A Multicenter Phase 1/2a, Open-Label Study of SQ3370 in Patients With Advanced Solid Tumors
Phase: PHASE1
Conditions: Cancer
Sponsor: Shasqi, Inc.

SQ3370-001 Protocol
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Shasqi, Inc.
Page 1 of 126
CONFIDENTIAL
TITLE:
A Multicenter Phase 1/2a, Open-Label Study of SQ3370 in 
Patients with Advanced Solid Tumors
PROTOCOL NUMBER:
SQ3370-001
INVESTIGATIONAL 
PRODUCT:
SQ3370
IND NUMBER: 137024
SPONSOR: Shasqi, Inc
665 3rd Street Suite 501
San Francisco, CA 94107, USA
Shasqi Australia, Ltd. Pty.
58 Gipps Street, Collingwood, 
3066 Victoria, Australia
MEDICAL MONITOR:
Steve Abella, M.D.
+1 (650) 529-4788 // Steve@Shasqi.com
VERSION, DATE:  Amendment 8 - Version 1.0, 2022-11-17
Amendment 7 - Version 1.0, 2022-07-25 (US only)
Amendment 7 - Version 1.0, 2022-06-03 (not implemented)
Amendment 6 - Version 1.0, 2021-08-10
Amendment 5 - Version 1.0, 2021-03-05
Amendment 4 - Version 1.0, 2020-11-18
Amendment 3 - Version 1.0, 2020-04-28 (COVID-19 Updates)
Amendment 2 - Version 1.0, 2020-01-30 (FDA Updates)
Amendment 1 - Version 1.0, 2019-12-05 (AU HREC Updates)
Original Protocol - Version 1.0, 2019-08-30
CONFIDENTIAL
This clinical study is being sponsored by Shasqi, Inc. The information contained in this 
document, especially any unpublished data, is the property of Shasqi, Inc. (or under its control) 
and therefore is provided to you in confidence as an Investigator, potential Investigator, or 
consultant, for review by you, your staff, and an applicable Ethics Committee or Institutional 
Review Board. It is understood that this information will not be disclosed to others without 
written authorization from Shasqi, Inc. except to the extent necessary to obtain informed 
consent from persons to whom the drug may be administered.
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PROTOCOL INVESTIGATOR SIGNATURE PAGE
TITLE:
A Multicenter Phase 1/2a, Open-Label Study of SQ3370 in Patients 
with Advanced Solid Tumors
PROTOCOL NUMBER:
SQ3370-001
INVESTIGATIONAL 
PRODUCT:
SQ3370
IND NUMBER: 137024
SPONSOR: Shasqi, Inc
665 3rd Street Suite 501
San Francisco, CA 94107, USA
Shasqi Australia, Ltd. Pty.
58 Gipps Street, Collingwood, 
3066 Victoria, Australia
MEDICAL MONITOR:
Steve Abella, M.D.
+1 (650) 529-4788 // Steve@Shasqi.com
VERSION, DATE:  Amendment 8 - Version 1.0, 2022-11-17
Amendment 7 - Version 1.0, 2022-07-25 (US only)
Amendment 7 - Version 1.0, 2022-06-03 (not implemented)
Amendment 6 - Version 1.0, 2021-08-10
Amendment 5 - Version 1.0, 2021-03-05
Amendment 4 - Version 1.0, 2020-11-18 
Amendment 3 - Version 1.0, 2020-04-28 (COVID-19 Updates)
Amendment 2 - Version 1.0, 2020-01-30 (FDA Updates)
Amendment 1 - Version 1.0, 2019-12-05 (AU HREC Updates)
Original Protocol - Version 1.0, 2019-08-30 
I have read this protocol, including all appendices. By signing this protocol signature page, I agree to 
conduct the clinical study, following approval by an Independent Ethics Committee/Institutional Review 
Board, in accordance with this protocol, the current International Conference on Harmonisation (ICH) 
Guideline for Good Clinical Practice (GCP), and applicable regulatory requirements. I will ensure that all 
personnel involved in the study under my direction will be informed about the contents of this protocol and 
will receive all necessary instructions for performing the study according to the protocol.
____________________________________
Principal Investigator’s Name (print)
_____________________________________             ________________________
Principal Investigator’s Signature                              Date (DD-MMM-YY)
Please retain the signed original of this form for your study files. Please return a copy to the 
Sponsor or designee.
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TABLE OF CONTENTS
PROTOCOL INVESTIGATOR SIGNATURE PAGE........................................................ 2
TABLE OF CONTENTS .................................................................................................. 3
LIST OF TABLES.......................................................................................................... 10
LIST OF FIGURES........................................................................................................ 11
PROTOCOL SYNOPSIS............................................................................................... 12
LIST OF ABBREVIATIONS........................................................................................... 20
1.
INTRODUCTION.......................................................................................... 23
1.1.
Disease and Treatment Background............................................................ 23
1.1.1.
Soft-tissue Sarcoma..................................................................................... 24
1.1.2.
Head and Neck Cancer................................................................................ 25
1.2.
SQ3370 Background.................................................................................... 26
1.2.1.
Summary of Nonclinical Experience............................................................. 27
1.2.2.
Summary of Clinical Experience .................................................................. 29
1.3.
Study Rationale............................................................................................ 29
1.3.1.
Experimental Doxorubicin-Based Therapeutics ........................................... 29
1.3.2.
Doxorubicin and the Immune System .......................................................... 30
1.4.
Benefit-Risk Assessment ............................................................................. 31
2.
OBJECTIVES AND ENDPOINTS ................................................................ 32
2.1.
Phase 1 Dose Escalation............................................................................. 32
2.1.1.
Objectives .................................................................................................... 32
2.1.1.1.
Primary Objective......................................................................................... 32
2.1.1.2.
Secondary Objectives .................................................................................. 32
2.1.1.3.
Exploratory Objectives ................................................................................. 32
2.1.2.
Endpoints ..................................................................................................... 32
2.1.2.1.
Primary Endpoint.......................................................................................... 32
2.1.2.2.
Secondary Endpoints................................................................................... 32
2.1.2.3.
Exploratory Endpoints.................................................................................. 33
2.2.
Phase 2a Expansion GROUPS.................................................................... 33
2.2.1.
Objectives .................................................................................................... 33
2.2.1.1.
Primary Objectives....................................................................................... 33
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2.2.1.2.
Secondary Objective.................................................................................... 33
2.2.1.3.
Exploratory Objectives ................................................................................. 33
2.2.2.
Endpoints ..................................................................................................... 34
2.2.2.1.
Primary Endpoints........................................................................................ 34
2.2.2.2.
Secondary Endpoint..................................................................................... 34
2.2.2.3.
Exploratory Endpoints.................................................................................. 35
3.
STUDY DESIGN .......................................................................................... 36
3.1.
Overview ...................................................................................................... 36
3.1.1.
Phase 1 Dose Escalation............................................................................. 36
3.1.2.
Phase 2a Expansion Groups ....................................................................... 36
3.1.3.
Screening..................................................................................................... 36
3.1.4.
Treatment..................................................................................................... 36
3.1.4.1.
Treatment Cycles......................................................................................... 36
3.1.4.2.
Treatment Delays......................................................................................... 38
3.1.4.3.
Treatment Duration ...................................................................................... 39
3.1.4.4.
Phase 1: 20 mL SQL70 Biopolymer (post-Cycle 1) Cohort.......................... 39
3.1.5.
End of Treatment ......................................................................................... 39
3.1.6.
Safety Follow-Up Visit.................................................................................. 40
3.1.7.
Long Term Follow-Up................................................................................... 40
3.2.
Phase 1 Dose Escalation............................................................................. 40
3.2.1.
Accelerated Titration (Stage 1)..................................................................... 41
3.2.2.
3+3 (Rolling 6) Design (Stage 2).................................................................. 41
3.2.3.
Phase 1: 20 mL SQL70 Biopolymer (from Cycle 1) Cohort.......................... 42
3.2.4.
Maximum Tolerated Dose ............................................................................ 43
3.2.5.
Recommended Phase 2 Dose ..................................................................... 43
3.2.6.
Dose-Limiting Toxicity.................................................................................. 43
3.2.7.
Safety Review Committee (Dose Escalation and Phase 2a)........................ 44
3.3.
Phase 2A Expansion Groups ....................................................................... 45
3.4.
Study-Wide Treatment Interruption Rules .................................................... 46
3.5.
Rationale for Study Design and Dose .......................................................... 46
3.5.1.
Rationale for Study Design and Objectives.................................................. 46
3.5.2.
Rationale for Dose and Dosing Interval........................................................ 48
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4.
PATIENT POPULATION.............................................................................. 50
4.1.
General Inclusion/Exclusion criteria for phase 1 cohorts and phase 2a 
expansion groups......................................................................................... 50
4.1.1.
Inclusion Criteria .......................................................................................... 50
4.1.2.
Exclusion Criteria ......................................................................................... 51
4.2.
Specific Inclusion/Exclusion criteria for phase 2a expansion groups ........... 53
4.2.1.
Expansion Group 1: Extremity STS.............................................................. 53
4.2.1.1.
Inclusion Criteria .......................................................................................... 53
4.2.1.2.
Exclusion Criteria ......................................................................................... 54
4.2.2.
Expansion Group 2: Unresectable STS ....................................................... 54
4.2.2.1.
Inclusion Criteria .......................................................................................... 54
4.2.2.2.
Exclusion Criteria ......................................................................................... 54
4.2.3.
Expansion Group 3a: Head and Neck.......................................................... 54
4.2.3.1.
Inclusion Criteria .......................................................................................... 54
4.2.3.2.
Exclusion Criteria ......................................................................................... 55
5.
INVESTIGATIONAL PRODUCT .................................................................. 56
5.1.
Investigational Product Formulation and Packaging .................................... 56
5.1.1.
SQL70 Biopolymer Formulation and Packaging........................................... 56
5.1.2.
SQP33 Protodrug Formulation and Packaging ............................................ 56
5.2.
Investigational Product Storage ................................................................... 56
5.3.
Investigational Product Dosage and Administration..................................... 57
5.3.1.
SQL70 Biopolymer Dosage and Administration ........................................... 57
5.3.2.
SQP33 Protodrug Dosage and Administration............................................. 58
5.4.
Investigational Product Supply..................................................................... 58
5.5.
Investigational Product Destruction.............................................................. 58
5.6.
Investigational Product Accountability.......................................................... 58
5.7.
Investigational Product Compliance............................................................. 59
5.8.
Post-Study Access to Investigational Product.............................................. 59
5.9.
Concomitant Therapy................................................................................... 59
5.9.1.
Permitted Concomitant Treatment ............................................................... 59
5.9.2.
Prohibited Concomitant Treatment............................................................... 60
6.
STUDY ASSESSMENTS ............................................................................. 62
6.1.
Informed Consent......................................................................................... 62
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6.2.
Screening and Re-Screening ....................................................................... 63
6.3.
Enrollment.................................................................................................... 64
6.4.
Medical History and Demographic Data....................................................... 64
6.5.
Physical Examination & Directed Medical History........................................ 64
6.6.
Vital Signs .................................................................................................... 64
6.6.1.
Phase 1 Dose Escalation............................................................................. 65
6.6.2.
Phase 2a Expansion Groups ....................................................................... 65
6.7.
Body Surface Area Calculation .................................................................... 66
6.8.
Echocardiogram/Multigated Acquisition Scan .............................................. 66
6.9.
Electrocardiogram........................................................................................ 66
6.9.1.
General Guidance........................................................................................ 66
6.9.1.1.
Phase 1 Dose Escalation............................................................................. 66
6.9.1.2.
Phase 2a Expansion Groups ....................................................................... 67
6.10.
Eastern Cooperative Oncology Group Performance Status......................... 67
6.11.
Adverse Event Review................................................................................. 67
6.12.
Concomitant Medication Review.................................................................. 67
6.13.
Safety Laboratory Sample Collection........................................................... 67
6.13.1.
Phase 1 Dose Escalation............................................................................. 67
6.13.2.
Phase 2a Expansion Groups ....................................................................... 68
6.13.3.
General Instructions for both Phase 1 and Phase 2a................................... 68
6.14.
Pharmacokinetic Laboratory Sample Collection........................................... 69
6.14.1.
General Guidance........................................................................................ 69
6.14.2.
Phase 1 Dose Escalation............................................................................. 69
6.14.3.
Phase 2a Expansion Groups ....................................................................... 69
6.15.
Peripheral Blood Mononuclear Cells and ctDNA.......................................... 71
6.16.
Cardiotoxicity Biomarkers for Phase 2a Expansion Groups Only................. 71
6.16.1.
General Guidance........................................................................................ 71
6.16.2.
Phase 2a Expansion Groups ....................................................................... 72
6.17.
Tumor Biopsies ............................................................................................ 72
6.17.1.
Dose Escalation ........................................................................................... 72
6.17.2.
Phase 2a Expansion Groups ....................................................................... 72
6.18.
CT/MRI Tumor Imaging & Measurements.................................................... 73
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6.18.1.
Target and Non-Target Tumor Baseline Recording ..................................... 74
6.18.2.
Tumor Response Evaluation........................................................................ 75
6.19.
Administration of Investigational Product ..................................................... 76
6.20.
Unscheduled Visits....................................................................................... 77
6.21.
Patient End of Study .................................................................................... 77
6.22.
Withdrawal of Consent................................................................................. 77
6.23.
Lost to Follow-Up ......................................................................................... 77
6.24.
Study Site or Study Termination................................................................... 77
7.
ADVERSE AND SERIOUS ADVERESE EVENTS....................................... 78
7.1.
Definitions .................................................................................................... 78
7.1.1.
Definition of Adverse Events ........................................................................ 78
7.1.1.1.
Assessment of Severity................................................................................ 78
7.1.1.2.
Relationship to Study Treatment.................................................................. 79
7.1.1.3.
Action Taken for Adverse Events................................................................. 79
7.1.2.
Definition of Adverse Events of Special Interest (AESI)............................... 79
7.1.2.1.
Dose-limiting Toxicity ................................................................................... 80
7.1.2.2.
Potential Myocardial Toxicity........................................................................ 80
7.1.2.3.
COVID-19 .................................................................................................... 80
7.1.2.4.
Overdose ..................................................................................................... 80
7.1.3.
Definition of Serious Adverse Event (SAE) .................................................. 80
7.2.
Reporting to Sponsor ................................................................................... 81
7.2.1.
Follow-up of Adverse Events ....................................................................... 81
7.2.2.
Serious Adverse Event Notification, Documentation, and Reporting............ 81
7.3.
Pregnancy Reporting ................................................................................... 82
7.4.
Regulatory Reporting ................................................................................... 83
7.5.
Management of Study-Specific Adverse Events .......................................... 84
7.5.1.
Management of SQL70 Biopolymer Injection Reactions.............................. 84
7.5.2.
Management of SQP33 Protodrug Infusion Reactions................................. 84
7.5.3.
Management of SQP33 Protodrug Extravasation ........................................ 85
7.5.4.
Management of Potential Myocardial Toxicity and ECHO / MUGA 
Changes....................................................................................................... 86
7.5.5.
Management of Myelosuppression .............................................................. 86
7.5.6.
Management of Hepatotoxic Risk ................................................................ 86
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7.6.
Dose Modifications....................................................................................... 87
7.6.1.
Missed Doses............................................................................................... 87
7.6.2.
Dose Reductions.......................................................................................... 87
7.6.3.
SQ3370 Treatment Interruptions.................................................................. 88
8.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN........................ 89
8.1.
Analysis Plan................................................................................................ 89
8.2.
Analysis Population...................................................................................... 89
8.3.
Determination of Sample Size...................................................................... 89
8.4.
Statistical analyses....................................................................................... 92
8.4.1.
Safety Analyses ........................................................................................... 92
8.4.2.
Efficacy Analyses......................................................................................... 92
8.4.2.1.
Primary Endpoint.......................................................................................... 92
8.4.2.2.
Secondary Endpoints................................................................................... 92
8.4.2.3.
Exploratory Endpoints.................................................................................. 93
8.4.3.
Biomarker Analyses ..................................................................................... 93
8.5.
Interim Analyses........................................................................................... 94
9.
DATA COLLECTION AND MANAGEMENT ................................................ 95
9.1.
Data Quality Assurance ............................................................................... 95
9.2.
Source Data Documentation ........................................................................ 95
9.3.
Case Report Forms...................................................................................... 95
9.4.
Use of Computerized Systems / Electronic Health Records ........................ 96
10.
QUALITY ASSURANCE & ETHICAL CONSIDERATIONS.......................... 97
10.1.
Compliance with Laws and Regulations....................................................... 97
10.2.
Research Outside the Terms of This Protocol.............................................. 97
10.3.
Institutional Review Board or Independent Ethics Committee...................... 97
10.4.
Informed Consent......................................................................................... 98
10.5.
Protocol Adherence & Deviations................................................................. 98
10.5.1.
Important Protocol Deviations ...................................................................... 98
10.6.
Monitoring and Study Site Inspections......................................................... 98
10.7.
Records and Record Retention.................................................................... 98
10.8.
Confidentiality............................................................................................... 99
10.9.
Financial Disclosure................................................................................... 100
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11.
STUDY PUBLICATION AND AMENDMENTS ........................................... 101
11.1.
Publication of Data and Protection of Trade Secrets.................................. 101
11.2.
Protocol Amendments................................................................................ 101
12.
REFERENCES........................................................................................... 102
APPENDIX A – SPONSOR APPROVAL..................................................................... 108
APPENDIX B – RECIST V1.1 ..................................................................................... 109
APPENDIX C – EASTERN COOPERATIVE ONCOLOGY GROUP 
PERFORMANCE STATUS ASSESSMENT............................................... 110
APPENDIX D – NATIONAL CANCER INSTITUTE COMMON TERMINOLOGY 
CRITERIA FOR ADVERSE EVENTS (CTCAE)......................................... 111
APPENDIX E – COLLECTION OF PREGNANCY INFORMATION ............................ 112
APPENDIX F – PK SCHEDULE.................................................................................. 113
APPENDIX G – SCHEDULE OF ASSESSMENTS – PHASE 1 DOSE 
ESCALATION ............................................................................................ 117
APPENDIX H – SCHEDULE OF ASSESSMENTS – EXPANSION GROUP 1: 
EXTREMITY STS....................................................................................... 119
APPENDIX I – SCHEDULE OF ASSESSMENTS – EXPANSION GROUP 2: 
UNRESECTABLE STS (5 DAY)................................................................. 121
APPENDIX J – SCHEDULE OF ASSESSMENTS – EXPANSION GROUP 2: 
UNRESECTABLE STS (3 DAY)................................................................. 123
APPENDIX K – SCHEDULE OF ASSESSMENTS – EXPANSION GROUP 3A: 
HEAD AND NECK...................................................................................... 125
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LIST OF TABLES
Table 1: Expansion Group SQ3370 Administration Overview ...................................... 37
Table 2: Group 2 SQP33 Protodrug RP2D (% Administered) Per Day......................... 38
Table 3: Modified Fibonacci Dose Escalation Scale (Stage 2) ..................................... 42
Table 4: Phase 2a Safety Evaluation Timing................................................................ 44
Table 5: Cytochrome p450 Strong Inducers and Inhibitors........................................... 61
Table 6: Evaluation of Target Lesions .......................................................................... 75
Table 7: Evaluation of Non-Target Lesions................................................................... 75
Table 8: Infusion-related Reaction Management Recommendations ........................... 85
Table 9: Simon 2-Stage Design.................................................................................... 90
Table 10: Continuous Reassessment Method Design Considerations ......................... 91
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LIST OF FIGURES
Figure 1: SQ3370 Local Drug Activation Approach...................................................... 26
Figure 2: Tolerability of Various Dox Products in Mouse, Dog, and Human................. 30
Figure 3: Schema of Single Patient Accelerated Dose Escalation Followed by 
3+3 Design with Modified Fibonacci Dose Escalation.................................. 41
Figure 4: Phase 2a Dose Expansion Groups ............................................................... 45
Figure 5: SQ3370 5-Day Administration Schedule....................................................... 76
Figure 6: SQ3370 3-Day Administration Schedule....................................................... 76
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PROTOCOL SYNOPSIS
Sponsor/Company:
Shasqi, Inc.
Investigational Product:
SQ3370
Study Number:
SQ3370-001
TITLE
A Multicenter, Phase 1/2a, Open-Label Study of SQ3370 in Patients with Advanced Solid Tumors
OBJECTIVES AND ENDPOINTS (Primary, Secondary and Exploratory)
Objectives
Endpoints
Primary
Phase 1: Dose Escalation
x
Assess the safety and tolerability of SQ3370, 
including determination of the maximum 
tolerated dose (MTD) and/or recommended 
Phase 2 dose (RP2D) of SQP33 protodrug 
administered with 10 mL and/or 20 mL of 
SQL70 biopolymer
Phase 2a: Expansion Groups
x
Further investigate the safety and tolerability
of SQ3370 in anthracycline naïve patients 
with:
x
Group 1: Patients with extremity Soft 
Tissue Sarcoma (STS)
x
Group 2: Patients with unresectable, 
locally advanced or metastatic STS. 
x
Group 3:  
o
3a) Patients with relapsed or 
metastatic squamous-cell head and 
neck cancer
Phase 1: Dose Escalation
x
Frequency of adverse events (AEs), Serious 
Adverse Events (SAEs) and dose-limiting 
toxicities (DLTs), as well as changes from 
baseline in vital signs, clinical laboratory 
parameters, physical examination findings,
ECHO/MUGA, and electrocardiogram (ECG) 
results
Phase 2a: Expansion Groups
x
Frequency of AEs and SAEs, as well as 
changes from baseline in vital signs, clinical 
laboratory parameters, physical examination 
findings, ECHO/MUGA, and 
electrocardiogram (ECG) results across all 
groups and treatment cycles
Secondary
Phase 1: Dose Escalation
x
Characterize the PK profile of SQP33 
protodrug and active doxorubicin (Dox)
following SQ3370 treatment
x
Assess preliminary signals of SQ3370 anti-
tumor activity
Phase 1: Dose Escalation
x
Objective response rate (ORR) per 
Response Evaluation Criteria in Solid 
Tumors (RECIST) v1.1
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Phase 2a: Expansion Groups
x
Assess preliminary signals of SQ3370 anti-
tumor activity
x
Characterize the PK profile of SQP33 
protodrug and active Dox following SQ3370 
treatment.
x
Plasma concentration and pharmacokinetics 
(PK) parameters for SQP33 protodrug and 
active Dox following SQ3370 treatment
Phase 2a: Expansion Groups
x
General for all Expansion Groups
x
Objective response rate (ORR) per 
RECIST v1.1
x
Overall survival (OS)
x
Plasma concentration and PK 
parameters for SQP33 protodrug and 
active Dox following SQ3370 treatment
x
Time from enrollment to first subsequent 
therapy (TFST)  
x
Group 1: Extremity STS
x
Histopathological Response
x
Surgical outcome amputation/limb-
salvage vs planned
x
Disease-free survival
x
Local recurrence-free survival
x
Distant recurrence-free survival
x
Symptomatic disease control
x
Group 2: Unresectable STS
x
Compare safety and tolerability of two 
infusion schedules of SQP33 (3-day vs 
5-day) 
x
Pharmacokinetic comparison of the two 
infusion schedules (3-day vs 5-day)
x
Duration of Response (DOR) per
RECIST v1.1
x
Progression Free Survival (PFS) per 
RECIST v1.1
x
Disease Control Rate (DCR) per 
RECIST v1.1
x
Group 3a: Head and Neck
x
Duration of Response (DOR) per 
RECIST v1.1
x
Progression Free Survival (PFS) per 
RECIST v1.1
x
Time to local-regional progression or 
distant progression per RECIST v1.1
x
Local-regional control per RECIST v1.1
x
Disease Control Rate (DCR) per 
RECIST v1.1
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Exploratory 
Phase 1: Dose Escalation
x Assess the concentration of active Dox and 
SQP33 protodrug following SQ3370 
treatment at the local site through analysis of 
tumor biopsies
x Assess immune response through biomarker 
analysis of tumor biopsies and peripheral 
blood specimens
Phase 2a: Expansion Groups
x
Assess the concentration of active Dox and 
SQP33 protodrug following SQ3370 
treatment at the local site through analysis 
of tumor biopsies.
x
Assess immune response through 
biomarker analysis of tumor biopsies and 
peripheral blood specimens 
Phase 1: Dose Escalation
x
Assess the presence of SQP33 protodrug 
and active Dox in tumor tissue. 
x
Characterize immune response in blood and 
tumor tissue over time following treatment 
with SQ3370.
Phase 2a: Expansion Groups
x
General for all Expansion Groups
x
Assess the presence of SQP33 
protodrug and active Dox in tumor 
tissue.  
x
Characterize immune response in blood 
and tumor tissue over time following 
treatment with SQ3370
OVERALL DESIGN
This multicenter, Phase 1/2a, first-in-human, single-arm, open-label, dose-escalation study will be 
conducted in 2 stages including a dose escalation to evaluate the safety and tolerability, PK, and 
preliminary efficacy of SQ3370 in patients with locally advanced or metastatic solid tumors, and a 
secondary Phase 2a to compare differing tumor types. 
Phase 1: Dose Escalation
The Phase 1 dose-escalation portion of the study will initially consist of an accelerated titration design 
and then switch to a 3+3 (Rolling 6) design. Patients will receive specific dose levels of SQP33 
protodrug assigned according to the dose escalation design described in section 3.2 Phase 1 Dose 
Escalation. 
20 mL SQL70 Biopolymer (from Cycle 1) Cohort: To evaluate the administration of 20 mL of SQL70 
biopolymer in one or two lesions starting at Cycle 1, patients will be enrolled in a separate cohort at a 
dose level of SQP33 protodrug that is lower than the current dose level being evaluated (see section 
3.2.3 Phase 1: 20 mL SQL70 Biopolymer (from Cycle 1) Cohort). The sponsor may choose doses up to
or less than the RP2D to include in the 20 mL polymer group or may discontinue dose escalation within
this group at any point in the study after enrollment of the initial 20 mL cohorts. 
Phase 2a: Expansion Groups 
Patients will be enrolled in the Phase 2a expansion groups (further defined below) to study the 
preliminary activity and gain additional SQ3370 safety data, dosing schedule comparisons, as well as 
PK and immune changes in blood and tumor tissue (see section 3.3 Phase 2A Expansion Groups).
STUDY POPULATION
Phase 1: Dose Escalation
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This study will enroll male or female patients  18 years of age with an Eastern Cooperative Oncology 
Group (ECOG) performance status score of 0 or 1 and adequate organ function. 
x
A key exclusion criteria is prior lifetime exposure to >300 mg/m2 of Dox HCl or DOXIL / 
CAELYX® or 600 mg/m2 of epirubicin HCl or 600 mg/m² daunorubicin prior to study dosing.
x
All patients must have a histologically or cytologically confirmed cancer or desmoid tumor.
x
All patients must be either refractory to or relapsed following standard of care or ineligible for 
standard of care therapy
Phase 2: Dose Expansion will treat anthracycline naïve patients  
x
Group 1: patients with STS of the extremity who are ineligible for primary surgical resection 
and under consideration for possible/probable amputation with predefined anthracycline 
sensitive tumors histologies. 
x
Group 2: unresectable, locally advanced or metastatic STS with predefined anthracycline 
sensitive histologies
x
Group 3: 
o
3a: relapsed or metastatic squamous-cell head and neck cancer (R/M HNSCC)
Phase 1 & 2a Tumor Requirements 
The injected local or metastatic solid tumor must meet all the following criteria:
x 
A tumor type that is defined in where clinical evidence suggests that anthracyclines have 
favorable clinical activity. An injectable tumor defined as:
o
measurable per RECIST v1.1 at Baseline
o
palpable or able to be injected percutaneously with imaging guidance (i.e., ultrasound) 
o
excluding the following organs/structures: pancreas and extrahepatic biliary tract, 
central nervous system, or heart and great vessels
o
accessible by repeated intra and/or peritumoral injection with a 18- to 22-gauge needle
x
Phase 1 additional criteria for the 20 mL SQL70 biopolymer (from Cycle 1) Cohort: 
o
Have at least two injectable tumors or, based on investigator clinical judgement 
documented in the medical record, a sufficiently large single lesion that can be injected 
with a 20 mL volume (i.e., 5 cm or larger).
x
Anthracycline sensitive tumors for Phase 2a Groups 1 & 2 include:
o 
Angiosarcomas
o 
Leiomyosarcoma
o 
Liposarcoma
o 
Synovial sarcoma
o 
Adult fibrosarcoma
o
Undifferentiated pleomorphic sarcoma
TREATMENT GROUPS AND REGIMENS
Phase 1: Dose Escalation
SQ3370 consists of 2 components: SQP33, a Dox protodrug, and SQL70, a biopolymer. SQL70 
biopolymer is injected on Day 1 of each 21-day cycle into a lesion or lesions followed by 5 consecutive 
daily infusions of SQP33 protodrug (Day 1-5). No more than 2 lesions may be injected during the 
treatment cycle with the exception of a “regional cluster of lesions”.
Patients may continue to receive treatment for up to 12 cycles. Treatment for more than 12 cycles 
requires approval by the Medical Monitor. All lesions should continue to be injected until either:
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x
they are no longer injectable (as determined by the investigator): this includes lesions that are 
resolved, no longer clearly seen on scan, no longer palpable, cannot continue to be safely 
injected, or are either suspected or confirmed on biopsy to no longer contain viable tumor. At 
this point the area of the tumor bed, if possible, should be treated for a minimum of at least two 
additional cycles.
x
they have progressed per RECIST v1.1
x
or other treatment discontinuation criteria are met (see section 3.1.5 End of Treatment)
x
See APPENDIX G – Schedule of Assessments – Phase 1 Dose Escalation for details.
Phase 2: Expansion Groups
x
Group 1: Extremity STS
o
Subjects with soft tissue sarcomas of the extremity AJCC Stage III OR IV (> 5 cm 
injectable tumors) locally advanced and or metastatic, not amendable to primary 
surgical intervention, according to the consensus of a multidisciplinary treatment team,
determined prior to screening.
o
Group 1 will be conducted in 2 phases with a possible expansion phase. The group will 
open with a) the initial phase safety run-in of 6 patients to establish the safety and 
initial feasibility of a 12-week delay in definitive surgical resection in patients with high-
risk STS of the extremity treated with SQ3370, and b) 31 additional patients initial 
adaptive design phase. 
o
Patients will enroll at the RP2D of SQ3370. It is anticipated that the size of tumors 
given the stage and inclusion criteria eligible for enrollment will be potentially larger 
than in Phase 1, this group will receive a fixed dose of SQL70 (20 mL). All patients are 
planned to receive 2 cycles of SQ3370 and undergo a disease reevaluation per 
RECIST 1.1.  All patients without evidence of disease progression after initial 2 cycles, 
will then undergo an additional 2 cycles of treatment and have a presurgical disease 
re-evaluation and proceed to definitive surgical procedure(s). (See APPENDIX H –
Schedule of Assessments – Expansion Group 1: Extremity STS for details).
o
Only patients who have had objective evidence of response or whom in the opinion of 
the multidisciplinary treatment team determined to have achieved a clinical benefit may 
defer surgery at this point. Note that the study will allow up to 4 additional cycles, at 
which point all patients should undergo exploratory surgery and or tumor resection. 
o
If a patient with Stage III had a radiological and surgical complete response (CR) they 
may receive up to 4 additional cycles, but no patient may exceed 12 cycles within the 
study. Stage IV patients may continue post op chemotherapy. Any patient group III or 
IV must have accessible lesions or the primary tumor that is deemed adequate for post 
operative intratumoral injection.  If a patient receives post-operative radiation which is 
allowed on study, they meet End of Treatment criteria and will not receive further 
SQP3370 (see section 3.1.5 End of Treatment).
o
Any patient at any point who has been determined to have progressive disease has 
reached end treatment and will proceed to a definitive surgical treatment, note pre-
operative radiation is allowed for patients with progressive disease pre-operatively on 
study at this point. 

