Clinical trial NCT04020185
Conditions: Solid Tumor, Adult
Sponsor: ImmuneSensor Therapeutics Inc.
Start date: 2019-09-23; Completion date: 2023-09-15
Enrollment: 40 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
Open-label, dose escalation (Phase I) and dose expansion (Phase IIA) study of patients receiving intra-tumoral IMSA101 alone or in combination with an immune checkpoint inhibitor (ICI) (Phase I and II)

Detailed description:
This is an open-label, dose escalation (Phase I), and dose expansion (Phase IIA) study designed to evaluate safety and efficacy of IMSA101 alone or in combination with an ICI (Phase I and II). Therefore, the study will be conducted in 2 phases. The dose of IMSA101 in Phase IIA will be based on the monotherapy and combination Recommended Phase 2 Doses (RP2Ds) from Phase I.

The following methodology applies to all patients (unless otherwise indicated):

* Pre-treatment screening radiographic tumor assessments will be collected within 30 days prior to initial dose for all patients. Photographic assessments for cutaneously-accessible lesions will be performed as detailed in a separate photography manual.
* Treatment cycles will be 28 days in duration with lesions injected weekly on Day 1 for the first three weeks of Cycle 1 and then every 2 weeks during cycles 2 and beyond.
* A single pre-defined lesion/lesion site (longest diameter ≥ 10 mm and ≤ 35 mm) shall be injected throughout study duration, if possible. Where the original injection site is considered by the investigator to become inaccessible, a second lesion/lesion site shall be selected as a replacement and this shall be used henceforth so long as it is considered accessible. Subsequent injection sites shall be replaced when they are considered inaccessible.
* Where no remaining accessible lesions are present and where benefit of IMSA101 therapy is, in the opinion of the investigator, being derived by the patient, continued injections of IMSA101 into the vicinity of an inaccessible lesion or, in the case that a lesion can no longer be radiographically visualized, into the last known location of the non-visible lesion shall be allowed.
* Patients will be admitted to the hospital for observation overnight following IT injection with IMSA101 on Day 1 of Cycle 1. Patients will be followed throughout the study for drug tolerability and safety by collection of clinical and laboratory data, including information on adverse events (AEs) using CTCAE v5.0 criteria, serious adverse events (SAEs), DLTs, concomitant medications, vital signs, and electrocardiograms (ECGs).
* Patients will be assessed for anti-tumor efficacy based on radiographic assessments and if applicable, photographic tumor assessments, and analysis of Objective Response Rate (ORR), Time to Progression (TTP), and Progression Free Survival (PFS) using RECIST criteria (Appendix 13.2) at screening and the end (≤ 7 days) of even numbered cycles (Cycle 2, Cycle 4, etc.) after the first dosing.

Arms: arm 1: * Dose escalation design in which administered dose levels of IMSA101 as monotherapy will be escalated stepwise in successive cohorts of 3 to 6 patients per dose group (using a standard 3+3 study design) of IMSA101 until the RP2D or maximum tolerated dose (MTD) level is identified.
* The first patient enrolled in each dose level must complete the first two weeks of Cycle 1 prior to enrolling the second and third patients.
* Dose levels to be evaluated include (although not necessarily limited to) 100 µg (representing 1/60th of the pre-clinical Highest Non-Severely Toxic Dose \[HNSTD\] dose), 200 µg, 400 µg, 800 µg, and 1,200 µg. arm 2: * Ph I combination dosing of IMSA101 shall be evaluated upon satisfaction of the following criteria:

  * A given dose level (combo dose level 1) has been confirmed as safe for monotherapy dosing (i.e. 2/6 patients experience Cycle 1 DLT).
  * The next higher dose level (combo dose level 2) has been confirmed as safe for monotherapy dosing (i.e. 2/6 patients experience Cycle 1 DLT).
  * The dose level (combo dose level 1) is found to demonstrate adequate IMSA101 pharmacodynamic (PD) activity based on exploratory endpoints.
* Eligible patients shall have demonstrated RECIST stable disease through ≥ 4 consecutive cycles of an approved PD-1/PD-L1-targeted ICI with no Grade ≥ 3 CTCAE events considered to be drug-related.
* Safety evaluations and dose escalation of IMSA101 administered in combination with current therapy shall proceed in a manner consistent with monotherapy escalation and shall proceed independently of monotherapy dose escalation. arm 3: * This dose-expansion arm of 20 patients is intended to confirm the tolerability of the RP2D and identify provocative signals of IMSA101 anti-tumor activity when administered as monotherapy
* Tumor type to be evaluated will be identified prior to Phase IIA commencement and will be documented in a protocol amendment. arm 4: * This dose-expansion arm of 20 patients is intended to confirm the tolerability of the RP2D and identify provocative signals of IMSA101 anti-tumor activity when administered as combination therapy with PD-1/PD-L1 targeted immune checkpoint inhibitors.
* This arm shall include a safety run-in of 5-10 patients.
* Tumor type and corresponding treatment combination will be identified prior to Phase IIA commencement and documented in a protocol amendment. arm 5: * This dose-expansion arm of 20 patients is intended to confirm the tolerability of the RP2D and identify provocative signals of IMSA101 anti-tumor activity when administered as combination therapy with non-PD-1/PD-L1-targeted immuno-oncology (IO) drugs approved by the FDA.
* This arm shall include a safety run-in of 5-10 patients.
* Tumor type and corresponding treatment combination will be identified prior to Phase IIA commencement and documented in a protocol amendment..
Interventions: intervention 1: IMSA101 intervention 2: Immune checkpoint inhibitor (ICI) intervention 3: Immuno-oncology (IO) therapy
Intervention descriptions: intervention 1: IMSA101 administered by intra-tumoral (IT) injection on Day 1 of Weeks 1, 2, and 3 for Cycle 1 and on Day 1 of Weeks 1 and 3 for all subsequent cycles. intervention 2: Administered according to product label intervention 3: Administered according to product label

Protocol documents:
Prot_SAP_000.pdf: 
IMSA101 
ImmuneSensor Therapeutics 
Clinical Study Protocol: IMSA101-101 
 
 
 
 
 
 
Amendment 9 FINAL (13-JUN-2022) 
Confidential 
Page 1 
 
 
Clinical Study Protocol 
Phase I/IIA Safety and Efficacy Study of IMSA101 in Patients 
with Advanced Treatment-Refractory Malignancies 
IMSA101-101 
 
Drug Development Phase: 
Phase I/IIA 
Investigational Product: 
IMSA101 
IND Number 
142445 
Indication: 
Advanced treatment-refractory malignancies 
Sponsor: 
ImmuneSensor Therapeutics 
2110 Research Row #610 
Dallas, TX 75235 
Protocol Amendment 
9 
Protocol Date and Version: 
13 June 2022  
FINAL 
 
 
Conduct: In accordance with the ethical principles that originate from the Declaration of Helsinki and that are 
consistent with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for 
Human Use (ICH) guidelines for Good Clinical Practice (GCP) and regulatory requirements as applicable. 
 
CONFIDENTIAL INFORMATION 
This document is the sole property of ImmuneSensor Therapeutics (ImmuneSensor). This document and any and 
all information contained herein has to be considered and treated as strictly confidential. This document shall be 
used only for the purpose of the disclosure herein provided. No disclosure or publication shall be made without 
the prior written consent of ImmuneSensor Therapeutics. 
 
 


IMSA101 
ImmuneSensor Therapeutics 
Clinical Study Protocol: IMSA101-101 
 
 
 
 
 
 
Amendment 9 FINAL (13-JUN-2022) 
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Page 2 
PROTOCOL APPROVAL SIGNATURE PAGE 
SPONSOR: IMMUNESENSOR THERAPEUTICS 
I have reviewed and approved this protocol, including appendices and confirm that it follows 
current regulations and GCP guidelines. 
 
 
 
 
Approved By (Signature): 
Date: 
 
 
 
Teresa Mooneyham 
 
 
 
Vice President, 
Clinical Operations and Project Management 
 
 
 
 
 
 


IMSA101 
ImmuneSensor Therapeutics 
Clinical Study Protocol: IMSA101-101 
 
 
 
 
 
 
Amendment 9 FINAL (13-JUN-2022) 
Confidential 
Page 3 
PRINCIPAL INVESTIGATOR’S AGREEMENT 
I have read and understand the contents of this clinical protocol for Study No. IMSA101-101 and 
will adhere to the study requirements as presented, including all statements regarding 
confidentiality. In addition, I will conduct the Study in accordance with current Good Clinical 
Practices and applicable FDA regulatory requirements: 
Name of Principal Investigator: 
 
_______________________________________________________ 
 
 
 
 
Signature 
 
Date 
 
 


IMSA101 
ImmuneSensor Therapeutics 
Clinical Study Protocol: IMSA101-101 
 
 
 
 
 
 
Amendment 9 FINAL (13-JUN-2022) 
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PROTOCOL SYNOPSIS 
Sponsor: 
ImmuneSensor Therapeutics 
Investigational Product: 
IMSA101 
Developmental Phase: 
Phase I/IIA 
Title of Study: Phase I/IIA Safety and Efficacy Study of IMSA101 in Patients with Advanced 
Treatment-Refractory Malignancies 
Protocol Number: IMSA101-101 
Study Center(s): Approximately 5 sites for Phase I and 20 sites for Phase IIA in the United 
States (US)  
Indication: Advanced treatment-refractory malignancies 
Study Population: Adult patients with advanced malignancies refractory to or ineligible for 
standard-of-care therapies 
Study Design: Open-label, dose escalation (Phase I) and dose expansion (Phase IIA) study of 
patients receiving IMSA101 alone or in combination with an immune checkpoint inhibitor 
(ICI) (Phase I and II) 
Objectives: 
Primary Objective: 
• Establish safe recommended Phase II doses (RP2Ds) of IMSA101 administered as 
monotherapy or in combination with an immune checkpoint inhibitor (ICI)  
Secondary Objectives: 
• Characterize the safety and tolerability of IMSA101 administered to cancer patients via 
intratumoral injections as monotherapy or in combination 
• Identify and characterize preliminary signals of anti-tumor activity including overall 
response rate (ORR), duration of treatment response (DOR), time-to-tumor progression 
(TTP), and progression-free survival time (PFS)  
• Characterize the pharmacokinetics (PK) of IMSA101 administered by intratumoral 
injection as monotherapy  
Exploratory Objective: 
• Assess the pharmacodynamics (PD) and biologic activity of IMSA101 
Methodology:  
All Patients: 
• Pre-treatment screening radiographic tumor assessments will be collected within 30 days 
prior to initial dose for all patients. Photographic assessments of skin lesions will be 
performed as detailed in a separate photography manual.  
• Treatment cycles will be 28 days in duration with lesions injected weekly on Day 1 for the 
first three weeks of Cycle 1 and then every 2 weeks during cycles 2 and beyond. 


IMSA101 
ImmuneSensor Therapeutics 
Clinical Study Protocol: IMSA101-101 
 
 
 
 
 
 
Amendment 9 FINAL (13-JUN-2022) 
Confidential 
Page 5 
Sponsor: 
ImmuneSensor Therapeutics 
Investigational Product: 
IMSA101 
Developmental Phase: 
Phase I/IIA 
• A single pre-defined lesion/lesion site (longest diameter ≥ 10 mm and ≤ 50 mm) shall be 
injected throughout study duration, if possible. Where the original injection site is 
considered by the investigator to become inaccessible, a second lesion/lesion site shall be 
selected as a replacement and this shall be used henceforth so long as it is considered 
accessible. Subsequent injection sites shall be replaced when they are considered 
inaccessible. 
• Where no remaining accessible lesions are present and where benefit of IMSA101 therapy 
is, in the opinion of the investigator, being derived by the patient, continued injections of 
IMSA101 into the vicinity of an inaccessible lesion or, in the case that a lesion can no 
longer be radiographically visualized, into the last known location of the non-visible lesion 
shall be allowed. 
• Patients will be admitted to the hospital for observation overnight following intratumoral 
injection with IMSA101 on Day 1 of Cycle 1. Patients will be followed throughout the 
study for drug tolerability and safety by collection of clinical and laboratory data, 
including information on adverse events (AEs) using Common Terminology Criteria for 
Adverse Events (CTCAE) v5.0 criteria, serious adverse events (SAEs), dose-limiting 
toxicities (DLTs), concomitant medications, vital signs, and electrocardiograms (ECGs). 
• Patients will be assessed for anti-tumor efficacy based on radiographic assessments and if 
applicable, photographic tumor assessments, and analysis of ORR, DOR, TTP, and PFS 
using response evaluation criteria in solid tumors (RECIST) v1.1 criteria at screening and 
at the end (≤ 7 days) of even numbered cycles (Cycle 2, Cycle 4, etc.) after the first 
dosing.  
RECIST v1.1 criteria do not mention including or excluding lesions that are being biopsied 
or injected. However, for the purposes of this protocol, the injected and biopsied lesions 
are to be captured as non-target lesions only (Phase I only), as follows: 
• Injected and biopsied lesion = non-target lesion #1 
• Non-injected and biopsied lesion = non-target lesion #2 (if applicable) 
• See Schedule of Assessments and Study Activities (Table 1 and Table 2) for details. 
The Phase I dose escalation is detailed in Figure 8 for monotherapy and Figure 9 and  
Figure 10 for combination therapy. 
Phase I Dose Escalation - Monotherapy: 
• Each dose escalation cohort will initially recruit at least 3 patients in a standard 3+3 
design. To proactively ensure at least 3 patients are considered evaluable, a fourth patient 
may be enrolled and treated in addition to the initial 3 patients in each cohort (the fourth 
patient may only be enrolled if they are identified at the time the third patient slot is being 
filled). 


IMSA101 
ImmuneSensor Therapeutics 
Clinical Study Protocol: IMSA101-101 
 
 
 
 
 
 
Amendment 9 FINAL (13-JUN-2022) 
Confidential 
Page 6 
Sponsor: 
ImmuneSensor Therapeutics 
Investigational Product: 
IMSA101 
Developmental Phase: 
Phase I/IIA 
• Dose escalation design in which administered dose levels will be escalated stepwise in 
successive cohorts of 3 to 6 (NOTE: 7 if fourth slot is filled and a single DLT is identified 
among the first 4 patients) patients per dose group until the RP2D or maximum tolerated 
dose (MTD) level is identified. 
• The first patient enrolled in each dose level must complete the first two weeks of Cycle 1 
prior to enrolling the second and third (fourth when applicable) patients. 
• Dose levels to be evaluated include (although not necessarily limited to) 100 µg 
(representing 1/60th of the pre-clinical highest non-severely toxic dose [HNSTD] dose), 
200 µg, 400 µg, 800 µg, and 1,200 µg. 
• IMSA101 will initially be administered by intratumoral injections on Day 1 of Weeks 1, 2, 
and 3 for Cycle 1 (i.e., weekly dosing 3 out of 4 weeks), and on Day 1 of Weeks 1 and 3 
(i.e., bi-weekly dosing) for all cycles thereafter. 
• No dose escalation decisions will be made until all patients in a dose level complete the 
first 28 days of treatment. NOTE: this includes a fourth additional patient when applicable. 
Dose-escalation/de-escalation decisions will be based on the occurrence of DLTs during 
Cycle 1 of the evaluated dose level and the recommendation of the Cohort Review 
Committee (CRC).  
• If no DLTs are observed among the initial 3 (4 when applicable) patients of an evaluated 
dose level, the dose will be escalated for the following 3 patients. 
• If a single DLT occurs among the initial 3 (4 when applicable) patients of an evaluated 
dose level, 3 additional patients will be enrolled at the same dose level. 
• If ≥ 2 DLTs occur among the initial 3 (4 when applicable) or 6 (7 when applicable) 
patients in an evaluated dose level, the dose level shall be considered unacceptably toxic 
and escalation will be discontinued. 
• Subsequent to invalidation of a given cohort (e.g., when ≥ 2/3 [4 when applicable] or 
≥ 2/6 [7 when applicable] patients in an evaluated dose level experience a DLT), a new 
cohort (e.g., dosing Cohort Xa) will be evaluated in which IMSA101 will be administered 
by intratumoral injection at the same dose level but with the Day 1 dose (priming dose) 
reduced to the next lower dose level. 
• For dosing Cohort Xa, if ≥ 2/3 (4 when applicable) or ≥ 2/6 (7 when applicable) patients 
experience a DLT, the amended dose level shall be considered unacceptably toxic and the 
next lower dose (DL-1) level shall be provisionally labeled the MTD.  
• If the amended dose level Xa is found to be safe, dose escalation shall proceed with the 
exception of the priming dose (Cycle 1, dose 1) which shall be held constant and not 
escalated further. 
• No fewer than 6 total patients shall be evaluated at a given dose level prior to confirmation 
of the dose level as the MTD or RP2D. 


IMSA101 
ImmuneSensor Therapeutics 
Clinical Study Protocol: IMSA101-101 
 
 
 
 
 
 
Amendment 9 FINAL (13-JUN-2022) 
Confidential 
Page 7 
Phase I Dose Escalation - Combination Therapy:  
• Combination therapy with IMSA101 + ICI includes the following IMSA101 dose levels: 
• 800 µg 
• 1,200 µg 
• 2,400 µg (with an initial “priming” dose of 1,200 µg) 
• 3,600 µg (with an initial “priming” dose of 2,400 µg) 
• 4,800 µg (with an initial “priming dose” of 3,600 µg) 
• Combination dosing of IMSA101 shall be evaluated in Phase I upon satisfaction of the 
following criteria: 
A. A given dose level (combo dose level 1) has been confirmed as safe for monotherapy 
dosing (i.e.,  2/6 [7 when applicable] patients experience Cycle 1 DLT). 
B. The next higher dose level (combo dose level 2) has been confirmed as safe for 
monotherapy dosing (i.e.,  2/6 [7 when applicable] patients experience Cycle 1 DLT). 
C. The dose level (combo dose level 1) is found to demonstrate adequate IMSA101 PD 
activity based on exploratory endpoints. 
• Eligible patients for Phase I combination dosing shall meet one of the following criteria: 
• have radiographically-confirmed RECIST stable disease through ≥ 2 consecutive 
cycles of an approved PD-1/PD-L1-targeted immune checkpoint inhibitor (ICI) 
administered as monotherapy 
• be clinically stable following a first (unconfirmed) follow-up radiographic scan 
demonstrating progression of disease on ICI monotherapy 
• have progression through prior ICI therapy administered either as mono or combination 
therapy 
• have received no prior ICI therapy but otherwise be ineligible for all available 
standards of care 
• Phase I combo patients have experienced no prior Grade ≥ 3 CTCAE adverse events on 
ICI therapy that were considered by the investigator to be at least possibly ICI drug-related 
• Phase I combo patients shall either receive de novo the combination of IMSA101 + an ICI 
of their investigator’s choosing or, in cases where they are already receiving ICI 
monotherapy, have IMSA101 added to their current therapy such that Day 1 of IMSA101 
shall represent Cycle 1, Day 1. 
• A radiographic tumor assessment shall have occurred within 30 prior days of adding 
IMSA101 to current therapy. 
• Phase I combination therapy IMSA101 doses of 800 µg and 1,200 µg will be administered 
by intratumoral injections each week for 3 weeks in Cycle 1 (Days 1, 8, and 15), and for 


IMSA101 
ImmuneSensor Therapeutics 
Clinical Study Protocol: IMSA101-101 
 
 
 
 
 
 
Amendment 9 FINAL (13-JUN-2022) 
Confidential 
Page 8 
Sponsor: 
ImmuneSensor Therapeutics 
Investigational Product: 
IMSA101 
Developmental Phase: 
Phase I/IIA 
Cycle 2 and all other cycles thereafter, every other week on Days 1 and 15. Additional 
combination therapy IMSA101 doses of 2,400 µg, 3,600 µg, and 4,800 µg require the 
following priming dose on Day 1 of Cycle 1: 1,200 µg for the 2,400 µg dose group, 
2,400 µg for the 3,600 µg dose group, and 3,600 µg for the 4,800 µg group. After Day 1 of 
Cycle 1, the full dose for these groups will be administered on Day 1 of Weeks 2 and 3 of 
Cycle 1 (i.e., weekly dosing 3 out of 4 weeks), and on Day 1 of Weeks 1 and 3 for all 
cycles thereafter (i.e., bi-weekly dosing). 
• Safety evaluations and dose escalation of IMSA101 administered in combination with 
current ICI therapy shall proceed in a manner consistent with monotherapy escalation, 
with the exception of allowed de-escalation, and shall proceed independently of 
monotherapy dose escalation and evaluations. 
• De-escalation: If ≥ 2 DLTs occur among the initial 3 (4 when applicable) or 6 (7 when 
applicable) patients, de-escalation of IMSA101 is allowed for the combination therapy 
dose levels as follows: 
- 
2,400 µg may be de-escalated to 1,800 µg (with a priming dose of 1,200 µg on Day 1 
of Cycle 1) 
- 
3,600 µg may be de-escalated to 3,000 µg (with a priming dose of 2,400 µg on Day 1 
of Cycle 1) 
- 
4,800 µg may be de-escalated to 4,200 µg (with a priming dose of 3,600 µg on Day 1 
of Cycle 1) 
If ≥ 2 DLTs occur among the initial 3 (4 when applicable) or 6 (7 when applicable) 
patients at a de-escalated dose level, the dose level shall be considered unacceptably toxic 
and escalation will be discontinued. 
• Administration of combination drug will follow the labeled instructions for the product. 
• IMSA101 dose escalation shall proceed such that there will be generated separate RP2Ds 
for IMSA101 administered alone or in combination with other agents (although it is 
possible these will be the same). 
• No fewer than 6 total patients shall be evaluated at a given dose level prior to confirmation 
of the dose level as the MTD or RP2D. 
Phase IIA Dose Expansion:  
• This dose-expansion stage is intended to confirm the tolerability of the RP2D and identify 
provocative signals of IMSA101 anti-tumor activity. 
• It is anticipated that the monotherapy and combination RP2Ds will be evaluated in 
3 discrete arms of 20 patients each with a single arm evaluating monotherapy (Arm A) and 
2 arms evaluating IMSA101 in combination with immuno-oncology (IO) therapies (Arm B 
and Arm C). 
• Arm B will be a combination of IMSA101 with PD-1/PD-L1-targeted ICIs. Dosing 
will be predicated by the combination RP2D identified in Phase I. 


