A little 
bit 
Some-what 
Quite 
a bit 
Very 
much 
 
GF1 
I am able to work (include work at home) 
0 
1 
2 
3 
4 
GF2 
My work (include work at home) is fulfilling 
0 
1 
2 
3 
4 
GF3 
I am able to enjoy life 
0 
1 
2 
3 
4 
GF4 
I have accepted my illness 
0 
1 
2 
3 
4 
GF5 
I am sleeping well 
0 
1 
2 
3 
4 
GF6 
I am enjoying the things I usually do for fun 
0 
1 
2 
3 
4 
GF7 
I am content with the quality of my life right now 
0 
1 
2 
3 
4 
 
 
 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 132 of 141 
Please circle or mark one number per line to indicate your response as it applies to the past 7 days. 
 
 
ADDITIONAL CONCERNS 
 
Not at 
all 
A little 
bit 
Some-what 
Quite 
a bit 
Very 
much 
 
HI7 
I feel fatigued 
0 
1 
2 
3 
4 
HI12 
I feel weak all over 
0 
1 
2 
3 
4 
An1 
I feel listless (“washed out”) 
0 
1 
2 
3 
4 
An2 
I feel tired 
0 
1 
2 
3 
4 
An3 
I have trouble starting things because I am tired 
0 
1 
2 
3 
4 
An4 
I have trouble finishing things because I am tired 
0 
1 
2 
3 
4 
An5 
I have energy 
0 
1 
2 
3 
4 
An6 
I have trouble walking 
0 
1 
2 
3 
4 
An7 
I am able to do my usual activities 
0 
1 
2 
3 
4 
An8 
I need to sleep during the day 
0 
1 
2 
3 
4 
An9 
I feel lightheaded (dizzy) 
0 
1 
2 
3 
4 
An10 
I get headaches 
0 
1 
2 
3 
4 
B1 
I have been short of breath 
0 
1 
2 
3 
4 
An11 
I have pain in my chest 
0 
1 
2 
3 
4 
An12 
I am too tired to eat 
0 
1 
2 
3 
4 
BL4 
I am interested in sex 
0 
1 
2 
3 
4 
An13 
I am motivated to do my usual activities 
0 
1 
2 
3 
4 
An14 
I need help doing my usual activities 
0 
1 
2 
3 
4 
An15 
I am frustrated by being too tired to do the things I 
want to do 
 
0 
 
1 
 
2 
 
3 
 
4 
An16 
I have to limit my social activity because I am tired 
0 
1 
2 
3 
4 
 
 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 133 of 141 
APPENDIX 7. FACT-LEU QOL 
Below is a list of statements that other people with your illness have said are important. Please circle or 
mark one number per line to indicate your response as it applies to the past 7 days. 
 
 
PHYSICAL WELL-BEING 
 
Not at 
all 
A little 
bit 
Some-what 
Quite a 
bit 
Very 
much 
 
GP1 
I have a lack of energy 
0 
1 
2 
3 
4 
GP2 
I have nausea 
0 
1 
2 
3 
4 
GP3 
Because of my physical condition, I have trouble 
meeting the needs of my family 
 
0 
 
1 
 
2 
 
3 
 
4 
GP4 
I have pain 
0 
1 
2 
3 
4 
GP5 
I am bothered by side effects of treatment 
0 
1 
2 
3 
4 
GP6 
I feel ill 
0 
1 
2 
3 
4 
GP7 
I am forced to spend time in bed 
0 
1 
2 
3 
4 
 
 
SOCIAL/FAMILY WELL-BEING 
 
Not at 
all 
A little 
bit 
Some-
what 
Quite a 
bit 
Very 
much 
 
GS1 
I feel close to my friends 
0 
1 
2 
3 
4 
GS2 
I get emotional support from my family 
0 
1 
2 
3 
4 
GS3 
I get support from my friends 
0 
1 
2 
3 
4 
GS4 
My family has accepted my illness 
0 
1 
2 
3 
4 
GS5 
I am satisfied with family communication about 
my illness 
 
0 
 
1 
 
2 
 
3 
 
4 
GS6 
I feel close to my partner (or the person who is my 
main support) 
 
0 
 
1 
 
2 
 
3 
 
4 
Q1 
Regardless of your current level of sexual activity, 
please answer the following question. If you prefer not 
to answer it, please mark this box           and go to the 
next section. 
 