Subjects will be treated with the RP2D of SQ3370 every 21 days (1 cycle) up 
to 12 cycles or until other treatment discontinuation criteria are met (see 
section 3.1.5 End of Treatment).  On Day 1 of each cycle, the subject will 
receive an injection of SQL70 biopolymer into the tumor (20 mL), followed by 5 
days of SQP33 infusion starting 3 hours r 30 min after the SQL70 biopolymer 
injection.
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x
Group 2: Unresectable STS locally advanced or metastatic.
o
Patients will enroll at the RP2D of SQ3370, maintaining the total dose per cycle 
constant and compare 2 different infusion schedules a 3-day vs a standard 5-day 
schedule. The 3-day cycle will administer the same dose on Day 1 as the 5-day cycle 
and 2x the doses on days 2 and 3 of the cycle. (See APPENDIX I – Schedule of 
Assessments – Expansion Group 2: Unresectable STS (5 day) and APPENDIX J –
Schedule of Assessments – Expansion Group 2: Unresectable STS (3 Day) for 
details).
o
Eleven (11) patients per group.  Subjects will be treated with the RP2D of SQ3370 
every 21 days (1 cycle) up to 12 cycles or until other treatment discontinuation criteria 
are met (see section 3.1.5 End of Treatment).  On Day 1 of each cycle, the subject will 
receive an injection of SQL70 biopolymer into the tumor (10 mL) followed by 3 or 5 
days of SQP33 infusion starting 3 hours r 30 min after the SQL70 biopolymer 
injection.
x
Group 3a: Head and Neck
o
Patients with histologically or cytologically confirmed relapsed or metastatic
squamous-cell carcinoma of the head and neck (R/M HNSCC), who have exhausted 
curative intent therapies or patients with distant metastases who may have received 
one or less chemotherapy regimen.
o
This will follow a Simon 2-stage design.  Thirteen (13) patients will be initially treated 
with the RP2D of SQ3370 every 21 days (1 cycle) up to 12 cycles or until other 
treatment discontinuation criteria are met (see section 3.1.5 End of Treatment).  On 
Day 1 of each cycle, the patient will receive a 10 mL injection of the SQL70 biopolymer 
into the tumor, followed by five (5) days of SQP33 infusion starting 3 hours r 30 min
after the SQL70 biopolymer injection. If t 4 patients have a response (CR or PR), then 
13 additional patients will be enrolled. (See APPENDIX K – Schedule of Assessments 
– Expansion Group 3A: Head and Neck for details).
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Sample Size
Phase 1: Dose Escalation: Sample size for the dose-escalation portion of the study is not predefined. 
Total enrollment will depend on the DLTs observed and number of escalation cohorts. 
Phase 2a: Expansion Groups 1 and 3a will be utilizing a Simon 2-stage (optimal) design to determine 
sample size (see below) based on historical objective responses per indication. Expansion Group 2 
will utilize the Continuous Reassessment Method (CRM) design.
Simon 2-Stage Optimal Design
x
Expansion Group 1: Extremity STS- up to 15 locally advanced unresectable, or metastatic,
intermediate, or high-grade soft-tissue sarcoma participants will be treated per study treatment 
in Stage 1
x
Expansion Group 3a: Head & Neck- up to 13 R/M HNSCC participants will be treated per study 
treatment in Stage 1.  
Simon 2-Stage Design Considerations
Stage 1 responders/ Stage 1 n
Stage 2 responders/ Stage 2 n
Cohort
Power
Historical 
ORR/Target 
ORR
Consider 
Futility 
Go to Stage 2
Consider 
Futility 
Consider 
Efficacy 
Expected 
Sample Size
H&N
85%
20%/45%
d3/13
t4/13
d8/26
t9/26
16.28
Extremity 
Sarcoma
70%
20%/35%
d3/15
t4/15
d13/46
t14/46
25.91
Continuous Reassessment Method
x
Expansion Group 2: Unresectable STS locally advanced or metastatic
o
Sample sizes for Expansion Group 2 participants are guided by the Continuous 
Reassessment Method (CRM) design (Wheeler 2019). The indicated population for the 
Expansion Group 2 participants is locally advanced or metastatic, unresectable, soft-tissue 
sarcoma of intermediate or high grade with evidence of disease progression and no prior 
anthracycline treatment, and thus the test statistics parameters for the CRM are based on 
historical toxicity and efficacy rates of said population (see below). The participants will 
receive SQ3370 at the RP2D administered IV as a 3-day dosing regimen per 21-day cycle 
or as a 5-day dosing regimen per 21-day cycle.  
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Continuous Reassessment Method Design Considerations
Expansion Groups 1 and 3a will treat up to approximately 28 participants in Stage 1 and Expansion 
Group 2 will treat up to a total of 22 participants. For all Expansion Groups: Patients may be replaced if 
they are enrolled into the study but do not receive (for reasons other than AEs/SAEs) the intended 
dose during Cycle 1. If Cycle 1 cannot be completed due to a COVID-19 infection, an additional patient 
may be enrolled in the cohort.
Safety/Tolerability
Electrocardiogram, vital signs, ECHO/MUGA and clinical laboratory data (observed and change from 
baseline) will be summarized by time point and treatment using descriptive statistics. The number and 
percentage of patients reporting any treatment-emergent AE will be summarized by system organ 
class and preferred term for each treatment (coded using Medical Dictionary for Regulatory Activities
[MEDRA]). Treatment-emergent AEs will be further classified by severity and relationship to treatment. 
Efficacy
Tumor dynamics will be summarized by dose, cycle, and overall follow-up. RECIST based tumor 
response such as ORR, DoR, PFS, DCR, BOR, Time to local-regional progression, and Local-regional 
control status will be summarized. Additionally, OS, TFST, TSST, histopathological response, disease-
free survival, and surgical outcome will be summarized. Sub-set summaries will be performed on both 
injected and non-injected individual lesions.
Biomarkers 
PK in tumor and plasma, markers of immune response in tumor and blood, and binary variable 
exploratory analyses will be described in the statistical analysis plan finalized before the database lock.
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LIST OF ABBREVIATIONS
Abbreviation or 
Special Term
Definition
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AV
atrioventricular
BOR
best objective response
BSA
body surface area
CHF
congestive heart failure
CNS
central nervous system
CI
confidence interval
CR
complete response
CRF
Case Report Form
CSF
colony-stimulating factor
CT
computed tomography
DILI
drug-induced liver injury
DLT
dose-limiting toxicity
DCR
disease control rate
DNA
deoxyribonucleic acid
DoR
duration of response
Dox
doxorubicin
Dox Eq
doxorubicin hydrochloride molar equivalent (1 g of SQP33 protodrug is 
equivalent to 0.7153 g of doxorubicin hydrochloride)
Dox HCl
doxorubicin hydrochloride 
DOXIL / CAELYX
Liposomal doxorubicin
EC
endometrial cancer
ECG
electrocardiogram
ECHO
echocardiogram
ECOG
Eastern Cooperative Oncology Group
EDC
electronic data capture
EU
European Union
FDA
Food and Drug Administration
FIH
First-in-human
GCP
Good Clinical Practice
GLP
Good Laboratory Practice
HBV
hepatitis B virus
HCV
hepatitis C virus
HFS
Hand-foot syndrome
HIPAA
Health Insurance Portability and Accountability Act
HNSCC
Head and neck squamous cell carcinoma
HNSTD
highest non-severely toxic dose
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Abbreviation or 
Special Term
Definition
HPV
Human papilloma virus
HR
Hazard ratio
ICF
Informed Consent Form
ICH
International Council for Harmonisation
IEC
Independent Ethics Committee
IM
intramuscular
IND
Investigational New Drug
IP
Investigational Product
IRB
Institutional Review Board
IS
Internal Standard
IV
intravenous(ly)
LFT
liver function test
LN
Lymph node
LVEF
left ventricular ejection fraction
MAD
maximum administered dose
MEDRA
Medical Dictionary for Regulatory Activities
MRI
magnetic resonance imaging
MTD
maximum tolerated dose
MUGA
multigated acquisition
NaHA
sodium hyaluronate 
NCI-CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NOAEL
no-observed-adverse-effect level
ORR
objective response rate
OS
overall survival
PR
partial response
PBMC
peripheral blood mononuclear cell
PD or DP
progressive disease or disease progression
PFS
progression-free survival
PLD
pegylated liposomal doxorubicin
PK or PK/PD
pharmacokinetic(s) or pharmacokinetic(s)/pharmacodynamics
RECIST
Response Evaluation Criteria in Solid Tumors
R/M
Relapsed or metastatic
RP2D
Recommended Phase 2 dose
SAE
serious adverse event
SC
subcutaneous
SCC
Squamous cell carcinoma
SD
stable disease
SQ3370
Shasqi’s local drug activation technology combining SQP33 protodrug and 
SQL70 biopolymer
SQL70
tetrazine-modified sodium hyaluronate biopolymer that can activate SQP33 
protodrug
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Abbreviation or 
Special Term
Definition
SQP33
chemically modified protodrug of doxorubicin with attenuated activity
SRC
Safety Review Committee
STS
Soft Tissue Sarcoma
TCO
trans-cyclooctene
TFST
time from enrollment to first subsequent therapy
TNT
time to next treatment
TSST
time from enrollment to second subsequent therapy
ULN
upper limit of normal
US
United States
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1.
INTRODUCTION
1.1.
DISEASE AND TREATMENT BACKGROUND
Cancer incidence and mortality are growing worldwide (Bray 2018). In 2018, the global 
incidence of new cancer diagnoses was estimated at over 18 million cases, and cancer-related 
deaths were estimated at over 9.6 million (Bray 2018). Of these cases, the vast majority were 
solid tumors (more than 16 million new cases and 8 million cancer deaths). For its part, soft 
tissue sarcoma (STS) is a heterogeneous group of aggressive malignant tumors. In the United 
States (US), it is estimated that over 12,000 people were diagnosed with STS in 2019, and that, 
of these diagnoses greater than 5,000 individuals will die from their cancer (Siegel 2019). In 
Australia, over 1500 new cases of STS were diagnosed in 2014 (Sarcoma Statistics 2019). 
Despite improvements in early detection and treatment protocols, most patients with solid 
malignancies die from metastatic burden (Chaffer & Weinberg 2011).
Anthracyclines are powerful, well-established anticancer agents and among the essential tools 
in the chemotherapy armamentarium of medical oncologists. Doxorubicin (Dox), a cytotoxic 
anthracycline antibiotic isolated from cultures of Streptomyces peucetius var. caesius, has been 
used successfully to produce tumor regression in a variety of neoplastic conditions such as 
STS, acute lymphoblastic leukemia, acute myeloblastic leukemia, breast cancer, ovarian 
cancer, small cell lung cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, gastric cancer, 
transitional cell bladder cancer, neuroblastoma, Kaposi’s sarcoma (Cooley 2007), thyroid 
cancer, Wilms’ tumor, and bronchogenic carcinoma (in which the small cell histologic type is the 
most responsive compared with other cell types) (Arcamone 1969; McGowan 2017).
The antitumor activity of doxorubicin (Dox) is attributed to its interference of deoxyribonucleic 
acid (DNA) replication by inhibiting topoisomerase II enzyme. Despite its potent broad-spectrum 
antitumor activity, the extended use of conventional Dox in clinical practice is limited by life-
threatening toxicities, with the most significant being largely irreversible and dose-dependent 
cardiotoxicity (Jain 2000). Cardiotoxicity includes short- and long-term toxic effects in the heart, 
ranging from alterations in myocardial structure and function, to severe cardiomyopathy and 
congestive heart failure (CHF). CHF was reported in > 4%, > 18%, or 36% of patients who had 
received cumulative conventional Dox doses of 500 to 550, 551 to 600, or > 601 mg/m2,
respectively (Lefrak 1973). Chronic cardiotoxicity occurred after prolonged administration of 
conventional Dox. Although the possibility of cardiotoxicity development is dose-dependent, it 
could occur even at lower doses due to individual patient variations (Lipshultz 1995). The exact 
causal mechanisms of Dox-induced cardiotoxicity remain elusive, making it difficult to predict or 
prevent its severe adverse events (AEs) in individual patients (Ghigo 2016; Whelan 2010;
Chiong 2011). The most commonly used dose schedule of conventional Dox, as a single agent, 
is 60 to 75 mg/m2 as a single intravenous (IV) injection every 3 weeks. The lower dosage is 
given to patients with inadequate marrow reserves due to old age, or prior therapy, or neoplastic 
marrow infiltration (ADRIAMYCIN Australian Product Information; ADRIAMYCIN US Package 
Insert).
The cytotoxic activity of conventional Dox also affects normal cells with high turnover rates such 
as hematopoietic cells in the bone marrow, cells of the immune system and the gut, as well as
skin and hair cells. This nonspecific cytotoxicity causes immune suppression (and associated 
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opportunistic infections), blood disorders, infertility, neuropathy, cognitive dysfunction, nausea, 
fatigue, pain, and hair loss (Liebner 2015). Bone marrow suppression is the most common 
acute dose-limiting toxicity (DLT) of conventional Dox; myelosuppression reaches its peak at 10 
to 14 days after treatment with recovery usually occurring by the 21st day. Thrombocytopenia 
and anemia may also occur. Severe clinical consequences of myelosuppression include fever, 
infections, sepsis/septicemia, septic shock, hemorrhage, tissue hypoxia, or death 
(ADRIAMYCIN Australian Product Information; ADRIAMYCIN US Package Insert). These 
cardiac and myelosuppressive toxicities limit the dose of conventional Dox and the combination 
of Dox with other antineoplastic agents.
The major side effects of conventional Dox are its narrow therapeutic window and limit the acute 
and lifetime doses in patients (Colombo 2015). Consequently, an unmet medical need exists for 
novel strategies to deliver chemotherapies such as Dox with improved safety, particularly with 
less cardiotoxicity and broader therapeutic windows (Frustaci 2001). Consequently, an unmet 
medical need exists for novel strategies to deliver chemotherapies such as Dox with improved 
safety, particularly with less cardiotoxicity and broader therapeutic windows (Frustaci 2001). 
SQ3370 has the potential to address this unmet medical need.
1.1.1. Soft-tissue Sarcoma
Soft tissue sarcomas are a rare group of heterogeneous malignancies with >50 histologic 
subtypes that have varying biological behavior and responsiveness to therapy. Surgery with 
radiotherapy is the most common treatment for localized disease when resection is possible, 
with associated 5-year overall survival of 55% (Seddon 2017). Survival outcomes for locally 
advanced or metastatic STS poor, with a median overall survival of 12.8-14.3 months after 
diagnosis (Verschoor 2020, Judson 2014).
With modern limb salvage techniques, amputation for extremity soft tissue sarcomas is now 
rare.  A study that reviewed patients where amputation was used for local control compared to 
limb conservation showed the rates of systemic relapse and disease-specific survival were 
poorer in the amputation patients, with a 3 year overall survival of only 50.3% following curative 
amputation, while those patients undergoing limb salvage had a greater than 75% overall 
survival. Of the 59 patients with localized disease at the time of amputation, 29 developed 
metastatic disease (49.2%), with a median time to first metastasis of 10 months (Smith 2017). 
Amputation patients are a high risk group of soft tissue sarcoma patients where improved 
treatments are needed.  
Doxorubicin has been the mainstay of first-line treatment for locally advanced, unresectable, or 
metastatic STS for decades, achieving objective response rates of 0–20% (Seddon 2017, 
Chawla 2015, Tap 2017), median progression-free survival (PFS) of 23.3 weeks (Seddon 2017),
and a median OS of 12.8 months (Verschoor 2020). More recent trials report slightly better 
median OS for doxorubicin monotherapy with 16.9 months (Ryan 2016), 17.6 months (Seddon 
2017), and 19.0 months (Tap 2017) respectively (Ryan 2016). A randomized controlled Phase 3 
trial (Judson 2014) comparing combination Dox and ifosfamide versus Dox alone showed a 
significant increase in PFS in the combination treatment group, but with no increase in OS. 
Further, in a recent retrospective database analysis of 2045 patients from 12 EORTC sarcoma 
trials (inclusion period 1980–2012) after completing 6-cycles of first line Dox monotherapy or 
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Dox plus ifosfamide at varied doses for locally advanced, unresectable, or metastatic STS, 
demonstrated that there was a significantly worse PFS in participants receiving Dox
monotherapy vs. Dox + high dose ifosfamide.  No significant difference of histology on PFS, and 
no significant difference of treatment regimen or histology on OS was observed (Verschoor 
2020). Although the addition of ifosfamide to Dox-based regimens for STS is standard and 
generally improves response rates and PFS, OS is not improved and the incidences of Grade 
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increased (Judson 2014).
Subsequently, two first-line phase 3 trials (Ryan 2016, Tap 2017) have combined doxorubicin 
with novel agents (doxorubicin and palifosfamide compared with doxorubicin and placebo, and 
doxorubicin and evofosfamide compared with doxorubicin alone), and neither study was able to 
show improved PFS or OS for the combination treatments. Thus, no regimen has proved to be 
unequivocally superior in efficacy or toxicity to doxorubicin monotherapy as first-line treatment 
for locally advanced, unresectable, or metastatic soft-tissue sarcoma. Patients who are beyond
the 1st relapse with STS, the benefit of treatment in the third-line was very limited for most 
histologies, with a median time to next treatment (TNT) and OS ranging between 2.3 and 3.7 
months and 5.4 and 8.5 months, respectively (Savina 2017). Therefore, better treatment options 
are needed in earlier lines of treatment while the tumors remain sensitive to treatment. 
1.1.2. Head and Neck Cancer
The prognosis of patients with recurrent or metastatic head and neck squamous cell cancer is 
generally poor.  The median survival in most series is 6 to 15 months depending on patient and 
disease-related factors (Pfirschke 2020). The median overall survival for recurrent or metastatic 
head and neck cancer (R/M HNSCC) remains less than 1 year despite modern chemotherapy 
and targeted agents. Palliative chemotherapy and the epidermal growth factor receptor inhibitor, 
cetuximab, constitute the backbone of treatment for patients with R/M HNSCC (Price 2012).  
From an initial trial of patients with R/M HNSCC, 36 were treated with doxorubicin and cisplatin, 
the overall response rate (complete + partial) was 30%, with a median duration of response of 4 
months (Sandler 1984). A Phase 2 trial of 36 patients with unresectable, recurrent, or metastatic 
squamous cell carcinoma arising from the upper respiratory or alimentary passages of the head 
and neck were accrued between April 1993 and February 1996, and treated with the drug 
combination of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) (Okuno 2002). The 
ORR over the first 4 cycles of treatment was 46%. Two of the 18 patients who responded had a 
complete response.  Among the 22 patients with unresected residual or recurrent disease, the 
median time to progression was 11 weeks, and 1-year PFS was 14%, and median OS was 24 
weeks, and the 1-year OS was 36%. Among the 13 patients with metastatic disease, the
median time to progression was 26 weeks, and the 1-year PFS was 23%, the median OS was 
54 weeks, and the 1-year OS was 54%. 
Caelyx, a liposomal anthracycline, was administrated as 1 hr infusion every 3 weeks at doses of 
35 mg/m2 (group A) and then subsequently given at 45 mg/m2 (group B). 26 patients received a 
total of 87 cycles. The median number of cycles was 3 (range 1–7). Four out of 24 evaluable 
patients (17%, 95% confidence interval (CI) 0.5–32%) showed significant evidence of antitumor
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activity, with tumor necrosis being observed in 2 patients. Grade 3–4 neutropenia was observed 
in only 2 patients. Myelosuppression, particularly severe leukopenia, and thrombocytopenia was 
observed in 81% and 7% of the patients during the entire course of their treatment. One patient 
developed sepsis and died after 3-cycles of therapy secondary to chemotherapy-induced 
neutropenia.
Liposomal doxorubicin was administered up to 45 mg/m2 to 24 evaluable patients with locally 
recurrent and/or metastatic squamous cell carcinoma of the head and neck, and 4 patients 
(17%) showed significant evidence of antitumor activity.  The median number of cycles was 3.  
Toxicities included 2 patients with Grade 3-4 non-febrile neutropenia, 2 patients with Grade 3 
allergic reaction, 1 patient with Grade 3 diarrhea, Grade 3 necrosis in 2 patients, and moderate 
bleeding in 2 patients (Faivre 2004). 
1.2.
SQ3370 BACKGROUND
SQ3370 is a novel Investigational Product (IP) that enables local targeting and activation of a 
cytotoxic protodrug without the need for specific molecular biomarkers. The therapeutic goal of 
SQ3370 is to enhance the antitumor efficacy of Dox by increasing its concentration at a specific 
tumor site while minimizing its systemic toxicity.
The SQ3370 IP consists of 2 components: 
x
SQL70 biopolymer made of tetrazine-modified sodium hyaluronate (NaHA). This 
biopolymer does not contain a therapeutically active ingredient. It functions by activating 
the SQP33 protodrug inside the body upon chemical reaction in situ that releases the 
active drug, Dox. Hence, SQL70 is considered to be an ‘activating article’.
x 
SQP33 protodrug, a trans-cyclooctene (TCO)-modified protodrug of Dox with attenuated 
cytotoxic activity. SQP33 is the active component.
Figure 1: SQ3370 Local Drug Activation Approach  
(1) SQL70 biopolymer is locally injected at the tumor site and (2) SQP33 protodrug is infused 
systemically. (3) SQP33 protodrug is captured by SQL70 biopolymer at the tumor site through a rapid
covalent reaction between tetrazine and trans-cyclooctene moieties, followed by chemical rearrangement 
to release active dox. 
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SQL70 biopolymer is locally injected at the tumor site and followed by IV infusions of SQP33 
protodrug. At the tumor site, SQL70 biopolymer selectively and rapidly captures SQP33 
protodrug via an irreversible covalent reaction between tetrazine and TCO (bioorthogonal 
chemical groups), followed by the release of active Dox (Figure 1). 
SQ3370 is being developed for the treatment of adult patients with solid tumors for which an 
anthracycline-containing regimen is appropriate and who have an injectable localized tumor or 
metastatic lesion.
Several key attributes make SQ3370 a suitable treatment for solid tumors: Favorable reaction 
kinetics ensure rapid capture of SQP33 protodrug by SQL70 biopolymer at the tumor site. 
SQP33 protodrug activation is dependent only on the chemical reaction with SQL70 biopolymer
and is independent of native biological processes or biomarkers. A single injection of SQL70 
biopolymer can capture multiple doses of SQP33 protodrug. SQP33 protodrug has attenuated 
activity compared with conventional Dox, minimizing off-target effects. As a result, it is 
hypothesized that the SQ3370 Investigational Product can result in higher local concentrations 
of active Dox at the tumor site. 
1.2.1. Summary of Nonclinical Experience
In support of the first-in-human (FIH) trial, a series of nonclinical studies have been conducted 
with SQ3370 and different prototypes (made of the same type of materials as SQ3370 and with 
analogous local drug activation functions). The nonclinical safety of Dox hydrochloride (Dox 
HCl) and various formulations such as liposomal Dox (e.g., DOXIL, CAELYX) have been 
extensively studied. As the clinical development program proceeds, those studies will 
supplement the nonclinical studies conducted with SQ3370. 
The types of DLTs observed with SQ3370 are consistent with those reported for conventional 
Dox; however, SQ3370 allows a significantly higher dose of cytotoxic therapy to be given safely. 
Nonclinical Pharmacology
Published in vitro results show that a prototype of the SQP33 protodrug, without SQL70 
biopolymer, is 57-fold less toxic than conventional Dox to human fibrosarcoma cells in culture 
(Mejia Oneto 2016). In a syngeneic mouse tumor model (MC38), SQ3370 enhanced overall 
survival and tumor growth inhibition of both injected and non-injected tumors compared with 
conventional Dox treatment. This technology also enabled a sustained antitumor response upon 
rechallenge with MC38 tumor cells, without additional treatments. At 2 weeks post SQ3370 
treatment, there was an increase in total T-cell infiltration in both injected and non-injected 
tumors compared with saline treatment. Together, these effects indicate that the antitumor 
efficacy observed in non-injected and/or rechallenged tumors was likely due to immune 
activation by SQ3370. 
Nonclinical Pharmacokinetics
Pharmacokinetic (PK) studies in mice, rats, and dogs confirm that SQL70 biopolymer captures 
SQP33 protodrug and removes it from circulation, followed by the release of active Dox. In 
mice, a fluorescently labeled version of SQL70 biopolymer remained detectable at the local 
injection site for approximately 2 months, with suggested clearance by lymphatic, hepatic, and 
renal routes. In a separate study in mice, 7 days after the last dose of SQP33 protodrug, active 
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Dox was detected at the local site. In rats, SQL70 biopolymer rapidly captured and rendered 
SQP33 protodrug undetectable in plasma samples within 30 minutes of administration, with 
measurable conversion to active Dox. SQP33 protodrug was stable in vivo, showing minimal 
nonspecific conversion to active Dox in the absence of SQL70 biopolymer, based on plasma 
exposure levels. Plasma exposure to active Dox was highest when SQP33 protodrug was given 
between 1 to 24 hours after SQL70 biopolymer injection. Liver exposure to active Dox peaked 
when SQP33 protodrug was given 24 hours after SQL70 biopolymer injection. Plasma and liver 
exposure to active Dox decreased drastically when SQP33 protodrug was given 96 hours (Day 
5) after SQL70 biopolymer injection. Active Dox concentrations at the SQL70 biopolymer site 
suggest local conversion of systemic SQP33 protodrug to active Dox even 5 days after SQL70 
biopolymer injection.
A Good Laboratory Practice (GLP)-compliant study in dogs showed that a single 10 mL local 
injection of SQL70 biopolymer could continue to capture 26.5% of the SQP33 protodrug given 
systemically on the fifth day of a 5-day regimen. In a separate GLP bridging study in dogs, 
plasma samples (collected up to 3 days after the animals received a single local SQL70 
biopolymer injection) and liver samples (collected on Day 6) reacted with a TCO-containing 
internal standard (IS), suggesting the presence of SQL70 biopolymer in the plasma and the 
liver. Plasma samples collected on Day 4 and 5 did not react with the IS. 
In summary, the studies suggest that a fraction of the locally injected SQL70 biopolymer
circulates in the plasma from Day 1 to Day 3, leading to active Dox exposure that peaks in the 
plasma between Day 1 and 2, and peaks in the liver around Day 2. Active Dox exposure in the 
plasma and liver decrease markedly by Day 4 and 5. SQL70 biopolymer at the local site 
continues to transform systemic SQP33 protodrug into active Dox at least until Day 5 following 
local SQL70 biopolymer injection.
Toxicology
SQ3370 is less toxic than conventional Dox in rodent and dog models, enabling higher doses to 
be administered safely. In a GLP study (5 days of dosing and 23 days of recovery) in dogs 
administered with a single 10 mL SQL70 biopolymer volume and 5 daily SQP33 protodrug
doses, the no-observed-adverse-effect level (NOAEL) was 0.72 mg/kg/day (3.6 mg/kg/cycle) 
Dox HCl equivalents (Dox Eq); the highest non-severely toxic dose (HNSTD) was 1.79 
mg/kg/day (8.9 mg/kg/cycle) Dox Eq. The DLTs observed at the HNSTD level were consistent 
with those reported for conventional Dox and included bone marrow hypocellularity and 
decreased hematopoiesis. All side effects showed evidence of reversibility in the recovery 
phase. When SQP33 protodrug was administered at the HNSTD level without SQL70 
biopolymer, no AEs were reported, highlighting the attenuated activity of the protodrug.     
Available safety findings do not support a vesicant effect for SQP33 when SQL70 is 
administered subcutaneous (SC). Other injection routes for SQL70 such as intramuscular (IM), 
do not indicate different safety profiles to date, with additional studies ongoing.
The tolerability of SQL70 biopolymer alone was also evaluated. In a GLP dog study, SQL70 
biopolymer-related clinical pathology effects were reversible, and magnitudes of change were 
similar for the affected groups regardless of the dose administered. Injection site reactions were 
consistent with an inflammatory response to a foreign material and inconsistent with notable 
tissue irritation. An earlier study with a prototype of SQL70 biopolymer demonstrated that 41% 
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of the injected material remained at the injection site for ~2.5 months with no evidence of
inflammatory changes on histopathology.
Overall, side effects of SQ3370 were consistent with the well-known side effect profile of 
conventional Dox and did not lead to any unique or new DLTs. In particular, no evidence of liver 
injury was noted in nonclinical studies. Further details are available in the Investigator’s 
Brochure.
1.2.2. Summary of Clinical Experience
The current study, SQ3370-001, is the first-in-human clinical trial to evaluate SQ3370. 
Therefore, aside from this ongoing SQ3370-001 study, no previous clinical data are available.
1.3.
STUDY RATIONALE
1.3.1. Experimental Doxorubicin-Based Therapeutics
Local drug activation approaches have been developed in which systemic Dox-based 
therapeutics are activated by inherent biological differences between cancerous and healthy 
tissue, such as pH (Mita 2015), oxygen level (Tap 2017), or protein expression (Schöffski 2017). 
Several of these Dox- based drugs have been developed by modifying the aminoglycoside 
portion of Dox with peptides, designed to be cleaved by proteases elevated in cancerous cells:
1) L-377202 (Merck; DeFeo-Jones 2002; DiPaola 2002), 2) DTS-201 (CPI-0004Na) (Diatos; 
Schöffski 2017), and 3) “Compound 5” (Bristol-Myers Squibb; Albright 2005). The main benefit 
of cancer-activated therapeutics is that they may eliminate cancerous cells while sparing healthy 
tissue from the cytotoxic effects. However, the extensive biological differences between 
cancerous and healthy tissue, as well as interpatient variabilities, are major limitations to these 
approaches.
SQ3370 is unique in that drug activation occurs through a bioorthogonal chemical reaction 
independent of differences in specific molecular markers between cancerous and healthy 
tissues. Activating agents in the locally injected SQL70 biopolymer enable the local activation of 
systemically administered SQP33 protodrug. SQ3370 is less susceptible to inherent differences 
in biomarker expression between healthy and tumor tissue and between different patients, 
which should lead to less off-target effects and less interpatient variability. A comparison of the 
tolerability of SQ3370 with several other Dox-based treatments is presented below. The MTD of 
SQ3370 in mice was 19.1-times higher than the MTD of conventional Dox therapy; no side 
effects were observed in mice receiving this dose of SQ3370. In dogs, SQ3370 treatment at a 
dose of 8.9-times higher than the veterinary clinical dose of conventional Dox was chosen as 
the highest non-severely toxic dose (SQ3370-TOX-108). To date, in human patients, SQ3370 
has been dosed at 15 times the standard clinical dose of Dox (75 mg/m2); although an MTD has 
not yet been reached, the MAD (maximum administered dose) is 15x in the Phase 1 clinical trial 
(Study SQ3370-001).
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Figure 2: Tolerability of Various Dox Products in Mouse, Dog, and Human 
The MTD of conventional Dox for mice is defined as 8.1 mg/kg (Bristol-Myers Squibb; Albright 
2005). The standard clinical dose is defined as 1 mg/kg for dogs and as 75 mg/m2 for humans 
(endpoint is dose-limiting toxicity). The MTD of SQ3370 in mice was 19.1 times the MTD of 
conventional Dox. In dogs, the HNSTD of SQ3370 treatment was established at 8.9-times 
higher than the veterinary clinical dose of conventional Dox (SQ3370-TOX-108). In human 
patients, SQ3370 has been dosed at 15-times the standard clinical dose of Dox (75 mg/m2); the 
MAD is 15x and the study defined DLT was not established. Doxil (Johnson and Johnson; 
Working 1996) and aldoxorubicin (Kratz 2007; Unger 2007) are not referenced in text but are 
included in this figure for further illustration of the tolerable doses (safety) of SQ3370 (Figure 2). 
1.3.2. Doxorubicin and the Immune System
Cytotoxic agents such as Dox are known to induce immunogenic cell death (Bezu 2015) and 
enhance tumor responsiveness to immune checkpoint blockade therapies (Pfirschke 2020; 
Zitvogel 2013). Addition of Dox-based therapies to anti-PD-1 and anti-CTLA-4 monoclonal
antibodies in pre-clinical experiments resulted in significantly improved antitumor response 
compared to antibodies alone (Rios Doria 2015). Conventional Dox treatment improved tumor 
antigen–specific CD8 T-cell proliferation in tumor-draining lymph nodes and promoted tumor 
infiltration of interferon-Ȗ–producing cytotoxic T lymphocytes in mice (Mattarollo 2011). Tumors 
such as STS that are accessible by injection can have microenvironments that are poorly 
immunogenic and are consequently poorly responsive to checkpoint inhibition therapies (Cancer 
Genome Atlas Research Network 2017). We hypothesize that SQ3370 can deliver higher 
concentrations of active Dox to the tumor, enhancing local immune response, while minimizing 
systemic immunosuppression associated with conventional Dox. 
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1.4.
BENEFIT-RISK ASSESSMENT
The study will be performed in accordance with ethical principles that have their origin in the 
Declaration of Helsinki and are consistent with International Council for Harmonisation (ICH),
Good Clinical Practice (GCP), and applicable regulatory guidelines.
Because this is the first study to evaluate SQ3370 in humans, its clinical benefits and safety are 
not fully known; however, both the SQL70 biopolymer and SQP33 protodrug are based on 
approved products with well-established safety profiles, and conventional Dox has 
demonstrated anticancer activity across a range of tumor types. Thirty-nine patients were 
enrolled and treated in the Phase 1, and thirty-eight patients are evaluable for safety as one 
patient’s treatment was halted day 2 due to COVID-19. Thirty-two of the thirty-nine patients are 
sarcomas. Thirty patients were treated on the dose expansion protocol with escalating doses of 
SQP33 from 0.38x to 15x Dox equivalent dose. Eight patients were treated in the 20 mL SQL70 
biopolymer cohort, five at the 4x Dox equivalent and three patients at the 6x doxorubicin 
equivalent dose of SQP33.  One patient was treated at the low dose/fragile cohort at 8x Dox
equivalent dose of SQP33. Note that patients remain on study treatment at the time of this 
update. In the Phase 1 the MAD was 15x while the study defined DLT was not established. The 
sponsor in consultation with the investigators decided not to continue dose escalations. The 
treatment was well tolerated as published in the ESMO Congress 2022 Poster 1499P, with the 
most frequent treatment emergent adverse events (TEAEs) being nausea, fatigue, diarrhea or 
constipation, and decreased appetite.  Hematologic toxicities were neutropenia, anemia, and 
thrombocytopenia.  As of 9/27/2022, an analysis of Grade 3 or greater TEAEs was performed 
through Cohort 8 (12x Dox equivalent).  In the 20 mL SQL70 biopolymer group, TEAEs >10% of 
the total and in >1 patient showed worsening anemia in 3 patients (37.5%) and neutropenia in 2 
patients (25%).  In the 10 mL SQL70 biopolymer dose expansion, grade 3 or greater TEAEs 
>10% of the total and in >1 patient showed worsening anemia in 4 patients (16.7%).  The 
totality of available data supports the continuation of the study and opening of the Phase 2a.
Nonetheless, SQ3370 is a new treatment and there may be both unexpected risks and benefits 
not previously associated with conventional Dox or NaHA treatments. See the Investigator’s 
Brochure for additional details. 
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2.
OBJECTIVES AND ENDPOINTS
In this study patients will be enrolled into a series of SQP33 protodrug dose escalation cohorts. 
Following completion of the dose escalation cohorts, the study will evaluate SQ3370 in three 
expansion groups. The study will also evaluate the administration of 10 mL and/or 20 mL of 
SQL70 biopolymer.
2.1.
PHASE 1 DOSE ESCALATION 
2.1.1. Objectives
2.1.1.1.
Primary Objective
x
Assess the safety and tolerability of SQ3370, including determination of the MTD and/or
RP2D of SQP33 protodrug administered with 10 mL and/or 20 mL of SQL70 biopolymer.
2.1.1.2.
Secondary Objectives
x
Characterize the PK profile of SQP33 protodrug and active Dox following SQ3370 
treatment.
x
Assess preliminary signals of SQ3370 anti-tumor activity.
2.1.1.3.
Exploratory Objectives
x
Assess the concentration of active Dox and SQP33 protodrug following SQ3370 
treatment at the local site through analysis of tumor biopsies.
x
Assess immune response through biomarker analysis of tumor biopsies and peripheral 
blood specimens.
2.1.2. Endpoints
2.1.2.1.
Primary Endpoint
x
Frequency of AEs, SAEs and DLTs, as well as changes from baseline in vital signs, 
clinical laboratory parameters, physical examination findings, ECHO/MUGA, and ECG 
results.
x
Establish RP2D (see section 3.2.5 Recommended Phase 2 Dose for details)
2.1.2.2.
Secondary Endpoints
x
Plasma concentration and PK parameters for SQP33 protodrug and active Dox following 
SQ3370 treatment.
x
ORR per RECIST v1.1.
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2.1.2.3.
Exploratory Endpoints
x
Assess the presence of SQP33 protodrug and active Dox in tumor tissue. 
x
Characterize immune response in blood and tumor tissue over time following treatment 
with SQ3370.
2.2.
PHASE 2A EXPANSION GROUPS
2.2.1. Objectives
2.2.1.1.
Primary Objectives
x
Further investigate the safety and tolerability profile of SQ3370 in anthracycline naïve 
patients with:
o
Group 1: Neo-adjuvant treatment of patients with STS of the extremity who are 
ineligible for primary surgical resection and under consideration for possible/probable 
amputation, with predefined anthracycline sensitive tumors.
o
Group 2: Patients with unresectable, locally advanced or metastatic STS, with 
predefined anthracycline sensitive tumors and compare safety and tolerability of the 
RP2D in two infusion schedules of SQP33 (3-day vs 5-day).
o
Group 3:  
x
3a) Patients with relapsed or metastatic squamous-cell head and neck cancer
2.2.1.2.
Secondary Objective 
x
Assess preliminary signals of SQ3370 anti-tumor activity.
x
Characterize the PK profile of SQP33 protodrug and active Dox following SQ3370 
treatment.
2.2.1.3.
Exploratory Objectives
x
Assess the concentration of active Dox and SQP33 protodrug following SQ3370 
treatment at the local site through analysis of tumor biopsies.
x
Assess immune response through biomarker analysis of tumor biopsies and peripheral
blood specimens. 
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2.2.2. Endpoints
2.2.2.1.
Primary Endpoints
x
Frequency of AEs and SAEs, as well as changes from baseline in vital signs, clinical 
laboratory parameters, physical examination findings, ECHO/MUGA, and ECG results 
across all treatment cycles and groups. 
2.2.2.2. 
Secondary Endpoint
x
ORR per RECIST v1.1. 
x
OS
x
Time from enrollment to first subsequent therapy (TFST)  
x
Plasma concentration and PK parameters for SQP33 protodrug and active Dox following 
SQ3370 treatment. 
x
Group 1: Advanced High-risk Soft Tissue Sarcoma of the Extremity
o
Histopathological Response 
o
Surgical outcome amputation/limb-salvage vs planned
o
Disease-free survival  
o
Local recurrence-free survival [Time Frame: 2 years]
o
Distant recurrence-free survival  
o
Symptomatic disease control  
x
Group 2: Comparison of the RP2D of SQ33 total dose in mg/m2 administered every 21 
days administered over 3 vs over 5 days
o
Compare safety and tolerability of two infusion schedules of SQP33 (3-day vs 5-
day) 
o
Pharmacokinetic comparison of the two infusion schedules
o
PFS per RECIST v1.1
o DoR per RECIST v1.1
o
DCR per RECIST v1.1
x
Group 3a: Head & Neck
o DoR per RECIST v1.1
o
PFS per RECIST v1.1
o
Time to local-regional progression or distant progression per RECIST v1.1
o
Local-regional control per RECIST v1.1
o
DCR per RECIST v1.1
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2.2.2.3.
Exploratory Endpoints
x
Assess the presence of SQP33 protodrug and active Dox in tumor tissue. 
x
Characterize immune response in blood and tumor tissue over time following treatment 
with SQ3370.
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3.
STUDY DESIGN
3.1.
OVERVIEW
This multicenter, Phase 1/2a, first-in-human, single-arm, open-label, dose-escalation study will 
evaluate the safety and tolerability, PK, and preliminary efficacy of SQ3370 in patients with 
locally advanced or metastatic solid tumors. The Screening, Treatment, Safety Follow Up and 
Long Term Follow Up schedules for both the escalation and Phase 2a groups in the study can 
be found in the Schedules of Assessments.
3.1.1. Phase 1 Dose Escalation
Patients will receive specific dose levels of SQP33 protodrug, assigned according to the dose 
escalation design described in section 3.2 Phase 1 Dose Escalation.
20 mL SQL70 Biopolymer (post-Cycle 1) Cohort: 
Patients on treatment who attain at least a 30% reduction in injected tumor size or have 
a tumor that is no longer injectable may have a second lesion injected with an additional 
10 mL of SQL70 biopolymer, thereby receiving a total of 20 mL of SQL70 biopolymer 
(see section 3.1.4.4 Phase 1: 20 mL SQL70 Biopolymer (post-Cycle 1) Cohort).
20 mL SQL70 Biopolymer (from Cycle 1) Cohort: 
To evaluate the administration of 20 mL of SQL70 biopolymer in one or two lesions 
starting at Cycle 1, patients will be enrolled in a separate cohort at a dose level of 
SQP33 protodrug that is lower than the current dose level being evaluated.
Also see the Schedule of Assessments Appendix G.
3.1.2. Phase 2a Expansion Groups
Patients will be enrolled in expansion groups to further study the preliminary activity and safety 
of SQ3370, dosing schedules, as well as PK and immune changes in blood and tumor tissue
(see section 3.3 Phase 2A Expansion).
3.1.3. Screening
Screening is up to 28 days prior to starting treatment (Day -28 to Day -1). Procedures performed 
per standard of care during the screening period, but prior to informed consent may be used 
rather than repeating procedures (see section 6.2 Screening and Re-Screening).
3.1.4. Treatment
3.1.4.1.
Treatment Cycles
An individual cycle of treatment is defined as a 3-week (21-day) period wherein the SQL70 
biopolymer is injected into a lesion or lesions on Day 1 followed by 3-5 consecutive daily 
infusions of SQP33 protodrug (Day 1-5 or in Phase 2a Group 2 subset will receive Day 1-3). In 
Phase 1 subjects assigned to receive 20 mL SQL70, no more than 2 lesions may be injected 
(10 mL each) during the treatment cycle with the exception of a “regional cluster of lesions” 
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defined as tumors that are contiguous, in apposition to each other, or are within 5 cm of each 
other. If there is a question whether a lesion or lesions are appropriate for injection, the Medical 
Monitor should be consulted.  
Phase 2a Groups Specific Treatment Cycles 
All patients treated at the RP2D in all groups within the Phase 2a will not be treated beyond 12 
cycles or approximately 8 months.
The table below provides an overview of the SQL70 volume administered per lesion, number of 
potential lesions to inject, number of SQP33 timepoints per cycle and the dose to be 
administered each day. 
Table 1: Expansion Group SQ3370 Administration Overview
Group 1: Advanced High-risk Soft Tissue Sarcoma of the Extremity
Patients will enroll at the RP2D of SQP33 given over 5 days and will receive a fixed dose of 
SQL70 (20 mL). On Day 1 of each cycle, the subject will receive an injection of the SQL70 
biopolymer into the tumor, followed by five (5) days of SQP33 infusion at the RP2D within 3 
hours r 30 minutes. All patients are planned to receive 2 cycles of SQ3370 and undergo a 
disease reevaluation per RECIST 1.1.  All patients without evidence of disease progression
(PD) after 2 cycles, will then undergo an additional 2 cycles of treatment and have a presurgical 
disease re-evaluation and proceed to definitive surgical procedure(s). 
Only patients who have had objective evidence of response, or whom in the opinion of the 
multidisciplinary treatment team, have achieved a clinical benefit may defer surgery at this point, 
and the study will allow up to 4 additional pre-op cycles, at which point patients should undergo 
exploratory surgery and or tumor resection. It is recommended that the surgical team place 
markers at the tumor margins to direct SQL70 dosing post resection. Post operatively subject 
with good responses may receive up to 4 additional cycles but not to exceed 12 cycles within 
the study. Surgical markers will be used to indicate the tumor bed for injection with SQL70.  
Any patient at any point who has been determined to have progressive disease has reached the 
end of treatment and will proceed to a definitive surgical treatment. Note: pre-operative radiation 
Group
SLQ70
Biopolymer 
(mL/Route)
SQP33
Protodrug
RP2D IV
Daily % Dose
1: Extremity STS
20 mL
intratumorally 
x 5 days 
20% daily x 5 
2: Unresectable STS 
(SQP33 comparison 3 day vs 
5 day)
10 mL 
intratumorally
x 5 days
20% daily x 5
x 3 days 
20% day 1 only 
40% day 2 and 3 
No Dosing on Day 4 or 
5
3a: Head and Neck
10 mL
intratumorally
x 5 days 
20% daily x 5 
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is allowed for patients with PD pre-operatively on study at this point. It is encouraged to keep 
subjects on study and to evaluate surgical specimens as per planned biomarker and 
pathological assessments.  See Schedules of Assessments Appendix H.  
Group 2: Unresectable Soft Tissue Sarcoma with a Comparison of the RP2D of SQP33 
administered over 3 vs 5 days 
Patients will enroll at the RP2D of SQP33 given over 3 or 5 days and will receive a fixed dose of 
SQL70 (10 mL) on Day 1 of each cycle.
To compare safety and tolerability of the RP2D in two infusion schedules of SQP33 (3-day vs 5-
day) in locally advanced, unresectable, each treatment group will maintain the total dose of 
SQP33 per cycle and compare two different infusion schedules while receiving the same dose 
and timing of SQL70.  All subjects will commence treatment with SQP33 within 3 hours ± 30
minutes.  
Table 2: Group 2 SQP33 Protodrug RP2D (% Administered) Per Day
Day 1
Day 2
Day 3
Day 4
Day 5
5-Day Administration  
20%
20%
20%
20%
20%
3-Day Administration 
20%
40%
40%
NO 
Treatment
NO 
Treatment
See Pharmacy Manual for additional details.  
Any patient at any point who has been determined to have progressive disease has reached the 
end of treatment, any subject completing 12 cycles of treatment will also have been deemed to 
have reached the end of treatment. See Schedules of Assessments Appendix I and Appendix J. 
Group 3a: Head and Neck
Patients will enroll at the RP2D of SQP33 given over 5 days and will receive a fixed dose of 
SQL70 (10 mL) on Day 1 of each cycle, except for patients with a secondary lymph node lesion. 
These patients may receive an additional 10 mL in that lesion for a total of 20 mL of SQL70 
injection. All subjects will commence treatment with SQP33 within 3 hours ± 30 minutes.
Any patient at any point who has been determined to have progressive disease has reached the 
End of Treatment, any subject completing 12 cycles of treatment will have been deemed to 
have reached the end of treatment. See Schedule of Assessments Appendix K. 
Note: All patients in Phase 2a expansion groups who are no longer on treatment should begin 
Long Term Follow Up per the Schedule of Assessments. 
3.1.4.2.
Treatment Delays
Cycles of treatment should be administered consecutively. Consult with the Medical Monitor 
regarding any unexpected delays in a patient starting their next cycle. Ideally, delays between 
cycles should not be more than 3 weeks, i.e., at most, the patient's next cycle should start on 
the 4th week following the end of the previous cycle. Please consult the medical monitor to 
discuss patients that need to delay their next cycle for more than 3 weeks. 
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3.1.4.3.
Treatment Duration
Patients may continue to receive treatment for up to 12 cycles (approximately 8 months).
Treatment for more than 12 cycles requires approval by the Medical Monitor.
Lesions should continue to be injected until they have progressed per RECIST v1.1.
x
In rare instances where the treating physician believes the patient is clearly benefiting 
from SQ3370 therapy despite modest radiographic progression of less than 20% that 
would not meet PD definition per RECIST v1.1, and following a discussion between the 
Medical Monitor and the treating physician, documentation in the medical record of
continuation of therapy duration and criteria for continuation 
x
or other treatment discontinuation criteria are met (see section 3.1.5 End of Treatment)
In the Phase 2a study all patients may receive up to 12 cycles.
3.1.4.4.
Phase 1: 20 mL SQL70 Biopolymer (post-Cycle 1) Cohort
For patients who have received treatment cycles with 10 mL of SQL70 biopolymer in Phase 1 
Dose Escalation:
If the injected lesion is considered no longer injectable by the Investigator (see section 3.1.4.3
Treatment Duration) then the area of the tumor bed, if possible, should be treated for two 
additional cycles. Additional lesion(s) may be treated with a further 10 mL of SQL70 biopolymer 
(for a total of 20 mL SQL70 biopolymer maximum administered per cycle) as considered 
appropriate by the investigator.
The administration of the additional 10 mL SQL70 biopolymer for patients already on study as 
described above is a separate group of patients from the cohort that will receive 20 mL SQL70 
biopolymer beginning at Cycle 1 (see section 3.2.3 Phase 1: 20 mL SQL70 Biopolymer (from 
Cycle 1) Cohort).
3.1.5. End of Treatment
The patient, Investigators, and/or the Sponsor may decide to end a patient’s treatment at any 
time. The Safety Follow-Up Visit should be performed approximately 30 days after the last dose 
of study drug (see section 3.1.6 Safety Follow-Up Visit).
Reasons that the patient, Investigators, and/or the Sponsor may decide to end (discontinue) a 
patient’s treatment include: 
x
Radiographic progression of disease per RECIST v1.1
x
Unacceptable AE(s)
x
Initiation of radiotherapy or non-protocol tumor directed treatment
x
Any medical condition or treatment that the Investigator or Sponsor determines may 
jeopardize the patient’s safety if he or she continues in the study 
x
Patient noncompliance with study procedures
x
Patient inability to attend visits (e.g., patient moves, change in caregiver)
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x
Patient withdrawal of consent to treatment
x
Patient withdrawal of consent to treatment and follow-up
x
Investigator decision
x
Sponsor decision
x
Lost to follow-up
x
Death
3.1.6. Safety Follow-Up Visit
The Safety Follow-Up visit is either:
x
within 28 to 34 days after the patient’s last dose of SQL70 biopolymer or SQP33 
protodrug, whichever was last administered
x
or prior to the start of a new anticancer treatment
3.1.7. Long Term Follow-Up
Long Term Follow-Up visits commence after the patient’s last cycle of treatment, every 12 
weeks (±7 days) for up to two years. See Schedule of Assessments for the list of procedures 
performed at the visits.  
All patients that discontinue treatment will be followed for information on progression, if 
treatment discontinuation was not RECIST 1.1 progression, and overall survival.  Additional 
information will be obtained for next line of treatment and survival status.
This long term follow-up information will be gathered during routine clinic visits, other study site 
contact with the subjects, or via telephone or e-mail with the subjects/caregivers or referring 
physician offices.
If the study is closed, Long Term Follow-Up visits will stop.
3.2.
PHASE 1 DOSE ESCALATION
The dose escalation portion of the study is based on Design 4 in Simon 1997 and comprises an 
initial period of accelerated titration cohorts (Stage 1) followed by 3+3 (Rolling 6) cohorts (Stage
2) as illustrated in Figure 3 below. This design is appropriate for cytotoxic therapies to minimize 
patient dosing at subtherapeutic levels. Additionally, two Phase 1 clinical trials with similar 
aminoglycoside-modified Dox-based drugs used similar accelerated dosing protocols and dose 
adjustment criteria (DiPaola 2002; Schöffski 2017).
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Figure 3: Schema of Single Patient Accelerated Dose Escalation Followed by 3+3 Design with 
Modified Fibonacci Dose Escalation
The SRC (see section 3.2.7 Safety Review Committee) will review all available safety data at 
the completion of Cycle 1 for each of the dose escalation cohorts and the cohort receiving 
20 mL SQL70 biopolymer from Cycle 1 to evaluate possible DLTs, recommend whether more 
patients should be enrolled at a given dose level / cohort, and recommend whether to dose 
escalate or to stop enrollment based on the definition of DLTs in addition to its members’ best 
clinical judgement.
3.2.1. Accelerated Titration (Stage 1)
In the absence of AEs considered by the SRC to be clinically relevant during any cycle, the
SQP33 protodrug accelerated dose titration stage includes 1 patient enrolled per cohort with a 
doubling of the SQP33 protodrug dose level between cohorts.  
Escalation transitions to a standard 3+3 modified Fibonacci design (see below) upon 
identification during the DLT period of either: 
x 
a DLT (see section 3.2.6 Dose-Limiting Toxicity), or  
x
any *UDGHAE considered to be at least possibly related to study drug
3.2.2. 3+3 (Rolling 6) Design (Stage 2)
The 3+3 (Rolling 6) design stage includes 3-6 patients enrolled per cohort and utilizes a 
modified Fibonacci scale to determine the dose level increase and minimum number of patients
enrolled per dose level (Table 3). In the Rolling 6 design, a minimum of three, and up to six 
patients may be concurrently enrolled at each dose level in the study prior to convening the 
SRC to evaluate the safety and tolerability of the dose level.  
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The first cohort of patients enrolled in the Stage 2 dose escalation portion will be at the same 
dose level as the highest evaluated Stage 1 dose level; an example of this is shown in Figure 3. 
This will ensure that any dose level resulting in a DLT is tested in additional patients prior to 
continued dose escalation. If 2 patients experience 1 or more DLTs in any cohort, no additional
patients will be enrolled at that dose level and further patients will be enrolled at a lower dose 
level. 
Decisions as to whether to allow additional enrollment beyond the minimum of three into a 
cohort or pause accrual for that cohort will be made by the Sponsor based on available data 
(i.e., the Sponsor will inform sites if a cohort is still open for additional accrual or if the cohort is 
closed to accruals). Dose level assignments are based on the number of participants currently 
enrolled in the cohort, the number of DLTs observed, the number of participants who have not 
completed the DLT period, general tolerability observed, and any available PK data. 
Table 3: Modified Fibonacci Dose Escalation Scale (Stage 2)
Number of Patients 
with DLTs in a 
Dose Level
Action
0 patients with DLTs 
across 3-6 patients 
in a dose level
Enroll an additional 3 to 6 patients at a dose level escalation of 50% 
1 patient with a DLT 
across 3-5 patients 
in a dose level
x Enroll additional patients (for a total of 6 at this dose level) 
o If no patients experience additional DLTs across the 6 total 
patients, then enroll 3 patients at a dose level escalation of 33%
o If a second patient experiences a DLT, see the below (DLTs 
across  3 patients at a dose level) 
patients with 
DLTs in a dose level
x Dose escalation will be stopped. 
o An intermediate dose level may be explored that is not higher 
than the MAD
DLT = dose-limiting toxicity; MAD = maximum administered dose.
3.2.3. Phase 1: 20 mL SQL70 Biopolymer (from Cycle 1) Cohort
During the Phase 1 portion of the study, to evaluate the administration of 20 mL of SQL70 
biopolymer in one or two lesions starting at Cycle 1, patients will be enrolled in a separate 
cohort at an initial dose level of SQP33 protodrug that is lower than the dose level being 
evaluated in the standard dose escalation at the time of initiation of this cohort. This 20 mL 
SQL70 biopolymer (from Cycle 1) cohort will follow the same 3+3 (Rolling 6) escalation design 
and DLT rules with 3-6 patients enrolled in the cohort. A per cohort SRC meeting will convene 
following the same guidelines as utilized for the SQP33 protodrug escalation. The SRC will 
decide if another cohort of patients should be enrolled at a higher SQP33 protodrug dose with 
the same 20 mL SQL70 biopolymer volume. 
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See section 4.1 General Inclusion/Exclusion Criteria for further details on the eligibility criteria 
for this cohort.
The 20 mL SQL70 biopolymer cohort described above is a unique and separate set of patients
(see section 3.1.4.4 Phase 1: 20 mL SQL70 Biopolymer (post-Cycle 1) Cohort).
3.2.4. Maximum Tolerated Dose
The MTD is defined as the dose level of SQP33 protodrug in which a total of 6 patients are 
treated at that dose level with t 2 patients experiencing a DLT during Cycle 1 of treatment 
across all 6 patients. An SQP33 protodrug MTD may be determined for both groups the 10 mL 
and 20 mL doses of SQL70 biopolymer.
3.2.5. Recommended Phase 2 Dose
A determination of the RP2D will be based on the safety and tolerability from every cycle of 
treatment, not just Cycle 1. The RP2D will be determined based on all available data, including 
PK/PD analysis, tolerability that will include the incidence and severity of DLTs, other AEs and 
the evidence for biological activity at each dose level tested. The RP2D will be defined by an 
SQP33 protodrug dose and a SQL70 biopolymer volume.
3.2.6. Dose-Limiting Toxicity
AE and serious adverse event (SAE) severity is based on the National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0.   
A DLT is defined as an AE that is at least possibly related to study treatment, occurs during the 
patient’s first cycle of treatment (21 days; also known as the DLT window), and is a:
x
Hematologic toxicity 
o
Febrile neutropenia 
o
*UDGHWKURPERF\WRSHQLDDVVRFLDWHGZLWK clinically significant bleeding
o
Grade 4 neutropenia or thrombocytopenia lasting >7 days
or 
x
*UDGHQRQ-hematologic toxicity except for:
o
*UDGHLVRODWHGDV\PSWRPDWLFODEoratory abnormalities or laboratory
abnormalities that resolve within 72 hours
o
Grade 3 nausea/vomiting/anorexia controlled by maximal medical management 
that does not persist for greater than 3 days
o
Grade 3 fatigue/asthenia that does not persist for more than 7 days
o
Grade GLDUUKHDRUFRQVWLSDWLRQWKDWUHVROYHVWR*UDGHRUEDVHOLQHZLWKLQ
hours with maximal medical management
o
Grade 3 or 4 elevation of amylase or lipase not associated with pancreatitis
o
*UDGHLQIXVLRQUHDFWLRQUHWXUQLQJWR*UDGHLQKRXUV
o
Grade 3 tumor lysis syndrome that is successfully managed and resolves within 
7 days without end-organ damage
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Hepatic abnormalities that resolve within 7 days.  
If a patient experiences a DLT, both SQP33 protodrug and SQL70 biopolymer should be
temporarily interrupted (see section 7.6.3 SQ3370 Treatment Interruptions). See section 3.1.5
End of Treatment if discontinuation of Investigational Product is permanent. 
3.2.7. Safety Review Committee (Dose Escalation and Phase 2a) 
The SRC will include the study team led by the medial monitor, and the active Investigator(s). 
The SRC will review all available safety data at the completion of Cycle 1 for each cohort to 
evaluate possible DLTs, recommend whether more patients should be enrolled at a given dose 
level / cohort, and whether to dose escalate or to stop enrollment based on the definition of 
DLTs in addition to its members’ best clinical judgement and will provide recommendations to 
the sponsor. 
With agreement from the sponsor, the dose escalation scheme may be modified (e.g., smaller 
increases or decreases in dose may be permitted, infusion timing, duration, or schedule may be 
modified) based on available PK and pharmacodynamic data, and/or the timing and severity of 
AEs observed. Changes that can only be made with a protocol amendment will include:
x
Dose level escalations that are increased by larger increments than the scheme in the 
protocol
x
Administration of more than 5 SQP33 infusions per cycle
x
Administration of more than 20 mL of SQL70 biopolymer per cycle
Phase 2a Responsibility 
In Phase 2a, the SRC will utilize the same criteria to evaluate the safety and tolerability of all 
available safety data at the completion of timing for each group to determine the initial safety 
and monitor the groups throughout the study overall safety and tolerability.  
Table 4: Phase 2a Safety Evaluation Timing
Group 
Run-in Evaluation 
N= (timing)
Simon 2 Stage 1 
evaluation
Final Assessment 
1: Extremity STS 
N=6 (after cycle 1)
N=15
N=46
2: STS unresectable
N=12 (6 per arm; after 
cycle 2) 
N.A. 
N=22
3a: Head and Neck 
N.A.
N=13 
N=26
N.A.= Not Applicable 
A run-in is not planned for the Head & Neck group (Group 3a) since they will be receiving the 
RP2D and schedule of SQ3370 without modifications (see Table 4).  
Group 1 will receive SLQ70 in a volume of 20 mL with the RP2D of SQP33 and therefore the 
safety lead-in to this group is warranted. The SRC may, after the planned initial review of any 
group, within its purview recommend additional monitoring to the sponsor.
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3.3.
PHASE 2A EXPANSION GROUPS
The Phase 2a Dose Expansion groups include approximately 94 patients:
Phase 2: Expansion Groups
x
Group 1: Extremity STS
o
Anthracycline naïve patients with soft tissue sarcomas of the extremity AJCC 
Stage III OR select IV (>5 cm injectable tumors) locally advanced and or 
metastatic disease not amendable to definitive surgical intervention at 
presentation, according to a multidisciplinary treatment team determined prior to
screening.  The following anthracycline sensitive histologies are allowed: 
angiosarcomas, leiomyosarcoma, liposarcoma, synovial sarcoma, adult 
fibrosarcoma, and undifferentiated pleomorphic sarcoma.  
x
Group 2: Unresectable STS
o
Anthracycline naïve patients with locally advanced or metastatic, unresectable, 
STS with defined anthracycline sensitive (expected historical ORR ~20%) 
histologies angiosarcomas, leiomyosarcoma, liposarcoma, synovial sarcoma, 
adult fibrosarcoma, and undifferentiated pleomorphic sarcoma.
x
Group 3a: Head and Neck
o
Anthracycline naïve patients with histologically or cytologically confirmed 
relapsed or metastatic squamous-cell carcinoma of the head and neck, not 
suitable for further radical local treatment or patients with distant metastases who 
are treatment naïve or may have received two or less systemic therapies 
(chemotherapy and/or immunotherapy). 
Figure 4: Phase 2a Dose Expansion Groups
STS of the extremity who are ineligible for primary 
surgical resection and under consideration for 
possible/probable amputation or metastatic
Extremity STS
Unresectable, locally advanced or metastatic 
STS 
Unresectable STS
Head and Neck relapsed or metastatic 
squamous-cell
Head and Neck
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3.4.
STUDY-WIDE TREATMENT INTERRUPTION RULES
The study may be interrupted or stopped at any time based upon the Sponsor’s and/or the
SRC’s review of the safety data. The study may resume once assessment by the SRC is 
complete, and an acceptable corrective action plan is implemented by the sponsor. 
If the study is temporarily interrupted or permanently terminated, the Sponsor will inform study 
sites, the Institutional Review Board (IRB) / Independent Ethics Committee (IEC), and the 
appropriate regulatory bodies.
3.5.
RATIONALE FOR STUDY DESIGN AND DOSE
3.5.1. Rationale for Study Design and Objectives
This is a first-in-human, Phase 1/2a study in patients with advanced solid tumors. Phase 1 will 
explore escalating doses of SQP33 protodrug and SQL70 biopolymer (see section 3.1
Overview) to identify the MTD and/or RP2D of SQP33 protodrug with 10 mL and/or 20 mL of 
SQL70 biopolymer. The accelerated titration and 3+3 (Rolling 6) design are being used to 
evaluate safety and tolerability of SQ3370. During the study, PK will be evaluated to determine 
the amount of systemic and localized active Dox following SQ3370 treatment. 
Phase 2a will utilize the RP2D determined in Phase 1.  Three Expansion Groups will further 
explore the safety and preliminary efficacy of SQ3370 in different patient populations.
Group 1: Advanced High-risk Soft Tissue Sarcoma of the Extremity
Resectable is defined for the study as a primary surgical intervention that is thought to produce 
a surgical cure and maintain a good functional outcome of the affected extremity. The study will 
enroll patients with unresectable soft tissue sarcomas of the extremity AJCC III OR select IV (>5 
cm injectable tumors) locally advanced and or metastatic that meet the preceding injectable 
tumor criteria not amendable to primary surgical intervention according to the consensus of 
multidisciplinary treatment team, determined prior to screening.  
The study will be conducted in 2 phases with a Simon 2 stage design in the 2nd phase. The 
group will open with the initial phase safety run-in of patients to establish the safety and initial 
feasibility of a 12-week delay in definitive surgical resection in patients with high-risk STS of the 
extremity treated with SQ3370, after review by the safety steering committee the Simon 2 stage 
design will initiate subjects enrolled in the lead-in will contribute to this phase of the study.  
Patients will enroll at the RP2D of SQ3370 as anticipated that the size of tumors given the stage 
(t2) will receive a fixed dose of SQL70 (20 mL). All patients are planned to receive 2 cycles of 
SQ3370 and undergo a disease reevaluation per RECIST 1.1.  All patients without evidence of 
disease progression after 2 cycles, will then undergo an additional 2 cycles of treatment and 
have a presurgical disease re-evaluation and proceed to definitive surgical procedure(s) of the 
extremity tumor. 
Only patients who have had objective evidence of response or whom in the opinion of the 
multidisciplinary treatment team determined to have achieved a clinical benefit may defer 
surgery at this point, the study will allow up to 4 additional cycles pre-operatively, at which point 
all patients should undergo exploratory surgery and or extremity tumor resection.  
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If a patient had a response, they may receive up to 4 additional cycles post operatively but not 
to exceed 12 cycles within the study. Surgical markers will be used to indicate the tumor bed for 
injection with SQL3370 or if suitable for the metastatic patients, a metastatic lesion may be 
injected.  
Any patient at any point who has been determined to have progressive disease has reached the 
end of treatment and will proceed to a definitive surgical treatment, note pre-operative radiation 
is allowed on study for patients with progressive disease preoperatively. It is encouraged to 
keep subjects on study and to evaluate surgical specimens as per planned biomarker and 
pathological assessments.  
Patients who undergo surgical resection and have had good response as defined by necrosis 
on histopathological resection may continue for additional treatment post-operatively. If post op 
radiation is administered the subjects come off treatment (see 3.1.5 End of Treatment for 
details) and will remain on study in Long Term Follow-up. 
Safety Monitoring  
The Study will use a safety-run-in to evaluate the PK and tolerability when at least 6 subjects 
have been enrolled and completed at least the planned Cycle 1. All available safety tolerability 
data will be presented and discussed at the SRC.  
If after the evaluation by the SRC the study proceeds after evaluation of the initial subjects a 
second evaluation as defined in the statistical section. An evaluation of the totality of the data 
available to complete the planned 4 cycles and to review efficacy and histopathological 
response data and will provide the sponsor a recommendation as to proceed with expansion or 
to halt enrollment of the group.
Group 2: Comparison of the RP2D of SQP33 Administered Over 3 vs 5 Days 
Compare safety and tolerability of the RP2D in two infusion schedules of SQP33 (3-day vs 5-
day) in locally advanced, unresectable, STS who are anthracycline naïve and with defined 
anthracycline sensitive (expected historical ORR ~20%) histologies angiosarcomas, 
leiomyosarcoma, liposarcoma, synovial sarcoma, adult fibrosarcoma, and undifferentiated 
pleomorphic sarcoma.
Each treatment group will maintain the total dose of SQP33 per cycle constant and compare 2 
different infusion schedules, a 3-day vs a 5-day schedule.  The study will be guided by the 
Continuous Reassessment Method (CRM) design. The CRM model provides an indication of 
whether to alter the RP2D regimen (3-day dosing per 21-day cycle vs. 5-day dosing per 21-day 
cycle) based on a comparison of toxicity and efficacy data collected from participants enrolled. 
The participants will receive SQP33 at the RP2D administered IV as a 3-day dosing regimen per 
21-day cycle or as a 5-day dosing regimen per 21-day cycle.   
$WR[LFLW\UDWHDWRUDERYHIRUP\HORVXSSUHVVLRQ*UDGHUHODWHGWUHDWPHQWHPergent 
adverse events (TEAEs) (anemia and febrile neutropenia) would be considered unsafe for the 
cohort, and enrollment would stop. If the 3-day infusion is not well tolerated that group will close, 
the study will continue with the RP2D and 5-day schedule with the initial adaptive design 
phase.  
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Safety Monitoring  
All available safety tolerability data will be presented and discussed at the SRC. The maximum 
inefficacy and minimum efficacy rates DUHEDVHGRQKLVWRULFDO255ZLWK255EHLQJ
undesirable, and >35% ORR being desirable. Up to 11 participants per arm will be enrolled. 
After approximately half (n=6 per arm) of participants in Expansion Group 2 have been enrolled 
and observed for at least 2 cycles or approximately 6-weeks and have had at least one post-
baseline tumor assessment, an evaluation of all available data (safety, efficacy, and PK from 
both the Expansion and Dose Escalation parts of the study) will be performed by the SRC. 
Group 3a: Head and Neck 
The study will enroll patients with relapsed or metastatic head and neck tumors with advanced 
disease and historically poor outcomes and limited objective responses to currently available 
therapies. Patients will be selected with histologically or cytologically confirmed squamous-cell 
carcinoma of the head and neck who meet any of the following 1) confirmed relapsed
squamous-cell carcinoma of the head and neck, 2) metastatic at initial presentation squamous-
cell carcinoma of the head and neck, 3) patients with locally advanced head and neck cancer 
pretreated with surgery and/or radiotherapy and not suitable for further radical local treatment, 
4) patients with distant metastases who may have received one or less chemotherapy regimen.
Patients will be treated with the RP2D of SQP33 with the SQL70 biopolymer dose fixed at 
10 mL, every 21 days (1 cycle) up to 12 cycles or until the subject has PD, withdraws consent, 
Investigator decision, or death.  On Day 1 of each cycle, the subject will receive an injection of 
the SQL70 biopolymer into the tumor, followed by five (5) days of SQP33 infusion at the RP2D. 
Sample sizes be guided by a Simon 2-stage (optimal) designs based on historical objective 
responses (see statistical section for details). Enrollment will be continued after reaching the 
indicated number of participants at Stage 1 while the initial efficacy evaluation is ongoing. 
Safety Monitoring 
All available safety tolerability data will be presented and discussed at the SRC after 13 
evaluable subjects have been enrolled and a recommendation will be made to the sponsor to 
continue or terminate the group enrollment based on ORR and totality of the data. 
  