IMSA101 
ImmuneSensor Therapeutics 
Clinical Study Protocol: IMSA101-101 
 
 
 
 
 
 
Amendment 9 FINAL (13-JUN-2022) 
Confidential 
Page 9 
Sponsor: 
ImmuneSensor Therapeutics 
Investigational Product: 
IMSA101 
Developmental Phase: 
Phase I/IIA 
• Arm C will be a combination of IMSA101 with non-PD-1/PD-L1-targeted IO drugs 
approved by the Food and Drug Administration (FDA).  
• Administration of approved drugs to be combined with IMSA101 will follow the labeled 
instructions for the product.  
• Combination arms evaluating IMSA101 combinations shall include a safety run-in of 
5-10 patients to be conducted as follows:  
o If ≤ 1 of 5 initial safety evaluable patients experience a DLT during Cycle 1, 
enrollment shall proceed to Patient 6. 
o If ≤ 3 of 10 initial safety evaluable patients experience a DLT during Cycle 1, 
enrollment shall proceed to its entirety (20 patients in that arm).  
o If ≥ 2 of 5 or ≥ 4 of 10 patients experience a DLT, dose de-escalation shall occur to the 
next lower dose level evaluated in Phase I and the run-in shall be repeated at the next 
lower dose. 
• Tumor types and corresponding treatment combinations to be evaluated will be identified 
prior to Phase IIA commencement with patients enrolled separately into tumor-specific 
arms of 20 patients each. This change will be documented in a protocol amendment 
before it occurs.  
• The need for futility criteria to be evaluated in any of the arms following enrollment of a 
pre-defined number of patients < 20 shall be determined at a later date depending on tumor 
types evaluated. This change will be documented in a protocol amendment before it 
occurs. 
• For all potential patients, there will be up to a 30-day screening and eligibility assessment 
period prior to enrollment. 
All patients will continue to receive their assigned treatment throughout the study until the 
occurrence of disease progression, death, or other unacceptable treatment-related toxicity, or 
until the study is closed by the sponsor.  


IMSA101 
ImmuneSensor Therapeutics 
Clinical Study Protocol: IMSA101-101 
 
 
 
 
 
 
Amendment 9 FINAL (13-JUN-2022) 
Confidential 
Page 10 
Inclusion Criteria:  
Phase I combination only:  
1. Eligible patients will meet one of the following criteria: 
• Have radiographically-confirmed RECIST stable disease through ≥ 2 consecutive 
cycles of an approved PD-1 or PD-L1 targeted ICI administered as monotherapy  
• Be clinically stable following a first (unconfirmed) follow-up radiographic scan 
demonstrating progression of disease on ICI monotherapy 
• Have progression through prior ICI therapy administered either as mono or 
combination therapy 
• Have received no prior ICI therapy but otherwise be ineligible for all available 
standards of care 
2. Have experienced no prior Grade ≥ 3 CTCAE adverse events on ICI therapy that were 
considered by the investigator to be at least possibly ICI drug-related. 
 
All patients (unless otherwise indicated):  
1. Signed informed consent and mental capability to understand the informed consent 
2. Male or female patients ≥ 18 years of age 
3. Histologically or cytologically documented locally advanced or metastatic solid tumor 
malignancies refractory to or otherwise ineligible for treatment with standard-of-care 
agents/regimens, including but not limited to: 
• Malignant melanoma 
• Hormone receptor negative breast cancer 
• Gastro-esophageal cancer 
• Non-small cell lung cancer 
• Head and neck cancer 
• Hepatoma 
• Renal cell carcinoma 
4. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1 
5. Evaluable or measurable disease as follows: 
• 2 or 3 RECIST-evaluable lesions: one that is suitable for injection and biopsied; an 
optional non-injected second lesion that will be biopsied for abscopal effect (only 1 
patient per cohort required to have non-injected lesion that is biopsied; optional for all 
other patients in that cohort); and one measurable lesion that will be followed for 
response only.  
• Injectable tumors shall be accessed by intralesional (cutaneous) or percutaneous 
injection only, including those lesions that are visible, palpable, or detectable by 
standard radiographic or ultrasound methods. Neither surgical procedures nor 
endoscopically-guided injections including those to endobronchial, endoluminal, or 
endosinusoidal spaces shall be allowed. While no anatomic locations are required or 


IMSA101 
ImmuneSensor Therapeutics 
Clinical Study Protocol: IMSA101-101 
 
 
 
 
 
 
Amendment 9 FINAL (13-JUN-2022) 
Confidential 
Page 11 
Sponsor: 
ImmuneSensor Therapeutics 
Investigational Product: 
IMSA101 
Developmental Phase: 
Phase I/IIA 
disallowed, lesions selected for intratumoral injection must, in the opinion of the 
investigator: 
• Not be immediately adjacent to blood vasculature or other physiologic landmarks in 
such a way that will accrue undue safety risk to the patient  
• Have longest diameter ≥ 10 mm and ≤ 50 mm 
• Be fully efficacy evaluable per RECIST v1.1 criteria  
6. Life expectancy > 3 months (Phase I) and > 6 months (Phase IIA) 
7. ECG without evidence of clinically meaningful conduction abnormalities or active 
ischemia as determined by the investigator 
8. Acceptable organ and marrow function as defined below: 
• Absolute neutrophil count > 1,500 cells/μL 
• Platelets > 50,000 cells/μL 
• Total bilirubin ≤ 1.5 times the upper limit of normal (ULN) 
• Aspartate aminotransferase (AST)/alanine transaminase (ALT) ≤ 2.5 times ULN. If 
liver metastases are present, AST/ALT < 5 times ULN 
• Serum creatinine < 1.5 mg/dL and a measured creatinine clearance ≥ 50 mL/min using 
the Cockcroft-Gault formula 
• Prothrombin time (PT)/partial thromboplastin time (PTT) ≤ 1.5 times ULN 
9. Women of child-bearing potential (defined as a female who has experienced menarche and 
who has not undergone successful surgical sterilization (hysterectomy, bilateral 
salpingectomy, or bilateral oophorectomy) or is not postmenopausal (defined as 
amenorrhea for at least 12 consecutive months with an appropriate clinical profile at the 
appropriate age, e.g., greater than 45 years) must have a negative serum pregnancy test 
prior to first dose of study drug 
10. Male and female patients with reproductive potential must agree to use two forms of 
highly effective contraception throughout the study 


IMSA101 
ImmuneSensor Therapeutics 
Clinical Study Protocol: IMSA101-101 
 
 
 
 
 
 
Amendment 9 FINAL (13-JUN-2022) 
Confidential 
Page 12 
Sponsor: 
ImmuneSensor Therapeutics 
Investigational Product: 
IMSA101 
Developmental Phase: 
Phase I/IIA 
Exclusion Criteria:  
All patients: 
1. Anti-cancer therapy within 4 weeks or < 5 half-lives of the first dose of study drug 
2. Failure to recover, to Grade 1 or less, from clinically significant AEs due to prior anti-
cancer therapy, as judged by the investigator. 
3. Known untreated brain metastases or treated brain metastases that have not been stable 
(scan showing no worsening of CNS lesion[s] and no requirement of corticosteroids) 
≥ 4 weeks prior to study enrollment 
4. Baseline prolongation of QT/QTc interval (QTc interval > 470) 
5. Uncontrolled intercurrent illness (including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or 
psychiatric illness/social situations) that in opinion of the investigator would limit 
compliance with study requirements 
6. Women who are pregnant or breastfeeding 
7. Sponsor reserves right to exclude any patient from the study on basis of pre-study medical 
histories, physical examination findings, clinical laboratory results, prior medications, or 
other entrance criteria. 
Test Product, Dose and Mode of Administration:  
Phase I (dose escalation):  
Monotherapy: IMSA101 dose levels of (but not necessarily be limited to) up to 100, 200, 400, 
800, and 1,200 µg through intratumoral injection as monotherapy. 
Combination therapy: IMSA101 in combination with current ICI therapy administered 
according to the label of that product. IMSA101 combination dose levels through intratumoral 
injection are as follows: 
• 800 and 1,200 µg 
• 2,400 µg (with an initial “priming” dose of 1,200 µg) 
• 3,600 µg (with an initial “priming” dose of 2,400 µg)  
• 4,800 µg (with an initial “priming” dose of 3,600 µg) 
 
1 mL IMSA101 total volume will be given as follows: 
Monotherapy: IMSA101 every week for 3 weeks in Cycle 1 (Days 1, 8, and 15) followed by 
every other week in Cycles 2+ (Days 1 and 15). 
Combination therapy: 
• IMSA101 dose levels of 800 and 1,200 µg doses every week for 3 weeks in Cycle 1 (Days 
1, 8, and 15) followed by every other week in Cycles 2+ (Days 1 and 15). 


IMSA101 
ImmuneSensor Therapeutics 
Clinical Study Protocol: IMSA101-101 
 
 
 
 
 
 
Amendment 9 FINAL (13-JUN-2022) 
Confidential 
Page 13 
Sponsor: 
ImmuneSensor Therapeutics 
Investigational Product: 
IMSA101 
Developmental Phase: 
Phase I/IIA 
• IMSA101 dose levels of 2,400, 3,600, and 4,800 µg: Day 1 of Cycle 1 priming dose of 
1,200 µg for the 2,400 µg dose group, 2,400 µg for the 3,600 µg dose group, and 3,600 µg 
for the 4,800 µg group through intratumoral injection. After Day 1 of Cycle 1, the full 
dose through intratumoral injections on Day 1 of Weeks 2 and 3 of Cycle 1 (i.e., weekly 
dosing 3 out of 4 weeks), and on Day 1 of Weeks 1 and 3 for all cycles thereafter 
(i.e., bi-weekly dosing). 
Phase IIA (dose expansion) 
Monotherapy: IMSA101 at RP2D dose through intratumoral injection. 
Combination therapy: IMSA101 at combination RP2D dose through intratumoral injection in 
combination with IO therapy administered according to the label of that product.  
1 mL IMSA101 total volume will be given every week for 3 weeks in Cycle 1 (Days 1, 8, 
and 15) followed by every other week in Cycles 2+ (Days 1 and 15). 
Number of Patients: Approximately: 115 
Phase I: Approximately 45 patients in 5 dose cohorts  
Phase IIA: Approximately 70 patients in 3 arms of approximately 20–25 patients each  
Estimated Study Duration:  
The expected duration of Phase I is approximately 18 months. 
The expected duration of Phase IIA is approximately 18 months.  
Study Endpoints: 
Primary Endpoint: 
• MTD/RP2D of IMSA101 administered by intratumoral injection alone or in combination 
with approved ICI therapy  
Secondary (Safety) Endpoints: 
• Safety of IMSA101 as determined by incidence of treatment-emergent adverse events 
(TEAEs), laboratory abnormalities, and other safety using CTCAE v5.0 criteria 
• Incidence of DLTs in patients administered IMSA101 by intratumoral injection 
Secondary (Efficacy) Endpoints including: 
• RECIST-based objective response rate (ORR) 
• Duration of response (DOR) 
• Time to RECIST-based tumor progression (TTP) 
• Progression-free survival time (PFS) 
 


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Sponsor: 
ImmuneSensor Therapeutics 
Investigational Product: 
IMSA101 
Developmental Phase: 
Phase I/IIA 
PK Endpoints (Phase I monotherapy only): 
• PK parameters of IMSA101 administered by intratumoral injection  
Exploratory PD Endpoints (Phase I only): 
• Blood levels of cytokines (pre-dose, 2h, 4h, 6h, 24 h post-dosing Cycle 1 Day 1 and 
Cycle 2 Day 15): IL6 and IP10, IFNγ, TNFα, IL-10, IL-1β, IFN-β, MCP-1 (CCL2)  
• Blood (pre-dose on Day 1 of Cycles 1, 2, and 3): Flow cytometry of Cryopreserved 
PBMCs CD3, CD4, CD8, CD45, CD69, CD19, CD56, FOXP3, PD-1, PD-L1, CD141, 
CD86, HLA-DR, CD14, CD16, CD11c 
• Tumor Biopsy for injected tumor and non-injected tumor, if applicable (non-injected 
tumor biopsy required in at least 1 patient per cohort) (pre-dose on Cycle 1 Day 1, Cycle 1 
Day 15, Cycle 2 Day 15): Multiplexed Immunofluorescence (mIF) including antibodies to 
CD45, CD4, CD8, CD11c, CD56(NK), FOXP3, DAPI, PD-1, and PD-L1  
An aliquot of tumor sample for injected and non-injected tumor is to be stored for later RNA 
isolation and sequencing when the analysis is warranted based on clinical or immunological 
responses.  


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Criteria for Evaluation: 
MTD/RP2D: 
• Definition of Maximum Tolerated Dose (MTD): The MTD is defined as the highest dose 
level of IMSA101 at which no more than 1 out of 6 (7 when applicable) patients 
experiences a DLT during the first cycle (28 days) of therapy.  
• Definition of Recommended Phase 2 Dose (RP2D): The RP2D is defined as the dose 
(either at MTD or below MTD) that is selected for evaluation in the Phase IIA component 
of the study. 
• The MTD/RP2D of IMSA101 will be determined by the sponsor and the CRC.  
Safety: 
• Safety assessments will include evaluation of TEAEs, DLTs, vital signs, 12-lead ECG, 
physical examination, and laboratory safety assessments. Toxicities will be graded using 
CTCAE v5.0. Patients will be observed for 1 hour in the clinic following intratumoral 
injections. In addition, following intratumoral injection on Day 1 of Cycle 1, patients will 
be admitted to the hospital for observation overnight.   
• Safety data will be listed by study site, patient number, and cycle. All TEAEs will be 
summarized by study phase and assigned dose. In addition, all SAEs, including deaths will 
be listed separately and summarized.  
• Grade 3 and 4 laboratory data will be summarized by study phase and assigned dose.  
• For patients who experience a DLT, data on AEs leading to treatment/study discontinuation 
will be listed. 
Dose Limiting Toxicity (DLT): DLT will be defined as the occurrence of any of the following 
events that is considered at least possibly related to IMSA101 in the first 28 days (first cycle) 
of treatment. The severity of AEs will be graded according to CTCAE v5.0.  
Hematologic AEs 
• ≥ Grade 4 neutropenia lasting for > 7 days 
• Febrile neutropenia (defined as ANC < 1000/mm3 with a single temperature of 38.3ºC 
(101°F) or a sustained temperature of 38ºC (100.4°F) for > 1 hour) 
• ≥ Grade 4 thrombocytopenia, or Grade 3 thrombocytopenia associated with Grade ≥ 2 
bleeding 
• ≥ Grade 4 anemia 
 
Non-hematologic AEs:  
• Elevation of ALT or AST by ≥ 3X ULN with concurrent elevation of serum total bilirubin 
≥ 2X ULN 
• Any ≥ Grade 3 non-hematologic AE of any duration will be considered a DLT with the 
following exceptions: 
• Nausea/vomiting/diarrhea: 
• To be considered a DLT, ≥ Grade 3 nausea/vomiting/diarrhea must be refractory to 
supportive care and last > 3 days.  


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Sponsor: 
ImmuneSensor Therapeutics 
Investigational Product: 
IMSA101 
Developmental Phase: 
Phase I/IIA 
• ≥ Grade 3 nausea/vomiting/diarrhea that lasts ≤ 3 days is not a DLT. 
• Fatigue: 
• 
To be considered a DLT, ≥ Grade 3 fatigue must last > 7 days. 
• 
≥ Grade 3 fatigue that lasts ≤ 7 days is not a DLT. 
Efficacy: 
Tumor Assessments 
• All known sites of disease must be documented at screening and re-assessed at each 
subsequent tumor evaluation.  
• Screening and subsequent tumor assessments must include CT scans (with IV contrast 
unless contraindicated and oral contrast as appropriate per institutional standards) or MRI 
of the chest, abdomen, and pelvis. Photographic assessments of skin lesions will be 
performed through a photography vendor as detailed in a separate photography manual.  
• If a CT scan for tumor assessment is performed in a positron emission tomography 
(PET)/CT scanner, the CT acquisition must be consistent with the standards for a full-
contrast CT scan.  
• Brain imaging (either MRI or contrast-enhanced CT) is required at screening for all 
patients displaying clinical signs of possible CNS involvement.  
• Further investigations such as bone scans should also be performed if there is any clinical 
suspicion of disease at any site that may not be demonstrated by the minimum schedule of 
assessments listed above.  
• The same radiographic procedures used to assess disease sites at screening should be used 
throughout the study (e.g., the same contrast protocol for CT scans). Assessments should 
be performed by the same evaluator if possible to ensure internal consistency across visits.  
• All findings will be assessed for response according to RECIST v1.1 criteria at the end 
(≤ 7 days) of every even numbered cycle (Cycle 2, Cycle 4, etc.).  
Pharmacokinetics (Phase I monotherapy only): 
Blood samples for PK will be collected at multiple time points. Plasma concentrations at each 
time point will be listed and summarized by each dose level. Plasma concentrations versus 
time profiles (with concentrations on both a log and linear scale) will be plotted for each 
patient; similar summary plots will be constructed for each dose level. PK parameters will be 
calculated by visit. 
Pharmacodynamics (Phase I only): 
Blood and tumor samples to be collected at multiple time points for exploratory assessment of 
several biomarkers. 


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Sponsor: 
ImmuneSensor Therapeutics 
Investigational Product: 
IMSA101 
Developmental Phase: 
Phase I/IIA 
Statistical Methods: 
Phase IIA statistics will be mainly descriptive and informed by the ultimate selection of tumor 
types to be evaluated. Statistical methods including pre-defined criteria for signal detection 
and drug differentiation from standard-of-care benchmarks as well as stage progression and 
futility assessment will be included in the final statistical analysis plan (SAP).  


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Table 1 
Phase I Schedule of Assessments and Study Activities 
Procedures 
Screening 
Days –30 to 1 
Cycle 1 14 
≥ Cycle 2 14 
EOT14 
EOS 15 
Study Day 
Day 1 
Day 8 
Day15 
Day 1 
Day 15 
End of 
Even 
Cycles 
Informed Consent 
X  
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
Medical history 1 
X 
 
 
 
 
 
 
 
 
Concomitant medications  
X 
X16  
X 
X 
X 
X 
 
X 
 
Demographic data 
X 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
Vital signs,  weight  
X 
X16 
X 
X 
X 
X 
 
X 
 
Physical examination 2 
X 
 
 
 
 
 
 
X 
 
Neurologic examination  
X 
X16 
X 
X 
X 
X 
 
X 
 
ECOG Performance Status  
X 
X16 
X 
X 
X 
X 
 
X 
 
ECG 3  
X 
X 
X 
X 
 
 
 
X 
 
Hematology 4 
X 
 
X 
X 
X 
X 
 
X 
 
Coagulation 4  
X 
 
 
 
 
 
 
 
 
Chemistry 4 
X 
 
X 
X 
X 
X 
 
X 
 
Urinalysis 4 
X 
 
 
 
 
 
 
 
 
Pregnancy test 5 
X 
 
 
 
 
 
 
X 
 
PK blood samples 6 
 
X 
 
 
 
C2D15 
 
 
 
PD blood samples 7  
 
X 
 
 
C2, C3 
C2D15 
 
 
 
PD tissue samples 7 
 
X 
 
X 
 
C2D15 
 
 
 
Disease assessment using RECIST 8 
X 
 
 
 
 
 
X 
X 
 
Drug administration 9 
 
X 
X17 
X17 
X 
X 
 
 
 
Patient Observation10 
 
X 
X 
X 
X 
X 
 
 
 
Hospital admission11 
 
X 
 
 
 
 
 
 
 
Assessment for AEs 12 
 
X 
X 
X 
X 
X 
 
X 
X 
Archival Tumor Tissue 13 
X 
 
 
 
 
 
 
 
 


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AE: adverse event; ECG: electrocardiogram; ECOG: Eastern Cooperative Oncology Group; EOS: end of study; EOT: end of treatment; PD: pharmacodynamics; 
PK: pharmacokinetics; RECIST: response evaluation criteria in solid tumors. 
1 
Full medical history at screening. 
2 
Full physical examinations will be done at screening and EOT visit only; all other endpoints will employ assessment of AEs and captured in AE and disease 
assessment CRFs. 
3 
ECGs will be performed at screening, 30 to 60 minutes post-dose on C1D1, C1D8, C1D15, and at EOT and at any other visit where the investigator believes 
the assessment is indicated. 
4 
Laboratory analyses will be performed by local lab and include hematology, coagulation, chemistry, and urinalysis. Screening labs must be performed 
< 72 hours prior to Cycle 1 Day 1. Refer to Section 6.6 for details.  
5 
If the patient is a woman of childbearing potential, a serum pregnancy test must be performed during screening and at EOT.  
6 
PK plasma samples will be collected from Phase I monotherapy patients only at pre-dose, 10, 20, and 30 minutes after treatment, and 1, 2, and 4 hours after 
treatment on Cycle 1, Day 1. If concentrations of IMSA101 are detectable at any timepoint in Cycle 1, samples will be collected on Cycle 2, Day 15 
pre-dose, 10, 20, and 30 minutes after treatment and 1, 2, and 4 hour after treatment. Additional time points (6 and 24 hours after treatment) will also be 
collected, if any concentrations of IMSA101 are detected at the Cycle 1, 4 hour measurement. The following time windows for plasma PK sample collection 
are allowed: ≤ 24 hours for the pre-dose sample, ± 5 minutes for the 10-, 20-, and 30-minute post-dose samples, ± 10 minutes for the 1-hour post-dose 
sample, ±15 minutes for the 2-, 4-, and 6-hour post-dose samples, and ± 2 hours for the 24-hour post-dose sample. For detailed instructions, refer to 
laboratory manual. 
7 
PD blood samples outlined in Section 2.4.5 will be collected on both blood and tumor tissue for all Phase I patients in Cycles 1, 2, and 3. The allowable time 
windows for PD sample collections are described in Section 6.8.1. Core biopsies should be obtained; if not appropriate, biopsies via fine needle aspirate 
(FNA) or excision are permitted. See laboratory manual for detailed instructions. 
8 
All findings will be assessed for response according to RECIST v1.1 criteria (Appendix 13.2). RECIST v1.1 criteria do not mention including or excluding 
lesions that are being biopsied or injected. However, for the purposes of this protocol, the injected and biopsied lesions are to be captured as non-target 
lesions only (Phase I only), as follows: injected and biopsied lesion = non-target lesion #1; non-injected and biopsied lesion = non-target lesion #2 (if 
applicable). Disease assessments will include radiographic assessments and if applicable, photographic assessments of skin lesions, prior to the end (≤ 7 
days) of every even numbered treatment cycle (Cycle 2, Cycle 4, etc.), and EOT. Photographic assessments of skin lesions will be performed through a 
photography vendor at the same time points as the radiographic assessments. Detailed instructions for photography will be included in a separate 
photography manual. In certain circumstances, a patient experiencing RECIST progression of disease may be allowed to continue therapy on study where 
there is agreement between the investigator and sponsor that the patient is deriving clinical benefit. 
9 
IMSA101 monotherapy doses of 100, 200, 400, 800, or 1,200 µg will be administered by intratumoral injection on Day 1 of Weeks 1, 2, and 3 for Cycle 1 
(i.e., weekly dosing 3 out of 4 weeks), and on Day 1 of Weeks 1 and 3 (i.e., bi-weekly dosing) for all cycles thereafter. IMSA101 combination therapy doses 
of 800 and 1,200 µg will be administered by intratumoral injection on Day 1 of Weeks 1, 2, and 3 for Cycle 1 (i.e., weekly dosing 3 out of 4 weeks), and on 
Day 1 of Weeks 1 and 3 (i.e., bi-weekly dosing) for all cycles thereafter, and IMSA101 doses of 2,400, 3,600, or 4,800 µg will be administered by 
intratumoral injections on Day 1 of Cycle 1 with a priming dose of 1,200 µg for the 2,400 µg dose group, 2,400 µg for the 3,600 µg dose group, and 3,600 
µg for the 4,800 µg group and after Day 1 of Cycle 1, the full dose for these groups will be administered by intratumoral injections on Day 1 of Weeks 2 and 
3 of Cycle 1 (i.e., weekly dosing 3 out of 4 weeks), and on Days 1 and 15 for all cycles thereafter (i.e., bi weekly dosing). For combo therapy patients, the 
partner drug will be administered as per product label. Where no remaining accessible lesions are present and where benefit of IMSA101 therapy is, in the 


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opinion of the investigator, being derived by the patient, continued injections of IMSA101 into the vicinity of an inaccessible lesion shall be allowed. In the 
case that a lesion can no longer be radiographically visualized, continued injections into the last known location of the non-visible lesion shall be allowed. 
10 
Patients will be observed in the clinic for 1 hour after each intratumoral injection. 
11 
Patients will be admitted to the hospital for observation overnight following intratumoral injection with IMSA101 on Day 1 of Cycle 1 and will be released 
from the hospital when clinically indicated. 
12 
AE reporting begins at the time of study drug administration and continues until 30 days after the last dose. 
13 
Collect archival tumor specimens if available. 
14 
A +/- 3 day visit window is allowed for each visit except for Cycle 1, Day 1 and the End of Even Cycle disease assessment. 
15 
Patients should be followed for safety after the EOT visit and return to clinic 30 days after the last dose for final assessment of interval changes and AEs. 
16 
Cycle 1 Day 1 assessments must be performed within 72 hours prior to Cycle 1 Day 1. 
17 
For Cycle 1 Day 8 and Cycle 1 Day 15, IMSA101 doses should be administered no less than 4 days apart.   
 
