Clinical trial NCT03058289
Conditions: Breast Cancer Head and Neck Cancer Squamous Cell Carcinoma Lymphoma Pancreatic Cancer Liver Cancer Colon Cancer Lung Cancer Bile Duct Cancer Chordoma of Sacrum Sarcoma
Keywords: Neoplasm Malignancy Intratumoral Intralesional anti-PD-1 antibodies Immuno therapy Dose escalation Platinum Intensity Therapeutics INT230-6 Cisplatin Vinblastine PD-1 Vinca KEYTRUDA® Pembrolizumab CTLA-4 Carcinoma Yervoy Ipilimumab Keynote A10 CA184-592
Sponsor: Intensity Therapeutics, Inc.
Start date: 2017-02-09; Completion date: 2023-02-22
Enrollment: 111 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This study evaluated the intratumoral administration of escalating doses of a novel, experimental drug, INT230-6. The study was conducted in patients with several types of refractory cancers including those at the surface of the skin (breast, squamous cell, head and neck) and tumors within the body such (pancreatic, colon, liver, lung, etc.). Sponsor also tested INT230-6 in combination with anti-PD-1 and anti-CTLA-4 antibodies.

Detailed description:
INT230-6 is comprised of 3 agents in a fixed ratio - a cell permeation enhancer and two, potent anti-cancer payloads (cisplatin and vinblastine sulfate). The penetration enhancer facilitates dispersion of the two drugs throughout injected tumors and enables increased diffusion into cancer cells. Nonclinical safety studies showed no findings following drug injection into healthy tissues.

Historically physicians administer the two active drugs comprising INT230-6 by intravenous (IV) infusion to achieve a systemic blood level at the limit of tolerability. The objective is destroy both visible tumors and unseen circulating cancer cells (micro-metastases). Unfortunately, dosing drugs IV delivers only a small amount with a low concentration at the tumor site. This approach especially for late stage cancers is not highly effective and often quite toxic to the patient.

Attempts at direct intratumoral injection with chemotherapeutic agents have not shown the ability to treat the injected tumor, non-injected tumors or micro-metastases. This lack of efficacy for local administration is due possibly to poor dispersion and a lack of cell uptake of the agents.

Due to the use of the novel cell penetration enhancing agent INT230-6 treatment demonstrated strong efficacy in animals having large tumors. The Sponsor's in vivo, non-clinical data shows that INT230-6 thoroughly saturates and kills injected tumors. In addition, the drug induces an adaptive (T-cell mediated) immune response that attacks not only the injected tumor, but non-injected tumors and unseen micro-metastases. Cured animals become permanently immunized against the type of cancer that INT230-6 eliminates.

Clinical trial IT-01 sought to determine the safety and potential efficacy of dosing INT230-6 directly into several different types of cancers. In addition, animal studies showed a strong synergy of INT230-6 with immune modulation agents. Thus, as part of study IT-01 the Sponsor seeks to understand the safety and efficacy of INT230-6 when administered in combination with immuno-therapeutic agents such as antibodies that target Programmed Cell Death (PD-1 or anti-PD-1) and Cytotoxic T-Lymphocyte Associated Protein 4 (CTLA-4 or anti-CTLA-4) receptors.

This study sought to understand whether tumor regression can be achieved, and patient outcomes improved.

Arms: arm 1: Dosing: \>=40% Total Tumor Burden

A1:INT230-6 injections into only superficial tumors, low starting dose, low concentration per tumor.

B1:INT230-6 injections into deep tumors, low starting dose, low drug concentration per tumor

Dosing schedule for A1 and B1 is every 28 days for 5 sessions

EA:INT230-6 injections into superficial tumors, medium starting dose, low drug concentration per tumor

EC:INT230-6 injections into superficial or deep tumors, moderately high starting dose, high drug concentration per tumor

EC2:INT230-6 injections into superficial or deep tumors, high starting dose, moderate drug concentration per tumor, higher number of tumors to be treated per session than EC.