3.5.2. Rationale for Dose and Dosing Interval
SQL70 biopolymer will be administered intra and/or peritumorally at a dose of either 10 mL or 
20 mL injection volume. The 10 mL dose is intended for a single lesion or cluster of lesions, and 
the 20 mL dose in Phase 1 was explored for concurrent treatment of 2 lesions, or for a single 
larger lesion (see sections 3.1.4.4 Phase 1: 20 mL SQL70 Biopolymer (post-Cycle 1) Cohort
and 3.2.3 Phase 1: 20 mL SQL70 Biopolymer (from Cycle 1) Cohort).  
The dose volume of SQL70 biopolymer is expected to provide sufficient coverage for tumors of 
varying sizes and enable the local release of active Dox from escalating doses of SQP33 
protodrug infusions, while taking into consideration practical limitations and historical precedent 
for local tumor injections. 
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High injection volumes of SQL70 biopolymer were performed in absolute terms (15 mL) in the 
GLP study SQ3370-TOX-108 in dogs and were well tolerated. The use of a single dose (10 mL) 
of SQL70 biopolymer was explored with escalating doses of SQP33 protodrug in SQ3370-TOX-
108 and SQ3370-TOX-109. Based on allometric scaling by body surface area (BSA), this 
design introduces an extra margin of safety for human patients who have approximately 3.24-
times the BSA of dogs but will still be injected locally with only 10 mL or 20 mL of SQL70 
biopolymer. 
The starting daily dose of SQP33 protodrug for this clinical study is 8 mg/m2/day
(5.72 mg/m2/day Dox Eq). 
The starting human dose of SQP33 protodrug with a fixed amount of SQL70 biopolymer was 
determined in accordance with ICH S9 guidelines, which propose using 1/6th of the human 
equivalent dose HNSTD taken from a GLP toxicology study in the relevant species.
The dose of SQP33 protodrug is rounded down from the suggested starting dose from the GLP 
toxicology study SQ3370-TOX-108 in dogs. SQP33 protodrug infusions are given daily on Day 1 
through Day 5. The starting total dose per cycle of SQP33 protodrug will be 40 mg/m2/cycle
(28.6 mg/m2/cycle Dox Eq).
This starting dose is anticipated to be well-tolerated, as the total dose per cycle is less than half
of the 75 mg/m2 recommended systemic clinical dose per cycle of Dox HCl. Additionally, the 
starting dose is less than half of the no-observed-adverse-effect level (NOAEL) found in the 
GLP toxicology study SQ3370-TOX-108. 
No additional safety margins were included as conventional Dox and Dox-containing products 
are well-characterized agents with known risks. The nonclinical studies suggest that the clinical 
side effect profile of SQ3370 would be similar to that of conventional Dox, with 
myelosuppression as the expected major toxicity.
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4.
PATIENT POPULATION
All patients in all Phase 1 cohorts and Phase 2a expansion groups must meet the inclusion and 
exclusion criteria below.
4.1.
GENERAL INCLUSION/EXCLUSION CRITERIA FOR PHASE 1 COHORTS 
AND PHASE 2A EXPANSION GROUPS
4.1.1. Inclusion Criteria
Patients are eligible to be included in the study only if all the criteria below apply.
1.
Able to provide written informed consent and understand and comply with the requirements 
of the study.
2.
Patients 18 years of age on the day of signing the Informed Consent Form (ICF). 
3.
Histologically or cytologically confirmed cancer or desmoid tumor. Confirmation is not 
required for each individual lesion, and it is not required for the tumor selected for injection.
x
Additional Criteria for Phase 1 Dose Escalation Cohorts: tumor is either refractory to or 
relapsed following standard of care or ineligible for standard of care therapy
4.
There must be an injectable tumor defined as all the following:
a.
measurable per RECIST v1.1 at baseline
b.
palpable or able to be injected percutaneously 
c.
not involving the following organs/structures: pancreas and extrahepatic biliary tract, 
central nervous system, or heart and great vessels
d.
accessible by repeated intratumoral or peritumoral injection with an 18- to 22-gauge 
needle
x
Additional criteria the 20 mL SQL70 biopolymer cohorts in Phase 1 Cohort: 
o
Have at least two injectable lesions or, based on investigator discretion and 
Medical Monitor approval, a large single lesion (approximately 5 cm or larger).
5.
Eastern Cooperative Oncology Group (ECOG) performance status score 0-1 (except for 
Group 3a, Head & Neck, where 0-2 is acceptable).
6.
Adequate hematologic function1 as defined by:
a.
DEVROXWHQHXWURSKLOFRXQWmL
b.
KHPRJORELQJG/
c.
platelet count 100,000/mL 
7.
Adequate hepatic function as defined by:
a.
WRWDOELOLUXELQ2 mg/dL (unless the elevation is due to Gilbert’s Syndrome)
1 This should reflect baseline hematological function and cannot be on growth factor supported agents, 
e.g. G-CSF, GM-CSF or erythropoietin stimulating.
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b.
aspartate transaminase (AST) and aODQLQHWUDQVDPLQDVH$/7x the upper 
limit of normal (ULN)
8.
$GHTXDWHUHQDOIXQFWLRQDVGHILQHGE\FUHDWLQLQHFOHDUDQFHP/PLQ according to the 
Cockcroft-Gault equation or a 24-hour urinary creatinine test.
9.
$GHTXDWHFRDJXODWLRQIXQFWLRQDVGHILQHGE\LQWHUQDWLRQDOQRUPDOL]HGUDWLRDQGD
SDUWLDOWKURPERSODVWLQWLPHVHFRQGVDERYHWKH8/1
10. Resolution to *UDGHAEs by the NCI-CTCAE v5.0 of all clinically significant toxic effects 
of prior locoregional treatment, surgery, chemoembolization, or other anticancer treatment. 
([FHSWLRQVWRWKLVDUH*UDGH 1 toxicities, which, in the opinion of the Investigator and the 
Sponsor, are stable, and should not exclude the patient (i.e., alopecia, neuropathy, and 
autoimmune complications of immunotherapy, such as well managed diabetes, 
hypothyroidism, or hyperthyroidism controlled on hormone replacement therapy).
11. Women of childbearing potential and sexually active males agree to use highly effective 
contraception for the duration of study participation and for 90 days after the last dose of 
study treatment
4.1.2. Exclusion Criteria
Patients are excluded from the study if any of the criteria below apply.
1.
Prior lifetime exposure to >300 mg/m2 of Dox HCl or DOXIL / CAELYX® or 600 mg/m2 of 
epirubicin HCl or 600 mg/m² daunorubicin prior to study dosing.
2.
CHF, severe myocardial insufficiency, or cardiac arrhythmia, including any one of the 
following: 
a.
Echocardiogram (ECHO) or multigated acquisition (MUGA) scan with an actual left 
ventricular ejection fraction (LVEF) ZLWKLQGD\VSULRUWR&\FOH'D\
b.
Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left 
bundle branch block, high-grade atrioventricular (AV) block (e.g., bifascicular block, 
Mobitz type II, and third-degree AV block).
c.
Conduction abnormalities that would prevent accurate diagnostic assessment of 
ventricular function, such as atrial fibrillation with rapid ventricular response.
d.
Symptomatic CHF.
e.
Screening QTc >470 msec and/or previous history of QT prolongation while taking 
other medications. 
f.
History or signs of active coronary artery disease with or without angina pectoris 
within the last 6 months.
3.
Any of the following within 28 days* prior to Cycle 1 Day 1 (i.e., Day -28 is the day after the 
last dose / procedure):
a.
Major surgery, as defined by the Investigator.
b.
Radiotherapy.
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c.
Chemotherapy, immunotherapy, and/or anticancer therapy. If the agent is a small 
molecule therapeutics, only 6 elimination half-lives are required before the patient is 
eligible.
d.
An investigational product. If the agent is a small molecule investigational product, 
only 6 elimination half-lives are required before the patient is eligible.
e.
Currently enrolled in a clinical study involving an investigational product, or 
concurrently enrolled in any other type of medical research judged not to be 
scientifically or medically compatible with this study.
*1-2 days less may be allowed with Medical Monitor approval so as not to delay the start 
of SQ3370 treatment which, due to the 5 days of dosing, typically needs to begin on 
a Monday
4.
Trastuzumab or trastuzumab emtansine dosed within 7 months prior to Cycle 1 Day 1.
5.
Any transfusion within 14 days prior to Cycle 1 Day 1.
6.
Pregnant or breast-feeding women.
7.
Patients that are either positive for hepatitis B surface antigen (HBsAg) and/or detectable 
hepatitis B virus (HBV) DNA. HBcAb positivity will be allowed if one or both of the following 
is true: a) hepatitis B surface antibody is present or b) hepatitis B DNA testing is negative 
and the patient is receiving hepatitis B reactivation prophylaxis with entecavir, tenofovir,
telbivudine or lamivudine.
8.
Patients with hepatitis C; unless they have completed a course of antiviral therapy and 
have undetectable levels of HCV ribonucleic acid.
9.
Has a known diagnosis of immunodeficiency or is receiving either chronic systemic steroid 
therapy or any other form of immunosuppressive therapy within 7 days prior to Day 1 Cycle 
1, except in the case of central nervous system (CNS) metastases. The use of physiologic
doses of prednisone 10 mg/day or its equivalent is permitted.
10. Patients with symptomatic concurrent conditions such as pleural effusion, ascites, or 
pericardial fluid requiring drainage. 
11. Evidence of any active, uncontrolled bacterial, viral, parasitic, or systemic fungal infections 
within 1 week of the first dose of study drug.
12. Known active CNS metastases and/or carcinomatous meningitis or symptomatic brain 
metastasis. Participants with previously treated brain metastases may participate provided 
they are radiologically stable, i.e., without any of the following: 
a.
Evidence of progression for at least 4 weeks by repeat imaging, 
b.
Steroid treatment or stereotactic radiosurgery for at least 14 days prior to Cycle 1 
Day 1,
c.
Whole brain radiation therapy for at least 28 days prior to Cycle 1 Day 1.
13. Known or active other malignancies that have needed treatment (excluding palliative 
radiation) within 2 years prior to Cycle 1 Day 1 are excluded except for the following:
a.
Curatively resected non-melanomatous skin cancer 
b.
Curatively treated cervical carcinoma in situ
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c.
Non-metastatic breast and prostate cancer patients with stable disease > 12 months
d.
Other stable malignancies may be permitted based on Medical Monitor approval
14. Elective or a planned major surgery to be performed during the study.
15. History of allergic reactions attributed to Dox or other anthracyclines.
16. History of allergic reactions attributed to NaHA, hyaluronic acid, or gram-positive bacterial 
proteins.
17. Patients who have received a live vaccine within 28 days of Cycle 1 Day 1. See section 
5.9.2 Prohibited Concomitant Treatment for examples. Note: Seasonal influenza vaccines 
for injection are generally inactivated flu vaccines and are allowed; however, intranasal 
influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines and are not allowed.
18. History or evidence of a clinically unstable/uncontrolled disorder, condition, or disease 
(including but not limited to cardiopulmonary, renal, metabolic, hematologic, or neurologic) 
other than their primary malignancy, that in the opinion of the Investigator would pose a risk 
to patient safety or interfere with the study evaluation, procedures, or completion.
4.2.
SPECIFIC INCLUSION/EXCLUSION CRITERIA FOR PHASE 2A EXPANSION 
GROUPS
4.2.1. Expansion Group 1: Extremity STS
4.2.1.1.
Inclusion Criteria
1.
Patients with unresectable soft tissue sarcomas of the extremity AJCC III OR select IV (>5 
cm injectable tumors) locally advanced and or metastatic, not amendable to primary surgical 
intervention according to the consensus of a multidisciplinary treatment team, determined 
prior to screening.  
x
Resectable is defined for the study as a primary surgical intervention that is 
thought to produce a surgical cure and maintain a good functional outcome of the 
affected extremity.
x
The assessment of resectability will be conducted by the multidisciplinary 
treatment team and study investigator and is typically defined by staging exams 
(CT scan of the chest, CT or MRI of the abdomen, MRI of the limb for extremity 
STS) and consultations with surgical oncology, radiology, and additional medical 
and surgical specialties as need.
2.
High grade STS, Grade 2/3, with an assessable/injectable lesion of at least diameter >5 cm 
by RECIST 1.1 criteria 
3.
No prior chemotherapy for STS, or radiation to affected limb
4.
Local disease candidates must meet one of the following criteria:
a.
Candidates for radical excision or removal of anatomic compartment  
b.
Candidate for amputation where the gross total resection is considered to result in a 
non-functional limb
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c.
Patients who refuse initial radical excision or amputation and who would prefer a 
neoadjuvant treatment approach  
d.
Patients who are candidates for limb salvage radiation but decline radiation therapy
5.
Patients who are candidates for neoadjuvant chemotherapy based on the location of the 
tumor and have clinical contraindications to standard of care or refuse neoadjuvant 
chemotherapy
6.
Patients who have a recommendation from the multidisciplinary tumor board for single agent 
anthracycline
7.
Only soft-tissue sarcomas of the following histologies are to be enrolled: leiomyosarcoma, 
liposarcoma, synovial sarcoma, adult fibrosarcoma, and undifferentiated pleomorphic 
sarcoma, angiosarcoma
8.
Surgery can be deferred up to 12 weeks, in a clinically monitored patient on study
4.2.1.2.
Exclusion Criteria
1.
Uncontrolled pain related to tumor  
2.
Open wounds or tissue necrosis related to tumor mass  
3.
Compartment syndrome or impending compartment syndrome
4.2.2. Expansion Group 2: Unresectable STS
4.2.2.1.
Inclusion Criteria
1.
Locally advanced or metastatic, unresectable, soft-tissue sarcoma of intermediate or high 
grade with measurable disease. 
2.
Only soft-tissue sarcomas of the following histologies are to be enrolled: leiomyosarcoma, 
liposarcoma, synovial sarcoma, adult fibrosarcoma, angiosarcoma, and undifferentiated 
pleomorphic sarcoma.
3.
Life expectancy >12 weeks (about 3 month)
4.2.2.2.
Exclusion Criteria
1.
Prior exposure to anthracyclines
2.
Treatment naïve extremity tumors (as they would enroll in Group 1)
4.2.3. Expansion Group 3a: Head and Neck
4.2.3.1.
Inclusion Criteria
1.
Patients with histologically or cytologically confirmed squamous-cell carcinoma of the head 
and neck (HNSCC) who meet any of the following  
a.
confirmed relapsed HNSCC  
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b.
metastatic at initial presentation HNSCC  
2.
Patients who may have received two or less systemic regimens (therapies include 
chemotherapy and/or immunotherapy)
3.
Biopsy-confirmed squamous-cell carcinoma (SCC) of the oral cavity, oropharynx, 
supraglottic larynx, or hypopharynx (archived biopsies are allowed)  
4.
For participants with oropharyngeal cancer, human papilloma virus (HPV) p16 status must 
be documented at screening
5.
Has at least 1 tumor lesion that can be accurately measured by CT or MRI according to 
RECIST 1.1 and is amenable for intratumoral injection, as determined by the Investigator  
6.
The primary tumor itself must be injected, if amenable for intratumoral injection, and must 
be noted at screening and targeted for intratumoral injection  
a.
A secondary lesion may be injected if, biopsy confirmed SCC that is eligible for 
intranodal injection*, 
x
Secondary lesions may include metastasis eg, soft tissue mass or lymph 
node (LN) LQWKHQHFNRIFP
*No lesion with 180-degree or more encasement of the carotid artery on MRI or CT 
scan may be selected 
7.
ECOG performance status of 0 to 2
8.
/LIHH[SHFWDQF\ 6 months
4.2.3.2.
Exclusion Criteria
1.
Airway obstruction by tumor mass that requires clinical intervention
2.
Prior treatment with anthracyclines or intratumorally directed treatment
3.
Ulceration or other characteristics that may, in the opinion of the Investigator, increase the 
risk of severe tumor bleeding
4.
SCC originating in the nasopharynx or paranasal sinus, from the salivary gland, or thyroid 
gland, or non-squamous histology (e.g., melanoma or neuroendocrine carcinoma), or SCC 
of unknown primary origin
5.
Prior or concurrent malignancy whose natural history or treatment has the potential to 
interfere with the safety or efficacy assessment of the investigational regimen
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5.
INVESTIGATIONAL PRODUCT
5.1.
INVESTIGATIONAL PRODUCT FORMULATION AND PACKAGING
The SQ3370 Investigational Product (IP) is comprised of SQP33 protodrug and SQL70 
biopolymer. There is only one active component or drug substance, SQP33 protodrug. SQL70 
biopolymer is considered an activating article rather than a drug substance.
x
The SQL70 biopolymer is considered an activating article in the SQ3370 Investigational 
Product and is made of NaHA that is chemically modified with tetrazine. It does not carry 
an active payload; rather, it captures the SQP33 protodrug upon chemical reaction in
situ and releases the active drug, Dox. 
x
The SQP33 protodrug is a formulated protodrug of dox with attenuated activity for 
intravenous infusion composed of a novel trans-cyclooctene substituent conjugated to 
Dox.
SQ3370 is an IP only and has not been shown to be safe or effective in the treatment of human 
disease. 
Drugs supplied for clinical investigation should be given personally or under the supervision of 
the Investigators throughout this study.
The SQL70 biopolymer and SQP33 protodrug are packaged separately given that the number 
of SQP33 protodrug vials needed will vary by patient/cohort dose level. 
5.1.1. SQL70 Biopolymer Formulation and Packaging
SQL70 biopolymer for intratumoral and peritumoral injections is supplied as a sterile, fully-
formulated liquid in single-use glass vials containing a 10 mL delivery volume. It is a light to dark 
pink clear aqueous solution of tetrazine-modified NaHA in sterile water for injection. It also 
contains sodium phosphate and sodium chloride as pharmaceutically-inert excipients to adjust 
the pH and osmolality respectively, within physiological ranges. SQL70 biopolymer is 
manufactured by Berkshire Sterile Manufacturing (Lee, MA, USA).
5.1.2. SQP33 Protodrug Formulation and Packaging
The drug product (SQP33 protodrug) is supplied in single-use vials as a sterile orange to 
red/brown lyophilized solid to be reconstituted in the clinic with sterile water prior to IV infusion. 
Dosage strength is expressed in terms of the active moiety, free acid form. It contains sucrose 
and citric acid as pharmaceutically inert excipients. SQP33 protodrug is manufactured by Curia 
Global (Glasgow, UK).
5.2.
INVESTIGATIONAL PRODUCT STORAGE
Both components, SQL70 biopolymer and SQP33 protodrug, must be stored refrigerated (at 
2°C to 8°C/36°F to 46°F) and protected from light. 
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The IP must be stored in accordance with the instructions in the protocol, study-specific 
Pharmacy Manual, Investigator’s Brochure, and any other instructions provided by the Sponsor 
or designee. 
Until dispensed to the patients, the IP must be stored protected from light in a temperature-
monitored and securely locked area, accessible to authorized personnel only. 
Unless prohibited by site policy, used IP, including residual solutions, should be retained for 
drug accountability but is not subject to the same temperature storage conditions. Used 
Investigational Product must still be stored in a securely locked area, accessible to authorized 
personnel only.
Report any temperature excursions to the Sponsor or designee immediately, as outlined in the 
study-specific Pharmacy Manual, and do not use impacted product unless written authorization 
is received from the Sponsor or designee. 
5.3.
INVESTIGATIONAL PRODUCT DOSAGE AND ADMINISTRATION
5.3.1. SQL70 Biopolymer Dosage and Administration
For reference, summary information is provided below. Details for study team members
handling or administering IP are listed in the protocol-specific Pharmacy Manual.
SQL70 biopolymer is only administered on Day 1 of each cycle. SQL70 biopolymer should be 
administered 3 hours (r 30 min) prior to SQP33 protodrug infusion. 
10 or 20 mL of SQL70 biopolymer should be injected per patient per cycle. Each vial contains 
10 mL delivery volume and additional overfill. Vial(s) should be removed from refrigeration and 
kept protected from light for 60 minutes to warm up to room temperature passively (22 ºC to 
28 ºC, not to exceed 28 ºC). The vial should NOT be warmed by placing in a microwave or in a 
hot water bath. 
Once at room temperature, prior to use, the vial should be gently swirled to ensure the contents 
are homogenous. The vial should NOT be vigorously shaken.
For the intratumoral/peritumoral injection
A 14- to 18-gauge needle is attached to a 10- to 15-mL syringe. The liquid is gently withdrawn 
into the syringe until the syringe is filled with 10 mL and ANY excess overfill available in a vial to 
protect against leakage losses while changing needles.
For the intratumoral/peritumoral injection, a needle with a bore size between and including 18 to 
22 gauge should be used. Great care should be taken to avoid any intravascular administration 
of SQL70 biopolymer.
Copies of redacted radiology reports and interventional radiology procedure notes may be 
obtained for assessing injection techniques and quality control.
Precautions: See section 7.5.1 Management of SQL70 Biopolymer Injection Reactions
regarding injection site reactions.
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5.3.2. SQP33 Protodrug Dosage and Administration
For reference, summary information is provided below. Details for study team members 
handling or administering IP are listed in the protocol-specific Pharmacy Manual.
SQP33 protodrug is administered once per day on Day 1 through 5 of each cycle (Expansion 
Group 2: Unresectable STS will also have a group receiving SQP33 protodrug once per day on 
Day 1 through 3 of each cycle). On Day 1, SQP33 protodrug infusion should start 3 hours (± 30 
min) after SQL70 biopolymer injection. On Day 2 through 5, SQP33 protodrug infusion should 
start each day within ± 2 hours of the Day 1 infusion start time for that cycle.
SQP33 protodrug vials should be removed from refrigeration and kept protected from light for 60 
minutes to warm up to room temperature passively (22 ºC to 28 ºC, not to exceed 28 ºC). The 
vial should NOT be warmed by placing in a microwave or in a hot water bath. 
Once at room temperature, SQP33 protodrug is reconstituted with sterile water within each 
product vial. During reconstitution, the vial should be gently swirled to ensure full dissolution. 
The vial should NOT be vigorously shaken or inverted. 
The reconstituted SQP33 protodrug solution is then added to saline IV bags at the appropriate 
concentration for IV infusion for the given dose level. One or more vials of SQP33 protodrug
may be needed depending on the dose level.
Precautions: See section 7.5.2 Management of SQP33 Protodrug Infusion Reactions regarding 
infusion reactions.
5.4.
INVESTIGATIONAL PRODUCT SUPPLY
The 2 components of the IP SQ3370, SQP33 protodrug and SQL70 biopolymer, will be provided 
by the Sponsor or designee. Instructions for requesting and confirming receipt of IP are
specified in the study-specific Pharmacy Manual.
5.5.
INVESTIGATIONAL PRODUCT DESTRUCTION
The Investigator must obtain written authorization from the Sponsor or designee each time prior 
to returning IP. The Investigator must store both used and unused IP according to section 5.2
Investigational Product Storage.
IP will either be disposed of at the study site according to the study site’s institutional standard 
operating procedure or returned to the Sponsor or designee with the appropriate 
documentation. Additional details and documentation requirements are outlined in the study-
specific Pharmacy Manual. 
5.6.
INVESTIGATIONAL PRODUCT ACCOUNTABILITY
IP accountability will be monitored throughout the study. Accurate records of IP received at, 
dispensed from, returned to, and disposed of/returned by the study site should be maintained by 
the Investigator.
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The Investigator shall not make the IP available to any individuals other than to enrolled patients 
or allow the IP to be used in any manner other than that specified in this protocol.
Additional details and documentation requirements are outlined in the study-specific Pharmacy 
Manual.
5.7.
INVESTIGATIONAL PRODUCT COMPLIANCE
IP compliance will be monitored throughout the study by review of records of study medication 
used, dosages administered, and intervals between visits.
5.8.
POST-STUDY ACCESS TO INVESTIGATIONAL PRODUCT
At this time, the Sponsor does not plan to provide the IP, any other study treatments, or 
interventions to patients who have participated in the study once their participation ends.
5.9.
CONCOMITANT THERAPY
Concomitant treatment includes any medication (e.g., prescription drugs, over-the-counter 
drugs, vaccines, herbal or homeopathic remedies, nutritional supplements) used by a patient 
from 30 days prior to the start of screening through the patient’s safety follow-up visit. All such 
medications should be reported to the Investigator and recorded on the Concomitant 
Medications Case Report Form (CRF). Note the use of herbal or homeopathic remedies, 
nutritional supplements should be discussed with the patient and wherever possible 
discontinued prior to treatment given the lack of data on the effects with SQ3370.
5.9.1. Permitted Concomitant Treatment
Necessary supportive measures for optimal medical care may be given throughout the study. 
Additional care will be administered as indicated by the treating physician and the patient’s
medical need. 
Permitted treatment includes: 
x
IV antibiotics to treat infections
x
Blood transfusions, except for Phase 1 Dose Escalation Cycle 1
x
Anti-emetics
x
Pain medications
x
Use of marijuana and its derivatives for treatment of symptoms related to cancer or 
cancer treatment is permitted if obtained by medical prescription or if its use (even 
without a medical prescription) has been legalized locally
x
Botanical/herbal medications or supplements are allowed unless there may be risk 
associated with their use. Patients should be encouraged to report all such agents so 
that they can be assessed for known or potential interactions with study treatments
x
Routine prophylactic use of a colony-stimulating factor (G-CSF or GM-CSF) should be 
used according to regional approved label or guidelines i.e., the American Society of 
Clinical Oncology guidelines
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x
Erythropoietin is to be used according to regional approved label or guidelines 
x 
Physiologic doses of prednisone 10 mg per day or its equivalent is permitted
5.9.2. Prohibited Concomitant Treatment
x
No concomitant treatment, whether conventional or investigational, will be allowed to 
treat the tumor during this study  
x
No concomitant radiotherapy, except palliative therapy (Dose escalation only not 
permitted in Phase 2a), whether conventional or investigational, will be allowed during 
this study. 
x
No strong inhibitors and inducers of CYP3A4 and CYP2D6 will be allowed during this 
study. See Table 5 below.
x
Chronic steroid use above physiologic doses is not permitted; however, a temporary 
course of steroids may be permitted with Medical Monitor approval.
x
Live vaccines, including measles/mumps/rubella (MMR), varicella, 
measles/mumps/rubella/varicella (MMRV), herpes zoster, yellow fever, Ty21a oral 
typhoid, BCG, and rotavirus. (Advisory Committee on Immunization Practices (ACIP 
2012)  
x
Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and 
are allowed; however, intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated 
vaccines and are not allowed. 
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Table 5: Cytochrome p450 Strong Inducers and Inhibitors
CYP 3A4 Inducers
CYP 3A4 Inhibitors
CYP 2D6 Inducers
CYP 2D6 Inhibitors
barbiturates
brigatinib
carbamazepine
efavirenz
enzalutamide
ethosuximide
glucocorticoids
modafinil
nevirapine
oxcarbazepine
phenytoin
pioglitazone
rifabutin
rifampin
St. John's wort
troglitazone
clarithromycin
indinavir
idelalisib
itraconazole
ketoconazole
nefazodone
nelfinavir
ribociclib
ritonavir
saquinavir
telithromycin
dexamethasone* 
oritavancin
Rifampin
buproprion
cinacalcet
fluoxetine
paroxetine
quinidine
ritonavir
sertraline
* dexamethasone is permitted if administered as a temporary course of steroids with Medical Monitor approval, as 
stated earlier in this section. 
Concomitant administration of certain agents may affect the toxicity or efficacy of Dox and/or the 
concomitantly administered agent, and so concomitant administration of the agents below are 
also prohibited: 
x 
Calcium-channel blocking agents may potentiate Dox HCl-induced cardiotoxicity
(amlodipine is an exception as it is likely cardioprotective)
x 
Live vaccines to immunosuppressed patients, including those undergoing cytotoxic 
chemotherapy, may be hazardous
x 
Phenobarbital may increase the elimination of Dox HCl (ADRIAMYCIN Australian 
Product Information; ADRIAMYCIN US Package Insert) 
x 
Phenytoin levels may be decreased by Dox HCl (ADRIAMYCIN Australian Product 
Information; ADRIAMYCIN US Package Insert) 
x 
Propranolol may inhibit cardiac mitochondrial CoQ10 enzyme (ADRIAMYCIN Australian 
Product Information) 
x 
Progesterone may worsen neutropenia and thrombocytopenia (ADRIAMYCIN US 
Package Insert) 
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6.
STUDY ASSESSMENTS
The schedules for all study assessments and procedures are outlined in Schedules of 
Assessments. The results of all assessments and procedures will be documented in the 
patient’s medical record and in study documentation, including the CRF, as applicable. 
6.1.
INFORMED CONSENT
Content: The Sponsor’s sample ICF will be provided to each Investigator. The Investigator or 
designee is responsible for the content of the study site-specific ICF, but the Sponsor or 
designee must review and approve any proposed deviations from the Sponsor sample ICFs, or 
any alternate consent forms proposed by the Investigator before IRB/IEC submission. 
Additionally, the study site-specific ICF must be approved by the IRB or IEC prior to use, and 
the approved document must be provided to the Sponsor or designee for regulatory purposes. 
The content of the ICF must comply with US Food and Drug Administration (FDA) regulations, 
Australian government’s National Statement on Ethical Conduct in Human Research (2007)
(National Statement (2007), and ICH guidelines. It should also include any additional 
information required by local laws relating to institutional review.
Language: The ICF must be in a language understandable to the study patient or to his or her 
representative. 
Timing: The Investigator or designee is responsible for obtaining and documenting informed 
consent from each patient prior to participating in the study. Informed consent must be obtained 
from the patient before any screening activity or treatment is undertaken for the purpose of the 
study.  
This includes, but is not limited to, the performance of diagnostic or therapeutic procedures, the 
discontinuation of any prohibited medications, and the administration of the first dose of 
Investigational Product.  
Patients who have signed the ICF to begin screening procedures must be documented as 
screened patients.
Process: 
The Investigator or designee is responsible for the informed consent process, which includes:  
1. Reviewing and discussing the ICF document and any other applicable study information 
with the patient (or the patient’s legally acceptable representative).  
2. Obtaining written consent on the ICF document as demonstrated by the signature and 
date of the patient (or by the patient’s legally acceptable representative) and the person 
who conducted the informed consent discussion. 
3. Providing a signed and dated copy of the ICF to the patient (or to the patient’s legally 
acceptable representative). 
4. Documenting the informed consent process (not just filing the ICF document) in the 
patient’s medical record/study documentation.  
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5. Storing the ICF document in a secure place (all signed and dated ICFs must remain in 
each patient’s study file or in the study site file and must be available for verification by 
study monitors at any time). 
Amendments: The ICF should be revised, and IRB/IEC approved whenever there are changes 
to study procedures or when new information becomes available that may affect the willingness 
of the patient to participate. All patients on study must be re-consented in a timely manner to the 
most current version of the ICF (or significant new information/findings addendum in accordance 
with applicable laws and IRB/EC policy) during their participation in the study. For any updated 
or revised ICFs, the process described above should be followed to document that written 
informed consent was obtained using the updated/revised ICF for continued participation in the 
study.  
Health Insurance Portability and Accountability Act (HIPAA; US Only): Each ICF may also 
include patient authorization to allow use and disclosure of personal health information in 
compliance with the US HIPAA of 1996. If the study site utilizes a separate authorization form 
for patient authorization for use and disclosure of personal health information under the HIPAA 
regulations, the review, approval, and other processes outlined above apply except that IRB/IEC
review and approval may not be required per study site policies. 
6.2.
SCREENING AND RE-SCREENING
Number Allocation: The individual patient number for all patients will be assigned at screening,
will be used to identify the patient throughout the study, and must be used on all study 
documentation related to the patient. An Interactive Voice/Web Response System will not be 
used in this study. 
Screening Period Calculation: The calculation for the screening period (i.e., Day -28) begins the 
day the ICF is signed. The second day of screening is therefore Day -27 and so on. There is no 
Day 0 in this study. The patient must be enrolled by Day 1 (i.e., the day following Day -1). 
Re-screening: A patient who fails the screening process may be re-screened up to 1 additional 
time or with approval from the Sponsor for additional re-screen attempts. 
The individual patient number should be retained (a new patient number should not be 
assigned), and only the data from the final screening procedures that qualified the patient for the 
study should be included in the CRFs, although documentation should be retained at the study 
site for all study procedures from each screening attempt.  
If the study site’s current IRB/IEC-approved ICF is the same as the ICF that the patient signed 
for their previous screening attempt, re-consent is not required, unless as required by local 
study site/IRB/IEC policy. If a new IRB/IEC-approved ICF (or new safety data that requires 
immediate communication to the patient) is available, the patient should be re-consented using 
the new ICF (or informed of new safety data that requires immediate communication to the 
patient) prior to performing any re-screening procedures. 
The re-screening period (i.e., Day -28) begins the day the ICF is signed (if applicable) or the first 
re-screening study procedure is performed if re-consent is not applicable. 
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6.3.
ENROLLMENT
Patients are considered enrolled:  
x 
Within 28 days of beginning screening  
x 
After the results for all screening procedures have been received by the study site
and
x 
After the patient has met all inclusion and exclusion criteria and therefore is deemed 
eligible for the study by the Principal Investigator or designee
and
x
After Sponsor approval is received and documented by signature per the agreed upon 
process
x
The enrollment date is the date of the Sponsor’s signature
6.4.
MEDICAL HISTORY AND DEMOGRAPHIC DATA
Medical history and demographic data will be collected at screening. Special attention will be 
made to identify all prior cancer therapies, the response to therapy, and the duration of the 
response.
6.5.
PHYSICAL EXAMINATION & DIRECTED MEDICAL HISTORY
A full physical examination will be done at screening, and a symptom-directed examination will 
be done at other time points. See Schedules of Assessments for specific time points.
Physical Examination: Should include, but is not limited to, a review of the following body 
systems: constitutional, skin, HEENT (head, eyes, ears, nose, and throat), neck, chest and 
lungs, cardiovascular, abdomen, neurological, and musculoskeletal in addition to genitourinary 
and gynecologic if indicated by the Investigator.  
Symptom-directed Physical Examinations: Should include an examination of organ systems 
related to patient symptoms to document potential AEs, AE severity, or AE resolution in addition 
to identifying any potential AE known or suspected to be associated with the treatment and 
procedures that the patient is receiving. Any new post-baseline abnormal physical examination
finding(s) assessed as clinically significant should be recorded as an AE or SAE. 
6.6.
VITAL SIGNS
Vital signs include height (at screening only), weight (once per cycle), temperature, blood
pressure (systolic and diastolic), heart rate, and respiratory rate. See Schedules of 
Assessments for specific time points. Post dose vital sign timings are based on the end time of 
the procedure (infusion / injection), not the start.
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6.6.1. Phase 1 Dose Escalation
Routine Dosing Vitals: Vital signs as outlined below should be obtained on IP administration 
Days 1 to 5: 
Routine Vital Time Points
Dosing Days 1-5
Pre-infusion
15 min mid infusion (± 5 min)
Immediately post-infusion (+ 5 min)
15 min post-infusion (± 5 min)
30 min post-infusion (± 5 min)
Cycle 1 Day 1 Only Dosing Vital Signs: Vital signs as outlined below should be obtained on IP
administration Cycle 1 Day 1 only:  
Cycle 1 Day 1* Vital Signs Time Points
In Relation to Administering
Vitals Time Points
SQL70 biopolymer
Pre-SQL70 injection
15 min post-SQL70 injection (± 5 min)
SQP33 protodrug
Pre-SQP33 infusion
15 min mid-SQP33 infusion (± 5 min)
Immediately post-SQP33 infusion (+ 5 min)
15 min post- SQP33 infusion (± 5 min)
30 min post- SQP33 infusion (± 5 min)
60 min post- SQP33 infusion (± 10 min)
*Day 2-5 of Cycle 1 vital signs time points should follow the routine dosing vitals
6.6.2. Phase 2a Expansion Groups
Routine Dosing Vitals: Vital signs as outlined below should be obtained on IP administration 
Days 1 to 5 (or Day 1 to 3 for the 3-day treatment Group 2 patients)
Routine Vital Time Points
Dosing Days 1-5
Pre-infusion
Immediately post-infusion (+ 5 min)
Prior to Discharge from treatment site
Cycle 1 Day 1 Only Dosing Vital Signs: Vital signs as outlined below should be obtained on IP
administration Cycle 1 Day 1 only:  
Cycle 1 Day 1* Vital Signs Time Points
In Relation to Administering
Vitals Time Points
SQL70 biopolymer
Pre-SQL70 injection
SQP33 protodrug
Pre-SQP33 infusion
Immediately post-SQP33 infusion (+ 5 min)
Prior to Discharge from treatment site
*Day 2-5 of Cycle 1 vital signs time points should follow the routine dosing vitals
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6.7.
BODY SURFACE AREA CALCULATION
The calculation of the dose per day of SQP33 protodrug will be based on the patient’s body
surface area (BSA) using the recommended Du Bois & Du Bois formula, however sites are 
allowed to use their institutional formula: 
BSA (m2) = 0.007184 x Height (cm)0.725 x Weight (kg)0.425  
The BSA will be calculated at Cycle 1 Day 1 is to be used throughout the protocol. If there has 
been a significant (> 10%) weight change from the previous weight used for BSA calculation, 
then the BSA should be recalculated. Patient’s BSA may be recalculated more frequently (at 
every cycle’s Day 1 for example) if required by institutional policy. 
Sites should follow their institutional policy on whether to round the BSA up or down. A weight 
measured up to 1 week prior to any Day 1 dose may be used to calculate the dose of SQP33 
protodrug.
6.8.
ECHOCARDIOGRAM/MULTIGATED ACQUISITION SCAN
ECHO/MUGA scans are included in the study given the cardiotoxicity risk associated with 
conventional Dox treatment. The frequency of the procedure increases after Cycle 5 to ensure 
heightened monitoring given the increased cumulative exposure to Dox.  
Screening: An ECHO or MUGA scan should be performed during the screening period.  
Treatment: An ECHO or MUGA scan (whichever was performed during screening) should be 
performed within 7 days from Cycle 3 Day 1, Cycle 5 Day 1, and Day 1 of every cycle thereafter.  
Safety Follow-Up: An ECHO or MUGA scan (whichever was performed during screening) 
should be performed at the Safety Follow-Up visit if not performed in the previous 14 days. 
6.9.
ELECTROCARDIOGRAM 
6.9.1. General Guidance
All ECGs for this study will be triplicate 12-lead ECGs, except for the screening ECG. Data 
collected will include heart rate, PR, QRS, QT, and QTc intervals as calculated using Fridericia’s 
formula.
Day 1 pre-dose ECGs may be performed up to 3 days prior to the visit.
All post SQP33 protodrug infusion ECGs should be performed within + 30 minutes of the end of 
the infusion time. 
ECGs will be reviewed, initialed, and dated by the Principal Investigator or designee within a 
timely manner. See Schedules of Assessments for specific time points.
6.9.1.1.
Phase 1 Dose Escalation
x
On Day 1 of each cycle ECGs will be performed both pre and post SQP33 protodrug 
infusion. 
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x
On Days 2-5 of Cycle 1 ECGs will be performed post SQP33 protodrug infusion only.
6.9.1.2.
Phase 2a Expansion Groups
x
On Day 1 of each cycle ECGs will be performed pre and post SQP33 protodrug infusion. 
6.10. EASTERN COOPERATIVE ONCOLOGY GROUP PERFORMANCE STATUS
The ECOG performance status should be documented in the patient’s medical record or study 
source documentation at applicable visits. A copy of the document is included in APPENDIX C – 
Eastern Cooperative Oncology Group Performance Status Assessment for reference.   See 
Schedules of Assessments for specific time points.
6.11. ADVERSE EVENT REVIEW
Investigators should assess AEs at each visit. See section 7 ADVERSE AND SERIOUS 
ADVERSE EVENTS.
6.12. CONCOMITANT MEDICATION REVIEW
Investigators should assess concomitant medications at each visit. 
In general, the use of any concomitant medication/therapies deemed necessary for the care of 
the patient is permitted except as specifically prohibited (see section 5.9.2 Prohibited 
Concomitant Treatment). The Medical Monitor should be contacted if there are any questions 
regarding concomitant or prior therapy.
All medications, procedures, and significant non-drug therapies (including physical therapy and 
blood transfusions) administered within 30 days prior to the start of the screening period through 
the patient’s final study visit will be recorded as a concomitant medication. Medications include 
not only physician-prescribed medications but also all over-the counter medications, herbal 
medications, and food or vitamin supplements, even if taken as a prophylaxis. 
6.13. SAFETY LABORATORY SAMPLE COLLECTION
6.13.1. 
Phase 1 Dose Escalation
Safety laboratory sample collection includes the following:
x
Hematology Panel: Includes complete blood count, including white blood cells with 
differential, hematocrit, hemoglobin, and platelets.  
x
Chemistry Panel: Includes sodium, potassium, calcium, creatinine, total protein, albumin, 
bilirubin (total, direct), AST/SGOT, ALT/SGPT, alkaline phosphatase, amylase, lipase, 
and glucose.  
x
Coagulation Studies: Includes prothrombin time, activated partial thromboplastin time 
and INR.  
x
Urinalysis: Includes protein, specific gravity, glucose, and blood. Can be performed by
dipstick or laboratory analysis.
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x
Serology Test: Includes hepatitis B antigen and hepatitis C.
x
Pregnancy Test: Women of childbearing potential must have a negative pregnancy test 
before starting study treatment and at the beginning of each cycle of treatment. Blood or 
urine pregnancy tests must have a minimum test sensitivity of at least 25 IU/L. Kits 
measuring either total KXPDQFKRULRQLFJRQDGRWURSLQRUWKHEHWDȕIUDFWLRQDUH
acceptable.
6.13.2.
Phase 2a Expansion Groups
Safety laboratory sample collection includes the following:
x
Hematology Panel: Includes complete blood count, including white blood cells with 
differential, hematocrit, hemoglobin, and platelets.  
x
Chemistry Panel: Includes sodium, potassium, calcium, creatinine, total protein, albumin, 
bilirubin (total and/or direct), AST/SGOT, ALT/SGPT, alkaline phosphatase, and 
glucose. 
x
Coagulation Studies: Includes prothrombin time, activated partial thromboplastin time 
and INR.  
x
Urinalysis: Includes protein, specific gravity, glucose, and blood. Can be performed by
dipstick or laboratory analysis.
x