 
 


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Table 2 
Phase IIA Schedule of Assessments and Study Activities 
Procedures 
Screening 
Days –30 to 
1 
Cycle 1 11 
≥ Cycle 2 11 
EOT11 
EOS12 
Study Day 
Day 1 
Day 8 
Day15 
Day 1 
Day 15 
End of 
Even 
Cycles 
Informed Consent 
X  
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
Medical history 1 
X 
 
 
 
 
 
 
 
 
Concomitant medications 
X 
X13  
X 
X 
X 
X 
 
X 
 
Demographic data 
X 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
Vital signs, weight 
X 
X13 
X 
X 
X 
X 
 
X 
 
Physical examination 2 
X 
 
 
 
 
 
 
X 
 
Neurologic examination 
X 
X13 
X 
X 
X 
X 
 
X 
 
ECOG Performance Status 
X 
X13 
X 
X 
X 
X 
 
X 
 
ECG 3 
X 
X 
X 
X 
 
 
 
X 
 
Hematology 4 
X 
 
X 
X 
X 
X 
 
X 
 
Coagulation 4  
X 
 
 
 
 
 
 
 
 
Chemistry 4 
X 
 
X 
X 
X 
X 
 
X 
 
Urinalysis 4 
X 
 
 
 
 
 
 
 
 
Pregnancy test 5 
X 
 
 
 
 
 
 
X 
 
Disease assessment using RECIST 6 
X 
 
 
 
 
 
X 
X 
 
Drug administration 7 
 
X 
X14 
X14 
X 
X 
 
 
 
Patient Observation8 
 
X 
X 
X 
X 
X 
 
 
 
Hospital admission 9 
 
X 
 
 
 
 
 
 
 
Assessment for AEs 10 
 
X 
X 
X 
X 
X 
 
X 
X 
AE: adverse event; ECG: electrocardiogram; ECOG: Eastern Cooperative Oncology Group; EOS: end of study; EOT: end of treatment; RECIST: response evaluation criteria in 
solid tumors. 
1 
Full medical history at screening. 
2 
Full physical examinations will be done at screening and EOT visit only; all other endpoints will employ assessment of AEs and captured in AE and disease 
assessment CRFs. 


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3 
ECGs will be performed at screening, 30 to 60 minutes post-dose on C1D1, C1D8, C1D15, and at EOT and at any other visit where the investigator believes 
the assessment is indicated. 
4 
Laboratory analyses will be performed by local lab and include hematology, coagulation, chemistry, and urinalysis. Screening labs must be performed < 72 
hours prior to Cycle 1, Day 1. Refer to Section 6.6 for details.  
5 
If the patient is a woman of childbearing potential, a serum pregnancy test must be performed during screening and at EOT.  
6 
Disease assessments will include radiographic assessments and if applicable, photographic assessments of skin lesions, prior to the end (≤ 7 days) of every 
even numbered treatment cycle (Cycle 2, Cycle 4, etc.), and EOT. Photographic assessments of skin lesions will be performed through a photography vendor 
at the same time points as the radiographic assessments. Detailed instructions for photography will be included in a separate photography manual. In certain 
circumstances a patient experiencing RECIST progression of disease may be allowed to continue therapy on study where there is agreement between the 
investigator and sponsor that the patient is deriving clinical benefit. 
7 
IMSA101 will be administered by intratumoral injection on Day 1 of Weeks 1, 2, and 3 for Cycle 1 (i.e., weekly dosing 3 out of 4 weeks), and on Day 1 of 
Weeks 1 and 3 (i.e., bi-weekly dosing) for all cycles thereafter. For combo therapy patients, the partner drug will be administered as per product label. (See 
Figure 11). Where no remaining accessible lesions are present and where benefit of IMSA101 therapy is, in the opinion of the Investigator, being derived by 
the patient, continued injections of IMSA101 into the vicinity of an inaccessible lesion shall be allowed. In the case that a lesion can no longer be 
radiographically visualized, continued injections into the last known location of the non-visible lesion shall be allowed. 
8 
Patients will be observed in the clinic for 1 hour after each intratumoral injection. 
9 
Patients will be admitted to the hospital for observation overnight following intratumoral injection with IMSA101 on Day 1 of Cycle 1 and will be released 
from the hospital when clinically indicated. 
10 
AE reporting begins at the time of study drug administration and continues until 30 days after the last dose. 
11 
A +/- 3 day visit window is allowed for each visit except for Cycle 1, Day 1 and the End of Even Cycle disease assessment. 
12 
Patients should be followed for safety after the EOT visit and return to clinic 30 days after the last dose for final assessment of interval changes and AEs. 
13 
Cycle 1 Day 1 assessments must be performed within 72 hours prior to Cycle 1 Day 1. 
14 
For Cycle 1 Day 8 and Cycle 1 Day 15, IMSA101 doses should be administered no less than 4 days apart.   
 
 


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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ..........................................................................................................4 
LIST OF ABBREVIATIONS AND DEFINITIONS ..............................................................29 
1 INTRODUCTION .............................................................................................................32 
1.1 
Background ............................................................................................................32 
1.2 
Study Drug .............................................................................................................34 
1.3 
Nonclinical Pharmacology Studies ........................................................................34 
1.3.1 
Pharmacokinetics and Product Metabolism in Animals ............................40 
1.3.2 
Pharmacodynamic Drug Interactions .........................................................40 
1.3.3 
Toxicology Studies ....................................................................................40 
1.3.4 
Safety Studies.............................................................................................41 
1.4 
Clinical Experience ................................................................................................42 
1.5 
Summary of Known Risks and Benefits ................................................................42 
1.6 
Rationale for the Study ..........................................................................................45 
2 STUDY OBJECTIVES AND ENDPOINTS .....................................................................46 
2.1 
Primary Objective ..................................................................................................46 
2.2 
Secondary Objectives.............................................................................................46 
2.3 
Exploratory Objectives ..........................................................................................46 
2.4 
Study Endpoints .....................................................................................................46 
2.4.1 
Primary Endpoint .......................................................................................46 
2.4.2 
Secondary (Safety) Endpoints ....................................................................46 
2.4.3 
Secondary (Efficacy) Endpoints ................................................................46 
2.4.4 
Pharmacokinetic Endpoints (Phase I Monotherapy only) .........................47 
2.4.5 
Exploratory Pharmacodynamic Endpoints (Phase I only) .........................47 
3 STUDY DESIGN...............................................................................................................48 
3.1 
Study Design Overview .........................................................................................48 
3.1.1 
Phase I – Dose Escalation Plan ..................................................................49 
3.1.2 
Phase IIA – Dose Expansion Plan .............................................................54 
3.1.3 
Dose-limiting Toxicities ............................................................................57 
3.1.4 
Maximum Tolerated Dose/Recommended Phase II Dose .........................57 
3.2 
Stopping Rules .......................................................................................................58 
3.3 
Cohort Review Committee ....................................................................................58 
3.4 
Blinding and Randomization .................................................................................58 
4 SELECTION OF PATIENTS ............................................................................................59 
4.1 
Number of Patients ................................................................................................59 


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4.2 
Inclusion Criteria ...................................................................................................59 
4.3 
Exclusion Criteria ..................................................................................................61 
4.4 
Patients of Reproductive Potential .........................................................................61 
5 STUDY PROCEDURES AND SCHEDULE ....................................................................62 
5.1 
Description of Study Days and Study Treatments .................................................62 
5.1.1 
Screening/Baseline (Day -30 to Day 1) .....................................................62 
5.1.2 
Cycle 1 Day 1 (± 0 Days) ..........................................................................62 
5.1.3 
Cycle 1 Day 8 (+/- 3 Days) ........................................................................63 
5.1.4 
Cycle 1 Day 15 (+/- 3 Days) ......................................................................64 
5.1.5 
Day 1 (+/- 3 Days) of Each Subsequent Cycle ..........................................64 
5.1.6 
Day 15 (+/- 3 Days) of Each Subsequent Cycle ........................................65 
5.1.7 
End of Even-numbered Cycle (< 7 Days) ..................................................65 
5.1.8 
End of Treatment Visit...............................................................................66 
5.1.9 
End of Study Visit (Safety Follow-up 30 days after Last Dose) ...............66 
5.1.10 
Cycle Extensions ........................................................................................66 
5.1.11 
Unscheduled Visits ....................................................................................66 
5.1.12 
Restrictions, Precautions, and Potential Adverse Effects ..........................66 
6 METHODS OF ASSESSMENT AND ENDPOINTS .......................................................68 
6.1 
MTD/RP2D ............................................................................................................68 
6.2 
Demographic Data .................................................................................................68 
6.3 
Medical History .....................................................................................................68 
6.4 
Concomitant Medications ......................................................................................68 
6.5 
Physical Examination and Vital Signs ...................................................................68 
6.6 
Safety Assessments ................................................................................................69 
6.7 
Pharmacokinetic Procedures ..................................................................................70 
6.7.1 
Blood Sampling and Processing ................................................................70 
6.8 
Pharmacodynamic Procedures ...............................................................................71 
6.8.1 
Blood and Tissue Sampling and Processing (Phase I only) .......................71 
6.9 
Tumor Assessments ...............................................................................................71 
7 DISCONTINUATION CRITERIA ...................................................................................73 
7.1 
Discontinuation of Individual Patients...................................................................73 
7.2 
Early Discontinuation of the Study ........................................................................73 
8 TREATMENT ...................................................................................................................75 
8.1 
Dosing and Administration of IMSA101 ...............................................................75 
8.1.1 
Preparation of IMSA101 ............................................................................75 


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8.1.2 
Administration of IMSA101 ......................................................................76 
8.2 
Storage of IMSA101 ..............................................................................................78 
8.3 
Rescue Medications and Concomitant Treatments ................................................78 
8.4 
Treatment Compliance ...........................................................................................78 
9 ADVERSE EVENTS .........................................................................................................79 
9.1 
Definitions..............................................................................................................79 
9.1.1 
Adverse Event ............................................................................................79 
9.1.2 
Serious Adverse Events .............................................................................79 
9.1.3 
Adverse Event by Severity or Intensity .....................................................80 
9.1.4 
Relationship between Adverse Events and Study Drug ............................81 
9.1.5 
Adverse Event Follow-up ..........................................................................81 
9.1.6 
Overdose ....................................................................................................82 
9.1.7 
Pregnancies ................................................................................................82 
9.2 
Serious Adverse Event Reporting ..........................................................................82 
9.2.1 
Reporting Requirements ............................................................................82 
10 STATISTICAL METHODS ..............................................................................................83 
10.1 
General Considerations ..........................................................................................83 
10.1.1 
Statistical and Analytical Plans ..................................................................83 
10.1.2 
Disposition of Patients ...............................................................................83 
10.1.3 
Blinding and Randomization .....................................................................83 
10.2 
Analysis Datasets ...................................................................................................83 
10.2.1 
Safety Population .......................................................................................83 
10.2.2 
Definition of Study Cycles.........................................................................83 
10.3 
Data Presentation ...................................................................................................84 
10.3.1 
Demographic ..............................................................................................84 
10.3.2 
Baseline Characteristics .............................................................................84 
10.3.3 
Medical History and Physical Examination ...............................................84 
10.3.4 
Concomitant Medications or Treatments ...................................................84 
10.3.5 
Safety Data .................................................................................................85 
10.3.6 
Adverse Events ..........................................................................................85 
10.3.7 
Tumor Assessments ...................................................................................85 
10.3.8 
Missing and Spurious Data ........................................................................85 
10.4 
Changes in the Conduct of the Study or Planned Analysis ...................................86 
11 REGULATORY, ETHICAL AND LEGAL OBLIGATIONS ..........................................87 
11.1 
Declaration of Helsinki ..........................................................................................87 


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11.2 
Good Clinical Practice ...........................................................................................87 
11.3 
Institutional Review Boards/Ethics Committees ...................................................87 
11.4 
Regulatory Authority Approval .............................................................................87 
11.5 
Informed Consent...................................................................................................87 
11.6 
Patient Confidentiality and Disclosure ..................................................................88 
11.7 
Protocol Amendment .............................................................................................88 
11.8 
Collection, Monitoring and Auditing Study Documentation .................................89 
11.8.1 
Data Collection ..........................................................................................89 
11.8.2 
Study Monitoring .......................................................................................89 
11.8.3 
Auditing of Study Documentation .............................................................90 
11.9 
Record Retention ...................................................................................................90 
11.10 Disclosure of Information ......................................................................................91 
11.11 Discontinuation of the Study .................................................................................91 
11.12 Study Report, Publication Policy and Archiving of Study Documentation ...........91 
11.12.1 
Data Capture ..............................................................................................91 
11.12.2 
Study Documents .......................................................................................92 
11.12.3 
Archiving of Documents ............................................................................92 
12 REFERENCES ..................................................................................................................93 
13 APPENDICES ...................................................................................................................94 
13.1 
Eastern Cooperative Oncology Group (ECOG) Performance Scale .....................94 
13.2 
RECIST Guideline (Version 1.1) ...........................................................................95 
13.3 
Creatinine Clearance ..............................................................................................99 
13.4 
Contact List ..........................................................................................................100 


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LIST OF IN-TEXT FIGURES 
Figure 1 
The cGAS-cGAMP-STING Pathway ...........................................................33 
Figure 2 
The Chemical Structure and Mechanism of IMSA101 ................................34 
Figure 3 
IMSA101-induced Cytokine Production in Wild-Type and STING-deficient 
Mouse Dendritic Cells ..................................................................................35 
Figure 4 
Cytokine Production Induced by IMSA101 in PBMCs ...............................36 
Figure 5 
Effect of Intratumoral Administration of IMSA101 on B16 Melanoma ......37 
Figure 6 
Abscopal Effect of IMSA101 on AG104A Fibrosarcoma............................38 
Figure 7 
IMSA101 Suppresses Melanoma Metastasis ................................................39 
Figure 8 
Phase I Dose Escalation for Monotherapy ....................................................52 
Figure 9 
Phase I Dose Escalation for Combination Therapy Doses 800 or 1,200 µg .53 
Figure 10 
Phase I Dose Escalation for Combination Therapy Doses 2400, 3,600, and 
4,800 µg ........................................................................................................54 
Figure 11 
Phase IIA Dose Expansion ...........................................................................56 
 


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LIST OF IN-TEXT TABLES 
Table 1 
Phase I Schedule of Assessments and Study Activities ................................18 
Table 2 
Phase IIA Schedule of Assessments and Study Activities ...........................21 
Table 3 
Safety Pharmacology Studies .......................................................................42 
Table 4 
Composition of IMSA101 for Injection........................................................75 
Table 5 
Dose Levels of IMSA101 for Injection ........................................................77 
Table 6 
Definitions of Adverse Events Severity........................................................80 
Table 7 
Guidelines for Determining the Relationship (if any) Between Adverse Event 
and the Study Drug .......................................................................................81 
 
 
 


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LIST OF ABBREVIATIONS AND DEFINITIONS 
Abbreviation 
Definition 
AE 
adverse event 
ALT 
alanine transaminase  
AMP 
adenosine monophosphate 
ANC 
absolute neutrophil count 
aPTT 
activated partial thromboplastin time 
AST 
aspartate transaminase  
ATP 
adenosine triphosphate 
AUC0-inf 
area under the plasma concentration-time curve from time zero to infinity 
AUC0-t 
area under the plasma concentration-time curve from time zero to time t 
CD 
cluster of differentiation 
CFR 
Code of Federal Regulations 
cGAMP 
cyclic-GMP-AMP 
cGAS 
cyclic GMP-AMP synthase 
CI 
confidence interval 
CK 
creatine kinase 
CRC 
Cohort Review Committee 
CRF 
case report form 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTLA4 
cytotoxic T-lymphocyte-associated protein 4 
DC 
Dendritic cells 
DL 
dose level 
DLT 
dose limiting toxicity 
DOR 
duration of treatment response 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EOS 
End of Study 
EOT 
End of Treatment 
F 
bioavailability 
Frel 
relative bioavailability 
FDA 
Food and Drug Administration 
FIH 
first-in-human 
FNA 
fine needle aspirate 


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Abbreviation 
Definition 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
GMP 
guanosine monophosphate 
hERG 
human ether-a-go-go related gene 
HIPAA 
Health Insurance Portability and Accountability Act 
HNSTD 
highest non-severely toxic dose 
IB 
Investigator’s Brochure 
IC50 
half maximal inhibitory concentration 
ICB 
immune checkpoint blockade 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use  
ICI 
immune checkpoint inhibitor 
IEC 
Institutional Ethics Committee 
IFN 
interferon 
IHC 
immunohistochemistry 
IO 
immuno-oncology 
INR 
international normalization ratio 
IL 
interleukin 
IP-10 
IFNγ-inducible protein 10 
IR 
Interventional Radiology 
IRB 
Institutional Review Board 
IV 
intravenous 
MABEL 
minimum anticipated biological effects level 
MCP-1 
monocyte chemoattractant protein 1 
MedDRA® 
Medical Dictionary for Regulatory Activities 
MOA 
mechanism of action 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
NHP 
non-human primate 
ORR 
overall response rate 
PBMCs 
peripheral blood mononuclear cells 
PD 
pharmacodynamics 
PD-1 
programmed cell death-1 
PD-L1 
programmed death-ligand 1 
PDF 
portable document format 


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Abbreviation 
Definition 
PFS 
progression-free survival time 
PK 
pharmacokinetic 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
QTc 
corrected QT interval 
REB 
research ethics board 
RECIST 
response evaluation criteria in solid tumors  
RP2D 
recommended Phase II dose 
SAEs 
serious adverse events 
SAP 
statistical analysis plan 
SEM 
standard error of the mean 
SmPC 
Summary of Product Characteristics 
STING 
stimulator of interferon genes 
TEAE 
treatment-emergent adverse event 
TILs 
tumor infiltrating leukocytes 
TNFα 
tumor necrosis factor α 
TTP 
time-to-tumor progression 
ULN 
upper limit of normal 
US 
United States 
USP 
United States Pharmacopeia 
WBC 
white blood cell 
 


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1 
INTRODUCTION 
1.1 
BACKGROUND 
The treatment of advanced solid tumor malignancies as well as many hematologic malignancies 
continues to be defined by high unmet medical need. In most settings, treatment with cytotoxic 
chemotherapy and targeted kinase inhibitors leads to the emergence of drug-resistant tumor 
clones and subsequent tumor progression and metastasis. 
In recent years, notable success has been achieved through alternate approaches oriented around 
activation of immune-mediated tumor destruction. The immune system plays a pivotal role in 
defending humans and animals against cancer. The anti-tumor effect is controlled by positive 
factors that activate anti-tumor immunity and negative factors that inhibit the immune system. 
Negative factors that inhibit anti-tumor immunity include immune checkpoint proteins, such as 
cytotoxic T-lymphocyte-associated protein 4 (CTLA4), programmed cell death-1 (PD1), and 
programmed death-ligand 1 (PDL1). Immuno-oncology (IO) approaches, including antibodies 
against these checkpoint proteins, have shown remarkable efficacy in several types of human 
cancers.  
However, existing cancer immunotherapy through immune checkpoint blockade (ICB) is 
effective for only a small fraction (on average 20-30%) of cancer patients. The patients who are 
refractory to ICB often have tumors that are not inflamed, or so-called “cold” tumor cells, i.e., 
they lack tumor-infiltrating leukocytes (TILs), such as cluster of differentiation 8 (CD8) T cells 
or the tumor microenvironment suppresses the functions of the TILs. A major thrust of ongoing 
cancer drug development research remains focused on transforming “cold” tumor cells into “hot” 
tumor cells in order to achieve better tumor control across a wider array of patients. 
The innate immune system, which is the first line of defense against pathogens and cancer cells, 
is important for turning the non-inflamed tumors (“cold”) into an inflamed (“hot”) 
microenvironment. A recently discovered innate immunity pathway, the Cyclic GMP-AMP 
Synthase (cGAS)- Stimulator of Interferon Genes (STING) pathway, plays a critical role in anti-
tumor immunity (Figure 1). cGAS is a DNA sensing enzyme that activates the type-I interferon 
pathway. Upon binding DNA, cGAS is activated to synthesize 2’3’ cyclic-GMP-AMP (2’3’-
cGAMP), which then functions as a secondary messenger that binds to and activates the adaptor 
protein STING. STING then activates a signal transduction cascade leading to the production of 
type-I interferons, cytokines and other immune mediators.  