EC3:INT230-6 injections at fixed maximal dose into superficial or deep tumors, unlimited number of tumors to be treated per session with retreatment once every 9 weeks for two years.

Dosing schedule for EA, EC, EC2 and EC3 is every 2 weeks for 5 sessions

Completed Cohorts arm 2: Dosing: \<40% Total Tumor Burden

A1:INT230-6 injections into only superficial tumors, low starting dose, low concentration per tumor.

B1:INT230-6 injections into deep tumors, low starting dose, low drug concentration per tumor

Dosing schedule for A1 and B1 is every 28 days for 5 sessions

EA:INT230-6 injections into superficial tumors, medium starting dose, low drug concentration per tumor

EC:INT230-6 injections into superficial or deep tumors, moderately high starting dose, high drug concentration per tumor

EC2:INT230-6 injections into superficial or deep tumors, high starting dose, moderate drug concentration per tumor, higher number of tumors to be treated per session than EC.

EC3:INT230-6 injections at fixed maximal dose into superficial or deep tumors, unlimited number of tumors to be treated per session with retreatment once every 9 weeks for two years.

Dosing schedule for EA, EC, EC2 and EC3 is every 2 weeks for 5 sessions

Completed Cohorts arm 3: DEC: INT230-6 injections every 2 weeks for 5 sessions with the possibility for INT230-6 retreatment into superficial tumors, with addition of anti-PD-1 antibody KEYTRUDA® (pembrolizumab) dosed concurrently starting at Day 1 every 3 weeks for two years for selected cancer types.

Completed Cohort

DEC2:INT230-6 per the dosing of cohort EC3 combined with KEYTRUDA® (pembrolizumab) dosed per DEC concurrently starting at Day 1 for selected cancers.

Completed Cohort arm 4: FEC: INT230-6 per the EC3 regimen combined with Yervoy (ipilimumab) dosed concurrently starting at Day 1 every 3 weeks for four treatments for selected cancer types.

Completed Cohort anti-CTLA-4 antibody: The anti-CTLA-4 antibody will be added concomitantly with INT230-6 as noted in cohort FEC.
Interventions: intervention 1: INT230-6 intervention 2: anti-PD-1 antibody intervention 3: anti-CTLA-4 antibody
Intervention descriptions: intervention 1: INT230-6 is clear sterile solution administered by injection directly into the tumor to be treated.

The product contains a cell permeation agent with cisplatin and vinblastine sulfate at fixed concentrations. intervention 2: The anti-PD-1 antibody will be added concomitantly with INT230-6 as noted in cohort DEC and DEC2 intervention 3: The anti-CTLA-4 antibody will be added concomitantly with INT230-6 as noted in cohort FEC

Protocol documents:
Prot_002.pdf: 
Intensity Therapeutics’ Confidential Information 
 
 
 
Protocol Number: IT-01 
Development Phase: Phase 1/2 
Date: March 23, 2021 
Version: Amendment 6.0 
 
 
 
 
 
 
A Phase 1/2 Safety Study of Intratumorally Administered INT230-6 in 
Adult Subjects with Advanced Refractory Cancers 
 
 
 
 
 
This document is the confidential and proprietary information of Intensity Therapeutics, Inc. 
(Sponsor). By reviewing this document, you agree to keep it confidential and to use and disclose it 
solely for the purpose of assessing whether your organization will participate in and/or the 
performance of the proposed Intensity Therapeutics-sponsored study. Any permitted disclosures will 
be made only on a confidential "need to know" basis within your organization or to your independent 
ethics committee(s). Any other use, copying, disclosure or dissemination of this information is strictly 
prohibited unless expressly authorized in writing by Intensity Therapeutics. Any supplemental 
information (e.g., amendments) that may be added to this document is also confidential and 
proprietary to Intensity Therapeutics and must be kept in confidence in the same manner as the 
contents of this document. Any person who receives this document without due authorization from 
Intensity Therapeutics is requested to return it to Intensity Therapeutics or promptly destroy it. All 
other rights reserved. 
 