Serology Test: Includes hepatitis B antigen and hepatitis C.
x
Pregnancy Test: Women of childbearing potential must have a negative pregnancy test 
before starting study treatment and at the beginning of each cycle of treatment. Blood or 
urine pregnancy tests must have a minimum test sensitivity of at least 25 IU/L. Kits 
PHDVXULQJHLWKHUWRWDOKXPDQFKRULRQLFJRQDGRWURSLQRUWKHEHWDȕIUDFWLRQDUH
acceptable.
6.13.3.
General Instructions for both Phase 1 and Phase 2a
See Schedules of Assessments for specific time points.  
Throughout the study, safety laboratory results from the previous visit need to be available prior 
to each day of dosing, but safety labs drawn on the day of the visit do not need to be available 
prior to dosing that same day - they will be evaluated following the visit. For example, safety lab 
results from Day 2 need to be available prior to dosing on Day 3, but safety labs drawn on Day 3 
do not need to be available prior to dosing on Day 3.
Safety laboratory data from screening will be used for study eligibility and the decision to move 
forward with dosing on Day 1; however, the Medical Monitor should be contacted if Day 1 
laboratory data are significantly different or do not align with the eligibility criteria.
Day 1, Day 10 and Safety Follow Up safety laboratory tests may be collected up to 3 days prior
to the visit so that the investigator may have the results available at the time of the patient’s 
visit.
Safety laboratory data will be reviewed (to assess the clinical significance of any analyte that is 
outside the normal range), initialed, and dated by the Principal Investigator or designee within a 
timely manner. It will be the Investigator’s responsibility to perform additional laboratory 
assessments more frequently if clinically indicated. 
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6.14. PHARMACOKINETIC LABORATORY SAMPLE COLLECTION
6.14.1.
General Guidance
Plasma PK bioanalysis will be conducted using a validated liquid chromatography-mass 
spectrometry methods for SQP33 protodrug and active Dox, following SQ3370 treatment. PK 
parameters will then be calculated (as data permits) from plasma SQP33 protodrug 
concentration, including the following:
x 
Cmax: maximum observed plasma concentration
x 
Tmax: timepoint of maximum observed plasma concentration
x
AUCt: area under the plasma concentration-versus-time curve from time zero to the last 
measurable time point for individual days and/or complete cycles
See also APPENDIX F – PK Schedule
6.14.2.
Phase 1 Dose Escalation
Blood (plasma) samples for determination of PK levels of SQP33 protodrug, SQL70 biopolymer
and active Dox following SQ3370 treatment as well as to explore the kinetics of SQP33 
protodrug degradation under pH, temperature, and other conditions to be collected from all 
patients during:
Cycle 1: 
x
Day 1 pre-infusion of SQP33 protodrug; at 5- and 30-minutes post-infusion; and at 1, 2, 
and 4 hours post-infusion.
x
Days 2, 3, and 4 pre-infusion of SQP33 protodrug and at 5 and 30 minutes post-infusion. 
x
Day 5 pre-infusion of SQP33 protodrug; at 5- and 30-minutes post-infusion; and at 1, 2, 
and 4 hours post-infusion. 
Cycles 2, 3 and 4: 
x
Day 1 pre-infusion of SQP33 protodrug; at 5- and 30-minutes post-infusion.
x
Days 2, 3, 4 and 5 pre-infusion of SQP33 protodrug. 
Note: Post dose PK timings are based on the end time of the SQP33 protodrug infusion, not the 
start.
6.14.3.
Phase 2a Expansion Groups
Blood (plasma) samples for determination of PK levels of SQP33 protodrug, SQL70 biopolymer 
and active Dox following SQ3370 treatment as well as to explore the kinetics of SQP33 
protodrug degradation under pH, temperature, and other conditions to be collected from patients 
in each of the Expansion Groups at the time points below: 
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Expansion Group 1: Extremity STS [Stage 1 Only]
Stage 1 Only
Cycle 1: 
x
Day 1 pre-infusion of SQP33 protodrug; at 15 minutes post-infusion; and at 2 and 4 
hours post-infusion.
x
Day 2, 3, and 4 pre-infusion of SQP33 protodrug and at 15 minutes post-infusion. 
x
Day 5 pre-infusion of SQP33 protodrug; at 15 minutes post-infusion; and at 2 and 4 
hours post-infusion.
Cycle 2: 
x
Days 1, 3, and 5 pre-infusion of SQP33 protodrug and at 15 minutes post-infusion.
Note: Post dose PK timings are based on the end time of the SQP33 protodrug infusion, not the 
start.
Expansion Group 2: Unresectable STS
3-Day Infusion cohort
Cycle 1: 
x
Day 1 pre-infusion of SQP33 protodrug; at 15 minutes post-infusion; and at 2 and 4 
hours post-infusion.
x
Day 2 pre-infusion of SQP33 protodrug and at 15 minutes post-infusion. 
x
Day 3 pre-infusion of SQP33 protodrug; at 15 minutes post-infusion; and at 2 and 4 
hours post-infusion.
Cycle 2: 
x
Day 1 pre-infusion of SQP33 protodrug and at 15 minutes post-infusion.
x
Day 3 pre-infusion of SQP33 protodrug and at 15 minutes post-infusion. 
5-Day Infusion cohort
Cycle 1: 
x
Day 1 pre-infusion of SQP33 protodrug; at 15 minutes post-infusion; and at 2 and 4 
hours post-infusion.
x
Day 2, 3, and 4 pre-infusion of SQP33 protodrug and at 15 minutes post-infusion. 
x
Day 5 pre-infusion of SQP33 protodrug; at 15 minutes post-infusion; and at 2 and 4 
hours post-infusion.
Cycle 2: 
x
Days 1, 3, and 5 pre-infusion of SQP33 protodrug and at 15 minutes post-infusion.
Note: Post dose PK timings are based on the end time of the SQP33 protodrug infusion, not the 
start.
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Expansion Group 3a: Head and Neck
Cycle 1: 
x
Days 1 and 5 pre-infusion of SQP33 protodrug; at 15 minutes post-infusion; and 2 and 4 
hours post-infusion.
Note: Post dose PK timings are based on the end time of the SQP33 protodrug infusion, not the 
start.
6.15. PERIPHERAL BLOOD MONONUCLEAR CELLS AND CTDNA
For both Phase 1 and Phase 2a, PBMCs and ctDNA (Phase 2a only and is optional) will be
collected, in separate tubes (both tubes included in the same kit), on Day 1 of Cycle 1, 2 and 3
(3-time points total) to assess immune response and minimal residual disease (MRD). In Phase 
2a for Expansion Groups 2, and 3a, additional plasma samples (PBMCs and ctDNA [optional]
will be collected every six weeks to coincide with the timing of the imaging scans, i.e. Cycle 4, 6, 
8, 10, and 12 (5 time points). Collection on Day 1 will be prior to SQL70 biopolymer
administration. See the Laboratory Manual for additional details on the collection process.
6.16. CARDIOTOXICITY BIOMARKERS FOR PHASE 2A EXPANSION GROUPS 
ONLY
6.16.1.
General Guidance
Cardiotoxicity is the highest risk in cumulative doxorubicin doses with a lifetime dose should not 
exceed 450-550 mg/m2 of body surface area (PDR.net). Cardiotoxicity has been defined as a 
decrease in the LVEF of greater than ten percentage points to a value below the average 
reference value (EF 53%). However, the LVEF measurements taken after doxorubicin exposure 
were not predictive of later cardiotoxicity (p=0.075) (Sawaya 2012). Combining ECHO, Troponin 
I and BNP serum levels have been used to monitor cardiotoxicity, i.e., elevated levels of 
troponin I (>30 pg/mL) and BNP (>100 pg/mL), and a decrease in LVEF from baseline 
(Skovgaard 2014). 
x
Other markers have been shown to have predictive values: 
o
6HUXPWRSRLVRPHUDVHEOHYHOVQJJDUHDVVRFLDWHGZLWK/9()decline 
(p=0.001). The log-rank test showed that patients expressing a higher Top2b 
OHYHOQJJKDGDKLJKHUSUREDELOLW\RI/9()GHFOLQHRYHUWLPHS 
(Win 2018).  
o
Myeloperoxidase, SDWLHQWVZLWKHOHYDWHG032OHYHOV!J/H[SHULHQFHGD
marked increased cardiac risk (adjusted hazard ratio [HR] 2.25 [1.32 to 3.82]; 
p=0.003) (Baldus 2003).  
x
Serum samples will be taken around the time of the ECHO/MUGA.
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6.16.2.
Phase 2a Expansion Groups
Blood (serum) will be collected at screening around the time of ECHO or MUGA scan, during 
treatment, and during safety follow-up (see Schedule of Assessments Appendices H-K).  
x
Screening: Blood (serum) will be drawn around the time of screening with an ECHO or 
MUGA scan
x
Treatment: within 7 days from Cycle 3 Day 1, Cycle 5 Day 1, and Day 1 of every cycle 
thereafter. 
x
Safety Follow-Up: during the Safety Follow-Up visit if not performed in the previous 14 
days. 
6.17. TUMOR BIOPSIES
6.17.1.
Dose Escalation 
Unless the tumor is considered too small to be biopsied (based on the investigator’s 
assessment) core needle tumor biopsies will be collected on Day 1* of Cycle 1, 2, and 3 (3-time
points total) prior to the SQL70 biopolymer injection for 3 purposes:
x 
To assess immune response
x
To measure minimal residual disease (MRD) and treatment responses
x 
To assess the concentration of active Dox and SQP33 following SQ3370 treatment at 
the local site 
*or the biopsy can be collected:
x
Cycle 1: during screening 
x
Cycle 2 & 3: up to 4 days prior to Day 1 (i.e., Day 18, 19, 20 or 21 of the previous 
cycle)
Per investigator assessment, additional optional biopsies may be collected of:  
x
non-injected tumors at the same timepoints as injected tumors
x
injected and non-injected tumors on Day 1 after Cycle 3  
6.17.2.
Phase 2a Expansion Groups  
See the Laboratory Manual for additional details on the collection process.  Tumor biopsies 
should be taken from the same tumor as that being injected with SQL70 biopolymer.  Tumor 
biopsies are optional for Phase 2a Expansion Groups 2 and 3a.  
Group 1 – Extremity STS
Core needle tumor biopsies will be collected on Day 1* of Cycle 1, 2, and 3 (3-time points total) 
prior to the SQL70 biopolymer injection for 3 purposes:
x
To assess immune response
x
To measure minimal residual disease (MRD) and treatment responses.
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x
To assess the concentration of active Dox and SQP33 following SQ3370 treatment at 
the local site 
*or the biopsy can be collected:
x
Cycle 1: during screening 
x
Cycle 2 & 3: up to 4 days prior to Day 1 (i.e., Day 18, 19, 20 or 21 of the previous 
cycle)
Per investigator assessment, resected tumors will be divided into two and stored as fresh-frozen 
and FFPE. 
x
These tissues will be used to evaluate transcriptomic biomarkers (Chibon 2019). 
Group 2 - Unresectable STS
Optional core needle tumor biopsies may be collected on Day 1* of Cycle 1, 2, and 3 (3-time 
points total) prior to the SQL70 biopolymer injection for 3 purposes:
x
To assess immune response
x
To measure minimal residual disease (MRD) and treatment responses.
x
To assess the concentration of active Dox and SQP33 following SQ3370 treatment at 
the local site 
*or the biopsy can be collected:
x
Cycle 1: during screening 
x
Cycle 2 & 3: up to 4 days prior to Day 1 (i.e., Day 18, 19, 20 or 21 of the previous 
cycle)
Group 3a – Head and Neck 
Optional core needle tumor biopsies may be collected on Day 1* of Cycle 1, 2, and 3 (3-time 
points total) prior to the SQL70 biopolymer injection for 3 purposes:
x
To measure minimal residual disease (MRD) and treatment responses.
x
To assess the concentration of active Dox and SQP33 following SQ3370 treatment at 
the local site 
*or the biopsy can be collected:
x
Cycle 1: during screening 
x
Cycle 2 & 3: up to 4 days prior to Day 1 (i.e., Day 18, 19, 20 or 21 of the previous 
cycle)
6.18. CT/MRI TUMOR IMAGING & MEASUREMENTS
All measurements should be taken and recorded in metric notation using a ruler, calipers, or a 
digital measurement tool.
The same method of assessment and the same imaging technique regarding modality, ideally 
the same scanner, and the use of contrast should be used in a participant throughout the study 
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to optimize the reproducibility of the assessment of existing and new tumor burden and improve 
the accuracy of the assessment of response or progression based on imaging.
Assessment should be performed:
x 
During screening
x 
Every 6 weeks (-7-day window) from Cycle 1 Day 1 until end of treatment
x 
At the Safety Follow-Up Visit, if not performed in the previous 6 weeks
x
If a patient comes off treatment due to non-RECIST progression, a scan should be 
obtained during Long Term Follow Up, until radiographic progression is noted.
x 
Additional scans may be conducted at other time points if deemed clinically appropriate
Scans will be read at the study site. Scans must include chest, abdomen, and pelvis, as well as 
any other areas of disease, whether or not measurable, present at screening and/or follow-up, 
including extremities.
Computed Tomography (CT) / Magnetic Resonance Imaging (MRI): Scans are required to
document disease status (including chest, abdomen, pelvis, and other regions as clinically 
indicated). A brain scan is required to exclude brain metastasis if clinically indicated.
Clinical Examination: Imaging-based evaluation is preferred to evaluation by clinical 
examination unless the lesion(s) being followed cannot be imaged but are assessable by clinical 
examination. Tumors may also be assessed utilizing visual or palpable lesions on physical 
examination, including full assessment of all known metastases. 
Copies of redacted radiology reports and interventional radiology procedure notes may be 
obtained for quality control. 
Clinical lesions will only be considered measurable when they are superficial (e.g., skin nodules 
DQGSDOSDEOHO\PSKQRGHVDQG 10 mm in diameter as assessed using calipers (e.g., skin 
nodules). In the case of skin lesions, either a CT scan or documentation by color photography, 
including a ruler to estimate the size of the lesion, is recommended. Ultrasound might also be 
useful to confirm the complete disappearance of superficial lesions usually assessed by clinical 
examination. If new lesions are identified by ultrasound in the course of the study, confirmation 
by CT or MRI is necessary.
6.18.1.
Target and Non-Target Tumor Baseline Recording
To assess objective response or future progression, it is necessary to estimate the overall tumor 
burden at screening and use it as a comparator for subsequent measurements. 
Target Lesions
When more than 1 measurable lesion is present at baseline, all lesions up to a maximum of 
5 lesions total (and a maximum of 2 lesions per organ) representative of all involved organs 
should be identified as target lesions and will be recorded and measured at baseline (this 
means that, in instances where patients have only 1 or 2 organ sites involved, a maximum of 
2 and 4 lesions, respectively, will be recorded).
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. The baseline sum of the
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diameters will be used as reference to further characterize any objective tumor regression in the 
measurable dimension of the disease.
If a lesion “fragments” as it shrinks, the individual lesion diameters should be added together to 
calculate the target lesion size. If lesions coalesce and become inseparable, the longest 
diameter of the merged lesions should be used as the lesion size.  
Note: Only target lesions can be selected for SQL70 biopolymer injection.
Non-Target Lesions
All other lesions (or sites of disease) should be identified as non-target lesions and should also 
be recorded at baseline. Measurements are not required, and these lesions should be followed 
as “present,” “absent,” or in rare cases “unequivocal progression.” 
See RECIST v1.1 (Eisenhauer 2009) for additional details.
6.18.2.
Tumor Response Evaluation
Tumor response will be evaluated using RECIST v1.1 (Eisenhauer 2009) as outlined in Table 6
and Table 7 below.  See RECIST v1.1 (Eisenhauer 2009) for additional details.
Table 6: Evaluation of Target Lesions
Response Type
Definition
Complete response
Disappearance of all target lesions; if a pathologic lymph node, 
UHGXFWLRQLQWKHVKRUWHVWD[LVWRPPa
Partial responseb
At least a 30% decrease in the sum of diameters of target lesions
relative to the baseline sum of diametersc
Stable diseaseb,d
Neither a sufficient reduction to qualify as a partial response nor 
sufficient increase to qualify for progressionc
Progressive diseaseb
At least a 20% increase in the sum of diameters relative to the 
smallest sum of diameters recorded (including the baseline sum of 
diameters) in conjunction with an increase of at least 5 mm in that 
smallest sum of diameters or the appearance of 1 or more new 
lesionsc,e
Table 7: Evaluation of Non-Target Lesions
Response Type
Definition
Complete response
Disappearance of all nontarget lesions; all lymph nodes must be 
non-SDWKRORJLFLQVL]HLHPPRQWKHVKRUWD[LV
Non-complete response or 
non-progressive disease
Persistence of one or more nontarget lesion(s) and/or maintenance 
of tumor marker level above the normal limits
Progressive disease
Unequivocal progressiona of any existing nontarget lesion or the 
appearance of 1 or more new lesionsb
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a )RUHDFKSDWKRORJLFO\PSKQRGHFRQVLGHUHGDWDUJHWOHVLRQWKHQRGHPXVWKDYHDVKRUWD[LVPHDVXULQJ 10 mm to
be considered as a complete response. In such cases, the sum diameters may not be zero (as a normal lymph 
QRGHFDQKDYHDVKRUWD[LVRI 10 mm). If a non-nodal lesion has decreased in size to the point where it is difficult 
to distinguish residual tumor from normal tissue, a biopsy may be performed to help clarify whether a response is a 
CR or PR.
b For each pathologic lymph node considered a target lesion, the measurement of the short axis of the node is to be
included in the sum diameters when determining partial response, stable disease, and progression.
c In this study, the “baseline sum diameter” is calculated based on the lesion measurements obtained at screening.
d Duration of stable disease is measured from the date of the first dose of Investigational Product until criteria for
progressive disease are met based on the smallest sum diameters recorded (including the baseline sum
diameters).
e The finding of a new lesion should be unequivocal and not possibly attributable to a difference in imaging modality 
or scanning technique. Post-baseline, fluorodeoxyglucose positron emission tomography (FDGPET) may be useful 
in assessing new lesions apparent on computed tomography (CT) scan.
6.19. ADMINISTRATION OF INVESTIGATIONAL PRODUCT
Figure 5 and Figure 6 below illustrates one cycle of IP administration. See section 5.3
Investigational Product Dosage and Administration and the study-specific Pharmacy Manual for 
additional details. Group 2: Unresectable STS will have a cohort that receives their dose of 
SQP33 protodrug in 3 days, instead of 5 days.
Figure 5: SQ3370 5-Day Administration Schedule
Figure 6: SQ3370 3-Day Administration Schedule
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6.20. UNSCHEDULED VISITS
The Investigator will be responsible for monitoring AEs and other toxicities. Any additional 
visit(s) to monitor patient safety that is performed outside of scheduled visits will be recorded as 
an Unscheduled Visit. Unscheduled Visits can occur at any time, based on clinical need. The 
assessments and procedures conducted during the visit will be at the discretion of the 
Investigator. Data from unscheduled visits should be recorded in the eCRF and source 
documentation maintained by the Investigator in the same manner that data and source 
documentation are available for routine study visits. 
6.21. PATIENT END OF STUDY
Patients end the study when either: 
x
Patients do not enter Long Term Follow-Up
x
Patients end Long Term Follow-Up
6.22. WITHDRAWAL OF CONSENT
Patients have the right to voluntarily withdraw consent from the study at any time for any 
reason. 
x
If the patient withdraws consent for disclosure of future information, the Sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 
x
The patient may withdraw consent for treatment and allow the sponsor to collect Long 
Term Follow-up information. 
x
If a patient withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the Investigator must document this in the study site study 
records and notify the Sponsor or designee.
6.23. LOST TO FOLLOW-UP
If a patient misses a visit and is not responding to telephone calls from the study center (all 
attempts to contact the patient should be documented), the center will need to take 
additional actions to locate the patient. 
1.
The center will make at least 2 attempts to contact the patient by telephone.
2.
When possible, 2 additional attempts should be made to contact the patient’s emergency 
contact by telephone. 
3.
If these attempts are not successful, when possible, a registered letter will be sent to the 
last known address of the patient. 
4.
If this is unsuccessful, the patient will be considered lost to follow-up. 
6.24. STUDY SITE OR STUDY TERMINATION 
The Sponsor has the right to terminate the participation of either an individual study site or the 
study at any time.
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7.
ADVERSE AND SERIOUS ADVERESE EVENTS
7.1.
DEFINITIONS
7.1.1. Definition of Adverse Events 
Per FDA 21CFR 312.32, an AE is an untoward medical occurrence associated with the use of a 
drug in humans, whether or not considered drug related.  An AE can be any unfavorable and 
unintended sign (e.g., including an abnormal laboratory finding), symptom or disease temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product. 
In this study, AEs will be captured from the time a subject signs the ICF to the last study visit 
and include the following:
x
Any new sign, symptom, or disease
x
Any new clinically significant or symptomatic laboratory/diagnostic test abnormality
x
Any clinically significant worsening of laboratory/diagnostic test abnormality
x
Any worsening (e.g., clinically significant change in frequency, nature and/or intensity) of 
a pre-existing condition
A pre-existing condition is a condition that is present prior to signing the ICF for the study. Pre-
existing conditions such as illnesses, reactions, symptoms, progression of disease state, and 
other comorbidities, as well as pre-existing laboratory/diagnostic test abnormalities, will be 
documented in the subject’s record as medical history.  The disease/disorder being studied or 
expected progression, signs, or symptoms from the disease/disorder, which is more severe than 
expected for the participant’s condition.  Findings that are clearly consistent with the expected 
progression of the underlying cancer should not be reported as an adverse event.  If there is 
any uncertainty about a finding being due solely to progression of disease, the finding should be 
reported as an AE or SAE as appropriate.
Signs and symptoms will be reported individually as non-serious AEs, unless a medical 
diagnosis was provided. Medical diagnosis, whenever provided, will be reported rather than 
individual signs and symptoms.
Any AE that meets seriousness criteria (section 7.1.3 Definition of Serious Adverse Event 
(SAE)) must be reported as outlined in section 7.2 Reporting to Sponsor after consent is 
obtained, but prior to the administration of the IP, only AEs/SAEs caused by a protocol 
mandated intervention (e.g., invasive procedures such as biopsies, discontinuation of 
medications) should be reported as AEs/SAEs. Any other untoward medical occurrences should 
be reported as medical history.
7.1.1.1.
Assessment of Severity 
The investigator will be asked to provide an assessment of the severity of the AE using the 
following categories:
x
Mild: Usually transient and may require minimal treatment or therapeutic intervention. 
The event does not generally interfere with usual activities of daily living.
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x
Moderate: Usually alleviated with additional specific therapeutic intervention. The event 
interferes with usual activities of daily living, causing discomfort but poses no significant 
or permanent risk of harm to the subject.
x
Severe: Interrupts usual activities of daily living, or significantly affects clinical status, or 
may require intensive therapeutic intervention.
7.1.1.2.
Relationship to Study Treatment
The investigator will make a determination of the relationship of the AE to study drug using a 
binary system according to the following guidelines:
Not Related: A relationship between the AE and study drug can reasonably be ruled out based 
on lack of any temporal relationship of the event to study drug administration, or when the 
subject’s underlying condition, medical history, or other therapy provide sufficient explanation for 
the observed AE.
Related: There is a reasonable possibility that the AE is associated with the use of the study 
drug, such as temporal relationship of the AE to study drug administration, or when other drugs, 
therapeutic interventions, or underlying conditions do not provide a sufficient explanation for the 
observed AE. Additionally, the AE abates upon discontinuation of the study drug, or follows a 
hypothesized cause and effect relationship and (if appropriate) re-appears when the study drug 
is reintroduced.
7.1.1.3.
Action Taken for Adverse Events
The investigator or designee will record the action(s) taken with respect to study drug for the AE 
in the eCRF. Actions taken but not limited to: 
x
None/Dosed Not Changed: The study drug schedule was not changed.
x
Drug Interrupted: The study drug schedule was modified by temporarily terminating the 
prescribed regimen of medication.
x
Drug Withdrawn: the study drug schedule was modified through termination of the 
prescribed regimen of medication.
x
Drug Reduced: The study drug schedule was modified by subtraction, either by 
changing the frequency, strength, or amount.
x
Not Applicable: If the AE started after the End of Treatment date.
7.1.2. Definition of Adverse Events of Special Interest (AESI)
An AESI is one of scientific and medical concern specific to the study drug, which requires 
ongoing safety monitoring and prompt communication by the investigator to the sponsor. 
Depending on the nature of the event, Regulatory Authorities should be notified. Per ICH E2F 
such an event might require further investigation in order to characterize and understand it.
AESIs in this study include Dose-limiting Toxicities (DLTs), potential myocardial toxicity, COVID-
19 infections, and AEs due to overdose.
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7.1.2.1.
Dose-limiting Toxicity
See section 3.2.6 Dose-Limiting Toxicity for definition.
7.1.2.2.
Potential Myocardial Toxicity
Since Dox is known to cause myocardial toxicity, especially at high cumulative doses, events 
such as myocardial infarction, elevated serum troponin-T, significantly decreased ejection 
fraction on echocardiogram or MUGA, symptoms or signs of new congestive heart failure, new 
onset of arrhythmias or heart block, etc. should be reported to the Sponsor immediately and IP
administration should be halted.  The patient should be evaluated and if there appears to be 
significant evidence of myocardial injury, study treatment should be discontinued permanently.
7.1.2.3.
COVID-19
Given information regarding COVID-19 infections and the global pandemic continue to evolve, 
the Sponsor will provide sites with separate guidance for how to report confirmed or suspected 
cases of COVID-19 infections and manage study treatment.  Guidance will include definitions 
for confirmed and suspected infections as well as rules for stopping or interrupting study 
treatment as applicable.
7.1.2.4.
Overdose
Study drug overdose is the accidental or intentional use of an Investigational Product in an 
amount higher than the dose indicated per protocol for a given subject.  Any study product 
overdose during the study should be recorded on the source document and eCRF.  In the event 
of overdose, the subject should be closely monitored for any potential AEs.
7.1.3. Definition of Serious Adverse Event (SAE)
A serious adverse event is an AE that in view of the Investigator or Sponsor, results in any of 
the following outcomes:
x
Death
x
Life-threatening
x
Inpatient hospitalization or prolongation of existing hospitalization
x
Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions
x
Congenital anomaly/Birth Defect
x
Other Important Medical Events: based on appropriate medical judgement, they may 
jeopardize the subject and may require medical or surgical intervention to prevent any of 
the outcomes listed in this definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias, or seizures/convulsions that do not result in hospitalization
In this study, elective, or pre-planned surgery (prior to study entry) or routine clinical procedures, 
which are not the result of an AE, will not be considered as an SAE, but will be entered in the 
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subject’s record and entered in the eCRF. If any serious untoward event is reported during the 
procedure, it will be reported as an SAE and assessed for causality and expectedness. SAEs 
that occurred after 30 days since the last dose of study drug should be reported only if they are 
deemed by the investigator to be “RELATED” to the investigational medicinal product. The 
investigator must review all AEs (serious and non-serious) and the outcome throughout the 
study.
7.2.
REPORTING TO SPONSOR
Certain events require immediate reporting to allow the Sponsor to take appropriate measures 
to address potential new risks in a clinical study.  The Investigator must report such events to 
the Sponsor immediately; under no circumstances should reporting take place more than 24 
hours after the Investigator learns of the event. The following is a list of events that the 
Investigator must report to the Sponsor within 24 hours after learning of the event, regardless of 
relationship to the Investigational Product:
x 
SAEs 
x
AEs of Special Interest (see section 7.1.2 Definition of Adverse Events of Special 
Interest (AESI)) 
x
Pregnancies
Investigators must also comply with local requirements for reporting SAEs to their local IRB/EC.
7.2.1. Follow-up of Adverse Events
Every reasonable effort will be made to follow-up with patients who have AEs.  AEs will be 
collected from the time the subject signs the ICF until 30 days after last dose of study drug, 
whether or not judged by the Investigator to be related to study drug. Any subject who has an 
ongoing AE that is related to study drug or study procedures at subsequent visits, will be 
followed-up, where possible, until resolution.  
Any subject who has an AE that is not related to study drug or study procedures at the Follow-
up Visit can be closed out as ongoing at the Investigator’s discretion.
7.2.2. Serious Adverse Event Notification, Documentation, and Reporting 
The investigator must report an SAE within 24 hours of becoming aware of the event. The 
Investigator must report such events to the Sponsor immediately by sending an SAE Report 
Form via email to SAE@shasqi.com; under no circumstances should reporting take place more 
than 24 hours after the Investigator learns of the event.
The initial report must not be delayed in order to obtain additional information. Any additional 
information will be reported as a follow-up to the initial report within 24 hours of collection. The 
following is a list of events that the Investigator must report to the Sponsor within 24 hours after 
learning of the event, regardless of relationship to the Investigational Product:
x 
SAEs 
x
AEs of Special Interest (see section 7.1.2 Definition of Adverse Events of Special 
Interest (AESI)) 
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Investigators must also comply with local requirements for reporting SAEs to IRB/IEC.
In the event of any SAE (other than death) occurring after the last dose of study drug and prior 
to the Follow-up Visit, the subject will be instructed to contact the investigator immediately using 
the instructions provided on the ICF.
The Medical Monitor will review reported SAEs and may contact the Investigator directly for 
further information.
The Sponsor will comply with all applicable local regulatory requirements related to reporting of 
SAEs to the appropriate Regulatory Authorities in the countries and regions this study is 
conducted, while the investigator and designated study personnel with applicable local 
regulatory requirements related to reporting of SAEs to the Institutional Review Board (IRB), 
Ethics Committee (EC), and the sponsor.
If the SAE is not previously documented in the Investigator Brochure (IB), it’s a new occurrence, 
and it’s thought to be related to the investigational treatment, the sponsor or designee may 
urgently (e.g., a change in study risk, diagnostic test results, laboratory reports) require further 
information from the investigator for Regulatory Authority reporting. 
It is the responsibility of the Sponsor to collect and report all AEs that meet criteria as 
Suspected Unexpected Serious Adverse Reactions (SUSARs) to Regulatory Authorities and 
relevant IRBs/ECs in accordance with national regulatory requirements, e.g., in the United 
States (US) such as FDA 21CFR 312.32 and Australia requirements as per Pharmacovigilance 
Responsibilities of Medicine Sponsors Australian Recommendations and Requirements 
Guidance.
The Sponsor will preserve the investigator’s assessment and will give due consideration to it 
when making regulatory reporting decisions. 
As applicable, the sponsor will also notify other participating investigators of all Safety Reports 
to ensure prompt notification of significant new AEs and safety risks with respect to study drug. 
This notification will occur as soon as possible and in compliance with country specific 
applicable regulations.
The Medical Monitor should be contacted by study sites requiring additional clarification on an 
SAE.
7.3.
PREGNANCY REPORTING
If a female subject becomes pregnant during the study and up to 30 days after the end of study, 
the subject must inform the study site as soon as possible. If a female partner of a male subject 
becomes pregnant during the study and up to 7 days after the end of study, the subject must 
inform the site. Upon confirmation of the pregnancy, the female subject will be discontinued 
from the study. The investigator or designee must complete a study specific pregnancy form 
upon confirmation of a pregnancy and send it to the sponsor as directed on the pregnancy form 
within 24 hours of confirmation of the pregnancy. Pregnancy itself is NOT an AE or SAE; 
however, maternal/fetal complications or abnormalities will be recorded as AEs or SAEs, as 
appropriate. The investigator will follow the pregnancy until resolution, and in case of a live-born 
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offspring, up to 1 month of age of the infant. See APPENDIX E – Collection of Pregnancy 
Information for additional details.
The investigator will notify the sponsor, as directed on the pregnancy report form, of the 
outcome as a follow-up of the initial pregnancy form. All pregnancies must be reported to the 
sponsor and as applicable to IRBs/ECs.
The effects of SQ3370 on the developing human fetus are unknown. For this reason, women of 
childbearing potential and men must agree to use highly effective contraception for the 
duration of study participation and for 90 days following completion of treatment. 
Periodic abstinence, the rhythm method, and the withdrawal method are not acceptable 
methods of contraception. Additionally, men should not donate sperm for the duration of study 
participation and for 90 days following completion of treatment. Highly effective contraception for 
this study is defined as one that results in a low failure rate (i.e., less than 1% per year) when 
used consistently and correctly.  
Women of non-childbearing potential for this study are defined as a woman who: 
x
Has undergone surgical sterilization (total hysterectomy, bilateral tubal ligation, bilateral 
salpingectomy or bilateral oophorectomy), or  
x
,V 60 years of age and has been naturally postmenopausal for at least 12 consecutive 
months (i.e., has not had menses at any time in the preceding 12 consecutive months)
and confirmed by elevated follicle-stimulating hormone levels (using local reference 
ranges). 
x
Is 60 years of age
Men of non-childbearing potential for this study are defined as a man who has:
x 
Azoospermia either from a vasectomy or from an underlying medical condition.
For individuals with permanent infertility due to an alternate medical cause other than the above, 
(e.g., Mullerian agenesis, androgen insensitivity), Investigator discretion should be applied to 
determining whether they should be considered women or men of childbearing potential.
Note: Documentation can come from the study site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview.
7.4.
REGULATORY REPORTING
The Sponsor will promptly evaluate all SAEs and AEs of Special Interest against cumulative 
product experience to identify and expeditiously communicate possible new safety findings to 
Investigators, IRBs/IECs, and applicable health authorities based on applicable legislation. 
The Sponsor has a legal responsibility to notify investigators, the local regulatory authority, and 
other regulatory agencies about the safety of an Investigational Product under clinical 
investigation. The Sponsor will comply with country-specific regulatory requirements relating to 
safety reporting to the regulatory authority, IRB/IEC, and Investigators.
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and Sponsor policy and will be forwarded 
to Investigators as necessary.
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An Investigator who receives an Investigator safety report describing a SAE or other specific 
safety information (e.g., summary or listing of SAEs) from the Sponsor will review and then file it 
along with the Investigator’s Brochure and will notify the IRB/IEC, if appropriate, according to 
local requirements.
7.5.
MANAGEMENT OF STUDY-SPECIFIC ADVERSE EVENTS
7.5.1. Management of SQL70 Biopolymer Injection Reactions
Investigators should monitor the patient for injection site reactions, including vitals as outlined in 
section 6.6 Vital Signs. 
Prevention: 
x
Consider administering a subcutaneous local anesthetic or topical anesthetic before 
SQL70 biopolymer injection.
x
Some lesions may accept SQL70 biopolymer more easily than others, and leakage may 
occur if the lesion is resistant to SQL70 biopolymer injection. In such cases, the health
care provider should apply slow, steady pressure, moving the needle slightly if 
necessary. 
Management:
x
If the patient reports pain after injection, apply an ice pack to the injection site for 5 to 10 
minutes, apply compression to the site, and elevate at or above heart level if possible.
x
In the event of any acute hypersensitivity reactions, the patient may be treated with 
histamine 1 blocking agents, histamine 2 blocking agents, and acetaminophen.  
x
In the unlikely event of a severe systemic reaction, corticosteroids and/or epinephrine 
may be appropriate followed by careful monitoring of vital signs and clinical status.
7.5.2. Management of SQP33 Protodrug Infusion Reactions
Investigators should monitor the patient for infusion reactions, including vitals as outlined in 
section 6.6 Vital Signs.
Investigator should monitor patients and precautions should be observed during the 
administration of SQP33 protodrug. Emergency agents including oxygen, oral and endotracheal 
airways, intubation equipment epinephrine, antihistamines, and corticosteroids should be 
available and used if required at the Investigator’s discretion.
Patients should be instructed that symptoms associated with cytokine release syndrome / 
infusion reaction can occur within 48 hours following the administration of SQP33 protodrug, 
and if such symptoms develop while they are at home, they should contact the Investigator 
and/or seek emergency medical care if appropriate.
x
Grade 2: stop infusion and treat symptoms following guidance in Table 8. If symptoms 
resolve within two hours, the infusion may be restarted at 50% of the original infusion 
rate (e.g., from 100 mL/hr to 50 mL/hr).  
x
Grade 3-4: stop infusion and treat symptoms following guidance in Table 8; no additional 
study treatment should be administered.
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Table 8: Infusion-related Reaction Management Recommendations
Suspected Infusion Reaction
Recommended Treatmentௗ
Mild toxicity requiring symptomatic 
treatment only (e.g., fever, nausea, 
IDWLJXHKHDGDFKHP\DOJLDPDODLVHௗ
x 9LJLODQWVXSSRUWLYHFDUHௗ
x 0DLQWDLQDGHTXDWHK\GUDWLRQௗ  
x Antipyretics, nonsteroidal anti-inflammatory drugs, 
antihistamines, anti-emetics, analgesics as 
QHHGHGௗ  
x In case of mild symptoms persisting for > 24 hours 
assess for infections; empiric treatment of 
concurrent bacterial infections
Symptoms or clinical findings requiring 
and responding to moderate 
LQWHUYHQWLRQVXFKDVௗ  
x 
O2 UHTXLUHPHQWௗ  
x
Hypotension responsive to 
fluids ± low dose of 1 
vasopressor 
HJPJPLQRI
SKHQ\OHSKULQHௗ
x
&7&$(*UDGHRUJDQWR[LFLW\ௗ  
No extensive 
comorbidities 
RUௗ  
Age  70 
\HDUVௗ
x $OORIWKHDERYH$1'ௗ
x Monitor cardiac and other organ 
IXQFWLRQVFORVHO\ௗ  
Extensive 
comorbidities 
RUௗ  
$JH
\HDUVௗ
x All of the above AND
x &RUWLFRVWHURLGVௗ    
Symptoms or clinical findings requiring 
DJJUHVVLYHLQWHUYHQWLRQVXFKDVௗ  
x 
O2 UHTXLUHPHQWௗ  
x
Hypotension requiring high 
dose or PXOWLSOHYDVRSUHVVRUVௗ  
x
9HQWLODWRUVXSSRUWUHTXLUHGௗ
x
&7&$(*UDGHRUJDQ
WR[LFLW\ௗ
x All of the above AND
x &RUWLFRVWHURLGVௗ  
7.5.3. Management of SQP33 Protodrug Extravasation
Upon IV administration of SQP33 protodrug, extravasation may occur with or without an 
accompanying burning or stinging sensation, even if blood returns well on aspiration of the 
infusion needle. Preclinical data from animals who received SQP33 did not suggest that SQP33 
acted as a vesicant. The preclinical findings at the injection site consisted of minimal to slight 
inflammation and changes typically associated with indwelling catheters (see SQ3370 
Investigators Brochure for details).  If any signs or symptoms of extravasation have 
occurred, the infusion should be immediately terminated and treated according to local 
study site procedures or per institutional practice for conventional Dox.   
The infusion should then be restarted in another vein.
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Although local tissue injury has not been observed in animal studies, if extravasation is 
suspected, the Sponsor recommends considering the precautions used for conventional Dox 
infusions: 
x
Intermittent application of ice to the site for 15 minutes, 4 times daily for 3 days may be 
useful.
x
Because of the progressive nature of conventional Dox extravasation reactions, close 
observation and plastic surgery consultation should be considered. 
7.5.4. Management of Potential Myocardial Toxicity and ECHO / MUGA Changes
SQ3370 should be stopped at the first sign of impaired cardiac function. ECG changes such as 
dysrhythmias or conduction delays may be indicative of anthracycline-induced cardiomyopathy.
A 10% decline in LVEF to below the lower limit of normal or an absolute LVEF of 45% or a 20% 
decline in LVEF at any level is indicative of deterioration in cardiac function. In general, if test 
results indicate deterioration in cardiac function associated with SQ3370, the benefit of 
continued treatment should be carefully evaluated against the risk of producing irreversible 
cardiac damage. Acute life-threatening arrhythmias have been reported to occur during or within 
a few hours after conventional Dox administration.
Other events such as myocardial infarction, anginal symptoms, elevated serum troponin-T, or 
symptoms or signs of new congestive heart failure should be reported to the Sponsor 
immediately and Investigational Product administration should be halted. The patient should be 
evaluated and if there appears to be significant evidence of myocardial injury, study treatment 
should be discontinued permanently.
7.5.5. Management of Myelosuppression
Myelosuppression is a well-known toxicity of Dox and may be dose-limiting for SQ3370. 
Standard oncologic management of cytopenias, including neutropenia, febrile neutropenia and 
sepsis or bleeding due to thrombocytopenia should be instituted if indicated.
7.5.6. Management of Hepatotoxic Risk
Investigators should monitor the patient for elevated levels of AST and/or ALT concurrent with
abnormal elevations in total bilirubin that meet the criteria outlined below in the absence of other 
causes of liver injury and investigational treatment should be stopped as they are considered 
potential cases of drug-induced liver injury (DILI). 
The following laboratory values should be evaluated for Hy’s Law cases taking into 
consideration specific clinical symptoms of the patient and evaluation of other causes of hepatic 
impairment:
x
Aminotransferases (AT), ALT or AST elevation > 3 times the upper limit of normal (ULN); 
AND
x
Total bilirubin (TBL) > 2 times ULN, without initial findings of cholestasis (elevated serum 
alkaline phosphatase); AND 
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x
No other immediately apparent possible causes of AT elevation and hyperbilirubinemia, 
including but not limited to viral hepatitis, pre-existing chronic or acute liver disease, or 
the administration of other drug(s) known to be hepatotoxic. 
Patients with labs that are suspicious of DILI should return to the clinic as soon as possible, or 