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Figure 1 
The cGAS-cGAMP-STING Pathway 
 
Cytosolic DNA binds to and activates the enzyme cGAS, which then catalyzes the synthesis of cyclic GMP-AMP 
(cGAMP). cGAMP functions as a second messenger that binds to and activates the endoplasmic reticulum 
membrane protein STING, which in turn leads to the production of type-I interferons and other immune stimulatory 
molecules. IMSA101 is an analogue of cGAMP and directly stimulates STING. 
When dying tumor cells are taken up and processed by dendritic cells (DCs), DNA from these 
tumor cells becomes a danger signal that triggers the cGAS–cGAMP-STING pathway to 
promote maturation of DCs and presentation of tumor antigens to T cells. Interferon and 
cytokines produced by DCs and other innate immune cells cooperatively stimulate T cell 
infiltration and function, leading to cytotoxic killing of tumor cells (Figure 2B) (Chen, 2016). 
There is mounting evidence that the cGAS pathway is essential for generating anti-tumor 
immunity (Bose, 2017: Wang 2017).  
As expected, surviving tumor cells develop mechanisms to antagonize host immunity. For 
example, high expression of immune checkpoint molecules such as PDL1 on their cell surface 
bind PD1 on T cells to inhibit the latter’s function. PDL1 inhibitor therapy can reverse the 
inhibition of anti-tumor immunity and restore T cell function. However, in patients with very low 
anti-tumor immunity, the PDL1 inhibitor will have little benefit. Instead, a positive signal is 
needed to boost intrinsic immunity. Toward this end, the administration of cGAMP directly 
stimulates STING and jump-starts antitumor immunity. This activity has demonstrated 
encouraging therapeutic efficacy in several mouse syngeneic tumor models (Li, 2016: Wang 
2017). 


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Figure 2 
The Chemical Structure and Mechanism of IMSA101 
A) Chemical structure of IMSA101. 
B) Mechanism of IMSA101 anti-tumor immunity 
through cGAS-STING pathway. Modified from 
(Chen, 2016). 
 
 
1.2 
STUDY DRUG 
IMSA101 is a small molecule analogue of cGAMP. It contains a trifluoroethyl modification at 
the 3’-OH of the ribose in the GMP moiety of 2’3’-cGAMP. The chemical structure of the 
IMSA101 is shown in Figure 2A. Unlike the natural product 2’3’-cGAMP, which is rapidly 
degraded by an enzyme called ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), 
IMSA101 is resistant to this degradation, thus displaying superior stability. It is more potent than 
the naturally occurring cGAMP and has improved pharmacokinetic/ pharmacodynamic (PK/PD) 
properties. Importantly, IMSA101 does not require the presence of cytosolic DNA for the 
activation of STING.  
The drug product (IMSA101 for Injection) is a sterile and nonpyrogenic solution containing 
10 mg of IMSA101 in 1.0 mL of sodium, potassium phosphate and saline buffer, which is used 
for intratumoral injection. 
1.3 
NONCLINICAL PHARMACOLOGY STUDIES 
In ex vivo cell culture experiments using human and mouse cells, IMSA101 induced production 
of IFNβ, IL6, and IL12 in a dose-dependent manner in wild-type cells, but not in STINGgt/gt cells 
(Figure 3A, B, and C). As a control, IFNβ production in response to Sendai virus, which 
activates the retinoic acid inducible gene I (RIG-I) dependent RNA-sensing pathway, was not 
affected (Figure 3D). 


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Figure 3 
IMSA101-induced Cytokine Production in Wild-Type and STING-deficient Mouse 
Dendritic Cells 
 
A, B, and C) Cytokine production by dendritic cells (DC) derived from either wild-type or STINGgt/gt mice after 
stimulation with different concentrations of IMSA101 as indicated. D) IFNβ production by DC derived from wild-
type and STINGgt/gt mice after infection with Sendai virus. PBS: phosphate-buffered saline; SeV: Sendai virus; WT: 
Wild type. 
IMSA101 also stimulated IFN and IL6 production in peripheral blood mononuclear cells 
(PBMCs) from mouse, rat, dog, monkey and human with similar potency (Figure 4). 


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Figure 4 
Cytokine Production Induced by IMSA101 in PBMCs 
 
PBMCs from human (A, B, C), monkey (D, E, F), dog (G, H), rat (I, J), and mouse (K, L). PBMC: peripheral 
blood mononuclear cell. Data are representative of at least 2 experiments for PBMC from each species. 
When delivered intratumorally in mice bearing tumors, IMSA101 was highly effective in 
inhibiting tumor growth in several syngeneic tumor models, including B16F10 (melanoma), 
MC38 (colon), 4T1 (breast), LL2 (lung) and AG104 (fibrosarcoma). Note that several of these 
tumors such as B16F10, 4T1, LL2 and AG104 are known to be refractory to antibodies against 
PD1, PDL1, or CTLA4. In the B16F10 tumor model, twice weekly injection of IMSA101 for 
two weeks was efficacious in a dose-dependent manner in the range from 0.1 µg to 10 µg (0.005-
0.5 mg/kg) (Figure 5). The combination with anti-PDL1 antibody showed improved efficacy at 
each dose level (Figure 5). Tumor growth was almost completely suppressed at the dose of 
0.05 mg/kg (1 g/mouse) of IMSA101 when combined with anti-PDL1 antibody (Figure 5C). 


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Figure 5 
Effect of Intratumoral Administration of IMSA101 on B16 Melanoma 
 
A, B, C) Tumor growth in mice with indicated treatments. D) Statistics on tumor growth curves. Numbers indicate 
p values between each comparison groups obtained using two-way ANOVA. E, F, G) Survival of mice with 
indicated treatments. H) Statistics on survival curves. Numbers indicate p values between each comparison groups 
obtained using log rank (Mantel Cox) test. ANOVA: analysis of variance; PD1: Programmed Death-Ligand 1. 
An abscopal effect, which is an immune-mediated phenomenon wherein direct treatment of a 
primary tumor can lead to a response in a distant tumor, of IMSA101 was demonstrated in two 
studies using the B16 melanoma model. In one study, there was a decrease in the sizes of non-
injected tumors and prolonged survival following the intratumoral administration of IMSA101 
(Figure 6). In another study, intratumoral administration of IMSA101 reduced lung metastases 
(Figure 7). 


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Figure 6 
Abscopal Effect of IMSA101 on AG104A Fibrosarcoma 
 
C3B6F1 mice (N=8) bearing AG104A tumors on both left and right flanks were treated intratumorally on the right 
flank (primary) with IMSA101 on Days 5, 8, 11, and 15. Tumors on the left flank (distant) were not treated. A) 
Primary tumor growth over time. Data are shown as mean  SEM. B) Distant tumor growth over time. Data are 
shown as mean  SEM. C) Statistical analysis of tumor growth data in A), P values between comparison groups 
were obtained using a two-way ANOVA. D) Statistical analysis of tumor growth data in B), P values between 
comparison groups were obtained using a two-way ANOVA. E) Survival over time. F) Statistical analysis of 
survival data in E). P values between comparison groups were obtained using log rank (Mantel Cox) test. ANOVA: 
analysis of variance; PDL1: Programmed Death-Ligand 1; SEM: standard error of the mean. 


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Figure 7 
IMSA101 Suppresses Melanoma Metastasis 
 
Mice were dose at Days 5, 8, and 11. A) Growth curves of primary tumors over time. Data are shown as mean 
 SEM of 5 mice. B) Statistical analysis of tumor growth data in A), P values between comparison groups were 
obtained using two-way ANOVA. C) Images showing lung metastasis in all groups. Right two panels show 
magnified images of lungs representing selected treatment groups. D) Quantification of lung metastasis in C), each 
symbol represents one mouse. E) Statistical analysis of lung metastasis in D). P values between comparison groups 
were obtained using unpaired t-test. ANOVA: analysis of variance; PDL1: Programmed Death-Ligand 1; SEM: 
standard error of the mean. 
 
 


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1.3.1 
Pharmacokinetics and Product Metabolism in Animals 
The evaluations of the pharmacokinetics (PK), including the absorption, protein binding, and 
metabolic stability of IMSA101 in species that were used in the pharmacology and toxicology 
studies (mouse, rat, and monkey) were conducted. These studies are described in detail in the 
Investigator Brochure, v 1.0, 2019. 
In summary, the PK parameters of IMSA101 were estimated following administration by 
intravenous, subcutaneous, or intratumoral routes in mice at doses of 0.1 or 0.5 mg/kg. IMSA101 
concentrations in plasma were measured using a qualified LC-MS/MS method. The calculated, 
dose corrected area-under-the curves (AUC0-t) were similar by each route. When administered at 
the dose of 0.5 mg/kg, the area-under-the-curve (AUC0-inf) of the intravenous dose was 
494 ng·hr/mL as compared to the AUC0-inf of 597 ng·hr/mL of the subcutaneous dose. The 
calculated bioavailability (F) of the subcutaneous dose was 1.21. The area-under-the-curve 
(AUC0-inf) of the intratumoral dose was 360 ng·hr/mL as compared to the AUC0-inf of 
312 ng·hr/mL of the subcutaneous dose. The calculated relative bioavailability (Frel) of the 
intratumoral dose was 1.12. The calculated half-life was approximately 10-15 minutes. IMSA101 
showed maximal absorption at the first sampling point of 15 minutes following administration.  
The observed comparability of the subcutaneous and intratumoral dose routes provided a 
rationale for using the subcutaneous route of administration in the toxicology studies to 
approximate the intratumoral route that will be used in the clinical studies. 
1.3.2 
Pharmacodynamic Drug Interactions 
No pharmacodynamics drug interactions were evaluated. 
1.3.3 
Toxicology Studies  
The toxicological evaluations of IMSA101 included studies in the rat and cynomolgus monkey 
(non-human primate [NHP]) and should be relevant to assessing potential human risk, as the 
STING pathway, the target of IMSA101, is conserved across species.  
The non-good laboratory practice (GLP) studies in the rat and NHP covered a broad range of 
doses and regimens. The objective of these studies was to evaluate the effects of IMSA101 
following multiple ascending doses, single doses, and multiple doses. The results of the studies 
provided guidance to the design of the subsequent GLP studies in the rat and NHP. 
The general findings in these studies were related to the mechanism of action (MOA) of 
IMSA101 and can be categorized as inflammatory responses characterized by dose-related 
increases in STING pathway factors including Type 1 Interferons (IFNs) and proinflammatory 
cytokines. The findings were similar in the rat and NHP. The most consistent dose related 
findings were increases in IFNα, TNFα, and IL6 in the rat and monkey; IL-8 in the rat; IL-1ra, 
IFNγ-inducible Protein 10 (IP-10), and Monocyte Chemoattractant Protein 1 (MCP-1) in the 
monkey. The cytokine levels showed increases in the first 3-6 hours with return to baseline in 
most cases by 6-24 hours. The innate immune response is characterized by a self-
regulating/modulation of the production of these factors. At low doses, the findings would be 


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characterized as pharmacological changes related to the MOA of IMSA101. With increasing 
doses, the changes could be characterized as “exaggerated” pharmacology, which is expected 
changes related to the MOA of IMSA101, but greater than the responses needed to affect a 
therapeutic response. At the highest dose levels, the IMSA101 pharmacology and exaggerated 
pharmacology resulted in toxicity. Mortality was seen in the GLP rat study in the high doses 
group at 10 and 30 mg/kg. Test article-related increased incidence or severity of minimal or 
slight white matter vacuolation in the brain (within the cerebellum) was noted in animals 
administered ≥1 mg/kg IMSA101 and necropsied at a scheduled or unscheduled interval. The 
observations were not dose-dependent. In recovery animals, white matter vacuolation was 
minimal in severity and the incidence was similar between control and high dose groups. There 
were no abnormal clinical observations that correlated to the brain lesions. Mortality was also 
seen at the 3.0 mg/kg dose level in the non-GLP NHP study. The deaths were attributed to 
pulmonary edema consistent with an IMSA101 mediated inflammatory response that was well 
beyond exaggerated pharmacology and caused the severe toxicity.  
The other common findings across species and across the dose ranges/regimens were dose-
related findings including a range of macroscopic, hematological, clinical chemistry, and 
microscopic findings. At the low doses, these changes were consistent with a desired therapeutic 
effect; at the highest doses, there were severe toxicities and mortality. In studies with recovery 
animals, there was either full recovery or a trend to recovery in the parameters showing dose-
related changes. 
The toxicokinetic findings showed no sex related differences, dose proportionality, and no 
accumulation in the multiple dose studies. 
Moribundity and death were seen at the mid and high dose levels in the GLP rat study. Although 
there was no clear cause of death, the finding was consistent with a dose-related inflammatory 
response, due to exaggerated pharmacology of the MOA of IMSA101. The 3000 to 10000-fold 
safety margins at the 10 and 30 mg/kg dose levels in the GLP rat study should reduce safety 
concerns related to the deaths seen in that study. 
The highest non-severely toxic dose (HNSTD) of IMSA101 was determined as 0.3 mg/kg in the 
monkey GLP study. The first-in-human (FIH) dose was calculated from this dose as 100 µg. 
Using the minimum anticipated biological effects level (MABEL) based on mouse data, FIH 
dose at 100 µg was estimated.  
1.3.4 
Safety Studies 
Two safety pharmacology studies were conducted with IMSA101 including an in vitro human 
ether-à-go-go-related gene (hERG) channel assay and in vivo study to evaluate cardiovascular 
function in monkeys. Both studies demonstrate that IMSA101 does not affect cardiovascular 
function in in vitro system and monkeys. 


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Table 3 
Safety Pharmacology Studies 
Organ/ 
Systems 
Evaluated 
Species/ 
Strain 
Method 
of Admin. 
Doses (mg/kg) 
No. 
per 
Group 
Noteworthy 
Findings 
GLP 
Compliance 
Study 
Number 
Blood 
pressure, 
ECG 
Macaca 
fasicularis 
SC 
0.03, 0.30, 0.60, 
0.10/1.0a 
10 per 
sex 
No dose 
related 
effect 
Yes 
8370304 
In vitro 
hERG  
Human 
In vitro 
incubation 
0.1, 1.0, 10.0 
and 100.0 µM 
3 per 
dose 
level 
Low 
potential for 
hERG 
activation 
Yes 
170520.
DPW 
ECG: electrocardiogram; GLP: good laboratory practice; hERG: human ether-à-go-go-related gene; 
SC: subcutaneous 
a Administration of 0.1 mg/kg of IMSA101 on Day 1. Administration of 1.0 mg/kg of IMSA101 beginning on 
Day 8 and weekly thereafter. 
To evaluate the potential effect of IMSA101 on the cardiovascular system, safety pharmacology 
endpoints of blood pressure and electrocardiogram were evaluated in the good laboratory 
practice (GLP) monkey study (Covance study 8370304). There are no dose-related findings 
noted (Table 3). 
The in vitro effects of IMSA101 on the hERG potassium channel current (a surrogate for IKr, the 
rapidly activating, delayed rectifier cardiac potassium current) expressed in mammalian cells was 
evaluated at ambient temperature using the QPatch HT® (Sophion Bioscience A/S, Denmark), an 
automatic parallel patch clamp system (Effects of Two Test Articles on Ion Channels Expressed 
in Mammalian Cells, hERG assay, Study No. 170520.DPW). IMSA101 was evaluated at 0.1, 
1.0, 10.0 and 100.0 µM, with each concentration tested in three cells (n = 3). The duration of 
exposure to each concentration was at least 3 minutes. On average, no more than 8.7% of hERG 
current was inhibited at concentrations up to 100 µM; therefore, the IC50 values for IMSA101 
was greater than 100 µM, indicating a low potential for hERG activation. 
1.4 
CLINICAL EXPERIENCE 
IMSA101 has not been tested clinically. 
Clinical trials of similar STING agonists are in progress. These include MIW815 from 
Novartis/Aduro Biotech (Aduro Biotech Inc. 2016) and MK-1454 from Merck (Merck Sharp & 
Dohme Corp. 2017). Early results of these studies demonstrate agonism of the STING pathway 
by cyclic dinucleotides similar to IMSA101. The dose-related findings are consistent with the 
findings seen in preclinical studies and related to the MOA of a CDN STING agonist. 
1.5 
SUMMARY OF KNOWN RISKS AND BENEFITS 
Anticipated risks based on findings from pre-clinical studies are listed below.  


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Consistent with the MOA of a STING agonist, the following IMSA101-related findings in these 
studies were noted: 
Dose-proportional Findings: 
• Minimal to mildly increases in body temperature 
Altered Hematology Parameters: 
• Minimal to mildly variable, mild-minimal decreases in platelets, mean corpuscular volume, 
MCH, and hemoglobin 
• Minimal to mildly variable, mild-minimal increases in absolute monocyte count, large 
unstained cells, eosinophils, white blood cells, RBC, hematocrits, and reticulocytes 
• Increases and decreases in basophils and absolute lymphocyte count 
Clinical Chemistries: 
• Minimal to mildly increased in alanine aminotransferase, aspartate aminotransferase, alkaline 
phosphatase, gamma-glutamyl transferase, creatine kinase (CK), inorganic phosphorus, urea 
nitrogen, and fibrinogen 
• Minimal to mildly lower creatinine, total calcium, potassium, globulin, total protein, CK, 
glucose, cholesterol, triglyceride, and sodium 
• Minimal to mildly prolonged activated partial thromboplastin time, prothrombin time 
• Increases in IL-8, TNFα, IL-6, IFNα, MCP-1, IP-10, IL-1ra 
The following drug-related events were reported in ongoing clinical trials evaluating other 
STING agonists being studied in clinical trials: 
Novartis/Aduro Biotech (MIW815) (Aduro Biotech Inc. 2016): 
• Headache 
• Injection site pain 
• Fever 
• Elevated lipase 
Merck (MK-1454) (Merck Sharp & Dohme Corp. 2017): 
• Vomiting 
• Fever 
• Injection site pain 
• Headache 
• Chills 
• Fatigue 
• Myalgia 


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• Tumor pain 
• Diarrhea 
Based on pre-clinical findings with IMSA101 and toxicity events reported in clinical trials 
evaluating other STING agonists, the following risks may reasonably be anticipated in clinical 
trials evaluating IMSA101:  
• Body temperature increases (fever)  
• Chills 
• Alterations in serum chemistries 
• Altered serum hematology parameters 
• Headache 
• Injection site pain 
• Vomiting 
• Fatigue 
• Myalgia 
• Diarrhea 
IMSA101 Combinations: 
Some patients in this study will be treated with a combination of IMSA101 and an immune 
checkpoint inhibitor (ICI) targeting either programmed cell death receptor-1 (PD-1) or 
programmed cell death-ligand 1 (PD-L1). Multiple drugs against PD-1 and PD-L1 are in 
development and have shown great promise across multiple cancer types. Nivolumab and 
pembrolizumab, both of which target PD-1, and atezolizumab, avelumab, and durvalumab, all of 
which target PD-L1, have been approved in various cancer types including melanoma, renal cell 
carcinoma, non-small cell and small cell lung cancer, head and neck cancer, urothelial cancer, 
Hodgkin lymphoma, Merkel cell carcinoma, as well as other solid tumors which demonstrate a 
high level of mutations (also known as microsatellite instability-high or mismatch repair 
deficient tumors). ICIs are associated with a variety of side effects termed immune-related 
adverse events. Believed to arise from general immunologic enhancement, these side effects can 
include skin, gastrointestinal, liver, endocrine/hormonal, and other less common inflammatory 
events. Although extremely rare, fulminant and even fatal side effects can occur with immune 
checkpoint inhibitors and prompt recognition and management is essential. These immune 
related adverse events are generally managed through interruption of the checkpoint inhibitor 
and temporary immunosuppression with corticosteroids and other drugs. The prescribing 
information and specific risks associated with particular ICIs selected by investigators will be 
discussed by investigators with their patients and referenced during informed consent.   


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1.6 
RATIONALE FOR THE STUDY 
Cancer progression is frequently associated with genetic changes and abnormalities - including 
mutations in Wnt, p53, AKT, and signal transducer and activator of transcription 3 (STAT3) – 
which suppress transcription of critical cytokines, leading, in turn, to immunosuppressive tumor 
microenvironments. It is hypothesized here that administration of the cGAMP analog IMSA101 
(either as monotherapy or in combination) can bypass immunosuppressive factors through the 
direct stimulation of dendritic cells (DCs). Preliminary mouse experiments suggest that 
IMSA101-mediated stimulation can super-activate residual DCs through the increased 
expression and secretion of CD86, interferon β, and cross-present antigens to CD8+ T cells. This 
approach is designed, in effect, to transform “cold” IO non-responding tumor cells into “hot” IO 
sensitive cells, addressing unmet medical need and achieving clinical benefit through intensified 
immuno-modulation of malignant cells. 
 