 
 
 
 
GS7 
I am satisfied with my sex life 
0 
1 
2 
3 
4 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 134 of 141 
 
Please circle or mark one number per line to indicate your response as it applies to the past 7 days. 
 
 
EMOTIONAL WELL-BEING 
Not at 
all 
A little 
bit 
Some-what 
Quite 
a bit 
Very 
much 
 
GE1 
I feel sad 
0 
1 
2 
3 
4 
GE2 
I am satisfied with how I am coping with my illness 
0 
1 
2 
3 
4 
GE3 
I am losing hope in the fight against my illness 
0 
1 
2 
3 
4 
GE4 
I feel nervous 
0 
1 
2 
3 
4 
GE5 
I worry about dying 
0 
1 
2 
3 
4 
GE6 
I worry that my condition will get worse 
0 
1 
2 
3 
4 
 
 
 
 
FUNCTIONAL WELL-BEING 
 
Not at 
all 
A little 
bit 
Some-what 
Quite 
a bit 
Very 
much 
 
GF1 
I am able to work (include work at home) 
0 
1 
2 
3 
4 
GF2 
My work (include work at home) is fulfilling 
0 
1 
2 
3 
4 
GF3 
I am able to enjoy life 
0 
1 
2 
3 
4 
GF4 
I have accepted my illness 
0 
1 
2 
3 
4 
GF5 
I am sleeping well 
0 
1 
2 
3 
4 
GF6 
I am enjoying the things I usually do for fun 
0 
1 
2 
3 
4 
GF7 
I am content with the quality of my life right now 
0 
1 
2 
3 
4 
 
 
 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 135 of 141 
 
Please circle or mark one number per line to indicate your response as it applies to the past 7 days. 
 
 
ADDITIONAL CONCERNS 
 
Not 
at all 
A little 
bit 
Some-what 
Quite 
a bit 
Very 
much 
BRM3 
I am bothered by fevers (episodes of high body 
temperature) 
 
0 
 
1 
 
2 
 
3 
 
4 
P2 
I have certain parts of my body where I experience pain 
0 
1 
2 
3 
4 
BRM2 
I am bothered by the chills 
0 
1 
2 
3 
4 
ES3 
I have night sweats 
0 
1 
2 
3 
4 
LEU1 
I am bothered by lumps or swelling in certain parts of 
my body (eg,  neck, armpits, or groin) 
 
0 
 
1 
 
2 
 
3 
 
4 
TH1 
I bleed easily 
0 
1 
2 
3 
4 
TH2 
I bruise easily 
0 
1 
2 
3 
4 
HI12 
I feel weak all over 
0 
1 
2 
3 
4 
BMT6 
I get tired easily 
0 
1 
2 
3 
4 
C2 
I am losing weight 
0 
1 
2 
3 
4 
C6 
I have a good appetite 
0 
1 
2 
3 
4 
An7 
I am able to do my usual activities 
0 
1 
2 
3 
4 
N3 
I worry about getting infections 
0 
1 
2 
3 
4 
LEU5 
I feel uncertain about my future health 
0 
1 
2 
3 
4 
LEU6 
I worry that I might get new symptoms of my illness 
0 
1 
2 
3 
4 
BRM9 
I have emotional ups and downs 
0 
1 
2 
3 
4 
LEU7 
I feel isolated from others because of my illness or 
treatment 
 
0 
 
1 
 
2 
 
3 
 
4 
 
 
 
 
 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 136 of 141 
APPENDIX 8. ASTHMA GUIDELINES 
 
Components of 
Severity 
Classification of Asthma Severity 
 
Intermittent 
Persistent 
Mild 
Moderate 
Severe 
0-4 
yrs 
5-11 yrs 
12 + yrs 
0-4 yrs 
5-11 yrs 12 + yrs 
0-4 yrs 
5-11 yrs 12 + yrs 
0-4 yrs 
5-11 yrs 12 + yrs 
 
 
 
 
 
 
 
 
 