at least within 48 hours, to be evaluated with laboratory tests, a detailed history and physical 
assessment.  
The possibility of other causes for elevated liver function tests should be evaluated. Further 
testing for acute hepatitis A, B, or C infection and liver imaging (e.g., biliary tract) at a minimum 
may be warranted.
If on the repeat laboratory testing for drug induce liver injury (DILI), results continue to meet the 
threshold listed above, and after a thorough evaluation for alternative explanations fail to 
provide a clear clinical explanation, the ongoing hepatic injury, per protocol, the diagnosis 
should be DILI. ALL investigational treatment should be stopped as they are considered 
potential cases of drug-induced liver injury.
7.6.
DOSE MODIFICATIONS
7.6.1. Missed Doses  
SQL70 Biopolymer Missed Doses: The injection of SQL70 biopolymer cannot be missed; it must 
be injected prior to SQP33 protodrug infusion. If the SQL70 biopolymer injection is missed on 
Day 1 of any cycle, alert the Medical Monitor immediately and do not inject SQP33 protodrug. 
SQP33 Protodrug Missed Doses: Missed infusions of SQP33 protodrug may be made up, but 
only on Day 6. The Medical Monitor should be alerted immediately in the case of any missed 
infusions. 
Example: SQP33 protodrug infusions occur as scheduled on Day 1 and Day 2, but, due to 
extenuating circumstances (snowstorm, family emergency, etc.), the patient cannot attend 
their Day 3 visit. The Day 3 SQP33 protodrug infusion and other study procedures are 
therefore skipped and dosing resumes on Day 4 and Day 5. The missed dose may be made 
up on Day 6. If the dose cannot be made up on Day 6, then the patient only receives 4 
infusions (Day 1, 2, 4, and 5) during that cycle. 
7.6.2. Dose Reductions
SQL70 Biopolymer Volume: The volumes of SQL70 biopolymer under study are 10 mL or 
20 mL.  Please consult the medical monitor if there are questions regarding the volume of 
SQL70 to be injected.  
x
Dose reductions: 
o
Phase 1: The SQL70 biopolymer volume in the 20 mL group may be reduced 
from 20 mL to 10 mL if 20 mL is not tolerated. If a dose reduction occurred and 
two lesions are being treated the investigator will need to choose a single lesion 
to inject with 10 mL of SQL70 biopolymer. 
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o
Phase 2a: The SQL70 biopolymer volume in the 20 mL group may be reduced 
from 20 mL to 10 mL if 20 mL is not tolerated.
SQP33 Protodrug Dose:  
x
Dose reductions: 
o
Phase 1 and Phase 2a: If a patient does not tolerate their initial or subsequent 
dose level of SQP33 protodrug the patient may be treated with a 25% reduction 
in SQP33 protodrug dose. 
7.6.3. SQ3370 Treatment Interruptions
The Medical Monitor should be notified if the Investigator intends to interrupt SQ3370 treatment
either during or in between cycles for any reason.  
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8.
STATISTICAL CONSIDERATIONS AND ANALYSIS PLAN
8.1.
ANALYSIS PLAN
The statistical analysis plan will be finalized prior to database lock, and it will include a more 
technical and detailed description of the statistical analyses and procedures for accounting for 
missing, unused, and spurious data described in this section. 
8.2.
ANALYSIS POPULATION
The following populations are defined for statistical purposes: 
Population
Description
Enrolled 
All patients who sign consent 
Treated/Full Analysis Set
All patients who receive at least 1 dose of SQL70 biopolymer 
and 1 dose of SQP33 protodrug  
Efficacy Evaluable
All patients who receive at least 1 dose of SQL70 biopolymer 
and 1 dose of SQP33 protodrug and undergo at least 1 post 
baseline tumor evaluation
Safety
All patients who received at least 1 dose of SQL70 biopolymer 
and/or SQP33 protodrug
PK 
All patients in the Safety Population who have the necessary 
Day 1 and on-study measurements to provide interpretable 
results for the specific parameters of interest
Biomarker
All patients with available biomarker data
8.3.
DETERMINATION OF SAMPLE SIZE
Phase 1 Dose Escalation: Sample size for the dose escalation portion of the study is not 
predefined; total enrollment will depend on the DLTs observed and number of escalation 
cohorts. 
Phase 2a Expansion Groups:  
Groups 1 (Extremity STS) and 3a (Head and Neck)
Sample sizes are guided by Simon 2-stage (optimal) designs based on historical objective 
responses per indication. Because of the different participant populations (sarcoma and H&N 
cancers), different criteria are applied to determine the number of participants for each stage 
and the strength of the efficacy signal that would recommend proceeding to the next stage. 
Details are described in subsequent sections and in Table 9.   
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Table 9: Simon 2-Stage Design  
Stage 1 responders/ Stage 1 n
Stage 2 responders/ Stage 2 n
Cohort 
Power 
Historical 
ORR/Target 
ORR
Consider 
Futility 
Go to Stage 
2 
Consider 
Futility 
Consider 
Efficacy 
Expected 
Sample Size 
H&N 
85% 
20%/45% 
d3/13
t4/13
d8/26
t9/26
16.28 
Extremity 
Sarcoma
70% 
20%/35% 
d3/15
t4/15
d13/46
t14/46
25.91 
For sample size calculation and for simplicity of description, recommendations for stopping 
or progressing to the next stage are based on the number of objective responses observed. 
However, since best overall response (BOR) does not necessarily capture the full extent of 
clinical benefit and since response can be delayed or of short duration, Shasqi will also review 
other aspects of clinical benefit that may better predict PFS or OS benefit, such as DOR, before 
making a final determination.  
Enrollment will be continued after reaching the indicated number of participants at Stage 1 
while the initial efficacy evaluation is ongoing. This will allow additional participants to enroll to 
account for unexpected trial impact, such as response non-evaluable participants due to early 
dropout, design parameter change (e.g., historical response rate update), etc. Although the 
sample size calculations are based on efficacy considerations, safety will also be continuously 
assessed and will be considered in the decision to continue or terminate a study treatment 
population.   
Under the optimal Simon 2-stage design criterion:  
Group 1 - Extremity STS: A sample size of 46 is required to test a null hypothesis of H΋ʌ
(20%) versus an alternative hypothesis of HΌʌ(Seddon 2017; Tapp 2017; 
Chawla 2015) with a one-VLGHGVLJQLILFDQFHOHYHORIDQGSRZHUZKHUHʌLVWKH
true proportion of successes. This design results in an expected sample size of 25.91 and a 
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out of 15 participants in the first stage, then the trial will be stopped. If the trial proceeds to the 
second stage, 46 subjects in total will be studied. If 13 or less responses are observed, then the 
drug is rejected.   
Group 3a - Head & Neck: A sample size of 26 is required to test a null hypothesis of H΋ʌ
(20%) versus an alternative hypothesis of HΌʌ(Sandler 1984; Harrington 2001) 
with a one-VLGHGVLJQLILFDQFHOHYHORIDQGSRZHUZKHUHʌLVWKHWUXHSURSRUWLRQRI
successes. This design results in an expected sample size of 16.28 and a probability of early 
termiQDWLRQRIௗ,IWKHQXPEHURIUHVSRQVHVLVOHVVWKDQRUHTXDOWRRXWRISDUWLFLSDQWV
in the first stage, then the trial will be stopped. If the trial proceeds to the second stage, 26 
subjects in total will be studied. If 8 or less responses are observed, then the drug is rejected.   
Continuous Reassessment Method (CRM) design
Group 2 (Unresectable STS)
Sample sizes for Group 2 participants are guided by the Continuous Reassessment Method 
(CRM) design (Wheeler 2019). The use of evaluating additional participants in the Expansion 
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Group 2 and the use of the CRM model provides an indication of whether to alter the RP2D 
regimen (3-day dosing per 21-day cycle vs. 5-day dosing per 21-day cycle) based on a 
comparison of toxicity and efficacy data collected from enrolled participants. The indicated 
population for the Group 2 participants is locally advanced or metastatic, unresectable, soft-
tissue sarcoma of intermediate or high grade with evidence of disease progression and no prior 
anthracycline treatment, and thus the test statistics parameters for the CRM are based on 
historical toxicity and efficacy rates of said population (Table 10). The participants will receive 
SQP33 at the RP2D administered IV as a 3-day dosing regimen per 21-day cycle or as a 5-day 
dosing regimen per 21-day cycle. Participants may be replaced if they are enrolled into the 
study but do not receive (for reasons other than AEs/SAEs) the intended dose during Cycle 1. If 
Cycle 1 cannot be completed due to a COVID-19 infection, an additional patient may be 
enrolled in the cohort.
Table 10: Continuous Reassessment Method Design Considerations
Test statistics parameters are based on historical toxicity and efficacy rates (Table 10). The 
acceptable threshold for toxicity is set at 15%, respectively. A toxicity rate at or above 15% for 
P\HORVXSSUHVVLRQ*UDGHUHODWHGWUHDWPHQWHPHUJHQWDGYHUVHHYHQWV7($(VDQHPLDand 
febrile neutropenia) would be considered unsafe for that cohort, and enrollment would stop. The 
maximum inefficacy and minimum efficacy rates are based on historical objective response 
UDWHV255ZLWK255EHLQJXQGHVLUDEOHDQG!255EHLQJGHsirable.  
After approximately half (n=6 per arm) of participants in Group 2 have been enrolled and 
observed for at least 2 cycles or approximately 6-weeks and have had at least one post-
baseline tumor assessment, an evaluation of all available data (safety, efficacy, and PK from 
both the Expansion and Dose Escalation) will be performed by the SRC, to determine whether 
to continue to enroll up to a total of 11 participants per arm or to stop enrollment of a cohort.  
Groups 1 and 3a will treat up to approximately 28 participants in Stage 1 and Group 2 will treat 
up to a total of 22 participants. For all Expansion Groups: Patients may be replaced if they are 
enrolled into the study but do not receive (for reasons other than AEs/SAEs) the intended dose 
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during Cycle 1. If Cycle 1 cannot be completed due to a COVID-19 infection, an additional 
patient may be enrolled in the group.  
8.4.
STATISTICAL ANALYSES
8.4.1. Safety Analyses
Safety and tolerability will be summarized using AEs, SAEs, DLTs, deaths, events of special 
interest, events leading to discontinuation, and laboratory parameters for all participants who 
have received at least 1 dose of study treatment. All treatment-emergent AEs will be 
summarized by system organ class and preferred terms within a system organ class for each 
treatment group and Grade per NCI-CTCAE (version 5). Only treatment-emergent AEs will be 
summarized in the tables. Treatment-emergent AEs are those that occur after the first dose of 
Investigational Product is given. Each preferred term will be counted only once for a given 
patient. The severity (intensity) and the relationship to study medication will be summarized by 
system organ class and preferred term within a system organ class for each treatment group. 
For severity, if a patient has multiple occurrences of the same preferred term, the highest 
severity will be assumed. Changes from baseline through the end of study will be descriptively 
summarized for the following: vital signs, ECG, ECHO/MUGA, coagulation, urinalysis, 
hematology, and clinical chemistry parameters.
8.4.2. Efficacy Analyses
8.4.2.1.
Primary Endpoint
There are no efficacy analyses planned as part of the primary endpoint.
8.4.2.2.
Secondary Endpoints
The endpoints below will be assessed by the Investigators. Time to event variables will be 
estimated using K-M methodology. Medians using the log-log transformation will be computed. 
Binary variables will be summarized by binomial response rates and their corresponding two-
sided 95% exact CI. Quantitative variables will be summarized using the mean, median, 
minimum, and maximum values, and standard deviation. Categorical variables will be 
summarized using tables presenting counts and percentages for each category. Further 
explanation, description, and landmark analyses (e.g., at 12, 24 months) will be provided in the 
statistical analysis plan finalized before the first database lock.
x
ORR is defined as the number and percentage of participants with a BOR of confirmed
CR or PR. BOR is defined as the best response designation, recorded between the date 
of enrollment and the date of the initial objectively documented tumor progression per
RECIST v1.1, date of death from any cause, or the date of subsequent therapy, 
whichever occurs first. For participants without documented progression or subsequent 
therapy, all available response designations will contribute to the BOR determination.
x
DCR is defined as the proportion of participants whose BOR is CR or PR or SD among 
all randomized participants.
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x
DoR is defined as the time recorded between the date of enrollment and the date of the 
initial objectively documented tumor progression per RECIST v1.1, date of death from 
any cause, or the date of subsequent therapy, whichever occurs first. DoR will be 
evaluated for responders (i.e., participants with confirmed CR or PR) only.
x
Histopathologic Response
x
Surgical outcome amputation/limb salvage vs. planned
x
Time to local-regional progression or distant progression is defined as the time between 
the date of enrollment and the date of local recurrence/relapse or distant progression.
x
Local-recurrence-free survival is defined as time between the date of enrollment and the 
date of local recurrence/relapse or death from any cause, whichever occurs first.
x
Distant-recurrence free survival is defined as time between the date of enrollment and 
the date of distant recurrence/relapse or death from any cause, whichever occurs first.
x
Disease-free survival is defined as the time between the date of enrollment and the date 
of recurrence/relapse or death from any cause, whichever occurs first.
x
PFS is defined as the time between the date of enrollment and the date of the initial 
objectively documented tumor progression per RECIST v1.1 or date of death from any 
cause, whichever occurs first.
x
Time from enrollment to first subsequent therapy (TFST) is defined as the time between 
the date of enrollment to the date of first new anti-cancer therapy.
x
OS is defined as the time between the date of enrollment to the date of death from any 
cause.
8.4.2.3.
Exploratory Endpoints
Will be described in the statistical analysis plan finalized prior to first database lock.
x
DoR of target lesion(s) (including both injected, if available, and non-injected tumors) is 
defined as the time recorded between the date of enrollment and the date of the initial 
objectively documented tumor progression per RECIST v1.1, date of death from any 
cause, or the date of subsequent therapy, whichever occurs first. DoR will be evaluated 
for responders (i.e., participants with confirmed CR or PR) only.
x
Change in size of target lesion(s) (including both injected, if available, and non-injected 
tumors) is defined as the best percent change from baseline in the sum of diameters.
8.4.3. Biomarker Analyses
Immune response will be evaluated based upon summaries of the biomarker data collected as 
part of the tumor biopsies and by summarizing the PBMC data. These data will be summarized 
by dose (Phase 1), Expansion Group (Phase 2a), time point measured, and changes over time. 
Listings of the individual measures will also be provided. Further description will be provided in 
the statistical analysis plan.
PK in tumor and plasma and binary variable exploratory analyses will be described in the 
statistical analysis plan finalized before the first database lock.
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8.5.
INTERIM ANALYSES
There will be no formal interim analyses performed for this study. Data will be reviewed by the 
SRC for each dose escalation cohort (Phase 1) and for the safety run-ins in the Expansion 
Groups (Phase 2a). See section 3.2.7 Safety Review Committee. 
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9.
DATA COLLECTION AND MANAGEMENT
9.1.
DATA QUALITY ASSURANCE
The Sponsor or designee maintains a study-specific Data Management Plan, which includes 
specific procedures to ensure data quality. Study sites are responsible for data entry into the 
study-specific EDC system. In the event of discrepant data, the Sponsor or designee will 
request data clarification from the study sites, which the study sites will resolve electronically 
within the EDC system. CRFs and correction documentation will be maintained in the EDC 
system’s audit trail. System backups for data stored by the Sponsor or designee and records 
retention for the study data will be consistent with the Sponsor or designee’s standard 
procedures. 
9.2.
SOURCE DATA DOCUMENTATION
The Principal Investigator and/or his/her designee will prepare and maintain adequate and 
accurate participant case histories with observations and data pertinent to the study. Source 
documents include all recordings of observations or notations of clinical activities and all reports 
and records necessary for the evaluation and reconstruction of the clinical research study.
Study Monitors will perform ongoing source data verification to confirm that critical protocol data 
(i.e., source data) entered onto the CRFs are accurate, complete, and verifiable from source 
documents. 
Source documents (paper or electronic) are those in which patient data are recorded and 
documented for the first time. They include, but are not limited to, hospital records, clinical and 
office charts, laboratory notes, memoranda, evaluation checklists, pharmacy dispensing 
records, recorded data from automated instruments, copies of transcriptions that are certified 
after verification as being accurate and complete, microfiche, photographic negatives, microfilm 
or magnetic media, X-rays, patient files, and records kept at pharmacies, laboratories, and 
medico-technical departments involved in a clinical trial. 
To facilitate source data verification, the Investigators and study sites must provide the Sponsor 
direct access to applicable source documents and reports for trial-related monitoring, Sponsor 
audits, and IRB/IEC review. The study site must also allow inspection by applicable health 
authorities. 
9.3.
CASE REPORT FORMS
CRFs are to be completed through use of a study-specific EDC system. Study sites will receive 
training and have access to guidelines for appropriate CRF completion. CRFs will be submitted 
electronically to the Sponsor or its designee and should be handled in accordance with 
instructions from the Sponsor or its designee. 
All CRFs should be completed by designated, trained study site staff. 
In accordance with Federal Regulations, the Investigator is responsible for the accuracy and 
authenticity of all clinical and laboratory data entered onto CRFs. The Principal Investigator will 
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approve all completed CRFs to attest that the information contained on the CRFs is true and 
accurate. 
At the end of the study, the Investigator will receive patient data for his or her study site in a 
readable format that must be kept with the study records. 
9.4.
USE OF COMPUTERIZED SYSTEMS / ELECTRONIC HEALTH RECORDS
When clinical observations are entered directly into a study site’s computerized medical record 
system (i.e., in lieu of original hardcopy records), the electronic record can serve as the source 
document if the system has been validated in accordance with health authority requirements 
pertaining to computerized systems used in clinical research. An acceptable computerized data 
collection system allows preservation of the original entry of data. If original data are modified, 
the system should maintain a viewable audit trail that shows the original data as well as the 
reason for the change, name of the person making the change, and date of the change. 
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10.
QUALITY ASSURANCE & ETHICAL CONSIDERATIONS
10.1. COMPLIANCE WITH LAWS AND REGULATIONS
The study will be initiated and conducted under the sponsorship of Shasqi, Inc. 
This study will be conducted in full conformance with the ICH E6 guideline for GCP and the 
principles of the Declaration of Helsinki, or the laws and regulations of the country in which the 
research is conducted, whichever affords the greater protection to the individual. The study will 
comply with the requirements of the ICH E2A guideline (Clinical Safety Data Management: 
Definitions and Standards for Expedited Reporting). Studies conducted in the US or under a 
US Investigational New Drug (IND) application will comply with US FDA regulations and 
applicable local, state, and federal laws. Studies conducted in the European Union (EU), or 
European Economic Area will comply with the EU Clinical Trial Directive (2001/20/EC). Studies 
conducted in Australia will comply with the National Statement (2007).
10.2. RESEARCH OUTSIDE THE TERMS OF THIS PROTOCOL
The Sponsor has a legal responsibility to report fully to the regulatory authorities all the results 
of administration of its Investigational Products. No investigative procedures other than those 
described in this protocol shall be undertaken on patients enrolled in this study (unless required 
for the care of the patient), without the agreement of the IRB/IEC and the Sponsor. The nature 
and results of any such procedures must be recorded and reported to the Sponsor or designee. 
The consent of the patients must be obtained before any such procedures are undertaken.
The investigational product provided to the Investigator for use under this protocol may not be 
used for any other purpose, including another study, compassionate use, or personal use.
10.3. INSTITUTIONAL REVIEW BOARD OR INDEPENDENT ETHICS COMMITTEE
This protocol, the ICFs, any information to be given to the patient, and relevant supporting 
information must be submitted to the IRB/IEC by the Principal Investigator and reviewed and 
approved by the IRB/IEC before the study is initiated. In addition, any patient recruitment 
materials must be approved by the IRB/IEC. 
The Principal Investigator is responsible for providing written summaries of the status of the 
study to the IRB/IEC annually or more frequently in accordance with the requirements, policies, 
and procedures established by the IRB/IEC. Investigators are also responsible for promptly 
informing the IRB/IEC of any protocol amendments. 
In addition to the requirements for reporting all AEs to the Sponsor, Investigators must comply 
with requirements for reporting SAEs to the local health authority and IRB/IEC. Investigators 
may receive written IND safety reports or other safety-related communications from the 
Sponsor. Investigators are responsible for ensuring that such reports are reviewed and 
processed in accordance with health authority requirements and the policies and procedures 
established by their IRB/IEC and archived in the site’s study file. 
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10.4. INFORMED CONSENT
See section 6.1 Informed Consent.
10.5. PROTOCOL ADHERENCE & DEVIATIONS
Each Investigator must adhere to the protocol as detailed in this document and agrees that any 
changes to the protocol must be approved by the Sponsor or designee prior to seeking approval 
from the IRB/IEC. Each Investigator will be responsible for enrolling only those patients who 
have met protocol eligibility criteria.
The Investigator should document and explain any protocol deviations. The Investigator should 
promptly report any deviations that might have an impact on patient safety and data integrity to 
the Sponsor or designee and to the IRB/IEC in accordance with established IRB/IEC policies 
and procedures. 
It is acknowledged that some protocol deviations may be inevitable due to COVID-19.  These 
should be documented as such and reported as per the above.  Consult with the Medical 
Monitor ahead of time, if possible, to discuss any necessary deviations to the protocol.
10.5.1.
Important Protocol Deviations
Important protocol deviations are defined as those that potentially impact patient safety and/or 
data integrity and may include but are not limited to the following:
x
Dosing errors
x
Procedural errors
x
Major violations of inclusion or exclusion criteria as determined by the Medical Monitor
x
Delayed or non-reporting of SAEs
x
Delays of greater than 14 days in scheduled CT scans
Important protocol deviations will be summarized and listed for the study using the Safety 
Population.
10.6. MONITORING AND STUDY SITE INSPECTIONS
This study will be monitored by an authorized Sponsor representative in accordance with 
current ICH GCP guidelines and other applicable regulations and guidelines. Study site visits 
will be performed for the purpose of inspection of all study-related materials and data, patients’ 
medical records, and eCRFs. At any time, each study site may be audited either by Sponsor
personnel, or by a contractor acting on behalf of the Sponsor, or by a regulatory agency such as 
the FDA.
10.7. RECORDS AND RECORD RETENTION
The Investigator must maintain adequate and accurate records to enable the conduct of the 
study to be fully documented, including, but not limited to, the protocol, protocol amendments, 
ICFs, and documentation of IRB/IEC and governmental approval. In addition, at the end of the 
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study, the Investigator will receive the patient data, including an audit trail containing a complete 
record of all changes to data. 
In accordance with US FDA regulations, the Investigator shall retain records for a period of: 
x 
At least 2 years following the date a marketing application is approved for the drug for 
the indication for which it is being investigated; or, 
x 
If no application is to be filed or if the application is not approved for such indication, until 
at least 2 years after the investigation is discontinued and FDA is notified.
In accordance with Australian TGA requirements, the sponsor shall retain records for a period of
at least 15 years following the completion of a clinical trial.
No records may be disposed of without the written approval of the Sponsor or designee. Written 
notification should be provided to the Sponsor prior to transferring any records to another party 
or moving them to another location. 
Records and documents pertaining to the conduct of this study and the distribution of 
Investigational Product include but are not limited to CRFs, ICFs, laboratory test results and 
shipping records, Investigational Product inventory records, the Investigator’s Brochure, signed 
Financial Disclosures, Delegation of Responsibilities log, training records, Sponsor-Investigator 
correspondence, monitoring logs/letters, and regulatory documents (e.g., protocol and 
amendments, IRB/IEC correspondence and approval, signed patient ICFs). 
10.8. CONFIDENTIALITY 
The information obtained during the conduct of this clinical study is confidential, and disclosure 
to third parties other than those noted below is prohibited. Information obtained during the 
conduct of this study will be collected, processed, and transmitted to or for the benefit of the 
Sponsor in accordance with applicable law, as discussed below. 
Information contained therein will be maintained in accordance with applicable law protecting 
patient privacy and may be inspected by the clinical researcher, the researcher’s staff, and the 
Sponsor and its representatives to check, process, evaluate, and use the information collected 
during the study. Processing, evaluation, or use of the information will be performed by a health 
professional for medical purposes and/or by those operating under a duty of confidentiality that 
is equivalent to that of a health professional. Information will be transmitted and processed as 
the Sponsor may direct, including to the Sponsor and its representatives in the US or 
elsewhere. 
Information obtained from the study will likely be used by the Sponsor in connection with the 
development of the study drug, including possible filing of applications with governmental 
authorities for marketing approval, and for other pharmaceutical and medical research 
purposes. The study Investigator is obliged to provide the Sponsor with complete test results 
and all data developed in this study. This information may be disclosed to other physicians who 
are conducting similar studies and to the FDA/applicable regulatory agencies as deemed 
necessary by the Sponsor. Patient-specific information may be provided to other appropriate 
medical personnel only with the patient’s permission.
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All Investigators and other research study personnel who process information from the study 
and are employed by or otherwise affiliated with the study site are bound by the confidentiality 
terms of the Clinical Study Agreement between the Sponsor or designee and the study site
covering the conduct of this clinical study. Investigators and other personnel should refer to the 
Clinical Trial Agreement for the specific measures that must be taken to prevent unauthorized or 
unlawful processing or disclosure of data.
To ensure compliance with current Federal Regulations and the ICH GCP guidelines, data 
generated by this study must be available for inspection upon request by representatives of the 
FDA, applicable health authorities, the Sponsor, and the IRB/IEC for each study site.
10.9. FINANCIAL DISCLOSURE
Investigators will provide the Sponsor or designee with sufficient, accurate financial information 
in accordance with local regulations to allow the Sponsor or designee to submit complete and 
accurate financial certification or disclosure statements to the appropriate health authorities. 
Investigators are responsible for providing information on financial interests during the course of 
the study and for 1 year after completion of the study. 
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11.
STUDY PUBLICATION AND AMENDMENTS
11.1. PUBLICATION OF DATA AND PROTECTION OF TRADE SECRETS
The Sponsor will comply with all requirements for publication of study results. 
The Sponsor intends to pursue publication of the results of the study both at scientific 
congresses and in peer-reviewed journals. 
Sponsor approval is required for publication of any data subsets. Patient names and other 
personal data relating to an identified or identifiable patient (such as photographs, audio, 
videotapes, or other factors specific to physical, physiological, mental, economic, cultural, or 
social identity) may not be disclosed in any publication without prior written authorization from 
the Sponsor and the patient.
Authorship criteria for all publications of Shasqi-sponsored clinical trials are based on the 
International Committee of Medical Journal Editors (ICMJE) guideline “Uniform Requirements 
for Manuscripts Submitted to Biomedical Journals” (ICMJE 2010). Authorship credit can be 
granted only to those who make substantial contributions to the publication. 
11.2. PROTOCOL AMENDMENTS
Any protocol amendments will be prepared by the Sponsor or designee. Protocol amendments 
will be submitted to the IRB/IEC and to regulatory authorities in accordance with local regulatory 
requirements.
Approval must be obtained from the IRB/IEC and regulatory authorities (as locally required) 
before implementation of any changes, except for changes necessary to eliminate an immediate 
hazard to patients or changes that involve logistical or administrative aspects only (e.g., change 
in Medical Monitor or contact information).
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12.
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Mita MM, Natale RB, Wolin EM, Laabs B, Dinh H, Wieland S, Levitt DJ, Mita AC. 
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Pisani, P., Airoldi, M., Allais, A., Aluffi Valletti, P., Battista, M., Benazzo, M., Briatore, R., 
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https://doi.org/10.14639/0392-100X-suppl.1-40-2020
Prescriber’s Digital Reference. Doxorubicin Hydrochloride – Drug Summary. Accessed 
November 16, 2022. https://www.pdr.net/drug-summary/Doxorubicin-Hydrochloride-doxorubicin-
hydrochloride-1876.2972
Price KA, Cohen EE. Current treatment options for metastatic head and neck cancer. Curr Treat 
Options Oncol. 2012 Mar;13(1):35-46. doi: 10.1007/s11864-011-0176-y. PMID: 22252884.
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CC, Hollingsworth R. Doxil synergizes with cancer immunotherapies to enhance antitumor 
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Ryan CW, Merimsky O, Agulnik M, Blay JY, Schuetze SM, Van Tine BA, Jones RL, Elias AD, 
Choy E, Alcindor T, Keedy VL, Reed DR, Taub RN, Italiano A, Garcia Del Muro X, Judson IR, 
Buck JY, Lebel F, Lewis JJ, Maki RG, Schöffski P. PICASSO III: A Phase III, Placebo-
Controlled Study of Doxorubicin With or Without Palifosfamide in Patients With Metastatic Soft 
Tissue Sarcoma. J Clin Oncol. 2016 Nov 10;34(32):3898-3905. doi: 
10.1200/JCO.2016.67.6684. Epub 2016 Sep 30. PMID: 27621408.
Sandler S, Bonomi P, Taylor B, Showel J, Slayton R, Lerner H. Doxorubicin and cisplatin for 
recurrent or metastatic squamous cell carcinoma of the head and neck. Cancer Treat Rep. 1984 
Sep;68(9):1163-5.
Sarcoma Statistics. Australian Government Cancer Australia Web site. 
https://sarcoma.canceraustralia.gov.au/statistics. Updated August 26, 2019. Accessed August 
30, 2019.
Savina M, Le Cesne A, Blay JY, Ray-Coquard I, Mir O, Toulmonde M, Cousin S, Terrier 
P,Ranchere-Vince D, Meeus P, Stoeckle E, Honoré C, Sargos P, Sunyach MP, Le Péchoux C, 
Giraud A, Bellera C, Le Loarer F, Italiano A. Patterns of care and outcomes of patients with 
METAstatic soft tissue SARComa in a real-life setting: the METASARC observational study. 
BMC Med. 2017 Apr 10;15(1):78. doi: 10.1186/s12916-017-0831-7. PMID: 28391775; PMCID: 
PMC5385590.
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Sawaya H, Sebag IA, Plana JC, Januzzi JL, Ky B, Tan TC, Cohen V, Banchs J, Carver JR, 
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HM, Beare S. Gemcitabine and docetaxel versus doxorubicin as first-line treatment in previously 
untreated advanced unresectable or metastatic soft-tissue sarcomas (GeDDiS): a randomised 
controlled phase 3 trial. Lancet Oncol. 2017 Oct;18(10):1397-1410. doi: 10.1016/S1470-
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designs for phase I clinical trials in oncology. J Natl Cancer Inst. 1997;89:1138-47.
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comparison with gated equilibrium radionuclide ventriculography. PLoS One. 2014;9(5), 
e96736, doi: 10.1371/journal.pone.0096736.
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SP, Riedel RF, Krarup-Hansen A, Toulmonde M, Ray-Coquard I, Hohenberger P, Grignani G, 
Cranmer LD, Okuno S, Agulnik M, Read W, Ryan CW, Alcindor T, Del Muro XFG, Budd GT,
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Lancet Oncol. 2018 Feb;19(2):e78. PMID: 28651927; PMCID: PMC7771354.
Unger C, Häring B, Medinger M, Drevs J, Steinbild S, Kratz F, Mross K. Phase I and 
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Verschoor AJ, Litière S, Marréaud S, Judson I, Toulmonde M, Wardelmann E, LeCesne A, 
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Wheeler, G.M., Mander, A.P., Bedding, A. et al. How to design a dose-finding study using the 
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Working PK, Dayan AD. Pharmacological-toxicological expert report. CAELYX. (Stealth 
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anticancer therapies: reinstating immunosurveillance. Immunity. 2013;39:74-88.
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APPENDIX A – SPONSOR APPROVAL
Clinical Development
Approved By
Name, Signature & Date
Scott Wieland, Ph.D, Sr. VP Clinical Development, Shasqi Inc.
Chief Medical Officer
Approved By
Name, Signature & Date
Steve Abella, M.D., Chief Medical Officer, Shasqi Inc.
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APPENDIX B – RECIST V1.1
The Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 (2009) can be viewed 
on-line at the following Web site:
https://ctep.cancer.gov/protocolDevelopment/docs/recist_guideline.pdf
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APPENDIX C – EASTERN COOPERATIVE ONCOLOGY GROUP 
PERFORMANCE STATUS ASSESSMENT
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APPENDIX D – NATIONAL CANCER INSTITUTE COMMON TERMINOLOGY 
CRITERIA FOR ADVERSE EVENTS (CTCAE)
The Cancer Therapy Evaluation Program NCI-CTCAE version 5.0 (November 27, 2017) can be 
viewed on-line at the following NCI Web site:
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm#ctc_50
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APPENDIX E – COLLECTION OF PREGNANCY INFORMATION
x
The Investigator will attempt to collect pregnancy information on:
o
Any dosed female patient who becomes pregnant while participating in this study 
o
Any dosed male patient’s female partner who becomes pregnant while the male 
patient is participating in this study (after obtaining the necessary signed ICF
from the pregnant female partner directly) 
x
The initial information will be recorded on the appropriate pregnancy form and submitted 
to the sponsor via email to SAE@shasqi.com, within 24 hours of learning of the 
pregnancy.
x
The mother will be followed to determine the outcome of the pregnancy. Information on 
the status of the mother and child will be forwarded to the Sponsor. Generally, follow-up 
will not be required for longer than 6 to 8 weeks beyond the estimated delivery date. Any 
termination of pregnancy will be reported, regardless of fetal status (presence or 
absence of anomalies) or indication for the procedure.
x
While pregnancy itself is an AESI and not considered to be an AE or SAE, any 
pregnancy complication or elective termination of a pregnancy for medical reasons will 
be reported as an AE or SAE. 
x
$VSRQWDQHRXVDERUWLRQRFFXUULQJDW 22 weeks gestational age) or still birth (occurring 
at > 22 weeks gestational age) is always considered to be an SAE and will be reported 
as such. 
x
Any post-study pregnancy-related SAE considered reasonably related to the 
Investigational Product by the Investigator will be reported to the Sponsor. While the 
Investigator is not obligated to actively seek this information in former study participants, 
he or she may learn of an SAE through spontaneous reporting.
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APPENDIX F – PK SCHEDULE  
Phase 1 Dose Escalation
CYCLE 1
DAY
PK 
Draw 
PK Time Point 
Relative to SQP33 Protodrug 
Infusion
Day 1
1 
Pre-infusion
2 
5 min post-infusion (+ 5 min)
3 
30 min post-infusion (± 5 min)
4
1 h post-infusion (± 5 min)
5
2 h post-infusion (± 10 min)
6 
4 h post infusion (± 10 min)
Day 2
7 
24 h post-infusion (± 2.5 h) and 
Day 2 pre-infusion
8 
5 min post-infusion (+ 5 min)
9 
30 min post-infusion (± 5 min)
Day 3
10
Pre-infusion 
11
5 min post-infusion (+ 5 min)
12
30 min post-infusion (± 5 min)
Day 4
13
Pre-infusion 
14
5 min post-infusion (+ 5 min)
15
30 min post-infusion (± 5 min)
Day 5
16
Pre-infusion
17
5 min post-infusion (+ 5 min)
18
30 min post-infusion (± 5 min)
19
1 h post-infusion (± 5 min)
20
2 h post-infusion (± 10 min)
21
4 h post infusion (± 10 min)
Note: Post dose PK timings are based on the end time of the SQP33 protodrug infusion, not the 
start. 
CYCLES 2, 3, & 4
DAY
PK 
Draw 
PK Time Point 
Relative to SQP33 
Protodrug Infusion
Day 1
1
Pre-infusion 
2 
5 min post-infusion (+ 5 min)
3 
30 min post-infusion (± 5 
min)
Day 2
4 
24 h post-infusion (± 2.5 h) 
and 
Day 2 pre-infusion
Day 3
5
Pre-infusion 
Day 4
6
Pre-infusion 
Day 5
7
Pre-infusion 
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Phase 2a Expansion Groups
Group 1: Extremity STS
Group 2: Unresectable STS (5-Day Infusion cohort)
CYCLE 1
DAY
PK DRAW
TIMEPOINT
Day 1
1
Pre-infusion
2
15 min post-infusion (± 10 min)
3
2 h post-infusion (± 30 min)
4
4 h post infusion (± 30 min)
Day 2
5
Pre-infusion
6
15 min post-infusion (± 10 min)
Day 3
7
Pre-infusion
8
15 min post-infusion (± 10 min)
Day 4
9
Pre-infusion
10
15 min post-infusion (± 10 min)
Day 5
11
Pre-infusion
12
15 min post-infusion (± 10 min)
13
2 h post-infusion (± 30 min)
14
4 h post infusion (± 30 min)
CYCLE 2
DAY
PK DRAW
TIMEPOINT
Day 1
1
Pre-infusion
2
15 min post-infusion (± 10 min)
Day 2
- 
No draws
Day 3
3
Pre-infusion
4
15 min post-infusion (± 10 min)
Day 4
- 
No draws
Day 5
5
Pre-infusion
6
15 min post-infusion (± 10 min)
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Phase 2a Expansion Groups
Group 2: Unresectable STS (3-Day Infusion cohort)
CYCLE 1
DAY
PK DRAW
TIMEPOINT
Day 1
1
Pre-infusion
2
15 min post-infusion (± 10 min)
3
2 h post-infusion (± 30 min)
4
4 h post infusion (± 30 min)
Day 2
5
Pre-infusion
6
15 min post-infusion (± 10 min)
Day 3
7
Pre-infusion
8
15 min post-infusion (± 10 min)
9
2 h post-infusion (± 30 min)
10
4 h post infusion (± 30 min)
CYCLE 2
DAY
PK DRAW
TIMEPOINT
Day 1
1
Pre-infusion
2
15 min post-infusion (± 10 min)
Day 2
-
No draws
Day 3
3
Pre-infusion
4
15 min post-infusion (± 10 min)
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Phase 2a Expansion Groups
Group 3a: Head and Neck
CYCLE 1
DAY
PK DRAW
TIMEPOINT
Day 1
1
Pre-infusion
2
15 min post-infusion (± 10 min)
3
2 h post-infusion (± 30 min)
4
4 h post infusion (± 30 min)
Day 2
-
No draws
Day 3
-
No draws
Day 4
-
No draws
Day 5
5
Pre-infusion
6
15 min post-infusion (± 10 min)
7
2 h post-infusion (± 30 min)
8
4 h post infusion (± 30 min)
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APPENDIX G – SCHEDULE OF ASSESSMENTS – PHASE 1 DOSE ESCALATION
CYCLES 1 - 4 TREATMENT SCHEDULE
Notes: 
A - Day 10 visit may be performed via 
telephone (using a lab closer to a patient’s 
home) or on-site. 
B - Written informed consent must be 
obtained prior to any study-specific 
procedures.
C - May be performed up to 3 days before 
the visit. 
D - May be performed up to 7 days prior to 
projected every 6 weeks from C1D1 date. 
E - ECG to be performed pre and post 
dose.
F - 7REHFROOHFWHGGD\VSULRUWR&\FOH
Day 1 for women of child-bearing potential.
G - Collect biopsy unless the tumor is 
considered too small to be biopsied; 
optional biopsy at Cycle 4 per investigator 
discretion
H - IP administration is the last procedure 
for each visit (aside from post-dose vitals, 
ECG, and PK draws).
I - SQP33 protodrug infusion occurs within 
2 hrs ± 30 mins after receiving SQL70 
biopolymer injection.
J - Biopsy can be performed during 
screening and up to 4 days prior to Day 1 
for other cycles 
K - Day 1-5 is typically Monday through 
Friday, however if the site can 
accommodate protocol procedures on the 
weekends Day 1 may start on any day of 
the week.
Reminder: Investigator can perform unscheduled labs, ECGs and physical exams as needed / clinically indicated.
Screening
Cycles 1 - 4 Treatment
  Study Day
Day -28 to 
Day -1
Day 1 K 
Day 
2 / 3 / 4
Day 5 
Day 10
± 2 days
Day 17
± 2 days
Week 1
Week 2
Week 3
On-Site
On-Site
On-Site
On-Site
Telephone or 
On-Site  A
On-Site
Screening
Informed consent B
X 
Medical history 
X 
Review Inc/Exc Criteria
X 
Confirm Eligibility
X 
Safety  
Physical Exam 
X 
Symptom-Directed PE 
X C
Cycle 1 only 
Vital Signs 
X 
X 
X 
X 
X 
ECHO or MUGA
X 
Cycle 3 only D
Triplicate 12-Lead ECG  
X 
X C, E
Cycle 1 only
Cycle 1 only 
Cycle 1 only 
ECOG 
X 
X 
AE Review 
X 
X 
X 
X 
X 
Conmed Review 
X 
X 
X 
X 
X 
X 
Labs 
Hematology & Chemistry  
X 
X C
Cycle 1 only 
X 
Cycle 1 only C
X C 
Coagulation & Urinalysis 
X 
X C 
Pregnancy Test 
X F
X C
Serology 
X 
Plasma PK
X 
X 
X 
PBMC
Cycle 1, 2, 3 
only
Tumor Biopsy G
X J
Tumor 
Evaluation
CT / MRI & RECIST 
X 
Every 6 
weeks D
IP H
Administer SQL70 Biopolymer
X 
Administer SQP33 Protodrug 
X I
X 
X 
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PHASE 1: DOSE ESCALATION - CYCLES 5+, SAFETY FU AND LONG-TERM FU SCHEDULE
Notes:
A - Day 1-5 is typically Monday through Friday, 
however if the site can accommodate protocol 
procedures on the weekends Day 1 may start on 
any day of the week.
B - May be performed up to 3 days before the visit.
C - May be performed up to 7 days before the 
visit.
D - ECG to be performed pre and post dose.
E - May be performed up to 7 days prior to the 
projected every 6 weeks from C1D1 date. 
F - IP administration is the last procedure for each 
visit (aside from post-dose vitals and ECG).
G - SQP33 protodrug infusion occurs within 2 hrs 
± 30 mins after receiving SQL70 biopolymer 
injection.
H - Optional biopsy per investigator discretion; can 
be performed up to 4 days prior to Day 1.  
I - ECHO or MUGA not required at the Safety 
Follow-Up visit if performed in the previous 14 
days.
K - CT / MRI & RECIST not required at the Safety 
Follow-Up visit if performed in the previous 6 
weeks.
L – for up to 2 years after treatment end; collected 
during routine clinic visits, telephone or e-mail with 
the subjects/caregivers or referring physician 
offices.
M – Until disease progression per RECIST; May 
be performed up to 14 days before the visit. 
  