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2 
STUDY OBJECTIVES AND ENDPOINTS 
2.1 
PRIMARY OBJECTIVE 
• Establish safe recommended Phase II doses (RP2Ds) of IMSA101 administered as 
monotherapy or in combination with an ICI  
2.2 
SECONDARY OBJECTIVES 
• Characterize the safety and tolerability of IMSA101 administered to cancer patients via 
intratumoral injections as monotherapy or in combination 
• Identify and characterize preliminary signals of anti-tumor activity including overall response 
rate (ORR), duration of treatment response (DOR), time-to-tumor progression (TTP), and 
progression-free survival time (PFS)  
• Characterize the PK of IMSA101 administered by intratumoral injection as monotherapy 
2.3 
EXPLORATORY OBJECTIVES 
• Assess the PD and biologic activity of IMSA101  
 
2.4 
STUDY ENDPOINTS 
2.4.1 
Primary Endpoint 
• Maximum tolerated dose (MTD)/RP2D of IMSA101 administered by intratumoral injection 
alone or in combination with approved ICI therapy 
 
2.4.2 
Secondary (Safety) Endpoints 
• Safety of IMSA101 as determined by incidence of treatment-emergent AEs (TEAEs), 
laboratory abnormalities, and other safety using Common Terminology Criteria for Adverse 
Events (CTCAE) v5.0 criteria 
• Incidence of dose limiting toxicities (DLTs) in patients administered IMSA101 by 
intratumoral injection 
 
2.4.3 
Secondary (Efficacy) Endpoints 
Secondary efficacy endpoints may include:  


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• Response evaluation criteria in solid tumors (RECIST)-based objective response rate 
(ORR) 
• Duration of response (DOR)  
• Time to RECIST-based tumor progression (TTP) 
• Progression-free survival time (PFS)  
2.4.4 
Pharmacokinetic Endpoints (Phase I Monotherapy only) 
• PK parameters of IMSA101 administered by intratumoral injection: 
 
Cycle 1 Day 1: 
Pre-Dose, 10 min, 20 min, 30 min, 1 h, 2 h, 4 h post-dose 
 
Cycle 2 Day 15 (if any detectable signal noted in Cycle 1): 
Pre-Dose, 10 min, 20 min, 30 min, 1 h, 2 h, 4 h post-dose. Additionally, 6 h, 24 h 
post-dose if previous 4 h post-dose measurement was found detectable in Cycle 1 
 
2.4.5 
Exploratory Pharmacodynamic Endpoints (Phase I only) 
• Blood levels of cytokines (pre-dose, 2h, 4h, 6h, 24 h post-dosing Cycle 1 Day 1 and Cycle 2 
Day 15): IL6 and IP10, IFNγ, TNFα, IL-10, IL-1β, IFN-β, MCP-1 (CCL2) 
• Blood (pre-dose on Day 1 of Cycles 1, 2, and 3): Flow cytometry of Cryopreserved PBMCs 
CD3, CD4, CD8, CD45, CD69, CD19, CD56, FOXP3, PD-1, PD-L1, CD141, CD86, 
HLA-DR, CD14, CD16, CD11c 
• Tumor Biopsy for injected tumor and non-injected tumor, if applicable (non-injected tumor 
biopsy required in at least 1 patient per cohort) (pre-dose on Cycle 1 Day 1, Cycle 1 Day 15, 
Cycle 2 Day 15:) Multiplexed Immunofluorescence (mIF) including antibodies to CD45, 
CD4, CD8, CD11c, CD56(NK), FOXP3, DAPI, PD-1, and PD-L1  
 
An aliquot of tumor sample for injected and non-injected tumor is to be stored for later RNA 
isolation and sequencing when the analysis is warranted based on clinical or immunological 
responses. 
 


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3 
STUDY DESIGN 
3.1 
STUDY DESIGN OVERVIEW 
This is an open-label, dose escalation (Phase I), and dose expansion (Phase IIA) study designed 
to evaluate safety and efficacy of IMSA101 alone or in combination with an ICI (Phase I and II). 
Therefore, the study will be conducted in 2 phases. The dose of IMSA101 in Phase IIA will be 
based on the monotherapy and combination RP2Ds from Phase I.  
The following methodology applies to all patients (unless otherwise indicated): 
• Pre-treatment screening radiographic tumor assessments will be collected within 30 days 
prior to initial dose for all patients. Photographic assessments of skin lesions will be 
performed as detailed in a separate photography manual.  
• Treatment cycles will be 28 days in duration with lesions injected weekly on Day 1 for the 
first three weeks of Cycle 1 and then every 2 weeks during Cycles 2 and beyond. 
• A single pre-defined lesion/lesion site (longest diameter ≥ 10 mm and ≤ 50 mm) shall be 
injected throughout study duration, if possible. Where the original injection site is considered 
by the investigator to become inaccessible, a second lesion/lesion site shall be selected as a 
replacement and this shall be used henceforth so long as it is considered accessible. 
Subsequent injection sites shall be replaced when they are considered inaccessible. 
• Where no remaining accessible lesions are present and where benefit of IMSA101 therapy is, 
in the opinion of the investigator, being derived by the patient, continued injections of 
IMSA101 into the vicinity of an inaccessible lesion or, in the case that a lesion can no longer 
be radiographically visualized, into the last known location of the non-visible lesion shall be 
allowed. 
• Patients will be admitted to the hospital for observation overnight following intratumoral 
injection with IMSA101 on Day 1 of Cycle 1. Patients will be followed throughout the study 
for drug tolerability and safety by collection of clinical and laboratory data, including 
information on adverse events (AEs) using CTCAE v5.0 criteria, serious AEs (SAEs), DLTs, 
concomitant medications, vital signs, and ECGs. 
• Patients will be assessed for anti-tumor efficacy based on radiographic assessments and if 
applicable, photographic tumor assessments, and analysis of ORR, DOR, TTP, and PFS 
using RECIST v1.1 criteria (Appendix 13.2) at screening and the end (≤ 7 days) of even 
numbered cycles (Cycle 2, Cycle 4, etc.) after the first dosing. 
RECIST v1.1 criteria do not mention including or excluding lesions that are being biopsied 
or injected. However, for the purposes of this protocol, the injected and biopsied lesions are 
to be captured as non-target lesions only (Phase I only), as follows: 
• Injected and biopsied lesion = non-target lesion #1 
• Non-injected and biopsied lesion = non-target lesion #2 (if applicable) 
See Schedule of Assessments and Study Activities (Table 1 and Table 2) for details. 


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3.1.1 
Phase I – Dose Escalation Plan 
The Phase I dose escalation is illustrated in Figure 8 for monotherapy and Figure 9 and Figure 10 
 for combination therapy.  
Phase I Dose Escalation – Monotherapy: 
• Each dose escalation cohort will initially recruit at least 3 patients in a standard 3+3 design. 
To proactively ensure at least 3 patients are considered evaluable, a fourth patient may be 
enrolled and treated in addition to the initial 3 patients in each cohort (the fourth patient may 
only be enrolled if they are identified at the time the third patient slot is being filled). 
• Dose escalation design in which administered dose levels will be escalated stepwise in 
successive cohorts of 3 to 6 (NOTE: 7 if fourth slot is filled and a single DLT is identified 
among the first 4 patients) patients per dose group until the RP2D or MTD level is identified. 
• The first patient enrolled in each dose level must complete the first two weeks of Cycle 1 
prior to enrolling the second and third (fourth when applicable) patients. 
• Dose levels to be evaluated include (although not necessarily limited to) 100 µg (representing 
1/60th of the pre-clinical HNSTD dose), 200 µg, 400 µg, 800 µg, and 1,200 µg. 
• IMSA101 will initially be administered by intratumoral injections on Day 1 of Weeks 1, 2, 
and 3 for Cycle 1 (i.e., weekly dosing 3 out of 4 weeks), and on Day 1 of Weeks 1 and 3 
(i.e., bi-weekly dosing) for all cycles thereafter. 
• No dose escalation decisions will be made until all patients in a dose level complete the first 
28 days of treatment. NOTE: this includes a fourth additional patient when applicable. 
Dose-escalation/de-escalation decisions will be based on the occurrence of DLTs during 
Cycle 1 of the evaluated dose level and the recommendation of the Cohort Review 
Committee (CRC).  
• If no DLTs are observed among the initial 3 (4 when applicable) patients of an evaluated 
dose level, the dose will be escalated for the following 3 patients. 
• If a single DLT occurs among the initial 3 (4 when applicable) patients of an evaluated dose 
level, 3 additional patients will be enrolled at the same dose level. 
• If ≥ 2 DLTs occur among the initial 3 (4 when applicable) or 6 (7 when applicable) patients 
in an evaluated dose level, the dose level shall be considered unacceptably toxic and 
escalation will be discontinued. 
• Subsequent to invalidation of a given cohort (e.g., when ≥ 2/3 [4 when applicable] or 
≥ 2/6 [7 when applicable] patients in an evaluated dose level experience a DLT), a new 
cohort (e.g., dosing Cohort Xa) will be evaluated in which IMSA101 will be administered by 
intratumoral injection at the same dose level but with the Day 1 dose (priming dose) reduced 
to the next lower dose level. 
• For dosing Cohort Xa, if ≥ 2/3 (4 when applicable) or ≥ 2/6 (7 when applicable) patients 
experience a DLT, the amended dose level shall be considered unacceptably toxic and the 
next lower dose (DL-1) level shall be provisionally labeled the MTD.  


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• If the amended dose level Xa is found to be safe, dose escalation shall proceed with the 
exception of the priming dose (Cycle 1, dose 1) which shall be held constant and not 
escalated further. 
• No fewer than 6 total patients shall be evaluated at a given dose level prior to confirmation of 
the dose level as the MTD or RP2D. 
Phase I Dose Escalation - Combination Therapy:  
• Combination therapy with IMSA101 + ICI includes the following IMSA101 dose levels: 
• 800 µg  
• 1,200 µg 
• 2,400 µg (with an initial “priming” dose of 1,200 µg) 
• 3,600 µg (with an initial “priming” dose of 2,400 µg) 
• 4,800 µg (with an initial “priming” dose of 3,600 µg) 
• Combination dosing of IMSA101 shall be evaluated in Phase I upon satisfaction of the 
following criteria: 
A. A given dose level (combo dose level 1) has been confirmed as safe for monotherapy 
dosing (i.e.,  2/6 [7 when applicable] patients experience Cycle 1 DLT). 
B. The next higher dose level (combo dose level 2) has been confirmed as safe for 
monotherapy dosing (i.e.,  2/6 [7 when applicable] patients experience Cycle 1 DLT).  
C. The dose level (combo dose level 1) is found to demonstrate adequate IMSA101 PD 
activity based on exploratory endpoints. 
• Eligible patients for Phase I combination dosing shall meet one of the following criteria: 
• have radiographically-confirmed RECIST stable disease through ≥ 2 consecutive cycles 
of an approved PD-1/PD-L1-targeted immune checkpoint inhibitor (ICI) administered as 
monotherapy 
• be clinically stable following a first (unconfirmed) follow-up radiographic scan 
demonstrating progression of disease on ICI monotherapy 
• have progression through prior ICI therapy administered either as mono or combination 
therapy 
• have received no prior ICI therapy but otherwise be ineligible for all available standards 
of care 
• Phase I combo patients have experienced no prior Grade ≥ 3 CTCAE adverse events on ICI 
therapy that were considered by the investigator to be at least possibly ICI drug-related 
• Phase I combo patients shall either receive de novo the combination of IMSA101 + an ICI of 
their investigator’s choosing or, in cases where they are already receiving ICI monotherapy, 


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have IMSA101 added to their current therapy such that Day 1 of IMSA101 shall represent 
Cycle 1, Day 1. 
• A radiographic tumor assessment shall have occurred within 30 prior days of adding 
IMSA101 to current therapy. 
• Phase I combination therapy IMSA101 doses of 800 µg and 1,200 µg will be administered by 
intratumoral injections each week for 3 weeks in Cycle 1 (Days 1, 8, and 15), and for Cycle 2 
and all other cycles thereafter, every other week on Days 1 and 15. Additional combination 
therapy IMSA101 doses of 2,400 µg, 3,600 µg, and 4,800 µg require the following priming 
dose on Day 1 of Cycle 1: 1,200 µg for the 2,400 µg dose group, 2,400 µg for the 3,600 µg 
dose group, and 3,600 µg for the 4,800 µg group. After Day 1 of Cycle 1, the full dose for 
these groups will be administered on Day 1 of Weeks 2 and 3 of Cycle 1 (i.e., weekly dosing 
3 out of 4 weeks), and on Day 1 of Weeks 1 and 3 for all cycles thereafter (i.e., bi-weekly 
dosing). 
• Safety evaluations and dose escalation of IMSA101 administered in combination with 
current ICI therapy shall proceed in a manner consistent with monotherapy escalation, with 
the exception of allowed de-escalation, and shall proceed independently of monotherapy dose 
escalation and evaluations. 
• De-escalation: If ≥ 2 DLTs occur among the initial 3 (4 when applicable) or 6 (7 when 
applicable) patients, de-escalation of IMSA101 is allowed for the combination therapy dose 
levels as follows: 
• 2,400 µg may be de-escalated to 1,800 µg (with a priming dose of 1,200 µg on Day 1 of 
Cycle 1) 
• 3,600 µg may be de-escalated to 3,000 µg (with a priming dose of 2,400 µg on Day 1 of 
Cycle 1) 
• 4,800 µg may be de-escalated to 4,200 µg (with a priming dose of 3,600 µg on Day 1 of 
Cycle 1) 
If ≥ 2 DLTs occur among the initial 3 (4 when applicable) or 6 (7 when applicable) patients 
at a de-escalated dose level, the dose level shall be considered unacceptably toxic and 
escalation will be discontinued. 
• Administration of combination drug will follow the labeled instructions for the product.  
• IMSA101 dose escalation shall proceed such that there will be generated separate RP2Ds for 
IMSA101 administered alone or in combination with other agents (although it is possible 
these will be the same). 
• No fewer than 6 total patients shall be evaluated at a given dose level prior to confirmation of 
the dose level as the MTD or RP2D. 
 
 


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Figure 8 
Phase I Dose Escalation for Monotherapy 
 
1 
Each dose escalation cohort will initially recruit at least 3 patients in a standard 3+3 design. To proactively 
ensure at least 3 patients are considered evaluable, a fourth patient may be enrolled and treated in addition to the 
initial 3 patients in each cohort (the fourth patient may only be enrolled if they are identified at the time the 
third patient slot is being filled). 
2 
Combination dosing and escalation will lead to separate RP2Ds for IMSA101 administered alone or in 
combination with other agents (although it is possible these will be the same). 
 
 


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Figure 9 
Phase I Dose Escalation for Combination Therapy Doses 800 or 1,200 µg 
 
DLT: dose limiting toxicity; RP2D: Recommended Phase II dose 
*MTD = one dose lower than discontinued dose 
1 
Each dose escalation cohort will initially recruit at least 3 patients in a standard 3+3 design. To proactively 
ensure at least 3 patients are considered evaluable, a fourth patient may be enrolled and treated in addition to the 
initial 3 patients in each cohort (the fourth patient may only be enrolled if they are identified at the time the 
third patient slot is being filled). 
2 
Combination dosing and escalation will lead to separate RP2Ds for IMSA101 administered alone or in 
combination with other agents (although it is possible these will be the same). 


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Figure 10 
Phase I Dose Escalation for Combination Therapy Doses 2400, 3,600, and 4,800 µg 
 
C1D1: Cycle 1, Day 1; DLT: dose limiting toxicity; RP2D: Recommended Phase II dose 
*MTD = one dose lower than discontinued dose 
1 
IMSA101 given on Days 1, 8, and 15 (Cycle 1) and bi-weekly thereafter. ICI therapy administered according to 
product instructions. 
2 
Each cohort will initially recruit at least 3 patients in a standard 3+3 design. To proactively ensure at least 
3 patients are considered evaluable, a fourth patient may be enrolled and treated in addition to the initial 
3 patients in each cohort (the fourth patient may only be enrolled if they are identified at the time the third 
patient slot is being filled). The first patient enrolled in each dose level must complete the first two weeks of 
Cycle 1 prior to enrolling the second and third (fourth when applicable) patients. 
3 
Combination dosing and escalation will lead to separate RP2Ds for IMSA101 administered alone or in 
combination with other agents (although it is possible these will be the same). 
 
3.1.2 
Phase IIA – Dose Expansion Plan 
The Phase IIA dose expansion is illustrated in Figure 11. 


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• This dose-expansion stage is intended to confirm the tolerability of the RP2D and identify 
provocative signals of IMSA101 anti-tumor activity. 
• It is anticipated that the monotherapy and combination RP2Ds will be evaluated in 3 discrete 
arms of 20 patients each with a single arm evaluating monotherapy (Arm A) and 2 arms 
evaluating IMSA101 in combination with IO therapies (Arm B and Arm C). 
• Arm B will be a combination of IMSA101 with PD-1/PD-L1-targeted ICIs. Dosing will 
be predicated by the combination RP2D identified in Phase I. 
• Arm C will be a combination of IMSA101 with non-PD-1/PD-L1-targeted immuno-
oncology drugs approved by the Food and Drug Administration (FDA).  
• Administration of approved drugs to be combined with IMSA101 will follow the labeled 
instructions for the product.  
• Combination arms evaluating IMSA101 combinations shall include a safety run-in of 5-10 
patients to be conducted as follows:  
o If ≤ 1 of 5 initial safety evaluable patients experience a DLT during Cycle 1, enrollment 
shall proceed to Patient 6. 
o If ≤ 3 of 10 initial safety evaluable patients experience a DLT during Cycle 1, enrollment 
shall proceed to its entirety (20 patients in that arm).  
o If ≥ 2 of 5 or ≥ 4 of 10 patients experience a DLT, dose de-escalation shall occur to the 
next lower dose level evaluated in Phase I and the run-in shall be repeated at the next 
lower dose. 
• Tumor types and corresponding treatment combinations to be evaluated will be identified 
prior to Phase IIA commencement with patients enrolled separately into tumor-specific arms 
of 20 patients each. This change will be documented in a protocol amendment before it 
occurs. 
• The need for futility criteria to be evaluated in any of the arms following enrollment of a 
pre-defined number of patients < 20 shall be determined at a later date depending on tumor 
types evaluated. This change will be documented in a protocol amendment before it 
occurs. 
• For all potential patients, there will be up to a 30-day screening and eligibility assessment 
period prior to enrollment. 
All patients will continue to receive their assigned treatment throughout the study until the 
occurrence of disease progression, death, or other unacceptable treatment-related toxicity, or 
until the study is closed by the sponsor.  


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Figure 11 
Phase IIA Dose Expansion 
 
C1: Cycle 1; DLT: dose limiting toxicity; IO: immuno-oncology; RP2D: Recommended Phase II dose 
*MTD = one dose lower than discontinued dose 


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3.1.3 
Dose-limiting Toxicities 
A DLT will be defined as the occurrence of any of the following hematologic or 
non-hematologic AEs that are considered definitely, probably, or possibly related to IMSA101 in 
the first 28 days (first cycle) of treatment. The severity of AEs will be graded according to 
CTCAE v5.0. For safety run-ins for Phase IIA combination arms, DLTs will be defined as 
DLT-qualifying events considered at least possibly related to the drug combination, including 
AEs already characterized for the partner drug.  
Hematologic AEs 
• ≥ Grade 4 neutropenia lasting for > 7 days 
• Febrile neutropenia (defined as absolute neutrophil count (ANC) < 1000/mm3 with a single 
temperature of 38.3ºC (101℉) or a sustained temperature of 38ºC (100.4℉) for > 1 h) 
• ≥ Grade 4 thrombocytopenia, or Grade 3 thrombocytopenia associated with Grade ≥ 2 
bleeding 
• ≥ Grade 4 anemia  
Non-hematologic AEs:  
• Elevation of alanine transaminase (ALT) or aspartate transaminase (AST) by ≥ 3X upper 
limit of normal (ULN) with concurrent elevation of serum total bilirubin ≥ 2X ULN 
• Any ≥ Grade 3 non-hematologic AE of any duration will be considered a DLT with the 
following exceptions:  
• Nausea/vomiting/diarrhea: 
• To be considered a DLT, ≥ Grade 3 nausea/vomiting/diarrhea must be refractory to 
supportive care and last > 3 days.  
• ≥ Grade 3 nausea/vomiting/diarrhea that lasts ≤ 3 days is not a DLT. 
• Fatigue: 
• To be considered a DLT, ≥ Grade 3 fatigue must last > 7 days. 
• ≥ Grade 3 fatigue that lasts ≤ 7 days is not a DLT. 
 
3.1.4 
Maximum Tolerated Dose/Recommended Phase II Dose 
The MTD is defined as the highest dose level of IMSA101 at which no more than 1 out of 
6 (7 when applicable) patients experiences a DLT during the first cycle (28 days) of therapy.  
The MTD/RP2D of IMSA101 will be determined by the sponsor and the CRC.  
The RP2D is defined as the dose (either at MTD or below MTD) that is selected for evaluation in 
the Phase IIA component of the study. 


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3.2 
STOPPING RULES 
The entire study or treatment of individual patients may be stopped under defined circumstances 
as outlined in Section 7. 
3.3 
COHORT REVIEW COMMITTEE 
An independent CRC will be organized to review the safety of IMSA101 during the study. The 
CRC will be composed of principal investigators (and their representatives), medical monitor, 
and sponsor representatives. Prior to escalating to next dose level, this committee will review all 
available safety data and determine whether to proceed with escalation. Meeting results will be 
documented and formal notification of decisions will be provided to all participants.  
3.4 
BLINDING AND RANDOMIZATION 
This is an open-label and non-randomized study; no blinding and randomization will be 
conducted. 
 
 


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4 
SELECTION OF PATIENTS 
4.1 
NUMBER OF PATIENTS 
Approximately 115 patients are expected to be treated in this study. 
• Phase I: approximately 45 patients in 5 dose cohorts. Any patient who discontinues the study 
before completing Cycle 1 (and before receiving all 3 doses of IMSA101) for reasons other 
than DLT, will be replaced. 
• Phase IIA: approximately 70 patients in 3 arms of approximately 20–25 patients each. Any 
safety lead-in patient who discontinues the study before completing Cycle 1 (and before 
receiving all 3 doses of IMSA101) for reasons other than DLT, will be replaced. 
 
4.2 
INCLUSION CRITERIA 
Patients meeting all of the following criteria will be considered for enrollment into the study. 
Phase I combination only:  
1. Eligible patients will meet one of the following criteria: 
• Have radiographically-confirmed RECIST stable disease through ≥ 2 consecutive cycles 
of an approved PD-1 or PD-L1 targeted ICI administered as monotherapy  
• Be clinically stable following a first (unconfirmed) follow-up radiographic scan 
demonstrating progression of disease on ICI monotherapy 
• Have progression through prior ICI therapy administered either as mono or combination 
therapy 
• Have received no prior ICI therapy but otherwise be ineligible for all available standards 
of care 
2. Have experienced no prior Grade ≥ 3 CTCAE adverse events on ICI therapy that were 
considered by the investigator to be at least possibly ICI drug-related. 
 