Impairment 
 
 
Normal 
FEV1/FVC : 
8-19 yr 85% 
20-39 yr 80% 
40-59 yr 75% 
60-80 yr 70% 
Symptoms 
≤ 2 days/week 
≥ 2 days/week but not daily 
Daily 
Throughout the day 
Nighttime 
awakenings 
 
0 
 
≤ 2x/month 
1-2x/ 
month 
 
3-4x/month 
3-4x/ 
month 
> 1x/week but not 
nightly 
> 1x/ 
month 
 
Often 7x/week 
 
SABA use for 
symptom control 
(not prevention 
of EIB) 
 
 
≤ 2 days/week 
 
 
≤ 2 days/week but not daily 
>2 days/ 
week but 
not daily, 
and 
not more 
than 1x 
 
 
Daily 
 
 
Several time per day 
Interference with 
normal activity 
 
None 
 
Minor limitation 
 
Some limitation 
 
Extremely limited 
Lung function 
 
FEV1 
 
FEV1/FVC 
 
 
N/A 
Normal FEV1 
between 
exacerbations 
> 80% 
 
> 85% 
Normal FEV1 
between 
exacerbations 
> 80% 
 
Normal 
 
 
N/A 
 
 
 
> 80% 
 
> 80% 
 
 
> 80% 
Normal 
 
 
N/A 
 
 
 
60-80% 
 
75-80% 
 
 
60-80% 
Reduced 
 
 
N/A 
 
 
 
< 60% 
 
< 75% 
 
 
< 60% 
Reduced 
 
 
 
 
 
Risk 
 
 
 
Exacerbations 
requiring oral 
systemic 
corticosteroids 
 
 
 
0-1/year 
≥ 2 exacerbations in 6 
months requiring oral 
steroids or >4 wheezing 
episodes/1 year lasting 
>1 day and risk factors 
for persistent asthma 
≥ 2/year 
 
Relative 
annual risk 
may be 
related to 
FEV1. 
≥ 2/year 
 
Relative 
annual risk 
may be 
related to 
FEV1. 
≥ 2 exacerbations in 6 
months requiring oral 
steroids or >4 wheezing 
episodes/1 year lasting 
>1 day and risk factors 
for persistent asthma 
≥ 2/year 
 
Relative 
annual risk 
may be 
related to 
FEV1. 
≥ 2/year 
 
Relative 
annual risk 
may be 
related to 
FEV1. 
≥ 2 exacerbations in 
6 months requiring 
oral steroids or >4 
wheezing episodes/1 
year lasting >1 day 
and risk factors for 
persistent asthma 
≥ 2/year 
 
Relative 
annual risk 
may be 
related to 
FEV1. 
≥ 2/year 
 
Relative 
annual risk 
may be 
related 
to FEV1. 
Consider severity and interval since last exacerbation. Frequency and severity may fluctuate over time for patients in any severity category. 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 137 of 141 
Recommended 
Step for 
Initiating 
Treatment 
Step 1 
Step 2 
Step 3 and consider 
short course of oral 
steroids 
Step 3: 
medium 
dose ICS 
and 
consider 
short 
course of
Step 3 and 
consider 
short course 
of oral 
steroids 
Step 3 and 
consider short 
course of oral 
steroids 
Step 3: 
medium dose 
ICS OR Step 4 
and consider 
short course of 
oral steroids 
Step 4 or 5 
and 
consider 
short 
course 
of oral 
steroids 
In 2-6 weeks, evaluate level of asthma control that is achieved. 
0-4 years: If no clear benefit is observed in 4-6 weeks, stop treatment and consider alternate diagnosis or adjusting therapy.  5-11 and 12+ years: adjust therapy accordingly. 
 