Reminder: Investigator can perform unscheduled labs, ECGs and physical exams as needed / clinically indicated.
Cycles 5+ Treatment
SFTY FU
LTFU
Study Day
Day 1 A
Day 
2 / 3 / 4
Day 5 
28-34 days after 
last dose of IP
every 12 weeks
(± 7 days)
On-site 
On-site 
On-site 
On-site 
Variable J
Safety 
Symptom-Directed PE 
X B
X 
Vital Signs 
X 
X 
X 
X 
ECHO or MUGA
X C
X I
Triplicate 12-Lead ECG 
X B, D
X 
ECOG 
X B
X 
AE Review 
X 
X 
X 
X 
Conmed Review 
X 
X 
X 
X 
Labs 
Hematology & Chemistry 
X B
X 
X B
Coagulation & Urinalysis 
X B
X B
Pregnancy Test 
X B
X B
Optional Tumor Biopsy 
X H
Tumor 
Evaluation
CT / MRI & RECIST 
Every 6 weeks E 
X K
X M
IP F
Administer SQL70 Biopolymer 
X 
Administer SQP33 Protodrug 
X G
X 
X 
Survival 
Vital Status L
X 
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APPENDIX H – SCHEDULE OF ASSESSMENTS – EXPANSION GROUP 1: EXTREMITY STS
Study Day
Screening 
Treatment
SFTY FU
LTFU
Week 1
Week 2
Day -28 to Day -1
Day 1 A 
Day 
2 / 3 / 4
Day 5 
Day 10
± 2 days
28-34 days after 
last dose of IP
every 12 weeks 
(± 7 days)
On-Site
On-Site
On-Site
On-Site
Telephone or On-
Site B
On-site
Variable M
Screening
Informed consent C
X
Medical history 
X 
Review Inc/Exc Criteria
X
Confirm Eligibility
X 
Safety  
Physical Exam 
X
Symptom-Directed PE 
X D
X 
Vital Signs
X
X
X
X
X
ECHO or MUGA
X 
Every other cycle E
X K
Triplicate 12-Lead ECG 
X
X D, F
Cycle 1 Only
Cycle 1 Only
X
ECOG 
X 
Cycle 2+ 
X 
AE Review
X
X
X
X
X
Conmed Review 
X 
X 
X 
X 
X 
X 
Labs 
Hematology & Chemistry 
X
X D
Cycle 1 Only
X
Cycle 1 Only D
X D
Coagulation & Urinalysis 
X 
X D
Pregnancy Test
X G
X D
X D
Serology 
X 
Plasma PK
Cycle 1 & 2 only; see separate PK Schedule
PBMC / ctDNA O
Cycle 1, 2, 3 only 
Cardio Tox Biomarkers
X
Every other cycle E
X
Tumor Biopsy 
Cycle 1, 2, 3 only H
CT / MRI & RECIST
X
Every 6 weeks I
X L
X N
IP 
Administer SQL70 Biopolymer
X 
Administer SQP33 Protodrug
X J
X
X
Survival 
Vital Status 
X 
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Notes For APPENDIX H – Schedule of Assessments – EXPANSION GROUP 1: EXTREMITY STS
A - Day 1-5 is typically Monday through Friday, however if the site can accommodate protocol procedures on the weekends Day 1 
may start on any day of the week.
B - Day 10 visit may be performed via telephone (using a lab closer to a patient’s home) or on-site.
C - Written informed consent must be obtained prior to any study-specific procedures.
D - May be performed up to 3 days before the visit.
E - ECHO/MUGA to be performed every other cycle starting at Cycle 3; may be performed up to 7 days before the visit.  Serum 
sample for cardiotoxicity biomarker analysis is to be collected on the same day.
F - ECG to be performed pre dose and post dose +30 minutes.
G - 7REHFROOHFWHGGD\VSULRUWR&\FOH'D\IRUZRPHQRIFKLOG-bearing potential.
H - Collect biopsy unless the tumor is considered too small to be biopsied; biopsy can be performed during screening and up to 4 
days prior to Day 1 for other cycles.  Resected tumor samples should be collected at the time of surgery.
I - May be performed up to 7 days prior to the projected every 6 weeks from C1D1 date presurgical disease re-evaluation.
J - SQP33 protodrug infusion occurs within 3 hrs ± 30 mins after receiving SQL70 biopolymer injection.
K - ECHO or MUGA not required at the Safety Follow-Up visit if performed in the previous 14 days.
L - CT / MRI & RECIST not required at the Safety Follow-Up visit if performed in the previous 6 weeks.
M - For up to 2 years after treatment end; collected during routine clinic visits, telephone or e-mail with the subjects/caregivers or 
referring physician offices.
N - Until disease progression per RECIST; May be performed up to 14 days before the visit.
O - PBMC and ctDNA tubes are included in the same kit but are separate tubes.  Collection is done on D1 of C1-3 only.  
Reminder: Investigator can perform unscheduled labs, ECGs and physical exams as needed / clinically indicated.