All patients (unless otherwise indicated):  
1. Signed informed consent and mental capability to understand the informed consent 
2. Male or female patients ≥ 18 years of age 
3. Histologically or cytologically documented locally advanced or metastatic solid tumor 
malignancies refractory to or otherwise ineligible for treatment with standard-of-care 
agents/regimens, including but not limited to: 
• Malignant melanoma 
• Hormone receptor negative breast cancer 
• Gastro-esophageal cancer 
• Non-small cell lung cancer 


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• Head and neck cancer 
• Hepatoma 
• Renal cell carcinoma 
4. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1 (Appendix 13.1)  
5. Evaluable or measurable disease as follows: 
• 2 or 3 RECIST evaluable lesions: one that is suitable for injection and biopsied; an 
optional non-injected second lesion that will be biopsied for abscopal effect (only 1 
patient per cohort required to have non-injected lesion biopsied; optional for all other 
patients in that cohort); and one measurable lesion that will be followed for response 
only. 
• Injectable tumors shall be accessed by intralesional (cutaneous) or percutaneous injection 
only, including those lesions that are visible, palpable, or detectable by standard 
radiographic or ultrasound methods. Neither surgical procedures nor endoscopically-
guided injections including those to endobronchial, endoluminal, or endosinusoidal 
spaces shall be allowed. While no anatomic locations are required or disallowed, lesions 
selected for intratumoral injection must, in the opinion of the investigator: 
• Not be immediately adjacent to blood vasculature or other physiologic landmarks in 
such a way that will accrue undue safety risk to the patient  
• Have longest diameter ≥ 10 mm and ≤ 50 mm 
• Be fully evaluable per RECIST v1.1 criteria (Appendix 13.2)  
6. Life expectancy > 3 months (Phase I) and > 6 months (Phase IIA) 
7. ECG without evidence of clinically meaningful conduction abnormalities or active ischemia 
as determined by the investigator 
8. Acceptable organ and marrow function as defined below: 
• Absolute neutrophil count > 1,500 cells/μL 
• Platelets > 50,000 cells/μL 
• Total bilirubin ≤ 1.5 times the ULN 
• AST/ ALT ≤ 2.5 X ULN. If liver metastases are present, AST/ALT < 5 times ULN 
• Serum creatinine < 1.5 mg/dL and a measured creatinine clearance ≥ 50 mL/min using 
the Cockcroft-Gault formula (Appendix 13.3) 
• Prothrombin time (PT)/partial thromboplastin time (PTT) ≤ 1.5 times ULN 
9. Women of child-bearing potential (defined as a female who has experienced menarche and 
who has not undergone successful surgical sterilization (hysterectomy, bilateral 
salpingectomy, or bilateral oophorectomy) or is not postmenopausal (defined as amenorrhea 
for at least 12 consecutive months with an appropriate clinical profile at the appropriate age, 
e.g., greater than 45 years) must have a negative serum pregnancy test prior to first dose of 
study drug 
10. Male and female patients with reproductive potential must agree to use two forms of highly 
effective contraception throughout the study 


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4.3 
EXCLUSION CRITERIA 
All patients: 
1. Anti-cancer therapy within 4 weeks or < 5 half-lives of the first dose of study drug 
2. Failure to recover, to Grade 1 or less, from clinically significant AEs due to prior anti-cancer 
therapy, as judged by the investigator. 
3. Known untreated brain metastases or treated brain metastases that have not been stable (scan 
showing no worsening of CNS lesion[s] and no requirement of corticosteroids) ≥ 4 weeks 
prior to study enrollment 
4. Baseline prolongation of QT/QTc interval (QTc interval > 470) 
5. Uncontrolled intercurrent illness (including, but not limited to, ongoing or active infection, 
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or 
psychiatric illness/social situations) that in opinion of the investigator would limit 
compliance with study requirements 
6. Women who are pregnant or breastfeeding 
7. Sponsor reserves right to exclude any patient from the study on basis of pre-study medical 
histories, physical examination findings, clinical laboratory results, prior medications, or 
other entrance criteria. 
 
4.4 
PATIENTS OF REPRODUCTIVE POTENTIAL 
Pregnancy and breastfeeding are exclusion criteria for this study. It is important that female 
patients and the female partners of male patients do not become pregnant during the study and 
for a recommended period of 30 days after last dose of IMSA101.  
Women of childbearing potential and male patients who are partners of women of childbearing 
potential must agree to use two forms of highly effective contraception during the study and for 
30 days following the last dose of study drug. Highly effective contraception is defined as use of 
one or more methods that result in a low failure rate (i.e., less than 1%). The following are 
examples of acceptable methods of contraception: oral, injected, or implanted hormonal 
methods, intrauterine devices (IUD), condoms with spermicide product, vasectomy, or tubal 
ligation or occlusion.  
A woman of childbearing or reproductive potential is defined as any female who has experienced 
menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral 
salpingectomy, or bilateral oophorectomy) or is not postmenopausal (defined as amenorrhea for 
at least 12 consecutive months with an appropriate clinical profile at the appropriate age, e.g., 
greater than 45 years). 
A serum pregnancy test for all women of childbearing potential will be performed during 
screening. A pregnancy test will also be carried out at the End of Study (EOS) visit. 
Female patients who become pregnant and male patients whose female partners become pregnant 
must report to the investigator and be removed from the study immediately.  
 


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5 
STUDY PROCEDURES AND SCHEDULE 
Study procedures will be performed as described in Section 3: Study Design and as shown in the 
Schedule of Assessments and Study Activities (Table 1 and Table 2). 
5.1 
DESCRIPTION OF STUDY DAYS AND STUDY TREATMENTS 
5.1.1 
Screening/Baseline (Day -30 to Day 1) 
• Obtain written informed consent before the start of any study-specific procedures.  
• Review inclusion and exclusion criteria.  
• Complete medical history including all previous cancer treatments. 
• Record concomitant medications including start dates, indication, dose, and frequency. 
• Record demographic data including year of birth, current age, age when informed consent is 
signed, gender, race, and smoking status. 
• Measure and record height (cm) and weight (kg).  
• Record vital signs (blood pressure, respiration rate, heart rate, body temperature). 
• Perform full physical examination. 
• Perform neurologic examination. 
• Assess and record ECOG performance status (Appendix 13.1). 
• Perform a 12-lead ECG. 
• Collect blood samples for hematology tests (including coagulation parameters and CBC with 
differential) within 72 h prior to Cycle 1 Day 1. 
• Collect blood samples for serum chemistry tests and creatinine clearance (using the 
Cockcroft-Gault formula, Appendix 13.3) within 72 hours of Cycle 1 Day 1. 
• Urinalysis  
• Perform a serum pregnancy test for female patients of childbearing potential. 
• Radiographic assessments and, if applicable, photographic assessments of skin lesions will 
be performed by a formal photography vendor at the same time points as the radiographic 
assessments. Detailed instructions for photography will be included in a photography 
manual. 
• Collect archival tumor tissue, if available (Phase I only). 
 
5.1.2 
Cycle 1 Day 1 (± 0 Days) 
• Record concomitant medications taken since screening including start dates, indication, dose, 
and frequency within 72 h prior to Cycle 1 Day 1. 


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• Measure and record weight (kg) within 72 h prior to Cycle 1 Day 1. 
• Record vital signs (blood pressure, respiration rate, heart rate, body temperature) within 72 h 
prior to Cycle 1 Day 1. 
• Perform neurologic examination within 72 h prior to Cycle 1 Day 1. 
• Assess and record ECOG performance status within 72 h prior to Cycle 1 Day 1 
(Appendix 13.1). 
• Perform a 12-lead ECG 30 to 60 minutes post-dose. 
• PK blood samples (Phase I monotherapy only). Detailed instructions outlined in the 
laboratory manual. 
• PD blood samples (Phase I monotherapy and combo therapy). Detailed instructions outlined 
in the laboratory manual. 
• 24 h post-dose sample will require patient to return to clinic on Cycle 1 Day 2. 
• PD tissue samples/biopsy of injected and non-injected tumor, if applicable (non-injected 
tumor biopsy required in at least 1 patient per cohort) (Phase I monotherapy and combo 
therapy). Core biopsies should be obtained; if not appropriate, biopsies via fine needle 
aspirate (FNA) or excision are permitted. Detailed instructions outlined in the laboratory 
manual. 
• Administer study drug(s). 
• Observe patient for 1 h following intratumoral injection. 
• Assess and record AEs. 
• Admit patient to the hospital for observation overnight. Patient may be released from the 
hospital when clinically indicated.  
 
5.1.3 
Cycle 1 Day 8 (+/- 3 Days) 
• Record concomitant medications taken since the last visit including start dates, indication, 
dose, and frequency. 
• Measure and record weight (kg).  
• Record vital signs (blood pressure, respiration rate, heart rate, body temperature). 
• Perform neurologic examination. 
• Assess and record ECOG performance status (Appendix 13.1). 
• Perform a 12-lead ECG 30 to 60 minutes post-dose. 
• Collect blood samples for hematology tests (coagulation parameters, not required).  
• Collect blood samples for complete serum chemistry.  


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• Administer study drug. For Cycle 1 Day 8 and Cycle 1 Day 15, IMSA101 doses should be 
administered no less than 4 days apart.   
• Observe patient for 1 h following intratumoral injection. 
• Assess and record AEs.  
 
5.1.4 
Cycle 1 Day 15 (+/- 3 Days) 
• Record concomitant medications taken since the last visit including start dates, indication, 
dose, and frequency. 
• Measure and record weight (kg).  
• Record vital signs (blood pressure, respiration rate, heart rate, body temperature). 
• Perform neurologic examination. 
• Assess and record ECOG performance status (Appendix 13.1). 
• Perform a 12-lead ECG 30 to 60 minutes post-dose. 
• Collect blood samples for hematology tests (coagulation parameters, not required).  
• Collect blood samples for serum chemistry tests. 
• PD tissue samples/biopsy of injected and non-injected tumor, if applicable (non-injected 
tumor biopsy required in at least 1 patient per cohort) (Phase I monotherapy and combination 
therapy). Core biopsies should be obtained; if not appropriate, biopsies via FNA or excision 
are permitted. 
• Administer study drug(s). For Cycle 1 Day 8 and Cycle 1 Day 15, IMSA101 doses should be 
administered no less than 4 days apart.    
• Observe patient for 1 h following intratumoral injection. 
• Assess and record AEs.  
 
5.1.5 
Day 1 (+/- 3 Days) of Each Subsequent Cycle 
• Record concomitant medications taken since the last visit including start dates, indication, 
dose, and frequency. 
• Measure and record weight (kg).  
• Record vital signs (blood pressure, respiration rate, heart rate, body temperature). 
• Perform neurologic examination. 
• Assess and record ECOG performance status (Appendix 13.1). 
• Collect blood samples for hematology tests (coagulation parameters, not required).  
• Collect blood samples for complete serum chemistry.  


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• Administer study drug(s). 
• Observe patient for 1 h following intratumoral injection. 
• Assess and record AEs.  
• PD blood samples (Phase I monotherapy and combo therapy). Samples to be collected pre-
dose Day 1 of Cycles 2 and 3. 
 
5.1.6 
Day 15 (+/- 3 Days) of Each Subsequent Cycle 
• Record concomitant medications taken since the last visit including start dates, indication, 
dose, and frequency. 
• Measure and record weight (kg).  
• Record vital signs (blood pressure, respiration rate, heart rate, body temperature). 
• Perform neurologic examination. 
• Assess and record ECOG performance status (Appendix 13.1). 
• Collect blood samples for hematology tests (coagulation parameters, not required).  
• Collect blood samples for complete serum chemistry.  
• PK blood samples (Phase I monotherapy patients but only if detectable signal was noted in 
Cycle 1 PK results) 
• PD blood samples (Phase I monotherapy and combo therapy Cycle 2 Day 15) 
• PD tissue samples/biopsy of injected and non-injected tumor, if applicable (non-injected 
tumor biopsy required in at least 1 patient per cohort) (Phase I monotherapy and combo 
therapy Cycle 2 Day 15 only). Core biopsies should be obtained; if not appropriate, biopsies 
via FNA or excision are permitted. 
• Administer study drug(s). 
• Observe patient for 1 h following intratumoral injection. 
• Assess and record AEs.  
 
5.1.7 
End of Even-numbered Cycle (< 7 Days) 
• Perform disease assessment according to RECIST Criteria (v1.1) (Appendix 13.2). In certain 
circumstances a patient experiencing RECIST progression of disease may be allowed to 
continue therapy on study where there is agreement between the investigator and sponsor that 
the patient is deriving clinical benefit.  
• Radiographic assessments and, if applicable, photographic assessments of skin lesions will 
be performed by a formal photography vendor at the same time points as the radiographic 
assessments. Detailed instructions for photography will be included in a photography 
manual. 


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5.1.8 
End of Treatment Visit  
• Record concomitant medications taken since the last visit including start dates, indication, 
dose, and frequency. 
• Measure and record weight (kg).  
• Record vital signs (blood pressure, respiration rate, heart rate, body temperature). 
• Perform and record full physical examination. 
• Perform neurologic examination. 
• Assess and record ECOG performance status (Appendix 13.1). 
• Perform a 12-lead ECG 30 to 60 minutes post-dose. 
• Collect blood samples for hematology tests (coagulation parameters, not required). 
• Collect blood samples for complete serum chemistry.  
• Perform a serum pregnancy test for female patients of childbearing potential. 
• Perform disease assessment according to RESIST Criteria (v1.1) as described in 
Appendix 13.2. If applicable, photographic assessments of skin lesions will be performed. 
Perform a CT scan (or MRI or other appropriate assessment), if a recent scan within the past 
month is not available in the medical records. 
• Assess and record AEs. 
  
5.1.9 
End of Study Visit (Safety Follow-up 30 days after Last Dose) 
• Assess and record AEs. 
5.1.10 
Cycle Extensions 
During this study, with the approval of the investigator and sponsor, a patient may be allowed a 
2 week delay or extension between cycles. Rationale for delay or extension should be 
documented. 
5.1.11 
Unscheduled Visits 
Additional visits may be performed as appropriate and at the discretion of the investigator. Any 
of the procedures or assessments may be performed based on the reason for the visit. 
5.1.12 
Restrictions, Precautions, and Potential Adverse Effects 
There are no known restrictions or precautions relative to nicotine, caffeine, alcohol, physical 
activity, fasting, diet, or medications for patients’ ongoing IMSA101 treatment. 


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Based on pre-clinical findings with IMSA101 and toxicity events reported in clinical trials 
evaluating other STING (stimulator of interferon genes) adapter protein agonists, the following 
risks may reasonably be anticipated in clinical trials evaluating IMSA101: body temperature 
increases (fever), chills, alterations in serum chemistries, altered serum hematology parameters, 
headache, injection site pain, vomiting, fatigue, myalgia, and/or diarrhea. 
 
 


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6 
METHODS OF ASSESSMENT AND ENDPOINTS 
6.1 
MTD/RP2D 
Definition of Maximum Tolerated Dose (MTD): The MTD is defined as the highest dose level of 
IMSA101 at which no more than 1 out of 6 (7 when applicable) patients experiences a DLT 
during the first cycle (28 days) of therapy.  
Definition of Recommended Phase 2 Dose (RP2D): The RP2D is defined as the dose (either at 
MTD or below MTD) that is selected for evaluation in the Phase IIA component of the study. 
The MTD/RP2D of IMSA101 will be determined by the sponsor and the CRC.  
6.2 
DEMOGRAPHIC DATA 
At screening, patient demographic data will be collected. These data include: year of birth, age, 
gender, race, smoking history, tumor type, and molecular abnormalities, if known. 
6.3 
MEDICAL HISTORY 
At screening, a complete medical history will be obtained from each patient. Medical history 
includes baseline symptoms as well as a detailed history of prior procedures and prior cancer 
therapies including therapy start and stop dates, best response, disease progression during or after 
therapy, as well as discontinuations due to intolerability or toxicity. For female patients of 
child-bearing potential, the date of the last menstrual period should be noted. Data will be 
updated at subsequent visits as appropriate. 
6.4 
CONCOMITANT MEDICATIONS 
A detailed history of medications and procedures will be documented for each patient at 
screening. Concurrent medications (especially changes in medication) will be documented for 
each patient at each scheduled visit. Necessary supportive care such as anti-emetic and anti-
diarrheal medications, etc., will be allowed (see Section 8.3). Prophylactic pretreatment for 
headache, nausea, and vomiting (after Cycle 1) is permitted. Any medication that in the 
opinion of the investigator will interfere with the MOA of IMSA101 is prohibited. 
6.5 
PHYSICAL EXAMINATION AND VITAL SIGNS 
Full physical examinations will be performed at screening and End of Treatment (EOT) Visit. An 
assessment of interval changes and AEs will be performed at each visit. 
• Height in centimeters (cm) will be measured at screening. 
• Body weight in kilogram (kg) will be measured at screening/baseline, and all study visits.  
• Vital signs including body temperature, blood pressure, respiration rate, and heart rate will be 
measured at all study visits.  


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Information about the physical examination must be present in the source documentation at the 
study site. The result of the physical examination prior to the start of study drug treatment must 
be included in the Relevant Medical History/Current Medical Conditions Case Report Form. 
Clinically relevant findings made after the start of study drug treatment, which meet the 
definition of an AE, must be recorded on the Adverse Event Case Report Form. 
6.6 
SAFETY ASSESSMENTS  
Safety assessments will include TEAEs, DLTs, vital signs, 12-lead ECG, physical examination, 
and laboratory safety evaluations. Toxicities will be graded according to CTCAE v5.0 criteria. 
Patients will be observed for 1 h in the clinic following intratumoral injections. In addition, 
following intratumoral injection on Day 1 of Cycle 1, patients will be admitted to the hospital for 
observation overnight.  
Safety data will be listed by study site, patient number, and cycle. All TEAEs will be 
summarized by study phase and assigned dose. In addition, all SAEs, including deaths will be 
listed separately and summarized.  
Grade 3 and 4 laboratory data will be summarized by study phase and assigned dose.  
For patients who experience a DLT, data on AEs leading to treatment/study discontinuation will 
be listed. 
Coagulation and urinalysis will be performed only at screening.  
Safety evaluations (vital signs, ECOG assessment, and clinical laboratory studies) will be 
conducted at screening, Cycle 1 Day 1; baseline, then on Days 8 and 15 of Cycle 1, then Day 1 
and Day 15 of every cycle thereafter for patients who continue treatment, or any time it is 
clinically indicated in the judgment of the investigator.  
Neurologic examinations and ECOG performance status assessments (Appendix 13.1) will be 
performed at each study visit. 
A complete standard 12-lead ECG recording (rhythm, VR, PR interval, QRS duration, QT and 
QTc) will be performed at screening, 30 minutes post-dose on C1D1, C1D8, C1D15, at EOT, and 
at any other visit where the investigator believes the assessment is indicated.  
The following clinical laboratory tests will be performed: 
• Hematology (blood sample with EDTA): hemoglobin, hematocrit, mean corpuscular volume, 
mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, white blood cell 
(WBC) count, WBC differential, red blood cell count, lymphocytes, monocytes, neutrophils, 
band neutrophils, eosinophils, basophils, platelets. The WBC differential may be automated or 
manual as per institutional standards. Reticulocytes should be done only when clinically 
indicated. 


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• Serum Chemistry (blood serum sample): Complete Serum Chemistry will include sodium, 
potassium, chloride, bicarbonate, blood urea nitrogen, creatinine, glucose, calcium, 
phosphate, magnesium, ALT, AST, alkaline phosphatase, total bilirubin, lactate 
dehydrogenase, total protein, albumin.  
• Coagulation (screening only): PT, international normalization ratio (INR), and activated 
partial thromboplastin time (aPTT).  
• Urinalysis (screening only): appearance, color, urine bilirubin, glucose, hemoglobin, 
ketones, pH, protein, specific gravity, urobilinogen, and microscopy. 
 
Any laboratory value that remains abnormal at the EOT and that is considered clinically significant 
will be followed according to accepted medical standards for up to 30 days after the last dose or 
until resolution of the abnormality. 
Toxicity will be assessed using the CTCAE v5.0 criteria. 
6.7 
PHARMACOKINETIC PROCEDURES 
6.7.1 
Blood Sampling and Processing 
Blood plasma samples for PK analysis will be collected from Phase I monotherapy patients at the 
times/days outlined below and in Table 1. Further details and instructions will be provided in a 
separate laboratory manual. 
Cycle 1 Day 1: 
Pre-Dose, 10 min, 20 min, 30 min, 1 h, 2 h, 4 h post-dose 
 
Cycle 2 Day 15 (if any detectable signal noted in Cycle 1): 
Pre-Dose, 10 min, 20 min, 30 min, 1 h, 2 h, 4 h post-dose. Additionally, 6 h, 24 h post-dose if 
previous 4 h post-dose measurement was found detectable in Cycle 1 
 
The following time windows for plasma PK sample collection are allowed: ≤ 24 h for the pre-
dose sample, ± 5 min for the 10-, 20-, and 30-min post-dose samples, ± 10 min for the 1-h post-
dose sample, ±15 min for the 2-, 4-, and 6-h post-dose samples, and ± 2 h for the 24-h post-dose 
sample. 
Plasma concentrations for all PK parameters at each time point will be listed and summarized by 
each dose level. Plasma concentrations versus time profiles (with concentrations on both a log 
and linear scale) will be plotted for each patient; similar summary plots will be constructed for 
each dose level. PK parameters will be analyzed by a validated bioanalytical method from a 
central laboratory. 


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6.8 
PHARMACODYNAMIC PROCEDURES 
6.8.1 
Blood and Tissue Sampling and Processing (Phase I only) 
Blood and tumor samples are to be collected at multiple time points as shown in Section 2.4.5 
and Table 1 for exploratory assessment of numerous biomarkers.  
The following time windows for PD cytokines sample collection are allowed: ≤ 24 h for the pre-
dose sample, ±15 min for the 2-, 4-, and 6-h post-dose samples, and ± 2 h for the 24-h post-dose 
sample. 
The following time windows for PD flow cytometry sample collection are allowed: ≤ 24 h for 
the pre-dose C1, C2, and C3 samples. 
The following time windows for PD mIF sample collection are allowed: ≤ 24 h for the pre-dose 
C1D1, C1D15, and C2D15 samples. 
An aliquot of tumor sample for injected and non-injected tumor is to be obtained and stored for 
later RNA isolation and sequencing when the analysis is warranted based on clinical or 
immunological responses. 
PD markers will be analyzed by a validated bioanalytical method from a central laboratory. 
Further details and instructions will be provided in a separate laboratory manual. 
6.9 
TUMOR ASSESSMENTS 
All known tumor sites will be documented at screening and re-assessed at each subsequent time 
point for tumor evaluation, using a single and consistent methodology throughout all evaluations. 
Assessments may include the following: 
• Screening (if a recent scan within the past month is not available in the medical records) and 
subsequent tumor assessments must include CT scans (with IV contrast unless 
contraindicated and oral contrast as appropriate per institutional standards) or MRI of the 
chest, abdomen, and pelvis (or other appropriate assessment). Photographic assessments of 
skin lesions will be performed through a photography vendor as detailed in a separate 
photography manual. At screening, photography assessment can be performed within 30 days 
prior to Day 1. 
• If a CT scan is performed in a positron emission tomography/CT scanner, the CT acquisition 
must be consistent with the standards for a full-contrast CT scan. 
• Brain imaging (by either MRI or contrast-enhanced CT) is required at screening for all 
patients displaying clinical signs of possible central nervous system involvement. 
• Further investigations such as bone scans should be performed if there is any clinical 
suspicion of disease at any site that may not be observed using the methods above. 