 
 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 138 of 141 
Components of  
Control 
Classification of Asthma Control 
Well Controlled 
Not Well Controlled 
Very Poorly Controlled 
0-4 yrs 5-11 yrs 12 + yrs 
0-4 yrs 5-11 
12 + yrs 
0-4 yrs 5-11 
12 + yrs 
Symptoms 
≤ 2 days/week but 
not more than once 
on each day 
≤ 2 days/ 
week 
> 2 days/week or 
multiple times on 
≤2 days/week 
> 2 days/ 
week 
Throughout the day 
Impairment 
Nighttime 
awakenings 
≤ 1x/month 
≤ 2x/month > 1x/month ≥ 
2x/month 
1-3x/week 
> 1x/week 
≥ 2x/week ≥ 4x/week 
Interference with 
normal activity 
None 
Some limitation 
Extremely limited 
SABA use for symptom 
control (not prevention of 
EIB) 
≤ 2 days/week 
> 2 days/week 
Several times per day 
Lung function 
FEV1 or peak flow 
FEV1/FVC 
N/A 
> 80% 
> 80% 
> 80% 
N/A 
60-80% 
75-80% 
60-80% 
N/A 
< 60% 
< 75% 
< 60% 
Validated questionnaires 
ATAQ 
ACQ 
ACT 
0 
≤ 0.75 
≥ 20 
 
1-2 
≥ 1.5 
16-19 
 
3-4 
N/A 
≤ 15 
Risk 
Exacerbations requiring 
oral systemic 
corticosteroids 
0-1/year 
≥ 2/year 
Consider severity and interval since last exacerbation
Reduction in lung growth/ 
Progressive loss of lung 
function 
Evaluation requires long-term follow-up 
• Maintain current step 
• Regular follow-up every 
1-6 months 
Step up 1 
step 
Step up at 
least 1 
step 
•  Step up 1 
step 
•  Reevaluate 
•  Consider short 
course of oral 
steroids 
•  Step up 1-2 steps 
•  Consider 
short course 
of oral 
steroids 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 139 of 141 
Recommended Action 
for 
Treatment 
• Consider step down if well 
controlled for at least 3 
months 
• Before step up: 
Review adherence to medication, 
inhaler technique, and environmental 
control. If alternative treatment was 
used, discontinue it and use preferred 
treatment for that step. 
• Reevaluate the level of asthma 
control in 2-6 weeks to achieve 
control. 
0-4 years: If no clear benefit is 
observed in 
4-6 weeks, consider alternative 
diagnoses or adjusting therapy. 
5-11 years: Adjust therapy accordingly. 
• For side effects, consider 
alternative treatment options. 
in 2-6 
weeks 
•  For side 
effects, 
consider 
alternative 
treatment 
options 
• Before step up: 
Review adherence to medication, 
inhaler technique, and environmental 
control. If alternative treatment was 
used, discontinue it and use preferred 
treatment for that step. 
• Reevaluate the level of asthma 
control in 2-6 weeks to achieve 
control. 
0-4 years: If no clear benefit is 
observed in 
4-6 weeks, consider alternative 
diagnoses or adjusting therapy. 
5-11 years: Adjust therapy 
accordingly. 
• For side effects, consider 
alternative treatment options. 
•  Step up 1-2 
steps 
•  Reevaluate 
in 2 weeks 
•  For side 
effects, 
consider 
alternative 
treatment 
options 
 
 
 
 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 140 of 141 
APPENDIX 9. THE FAMILY OF ANTIHISTIMINE MEDICATIONS 
 
The following antihistamines may be used for daratumumab preinfusion medication (including, 
but not limited to): 
• Diphenhydramine 
• Cetirizine 
• Fexofenadine 
• Loratadine 
• Clemastine 
• Dexchlorpheniramine 
• Promethazine* 
* The IV use of promethazine should be avoided. 
 
 
 

PROTOCOL SY-1425-201 
Syros Pharmaceuticals, Inc. 
SY-1425 (tamibarotene) 
 
Amendment 7 (31 August 2022)                       Confidential  
Page 141 of 141 
APPENDIX 10. CONVERSION TABLE FOR GLUCOCORTICOID DOSE 
 
Glucocorticoid 
Approximate Equivalent 
Dose (mg) 
Half-life (Biologic) hours 
Intermediate-Acting 
Methylprednisolone 
4 
18-36 
Prednisolone 
5 
18-36 
Prednisone 
5 
18-36 
Triamcinolone 
4 
18-36 
Long-Acting 
Betamethasone 
0.6 – 0.75 
36-54 
Dexamethasone 
0.75 
36-54