	
	


SQ3370-001 Protocol
Amendment 8: 2022-11-17 
Shasqi, Inc.
Page 121 of 126
CONFIDENTIAL 
APPENDIX I – SCHEDULE OF ASSESSMENTS – EXPANSION GROUP 2: UNRESECTABLE STS (5 DAY)
Study Day
Screening 
Treatment
SFTY FU
LTFU
Week 1
Week 2
Day -28 to 
Day -1
Day 1 A 
Day 
2 / 3 / 4
Day 5 
Day 10
± 2 days
28-34 days after 
last dose of IP
every 12 weeks 
(± 7 days)
On-Site
On-Site
On-Site
On-Site
Telephone or 
On-Site B
On-site
Variable M
Screening
Informed consent C
X
Medical history 
X 
Review Inc/Exc Criteria
X
Confirm Eligibility
X 
Safety  
Physical Exam 
X
Symptom-Directed PE 
X D
X 
Vital Signs
X
X
X
X
X
ECHO or MUGA
X 
Every other cycle 
E
X K
Triplicate 12-Lead ECG 
X
X D, F
Cycle 1 Only
Cycle 1 Only
X
ECOG
X
Cycle 2+
X
AE Review
X
X
X
X
X
Conmed Review
X
X
X
X
X
X
Labs 
Hematology & Chemistry 
X
X D
Cycle 1 Only
X
Cycle 1 Only D
X D
Coagulation & Urinalysis
X
X D
Pregnancy Test
X G
X D
X D
Serology
X
Plasma PK
See Separate PK Schedule
PBMC/ ctDNA
Cycle 1, 2, 3 O
Cardio Tox Biomarkers 
Every other cycle 
E
X 
Tumor Biopsy 
Cycle 1, 2, 3 only
H
CT / MRI & RECIST
X
Every 6 weeks I
X L
X N
IP 
Administer SQL70 Biopolymer 
X 
Administer SQP33 Protodrug
X J
X
X
Survival 
Vital Status 
X 