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• The same radiographic procedures used to assess disease sites at screening should be used 
throughout the study (e.g., the same contract protocol for CT scans). Assessments should be 
performed by the same evaluator if possible to ensure internal consistency across visits.  
• All findings will be assessed for response according to RECIST v1.1 criteria as defined in 
(Appendix 13.2) and according to the Schedule of Assessments and Study Activities (Table 1 
and Table 2). 
RECIST v1.1 criteria do not mention including or excluding lesions that are being biopsied or 
injected. However, for the purposes of this protocol, the injected and biopsied lesions are to be 
captured as non-target lesions only (Phase I only), as follows: 
• Injected and biopsied lesion = non-target lesion #1 
• Non-injected and biopsied lesion = non-target lesion #2 (if applicable) 
 
• In certain circumstances a patient experiencing RECIST progression of disease may be 
allowed to continue therapy on study where there is agreement between the investigator and 
sponsor that the patient is deriving clinical benefit. 


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7 
DISCONTINUATION CRITERIA 
7.1 
DISCONTINUATION OF INDIVIDUAL PATIENTS 
Patients are free to withdraw from the study at any time without providing reason(s) for 
withdrawal and without prejudice to further treatment. The treatment of individual patient(s) may 
be stopped by the investigator under defined circumstances as outlined below.  
• Patient request 
• Use of non-permitted concurrent therapy 
• Non-compliance with the study drug or study schedule 
• Patient lost to follow-up 
• Occurrence of AEs not compatible with the continuation of patient participation in the study, 
in the investigator’s opinion, or unacceptable to the patient to continue 
• Investigator/sponsor request  
• Intercurrent illness warranting removal by the investigator 
• Disease progression warranting removal by the investigator 
 
The reason(s) for withdrawal (by the patient or investigator) and date will be documented in the 
electronic case report form (eCRF).  
All patients who withdraw from the study with an ongoing AE must be followed until the event 
is resolved or deemed stable. Any patient who withdraws consent as a result of an AE, regardless 
of intensity or investigator’s opinion, must be reported as a discontinuation due to AE. Patients 
withdrawing from the study will be encouraged to complete the final evaluations as detailed for 
termination in the Schedule of Assessments (Table 1 and Table 2), particularly safety 
evaluations.  
If a patient refuses to complete early termination procedures, this information will be recorded in 
the source documentation. A patient who prematurely discontinues from the study for any reason 
will not be allowed to re-enter the study. 
In certain circumstances, a patient experiencing RECIST progression of disease may be allowed 
to continue therapy on study where there is agreement between the investigator and sponsor that 
the patient is deriving clinical benefit. 
7.2 
EARLY DISCONTINUATION OF THE STUDY 
The sponsor has the right to terminate the study at any time in case of SAEs or if special 
circumstances concerning the IMSA101 or the company itself occur, making further treatment of 
patients impossible. In this event, the investigator(s) will be informed of the reason for study 
termination. 


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In particular cases, the study may be terminated at a single study site at any time if it becomes 
apparent that patient enrolment or quality of the data is unsatisfactory, or the conduct of the 
study at this site is not in accordance with the Good Clinical Practice (GCP) guidelines. 
Study materials must be returned, disposed of or retained as directed by the sponsor. 
 
 


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8 
TREATMENT 
8.1 
DOSING AND ADMINISTRATION OF IMSA101 
IMSA101 is a sterile, nonpyrogenic solution containing 10 mg of IMSA101 in 1.0 mL of 
sodium, potassium phosphate, and saline buffer. Prior to dosing, IMSA101 will be thawed and 
further diluted in normal saline in order to be delivered intratumorally at the following dose 
levels: 
Monotherapy: 100, 200, 400, 800, and 1,200 µg.  
Combination Therapy IMSA101 + current ICI therapy (administered according to the label of 
that product): 
• 800 and 1,200 µg 
• 2,400 µg (with an initial “priming” dose of 1,200 µg) 
• 3,600 µg (with an initial “priming” dose of 2,400 µg) 
• 4,800 µg (with an initial “priming” dose of 3,600 µg) 
 
This drug is NOT SAFE to be administered without proper dilution. Composition of IMSA101 
is presented in Table 4. 
Table 4 
Composition of IMSA101 for Injection 
Ingredients 
Grade 
Function 
Composition 
(1.2 mL per vial) 
IMSA101 
In-house 
Active Ingredient 
12 mg 
Potassium phosphate 
monobasic 
NF 
Buffering 
0.2 mg 
Sodium phosphate 
dibasic, heptahydrate 
USP 
Buffering 
0.3 mg 
Sodium chloride 
USP 
Diluent 
10.8 mg 
Water for injection 
USP 
Diluent 
As needed 
1 N Sodium hydroxide 
NF 
Adjust pH 
As needed 
1 N Hydrochloric acid 
NF 
Adjust pH 
As needed 
NF: National Formulary; USP: United States Pharmacopeia 
8.1.1 
Preparation of IMSA101 
Prior to dosing, IMSA101 will be thawed and diluted in normal saline as detailed in a separate 
pharmacy manual. A single pre-defined tumor/tumor site per patient will be selected and injected 
intratumorally throughout study participation. Injections of tumors that are not superficial will be 
performed under image guidance.  


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8.1.2 
Administration of IMSA101 
Phase I (dose escalation): 
For monotherapy, IMSA101 will be administered at dose levels of (but not necessarily be limited 
to) 100, 200, 400, 800, and 1,200 µg (Table 5). One mL total volume will be administered each 
week for 3 weeks in Cycle 1 (Days 1, 8, and 15). For Cycle 2 and all other cycles thereafter, 
study drug will be given by intratumoral injection every other week on Days 1 and 15.  
For combination therapy, IMSA101 will be administered at dose levels of 800 and 1,200 µg. One 
mL total volume will be administered each week for 3 weeks in Cycle 1 (Days 1, 8, and 15). For 
Cycle 2 and all other cycles thereafter, study drug will be given by intratumoral injection every 
other week on Days 1 and 15. Additional combination therapy dose levels of 2,400, 3,600, and 
4,800 µg require the following priming dose on Day 1 of Cycle 1: 1,200 µg for the 2,400 µg 
dose, 2,400 µg for the 3,600 µg dose, and 3,600 µg for the 4,800 µg dose. After Day 1 of 
Cycle 1, the full dose for these groups will be administered on Day 1 of Weeks 2 and 3 of 
Cycle 1 (i.e., weekly dosing 3 out of 4 weeks), and on Day 1 of Weeks 1 and 3 for all cycles 
thereafter (i.e., bi-weekly dosing). 
IMSA101 is injected directly into the selected tumor. Patients will be observed for 1 h following 
each intratumoral injection. In addition, following intratumoral injection on Day 1 of Cycle 1, 
patients will be admitted to the hospital for observation overnight.   
Injectable tumors shall be accessed by intralesional (cutaneous) or percutaneous injection only, 
including those lesions that are visible, palpable, or detectable by standard radiographic or 
ultrasound methods. The administration technique and procedures for internal lesions (i.e., 
whether CT or ultrasound guided) will be per institutional policy and guidelines. Neither surgical 
procedures nor endoscopically-guided injections including those to endobronchial, endoluminal, 
or endosinusoidal spaces shall be allowed. While no anatomic locations are required or 
disallowed, lesions selected for intratumoral injection must, in the opinion of the investigator: 
• Not be immediately adjacent to blood vasculature or other physiologic landmarks in such a 
way that will accrue undue safety risk to the patient  
• Have longest diameter ≥ 10 mm and ≤ 50 mm 
• Be fully efficacy evaluable per RECIST v1.1 criteria (Appendix 13.2)  
 
Where no remaining accessible lesions are present and where benefit of IMSA101 therapy is, in 
the opinion of the investigator, being derived by the patient, continued injections of IMSA101 
into the vicinity of an inaccessible lesion shall be allowed. In the case that a lesion can no longer 
be radiographically visualized, continued injections into the last known location of the non-
visible lesion shall be allowed. 
For those patients receiving a combination regimen, the combination partner drug will be 
administered per product label. 


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Table 5 
Dose Levels of IMSA101 for Injection 
Dose Level 
IMSA101 Dose 
Monotherapy 
1 
100 µg* 
2 
200 µg 
3 
400 µg 
4 
800 µg 
5 
1,200 µg 
Combination Therapy 
1 
800 µg 
2 
1,200 µg 
3 
2,400 µg with an initial priming dose of 1,200 µg 
4 
3,600 µg with an initial priming dose of 2,400 µg 
5 
4,800 µg with an initial priming dose of 3,600 µg 
* 
The lowest dose (100 µg) represents 1/60th of the preclinical highest non-severe toxic dose (HNSTD).  
Dose escalation design in which administered dose levels will be escalated stepwise in 
successive cohorts of 3 to 6 (4 to 7 when applicable) patients each (standard 3+3 study design) 
until the MTD or RP2D level is identified. 
Phase I (dose de-escalation for combination therapy): 
If ≥ 2 DLTs occur among the initial 3 (4 when applicable) or 6 (7 when applicable) patients, 
de-escalation of IMSA101 is allowed for the combination therapy dose levels as follows: 
• 2,400 µg may be de-escalated to 1,800 µg (with a priming dose of 1,200 µg on Day 1 of 
Cycle 1) 
• 3,600 µg may be de-escalated to 3,000 µg (with a priming dose of 2,400 µg on Day 1 of 
Cycle 1) 
• 4,800 µg may be de-escalated to 4,200 µg (with a priming dose of 3,600 µg on Day 1 of 
Cycle 1) 
If ≥ 2 DLTs occur among the initial 3 (4 when applicable) or 6 (7 when applicable) patients at a 
de-escalated dose level, the dose level shall be considered unacceptably toxic and escalation will 
be discontinued. 
Phase IIA (dose expansion):  
IMSA101 will be given at the RP2D through intratumoral injection as described for Phase I 
above. 
Patients will receive either IMSA101 monotherapy or in combination with IO therapy. A safety 
run-in component will establish safety of the combination before further patients are enrolled 
(Section 3.1.2). 


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8.2 
STORAGE OF IMSA101 
The drug product is packaged in a container-closure system that is composed of pharmacopoeia-
compliant components. The primary container, composed of United States Pharmacopeia (USP) 
Type 1 glass, is stoppered with a 13 mm Fluortec coated lyophilization stopper, and sealed with a 
13 mm flip-off overseal and 13 mm cap. A 24-unit paper carton is used to distribute the product 
to clinical sites. 
The product (IMSA101 for Injection) is stored at -20 ± 5℃ and is being tested for 5 years of 
shelf-life through a stability protocol. Currently, the product has completed the 3-year time point 
for stability with all tests meeting specification. Clinical trial sites will be provided specific 
expiry and stability updates via memoranda as new data become available.  
8.3 
RESCUE MEDICATIONS AND CONCOMITANT TREATMENTS 
All medications administered from the beginning of study treatment (Cycle 1 Day 1, including 
during the overnight hospitalization) through the end of treatment and study participation will be 
recorded on the eCRF. Any change in medication dosage will also be noted. 
Necessary supportive care (i.e., antiemetic and/or antidiarrheal medications, etc.) will be allowed. 
Prophylactic pretreatment for headache, nausea, and vomiting (after Cycle 1) is permitted.  
8.4 
TREATMENT COMPLIANCE 
The investigator and/or his study staff will administer IMSA101 study medication only for use by 
patients enrolled in the study as described in this protocol. The study medication is not to be used 
for reasons other than those described herein. 
The investigator or other study staff will supervise study drug treatment given in the clinic and 
record all treatments in the eCRF. Study personnel associated with the sponsor will monitor 
IMSA101 drug treatment compliance.  
 
 


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9 
ADVERSE EVENTS 
9.1 
DEFINITIONS 
9.1.1 
Adverse Event 
An AE is defined as any undesired medical occurrence in a patient or clinical investigation 
patient receiving a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable sign and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporarily associated 
with the use of a study drug, whether or not related to the study drug. AE reporting begins at the 
time of study drug administration and continues until 30 days after the last dose. 
9.1.2 
Serious Adverse Events 
An SAE is any untoward medical event that occurs at any dose from the time of study drug 
administration and continuing until 30 days after the last dose that: 
• results in death 
• is life-threatening (patient is at immediate risk of death from the event as it occurred) 1 
• requires inpatient hospitalization (formal admission to a hospital for medical reasons) or 
prolongation of existing hospitalization 2 
• results in persistent or significant disability/incapacity 3 
• results in a congenital anomaly/birth defect 
• is an important medical event 4 
 
1 “Life-threatening” means that the patient was at immediate risk of death at the time of the 
SAE; it does not refer to a SAE that hypothetically might have caused death if it were more 
severe. 
2 This means that hospital inpatient admission or prolongation of hospital stay was required for 
the treatment of the AE, or that one or the other occurred as a consequence of the event. 
Hospitalizations for elective surgery or other medical procedures that are not related to a 
TEAE are not considered SAEs. The planned overnight hospitalization on Day 1 of Cycle 1 is 
exempt from this definition and is not considered an SAE since it is a study procedure and not 
for treatment of an SAE, unless an AE occurs during the hospitalization that meets the criteria 
above. 
3 “Persistent or significant disability or incapacity” means a permanent or significant and 
substantial disruption of a person’s ability to carry out normal life functions. 
4 Important medical events that may not result in death, are not life-threatening, or do not 
require hospitalization may be considered SAEs when, based on appropriate medical 
judgment, they may jeopardize the patient and may require medical or surgical intervention to 


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prevent one of the outcomes listed in this definition. Examples of such events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse. 
Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in situations where none of the outcomes listed above occurred. Important medical 
events that may not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the patient or may require intervention to prevent one of the other outcomes listed in 
the definition above should also usually be considered serious. 
All other AEs are considered non-serious. All non-serious AEs will be followed to resolution, or 
until the study ends, and reported to the sponsor as requested, to the Institutional Review Boards 
(IRBs)/Institutional Ethics Committees (IECs) according to IRB/IEC policies (to include annual 
Continuing Review Reports), to the CRC as required, and to the U.S. Food and Drug 
Administration (FDA) as required for the annual report. 
AEs meeting the stopping criteria outlined in Section 7 of this protocol will be reported to the 
sponsor, the IRBs/IECs, and the CRC following the SAE reporting guidelines. 
Management of all AEs including hypersensitivity or hyperimmune reactions will be managed 
by treating physicians in conjunction with relevant institutional guidelines and with the 
consultation of the sponsor’s medical monitor. 
9.1.3 
Adverse Event by Severity or Intensity 
The assessment of severity of an AE will be rated according to the criteria in Table 6.  
Table 6 
Definitions of Adverse Events Severity 
Grade 1 (Mild) 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. The adverse event (AE) does not interfere 
with routine activities. The patient may experience slight discomfort. 
Grade 2 (Moderate) 
Moderate; minimal, local or noninvasive intervention indicated; The AE 
interferes with routine activities. The patient may experience significant 
discomfort. 
Grade 3 (Severe) 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated. The patient is 
unable to perform routine activities. The patient may experience intolerable 
discomfort or pain. 
Grade 4 (Life-Threatening) 
Life-threatening consequences; urgent intervention indicated. 
Grade 5 (Fatal) 
Death related to AE 
Based on the Common Terminology Criteria for Adverse Events v 5.0 (CTCAE). 
 
The term “severe” is used to describe the intensity of an AE; the event itself could be of 
relatively minor clinical significance (e.g., ‘severe’ headache). This is not the same as “serious”. 


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Seriousness of AEs is based on the outcome of an AE and usually associated with events that 
pose a threat to a patient’s life or functioning. 
9.1.4 
Relationship between Adverse Events and Study Drug 
Determination of the relationship (if any) between the AE and the study drug will be made using 
the guidelines presented in Table 7. 
Table 7 
Guidelines for Determining the Relationship (if any) Between Adverse Event and 
the Study Drug 
Definitely Related: 
This causal relationship is assigned if the AE starts a reasonable time after the 
administration of study drug, stops/improves when the study drug is stopped, and could 
reasonably be explained by known characteristics of the study drug. 
Probably Related: 
This causal relationship is assigned when the AE starts a reasonable time after the 
administration of study drug, stops/improves when the study drug is stopped, and could 
not be reasonably explained by known characteristics of the patient’s clinical state. 
Possibly Related: 
This causal relationship is assigned when the AE starts a reasonable time after the 
administration of study drug, but could be produced by the patient’s clinical state or 
other modes of therapy administered to the patient. 
Unlikely Related 
This causal relationship is assigned when the time association or the patient’s clinical 
state is such that the study drug was not likely to have had an association with the 
observed AE. 
Not Related: 
This causal relationship is assigned when there is clearly no evidence of association 
with the study drug and the observed AE. 
Pregnancy or lactation are exclusion criteria for this study. Pregnancy per se is not considered an 
AE unless there is cause to believe that the investigational drug may have interfered with the 
effectiveness of a contraceptive medication. Refer to Section 4.4 for details. 
9.1.5 
Adverse Event Follow-up 
All AEs occurring during the study are to be followed up in accordance with good medical 
practice until they are resolved, stabilized or judged no longer clinically significant or, if a 
chronic condition, until fully characterized. Any AEs that are considered drug-related (possibly 
related, probably related, or definitely related) must be followed until resolution or until 
stabilization. 
All unresolved AEs following the study should be followed by the investigator until the events 
are resolved, the patient is lost to follow-up, or the AE is otherwise explained. At the last 
scheduled visit, the investigator should instruct each patient to report any subsequent event(s) 
that the patient, or the patient’s personal physician, believes might reasonably be related to 
participation in this study. 
Prior to the conclusion of the study at the site, the investigator should notify the ImmuneSensor 
Therapeutics (ImmuneSensor), Safety Associate, or designee of any death or AE occurring at 
any time after a patient has discontinued or terminated study participation that may reasonably be 


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related to this study. After study conclusion, the investigator should notify ImmuneSensor of any 
death or AE they are aware of occurring at any time after a patient has discontinued or 
terminated study participation that may reasonably be related to this study.  
The investigator should notify ImmuneSensor or its designee, of any death or AE occurring at 
any time after a patient has discontinued or terminated study participation that may reasonably be 
related to this study. 
9.1.6 
Overdose 
Any dosing errors should be immediately reported to the sponsor. The dosing error should be 
fully documented in the patient’s source documentation/case report form (CRF) and where 
applicable, filed promptly with IRB and regulatory authorities.  
Subsequent dosing shall be discontinued until the investigator and sponsor have both determined 
it’s safe to resume treatment.  
9.1.7 
Pregnancies 
No clinical data on the effects on pregnancy or lactation are available. Precautions relative to 
patients of reproductive potential are discussed in Section 4.4. 
9.2 
SERIOUS ADVERSE EVENT REPORTING 
9.2.1 
Reporting Requirements 
Any SAE made known to the investigator must be reported by the investigator if it occurs during 
the clinical study, whether or not the SAE is considered to be related to the IMSA101 treatment. 
An SAE report consists of the SAE form, the AE form, and the concomitant medication form.  
A copy of these forms must be forwarded within 24 h of awareness. Contact details will be 
provided in the study reference manual.  
The investigator should not wait to receive additional information to document fully the event 
before notification of an SAE, though additional information may be requested. Where 
applicable, information from relevant laboratory results, hospital case records, and autopsy 
reports should be obtained. 
Instances of death, congenital abnormality, or an event that is of such clinical concern as to 
influence the overall assessment of safety, if brought to the attention of the investigator at any 
time after cessation of study drug administration and linked by the investigator to this study, 
should be reported to the medical monitor. 
Progression of disease by itself is not considered an AE but rather an expected outcome and a 
study endpoint and should not be reported as AEs or SAEs, unless it results in hospitalization or 
death. AEs associated with progressive disease (such as a pleural effusion or gastrointestinal 
obstruction) and associated hospitalizations to treat the AE or SAE are reportable events. 


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10 STATISTICAL METHODS 
10.1 GENERAL CONSIDERATIONS 
10.1.1 
Statistical and Analytical Plans 
A formal detailed statistical analysis plan (SAP) will be created prior to the analysis of any data. 
The purpose of the Phase I dose escalation study is to determine the safety and tolerability of 
IMSA101 and to define the MTD/RP2D of the drug when administered by intratumoral 
injection. Groups of 3 to 6 patients will be treated at each dose level until the MTD is reached as 
detailed in Section 3.1. All patients meeting the eligibility criteria and receiving at least 1 dose of 
IMSA101 will be evaluable for safety in the Safety Population. 
Phase IIA statistics will be mainly descriptive and informed by the ultimate selection of tumor 
types to be evaluated. Statistical methods including pre-defined criteria for signal detection and 
drug differentiation from standard-of-care benchmarks as well as stage progression and futility 
assessment will be included in the final SAP. 
10.1.2 
Disposition of Patients 
A tabulation of patient disposition will be presented, including the number in each analysis 
population, the number lost to follow-up, the number that withdrew prior to completing the 
study, and reason(s) for withdrawal. 
10.1.3 
Blinding and Randomization 
This clinical study is open-label and non-randomized.  
10.2 ANALYSIS DATASETS 
10.2.1 
Safety Population 
The safety population will consist of all patients receiving at least 1 dose of study medication. 
10.2.2 
Definition of Study Cycles  
Each treatment cycle will be 4 weeks (28 days) in duration. There will be 3 clinic visits in 
Cycle 1 (Day 1, on Day 8, and Day 15). Thereafter for all other cycles, there will be 2 clinic 
visits on Day 1 and Day 15. Study drug will be administered at all visits following screening 
except the EOT and EOS visits. 