	
	


SQ3370-001 Protocol
Amendment 8: 2022-11-17 
Shasqi, Inc.
Page 122 of 126
CONFIDENTIAL 
Notes For APPENDIX I – Schedule of Assessments –EXPANSION GROUP 2: UNRESECTABLE STS (5 DAY)
A - Day 1-5 is typically Monday through Friday, however if the site can accommodate protocol procedures on the weekends Day 1 
may start on any day of the week.
B - Day 10 visit may be performed via telephone (using a lab closer to a patient’s home) or on-site.
C - Written informed consent must be obtained prior to any study-specific procedures.
D - May be performed up to 3 days before the visit.
E - ECHO/MUGA to be performed every other cycle starting at Cycle 3; may be performed up to 7 days before the visit.  Serum 
sample for cardiotoxicity biomarker analysis is to be collected on the same day.
F - ECG to be performed pre dose and post dose +30minutes. 
G - 7REHFROOHFWHGGD\VSULRUWR&\FOH'D\IRUZRPHQRIFKLOG-bearing potential.
H - Collect optional biopsy unless the tumor is considered too small to be biopsied; biopsy can be performed during screening and up 
to 4 days prior to Day 1 for other cycles. 
I - May be performed up to 7 days prior to the projected every 6 weeks from C1D1 date.
J - SQP33 protodrug infusion occurs within 3 hrs ± 30 mins after receiving SQL70 biopolymer injection.
K - ECHO or MUGA not required at the Safety Follow-Up visit if performed in the previous 14 days.
L - CT / MRI & RECIST not required at the Safety Follow-Up visit if performed in the previous 6 weeks.
M - Capture and report next line of therapy x1 then for up to 2 years after treatment end; collected during routine clinic visits, 
telephone or e-mail with the subjects/caregivers or referring physician offices.
N - Until disease progression per RECIST; May be performed up to 14 days before the visit.
O - In addition to Day 1 of Cycles 1, 2, and 3, plasma samples should be taken at the time of the CT / MRI scans for RECIST
between Cycles 4 -12 (see footnote I).  PBMC and ctDNA tubes are included in the same kit but are separate tubes.
Reminder: Investigator can perform unscheduled labs, ECGs and physical exams as needed / clinically indicated.

	
	


SQ3370-001 Protocol
Amendment 8: 2022-11-17 
Shasqi, Inc.
Page 123 of 126
CONFIDENTIAL 
APPENDIX J – SCHEDULE OF ASSESSMENTS – EXPANSION GROUP 2: UNRESECTABLE STS (3 DAY)
  Study Day
Screening 
Treatment
SFTY FU
LTFU
Week 1
Week 2
Day -28 to 
Day -1
Day 1 A 
Day 2 
Day 3 
Day 10
± 2 days
28-34 days after 
last dose of IP
every 12 weeks 
(± 7 days)
On-Site
On-Site
On-Site
On-Site
Telephone or 
On-Site B
On-site
Variable M
Screening
Informed consent C
X
Medical history 
X 
Review Inc/Exc Criteria
X
Confirm Eligibility
X 
Safety  
Physical Exam 
X
Symptom-Directed PE 
X D
X 
Vital Signs
X
X
X
X
X
ECHO or MUGA
X 
Every other cycle E
X K
Triplicate 12-Lead ECG 
X
X D, F
Cycle 1 Only
Cycle 1 Only
X
ECOG 
X 
Cycle 2+ 
X 
AE Review
X
X
X
X
X
Conmed Review 
X 
X 
X 
X 
X 
X 
Labs 
Hematology & Chemistry 
X
X D
Cycle 1 Only
X
Cycle 1 Only D
X D
Coagulation & Urinalysis 
X 
X D
Pregnancy Test
X G
X D
X D
Serology 
X 
Plasma PK
See Separate PK Schedule
PBMC / ctDNA 
Cycle 1, 2, 3 O
Cardio Tox Biomarkers
X
Every other cycle E
X
Tumor Biopsy 
Cycle 1, 2, 3 only H
CT / MRI & RECIST
X
Every 6 weeks I
X L
X N
IP 
Administer SQL70 Biopolymer
X 
Administer SQP33 Protodrug
X J
X
X
Survival 
Vital Status 
X 

	
	


SQ3370-001 Protocol
Amendment 8: 2022-11-17 
Shasqi, Inc.
Page 124 of 126
CONFIDENTIAL 
Notes For APPENDIX J – Schedule of Assessments –EXPANSION GROUP 2: UNRESECTABLE (3 DAY)
A - Day 1-3 can begin on any day that allows for the completion of the three consecutive treatments within the week.
B - Day 10 visit may be performed via telephone (using a lab closer to a patient’s home) or on-site.
C - Written informed consent must be obtained prior to any study-specific procedures.
D - May be performed up to 3 days before the visit.
E - ECHO/MUGA to be performed every other cycle starting at Cycle 3; may be performed up to 7 days before the visit.  Serum 
sample for cardiotoxicity biomarker analysis is to be collected on the same day.
F - ECG to be performed pre dose and post dose +30 minutes. 
G - 7REHFROOHFWHGGD\VSULRUWR&\FOH'D\IRUZRPHQRIFKLOG-bearing potential.
H - Collect optional biopsy unless the tumor is considered too small to be biopsied; biopsy can be performed during screening and up 
to 4 days prior to Day 1 for other cycles. 
I - May be performed up to 7 days prior to the projected every 6 weeks from C1D1 date.
J - SQP33 protodrug infusion occurs within 3 hrs ± 30 mins after receiving SQL70 biopolymer injection.
K - ECHO or MUGA not required at the Safety Follow-Up visit if performed in the previous 14 days.
L - CT / MRI & RECIST not required at the Safety Follow-Up visit if performed in the previous 6 weeks.
M - Capture and report next line of therapy x1 then for up to 2 years after treatment end; collected during routine clinic visits, 
telephone or e-mail with the subjects/caregivers or referring physician offices.
N - Until disease progression per RECIST; May be performed up to 14 days before the visit. 
O - In addition to Day 1 of Cycles 1, 2, and 3, plasma samples should be taken at the time of the CT / MRI scans for RECIST 
between Cycles 4 -12 (see footnote I).  PBMC and ctDNA tubes are included in the same kit but are separate tubes.   
  
Reminder: Investigator can perform unscheduled labs, ECGs and physical exams as needed / clinically indicated.

	
	


SQ3370-001 Protocol
Amendment 8: 2022-11-17 
Shasqi, Inc.
Page 125 of 126
CONFIDENTIAL 
APPENDIX K – SCHEDULE OF ASSESSMENTS – EXPANSION GROUP 3A: HEAD AND NECK
  Study Day
Screening 
Treatment
SFTY FU
LTFU
Week 1
Week 2
Day -28 to 
Day -1
Day 1 A 
Day 
2 / 3 / 4
Day 5 
Day 10
± 2 days
28-34 days after 
last dose of IP
every 12 weeks 
(± 7 days)
On-Site
On-Site
On-Site
On-Site
Telephone or 
On-Site B
On-site
Variable M
Screening
Informed consent C
X
Medical history 
X 
Review Inc/Exc Criteria
X
Confirm Eligibility
X 
Safety  
Physical Exam 
X
Symptom-Directed PE 
X D
X 
Vital Signs
X
X
X
X
X
ECHO or MUGA
X 
Every other cycle E
X K
Triplicate 12-Lead ECG 
X
X D, F
Cycle 1 Only
Cycle 1 Only
X
ECOG 
X 
Cycle 2+ 
X 
AE Review
X
X
X
X
X
Conmed Review 
X 
X 
X 
X 
X 
X 
Labs 
Hematology & Chemistry 
X
X D
Cycle 1 Only
X
Cycle 1 Only D
X D
Coagulation & Urinalysis 
X 
X D
Pregnancy Test
X G
X D
X D
Serology 
X 
Plasma PK
See Separate PK Schedule
PBMC / ctDNA 
Cycle 1, 2, 3 O
Cardio Tox Biomarkers
X
Every other cycle E
X
Tumor Biopsy 
Cycle 1, 2, 3 only H
CT / MRI & RECIST
X
Every 6 weeks I
X L
X N
IP 
Administer SQL70 Biopolymer
X 
Administer SQP33 Protodrug
X J
X
X
Survival 
Vital Status 
X 

	
	


SQ3370-001 Protocol
Amendment 8: 2022-11-17 
Shasqi, Inc.
Page 126 of 126
CONFIDENTIAL 
Notes For APPENDIX K – Schedule of Assessments –EXPANSION GROUP 3A: HEAD AND NECK
A - Day 1-5 is typically Monday through Friday, however if the site can accommodate protocol procedures on the weekends Day 1 
may start on any day of the week.
B - Day 10 visit may be performed via telephone (using a lab closer to a patient’s home) or on-site.
C - Written informed consent must be obtained prior to any study-specific procedures.
D - May be performed up to 3 days before the visit.
E - ECHO/MUGA to be performed every other cycle starting at Cycle 3; may be performed up to 7 days before the visit. Serum 
sample for cardiotoxicity biomarker analysis is to be collected on the same day.
F - ECG to be performed pre dose and post dose +30 minutes. 
G - 7REHFROOHFWHGGD\VSULRUWR&\FOH'D\IRUZRPHQRIFKLOG-bearing potential.
H - Collect optional biopsy unless the tumor is considered too small to be biopsied; biopsy can be performed during screening and up 
to 4 days prior to Day 1 for other cycles. 
I - May be performed up to 7 days prior to the projected every 6 weeks from C1D1 date.
J - SQP33 protodrug infusion occurs within 3 hrs ± 30 mins after receiving SQL70 biopolymer injection.
K - ECHO or MUGA not required at the Safety Follow-Up visit if performed in the previous 14 days.
L - CT / MRI & RECIST not required at the Safety Follow-Up visit if performed in the previous 6 weeks.
M - Capture and report next line of therapy x1 then for up to 2 years after treatment end; collected during routine clinic visits, 
telephone or e-mail with the subjects/caregivers or referring physician offices.
N - Until disease progression per RECIST; May be performed up to 14 days before the visit. 
O - In addition to Day 1 of Cycles 1, 2, and 3, plasma samples should be taken at the time of the CT / MRI scans for RECIST 
between Cycles 4 -12 (see footnote I).  PBMC and ctDNA tubes are included in the same kit but are separate tubes.   
Reminder: Investigator can perform unscheduled labs, ECGs and physical exams as needed / clinically indicated.

	
	