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10.3 DATA PRESENTATION 
10.3.1 
Demographic 
Demographic characteristics of patients will be summarized in appropriate tables and analyzed 
with descriptive statistics. 
Demographic variables to be captured include (but not necessarily limited to): 
• Age 
• Gender 
• Race 
• Smoking history 
• Tumor type 
 
10.3.2 
Baseline Characteristics 
Baseline characteristics will be summarized in appropriate tables with descriptive statistics. 
Baseline characteristics to be captured include (but not necessarily limited to):  
• Body weight 
• Height 
• ECOG performance status 
• Previous chemotherapy 
• Previous immunotherapy 
 
10.3.3 
Medical History and Physical Examination 
Descriptive statistics will be generated to summarize data. For continuous variables, descriptive 
statistics may include the number of patients, mean, standard deviations, medians, minimums, 
and maximums. Frequencies and percentages may be displayed for categorical data. 
10.3.4 
Concomitant Medications or Treatments 
The number and percentage of patients taking concomitant medication will be summarized. All 
data will be recorded as follows: 
• Prior use ended before first day of study medication 
• Concomitant use on or after first day of study medication (initiation date, stop date) 
 


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10.3.5 
Safety Data 
• All safety summaries will be provided for the Safety Population. 
• Summaries for safety variables (TEAEs, DLTs, vital signs, 12-lead ECG, physical 
examination, and laboratory safety assessments) will be given. Toxicities will be graded 
using CTCAE v5.0 criteria. 
• All safety variables will be presented in by-patient listings. Safety data will be listed by study 
site, patient number, and cycle.  
• All TEAEs will be summarized by study phase and assigned dose. 
• In addition, all SAEs, including deaths will be listed separately and summarized.  
• Grade 3 and 4 laboratory data will be summarized by study phase and assigned dose.  
• For patients who experience a DLT, data on AEs leading to treatment/study discontinuation 
will be listed. 
 
10.3.6 
Adverse Events  
• AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) coding 
dictionary. A listing of all events, with seriousness, severity, relationship, sequelae, and 
beginning and end times will be provided.  
• Narratives for any SAEs will be provided.  
• Deaths, SAEs, and AEs leading to discontinuation of trial medication will be summarized by 
primary system organ class and preferred terms.  
• Listings will be provided. 
 
10.3.7 
Tumor Assessments  
All known sites of disease must be documented at screening and re-assessed at each subsequent 
tumor evaluation according to procedures described in Section 6.9.  
Patients will be assessed for anti-tumor efficacy using RECIST v1.1 criteria (Appendix 13.2) at 
the end (≤ 7 days) of every even numbered cycle (Cycle 2, Cycle 4, etc.) after the first dosing.  
10.3.8 
Missing and Spurious Data 
No imputation of missing or spurious data is planned. 
For AEs, missing dates will not be imputed; however if partial dates are available, they will be 
used to assess if the AE occurred during the treatment period. Missing severities of AEs will not 
be imputed and will be considered missing in any tabulations of AE severity. If an AE is missing 
a response to the question regarding relationship to treatment, the event will be considered to be 
related. 


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10.4 CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED 
ANALYSIS 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by the sponsor, the IRB/IEC, and the Health Authorities prior to implementation. 
 
 


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11 REGULATORY, ETHICAL AND LEGAL OBLIGATIONS 
11.1 DECLARATION OF HELSINKI 
The Principal Investigator will ensure that this study is conducted in accordance with the ethical 
principles that have their origin in the Declaration of Helsinki and applicable national and local 
laws (World Medical Association (WMA) 2013). 
11.2 GOOD CLINICAL PRACTICE 
The study will be conducted according to the study protocol and to Standard Operating 
Procedures (SOPs) that meet the guidelines provided by the International Council for 
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) for Good 
Clinical Practice in clinical studies (ICH E6 R2). 
11.3 INSTITUTIONAL REVIEW BOARDS/ETHICS COMMITTEES 
Before implementing this study, the protocol, amendments (if any), the proposed informed 
consent forms (ICFs), patient recruitment procedures (e.g., advertisements), and other 
information for the patients must be reviewed by the appropriate IRB/IEC at each study center in 
conformance with ICH E6 R2, the Code of Federal Regulations (CFR), Title 21, Part 56 and any 
other applicable local laws. The IRB/IEC written, signed approval letter/form must contain 
approval of the designated principal investigator, the protocol (identifying protocol title, date, 
and version number), and of the informed consent form (date, version). 
The investigator is responsible for supplying the IRB/IEC with a copy of the current 
Investigator’s Brochure (IB), Package Insert, or Summary of Product Characteristics (SmPC) as 
well as any updates issued during the study. During the course of the study, the investigator will 
provide timely and accurate reports to the IRB/IEC on the progress of the study, at intervals not 
exceeding 1 year (or as appropriate), and will notify the IRB/IEC of SAEs or other significant 
safety findings, per the policy of the IRB/IEC. 
11.4 REGULATORY AUTHORITY APPROVAL 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by the sponsor, the IRB/IEC, and/or other agency if applicable. 
11.5 INFORMED CONSENT 
The investigator must fully inform the patient (or the patient’s legal representative, if applicable) 
of all pertinent aspects of the study including the written information approved by the IRB/IEC. 
Prior to the start of the pre-study examination, the written ICF must be signed and personally 
dated by the patient and by the physician who conducted the informed consent discussion. One 
copy of the written information and signed consent form must be given to the patient and the 
original copy must be retained in the investigator’s study records. 


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11.6 PATIENT CONFIDENTIALITY AND DISCLOSURE 
In compliance with federal regulations/ICH GCP Guidelines, it is required that the investigator 
and institution permit authorized monitors, auditors, and other authorized agents of the sponsor 
and/or its designee, the IRB/IEC approving this research, and the United States (US) FDA, as 
well as that of any other applicable agency or agencies, direct access to review the patient’s 
original medical records for verification of study-related procedures and data. The investigator is 
obligated to inform the patient that his/her study-related records will be reviewed by the 
above-named representatives without violating the confidentiality of the patient.  
All personal data collected and processed for the purposes of this study should be managed by 
the investigator and his/her staff with adequate precautions to ensure confidentiality of those 
data, and in accordance with the Health Insurance Portability and Accountability Act (HIPAA), 
applicable to national and/or local laws and regulations on personal data protection (US HHS 
2002). 
The investigator must ensure that each patient’s anonymity will be strictly maintained. On 
CRF/eCRFs or other documents submitted to the sponsor, patients must not be identified by their 
name, but by an identification code consisting of the identification number. If patients’ names are 
included on copies of documents submitted to the sponsor, the names must be obliterated and the 
assigned identification number must be added to the documents instead. 
11.7 PROTOCOL AMENDMENT 
Before the start of the study, the study protocol, informed consent document, and any other 
appropriate documents (or amendments) will be submitted to the appropriate authorities such as 
the FDA and/or local IRB/IEC with a cover letter or a form listing the documents submitted, 
their intended dates of issue, and the site (or region or area of jurisdiction, as applicable) for 
which approval is sought. If applicable, the documents will also be submitted to the authorities in 
accordance with local legal requirements. 
The investigator should not implement any deviation from, or changes of, the protocol without 
agreement by the sponsor and prior review and documented approval from the IRB/IEC of an 
amendment. The only exceptions are where necessary to eliminate an immediate hazard(s) to 
study patients, or when the change(s) involves only logistical or administrative aspects of the 
study (e.g., change in monitor[s], change of telephone number[s]). Non-substantial protocol 
amendments may or may not be required to be submitted for approval/notification to the 
appropriate authorities (i.e., FDA, IRB/IEC).  
As soon as possible, the implemented deviation or change, the reasons for it, and, if appropriate, 
the proposed protocol amendment(s) should be submitted: 
• to the appropriate authorities for review and approval/favorable opinion 
• to the sponsor for agreement 


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The party initiating an amendment must confirm it clearly in writing and it must be signed and 
dated by the sponsor and the principal investigator. The sponsor or its designee will ensure that 
the investigators submit necessary protocol amendments to the appropriate IRB/IEC. 
All agreed protocol amendments must be clearly documented using standard procedures as 
defined by the sponsor, and must be signed and dated by the sponsor and the investigator. 
11.8 COLLECTION, MONITORING AND AUDITING STUDY 
DOCUMENTATION 
11.8.1 
Data Collection 
The sponsor or the designee will utilize qualified monitors to review and evaluate activities 
conducted at investigator sites for Quality Assurance. 
Data for each patient will be recorded on an eCRF. Data collection must be completed for each 
patient who signs an ICF and is administered treatment. 
The data will be entered into the clinical study database and verified for accuracy, following 
procedures defined by the sponsor (or designee). Data will be processed and analyzed following 
procedures defined by the sponsor (or designee). 
The medical monitor will review any SAEs that occur during the study.  
In accordance with ICH GCP guidelines, the study monitor will carry out source document 
verification at regular intervals to ensure that the data collected in the eCRF are accurate and 
reliable. 
Data that is not captured directly via an electronic device or instrument will be collected from 
source documents and entered into an eCRF within an electronic data capture system. Electronic 
data capture security features will include the requirement for a unique user identification and 
password for each individual who make entries, reviews, or makes changes to the data. 
The investigator will be responsible for ensuring data is electronically captured or that it is 
entered into the eCRF in a timely manner relative to the patient visit. The investigator will ensure 
the accuracy and completeness of all patient data specified in the protocol. Upon study 
completion, the data collected in the eCRF will be provided to each study center in portable 
document format (PDF). 
11.8.2 
Study Monitoring 
A representative of the sponsor or the designee will meet with the investigator and his/her staff 
prior to the entrance of the first patient to review study procedures and methods of recording 
study data.  
After enrollment of the first patient, representative of the sponsor or the designee will be 
assigned to monitor at least once a year each study site for study progress and to verify that 


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standards of GCP and/or ICH guidelines were followed. The investigator is expected to prepare 
for the monitor visit, ensuring that all source documents, completed eCRFs, signed consent 
forms, and other study-related documents are readily available for review. Source documents that 
will be reviewed include but are not limited to accuracy of CRFs, protocol compliance, accuracy 
of entries and AE/SAE management and reporting. Documentation of monitoring will be 
maintained along with other protocol-related documents and will be reviewed during internal 
audit. 
11.8.3 
Auditing of Study Documentation 
Study centers and study documentation may be subject to a Quality Assurance audit at any time 
during or after the study. In addition, inspections may be conducted by regulatory authorities at 
their discretion.  
The investigator must permit the monitor, the IRB/IEC, the sponsor’s internal auditors, and 
representatives from regulatory authorities, direct access to all study-related documents and 
pertinent hospital or medical records for confirmation of data contained within the eCRFs. 
The study will be monitored and/or audited at intervals to ensure that the clinical study is 
conducted and data are generated, documented (recorded), and reported in compliance with the 
study protocol; ICH E6 R2 consolidated guidelines; and other applicable regulations. The extent, 
nature, and frequency of monitoring and/or audits will be based on such considerations as the 
study objectives and/or endpoints, the purpose of the study, study design complexity, and 
enrollment rate. At the conclusion of a program, a compliance statement will be generated by the 
sponsor (or designee) listing all audit activities performed during the clinical study. 
All data recordings and source documentation (including electronic health records) must be made 
available to the sponsor (or designee), FDA, IRB/IEC, and any other regulatory agencies that 
request access to study records, including source documents, for inspection and copying, in 
keeping with federal and local regulations. 
11.9 RECORD RETENTION 
According to ICH guidelines, source documentation and other “essential documents” must be 
archived. Essential documents include those documents which individually and collectively 
permit the evaluation of the conduct of a study and the quality of the data produced (ICH 2016). 
This may include observations and source data contained in medical records (certified copies or 
originals are acceptable for archiving purposes), data collection forms or eCRFs and research-
related records held in support departments. All hard copies of source documents must be 
retained. If electronic records of documents exist, these must be backed up and retained with the 
hard copies.  
Essential documents should be retained for a minimum of 2 years after the last approval of a 
marketing application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or at least 2 years have elapsed since the formal discontinuation of 
clinical development of the study drug. However, these documents should be retained for a 


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longer period if required by the applicable legal requirements and/or written agreements with the 
sponsor (i.e., Master Service Agreement).  
The IRB/IEC should retain all relevant records (e.g., written procedures, membership lists, lists 
of occupations/affiliations of members, submitted documents, minutes of meetings, and 
correspondence) for a period of at least 3 years after completion of the study and make them 
available upon request from the regulatory authorities.  
11.10 DISCLOSURE OF INFORMATION 
All information provided to the investigator by ImmuneSensor or its designee, will be kept 
strictly confidential. No disclosure will be made except in accordance with a right of publication 
granted to the investigator. 
No information about this study or its progress will be provided to anyone not involved in the 
study other than to ImmuneSensor or its authorized representatives, or in confidence to the IRB, 
or similar committee, except if required by law. 
11.11 DISCONTINUATION OF THE STUDY 
It is agreed that, for reasonable cause, either the investigator or ImmuneSensor may terminate the 
investigator’s participation in this study after submission of a written notice. ImmuneSensor may 
terminate the study at any time upon immediate notice for any reason, including the sponsor’s 
belief that discontinuation of the study is necessary for the safety of patients. 
11.12 STUDY REPORT, PUBLICATION POLICY AND ARCHIVING OF STUDY 
DOCUMENTATION 
An ICH-compliant integrated clinical and statistical report will be prepared upon completion of 
the study and data analysis. The results of the study will be published in a relevant peer-reviewed 
journal, with authorship status and ranking designated according to the acknowledged 
contributions of participating investigators, institutions, and the sponsor.  
11.12.1 Data Capture 
This study will use a 21 CFR Part 11 compliant electronic data capture system. An eCRF will be 
used for data recording. Any data requested on the eCRF must be entered and a reasonable effort 
should be made to retrieve any missing data.  
The data will be checked for completeness and correctness and discrepancy reports will be 
generated accordingly and transferred to the study center for resolution by the investigator or 
his/her designee. 
Accurate and reliable data collection will be assured by verification and cross–check of the eCRF 
against the investigator’s records by the study monitor (source document verification), and the 
maintenance of a study drug accountability log by the investigator. 


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11.12.2 Study Documents 
The investigator must maintain source documents for each patient in the study, including all 
demographic and medical information, laboratory data, ECGs, etc., and keep a copy of the 
signed and dated ICFs. All information on the eCRFs must be traceable to these source 
documents in the patient’s file. Data without a written or electronic record will be defined before 
study start and will be recorded directly on the eCRFs, which will be documented as being the 
source data. 
11.12.3 Archiving of Documents 
Essential documents, as listed below, must be retained by the investigator for as long as needed 
to comply with national and international regulations. The sponsor will notify the 
investigator(s)/institution(s) when the study-related records are no longer required. The 
investigator agrees to adhere to the document retention procedures by signing the protocol. 
Essential documents include: 
1. IRB/IEC/REB approvals for the study protocol and all amendments 
2. All source documents and laboratory records 
3. CRF copies (electronic copies on a CDROM) 
4. Patients’ ICFs (with study number and title of trial) 
5. FDA form 1572 
6. Any other pertinent study documents 
 
 


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12 REFERENCES 
Aduro Biotech Inc.2016. ClinicalTrials.gov ID#: NCT02675439. Safety and Efficacy of 
MIW815 (ADU-S100) +/- Ipilimumab in Patients with Advanced/Metastatic Solid Tumors or 
Lymphomas. from https://clinicaltrials.gov/ct2/show/NCT02675439. 
Bose, D. cGAS/STING Pathway in Cancer: Jekyll and Hyde Story of Cancer Immune Response. 
2017. Int J Mol Sci. 18(11). 
Chen, Q., L. Sun and Z. J. Chen. Regulation and function of the cGAS-STING pathway of 
cytosolic DNA sensing. 2016. Nat Immunol. 17(10):1142-1149. 
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 
1976;16(1):31–41. 
Eisenhauer, E. A., P. Therasse, J. Bogaerts, L. H. Schwartz, D. Sargent, R. Ford, J. Dancey, S. 
Arbuck, S. Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan, D. Lacombe 
and J. Verweij. New response evaluation criteria in solid tumours: revised RECIST guideline 
(version 1.1). 2009. Eur J Cancer. 45(2):228-247. 
ICH.2016. The International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use (ICH). Integrated Addendum to ICH E6(R1): 
Guideline for Good Clinical Practice E6(R2). 9 November 2016., from 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/E6/E6_R2__
Step_4_2016_1109.pdf. 
Li, T., H. Cheng, H. Yuan, Q. Xu, C. Shu, Y. Zhang, P. Xu, J. Tan, Y. Rui, P. Li and X. Tan. 
Antitumor Activity of cGAMP via Stimulation of cGAS-cGAMP-STING-IRF3 Mediated Innate 
Immune Response. 2016. Sci Rep. 6:19049. 
Merck Sharp & Dohme Corp. ClinicalTrials.gov ID#: NCT03010176. Study of MK-1454 Alone 
or in Combination with Pembolizumab in Participants with Advanced/Metastatic Solid Tumors 
or Lymphomas (MK-1454-001). 2017. 
Oken, M. M., R. H. Creech, D. C. Tormey, J. Horton, T. E. Davis, E. T. McFadden and P. P. 
Carbone. Toxicity and response criteria of the Eastern Cooperative Oncology Group. 1982. Am J 
Clin Oncol. 5(6):649-655. 
US HHS. Health Insurance Portability and Accountability (HIPAA). 5 CFR Part 160 and 
Subparts A and E of Part 164. August 14, 2002.  
Wang, H., S. Hu, X. Chen, H. Shi, C. Chen, L. Sun and Z. J. Chen. cGAS is essential for the 
antitumor effect of immune checkpoint blockade. 2017. Proc Natl Acad Sci U S A. 114(7):1637-
1642. 
World Medical Association (WMA). The World Medical Association (WMA) Declaration of 
Helsinki - Ethical Principles for Medical Research Involving Human Patients. 2013. 


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13 APPENDICES 
 
13.1 EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) 
PERFORMANCE SCALE  
ECOG PERFORMANCE STATUS* 
Grade 
ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% 
of waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed 
or chair 
5 
Dead 
* As published in Am. J. Clin. Oncol (Oken, 1982) 
 


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13.2 RECIST GUIDELINE (VERSION 1.1) 
All findings will be assessed for response according to RECIST v1.1 criteria (Eisenhauer, 2009) 
at the end (≤ 7 days) of every even numbered cycle (Cycle 2, Cycle 4, etc.), and EOT. Refer to 
Section 6.9 for details. 
RECIST v1.1 criteria do not mention including or excluding lesions that are being biopsied or 
injected. However, for the purposes of this protocol, the injected and biopsied lesions are to be 
captured as non-target lesions only (Phase I only), as follows: 
• Injected and biopsied lesion = non-target lesion #1 
• Non-injected and biopsied lesion = non-target lesion #2 (if applicable) 
 
All patients will have their BEST RESPONSE on study classified as outlined below: 
Complete Response (CR) 
Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) 
must have reduction in the short axis to < 10mm. 
Partial Response (PR) 
At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline 
sum LD. 
Stable Disease (SD) 
Steady state of disease. Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD. 
Progressive Disease 
At least a 20% increase in the sum of diameters of measured lesions taking as references the 
smallest sum of diameters recorded since the treatment started. In addition to the relative increase 
of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. Appearance of one 
or more new lesions will also constitute progressive disease.  
Response Duration 
Response duration will be measured from the time measurement criteria for CR/PR (whichever is 
first recorded) are first met until the first date that recurrent or progressive disease is objectively 
documented, taking as reference the smallest measurements recorded since the treatment started. 


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Stable Disease Duration 
Stable disease duration will be measured from the time of start of therapy until the criteria for 
progression are met, taking as reference the smallest measurements recorded since the treatment 
started. 


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Evaluation of Best Overall Response – Patient with Target (+/- non-target) disease 
Target lesions 
Non-Target lesions 
New Lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Non-CR-Non-PD 
No 
PR 
CR 
NE 
No 
PR 
PR 
Non-PD/ 
or not all evaluated 
No 
PR 
SD 
Non-PD/ 
or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
Evaluation of Best Overall Response – Patient with Non-Target Disease 
Non-Target lesions 
New Lesions 
Overall response 
CR 
No 
CR 
Non-CR-Non-PD 
No 
Non-CR/Non-PD 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
 
Note: Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as “symptomatic 
deterioration”. Every effort should be made to document the objective progression even after 
discontinuation of treatment. 


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Method of Measurement 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up.  
Clinical Lesions 
Clinical lesions will only be considered measurable when they are superficial (e.g., skin nodules, 
palpable lymph nodes). For the case of skin lesions, documentation by color photography including 
a ruler to estimate the size of the lesion is recommended.  
Chest X-ray 
Lesions on chest X-ray are acceptable as measurable lesions when they are clearly defined and 
surrounded by aerated lung. However, CT is preferable.  
CT / MRI.  
CT and MRI might be the best currently available and reproducible methods to measure target 
lesions selected for response assessment. Conventional CT and MRI should be performed with 
cuts of 10 mm or less in slice thickness contiguously. Spiral CT should be performed using a 5 mm 
contiguous reconstruction algorithm. This applies to the chest, abdomen and pelvis. Head & neck 
and extremities usually require specific protocols. 
Ultrasound 
When the primary endpoint of the study is objective response evaluation, ultrasound should not be 
used to measure tumor lesions that are clinically not easily accessible. It is a possible alternative 
to clinical measurements for superficial palpable nodes, subcutaneous lesions and thyroid nodules. 
Ultrasound might also be useful to confirm the complete disappearance of superficial lesions 
usually assessed by clinical examination. 
Cytology / Histology 
These techniques can be used to differentiate between PR and CR in rare cases (for example, 
residual lesions in tumor types such as germ cell tumors, where known residual benign tumors can 
remain). The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or stable 
disease is mandatory to differentiate between response or stable disease (an effusion may be a side 
effect of the treatment) and progressive disease. 
 


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13.3 CREATININE CLEARANCE  
Creatinine clearance will be calculated using the Cockcroft-Gault formula (Cockcroft, 1976) as 
follows: 
Females: 
For serum creatinine concentration in mg/dL: 
CrCl = (140 –age in years) x weight in Kg x 0.85  
72 x serum creatinine in mg/dL 
 
Males: 
For serum creatinine concentration in mg/dL: 
CrCl = (140 – age in years) x weight in Kg x 1.00  
72 x serum creatinine in mg/dL 
 
 


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13.4 CONTACT LIST 
SPONSOR: 
Teresa Mooneyham  
 
Senior Director, 
Clinical Operations and Project Management