 
 


Protocol IT-01 Version Amendment 6 
Intensity Therapeutics’ Confidential Information                                                Page 2 of 212 
The Following changes are summarized  
Document 
Date of Issue 
Summary of changes 
Amendment 6 
March 2021 
This protocol amendment incorporates previous changes 
encompassed by administrative letters dated June 2020 
and July 2020. This amendment focuses on simplifying 
the clinical trial: 
• 
Modified inclusion criteria: Subjects with 
metastatic disease who have failed one or more approved 
standard therapies, or have no alternate indicated therapy 
available. 
• 
New exclusion criteria: Subjects with tumors >15 
cm (in longest diameter). Treatment plan for subjects 
with tumors that are 9 to15 cm must be discussed with 
and approved by the medical monitor. 
• 
Removed blood biomarkers and PK collection, 
processing and shipping. 
• 
Text has been added to introduce a simpler 
method to calculate the INT230-6 dose for tumor 
injections. 
• 
Added an additional clinical site- Houston 
Methodist. 
• 
Minor grammatical, editorial, and formatting 
changes for clarification purposes. 
Amendment 5 
April 2020 
This amendment focuses on simplifying the dosing 
regimen of INT230-6 creating new monotherapy cohort 
EC3 and aligning this across all combination arms as 
seen in the DEC/DEC2 and FEC supplements: 
• 
INT230-6 dosing is simplified to allow up to a 
maximum 175ml total into as many lesions as feasible, 
and intrapatient dose escalation is removed. 
• 
INT230-6 dosing is divided into two periods, the 
Q 2wk for 5 doses as induction and then once every 9 
weeks +/- 10 days for maintenance.  Note retreatment has 
been removed. 
• 
The criteria for assessing response has been 
changed from RECIST 1.1 to iRECIST. 
• 
Other minor changes to improve the clarify and 
consistency of the protocol and supplements. 
Amendment 4 
June-2019 
 
 
 
 
 
 
 
 
 
• This protocol amendment incorporates previous 
changes encompassed by administrative letters 
dated November 2017, January 2018, June 2018 
and March 2019 plus additional 
recommendations by the Study Steering 
Committee in February 2019: 
• Allows for different combinations to be 
incorporated by supplements. 
 
 
 
 


Protocol IT-01 Version Amendment 6 
Intensity Therapeutics’ Confidential Information                                                Page 3 of 212 
• Incorporates new investigators (Administrative 
letter November 2017). 
• Incorporates cohort E-A (Administrative letter: 
January 2018) every two-week dosing with 
higher starting dose. 
• Incorporates Cohort EC (Administrative Letter: 
June 2018) every two-week dosing at higher 
dosing and 1:2 drug to tumor volume loading 
ratio. 
• Administrative letter March 2019. 
• New cohort EC2 superficial and deep tumors 
dosed every 14 days at a 1:3 drug to tumor 
volume loading ratio. 
• Change in schedule for PK moving day 7 post to 
1 hour post next dose; no change in number of 
PK sample collections. 
• Removed Cohort Schema 
• Include Schedule of Events for “E” (every two-
week dosing) cohorts. 
• Clarified Post dose follow up. 
• Clarified retreatment process criteria. 
• Include availability of a 30 mL drug product vial. 
Amendment 3 
14-August-2017 
This protocol amendment was made per requests by and 
in agreement with the FDA as follows: 
• Two inclusion criteria were changed (former #2 
and #10). 
• A new exclusion criterion was added regarding 
refusal. 
• Exclusion criterion #6 (PD-1 combo) was 
modified. 
• Baseline in section 13.1 was clarified to be cycle 
1, day 0. 
• Table 9 footnote 4 typographical error was 
corrected. 
• Corrected typographical and spelling errors 
throughout the document. 
Amendment 2 
19 -July-2017 
This protocol was updated per the rational below. 
• Modified section 6 Cohort A1 per rational, others 
for improved clarity. 
• Section 7.1, modified inclusion criteria #2 and 
#10. 
• Updated Sponsor’s address and list of 
investigators, abbreviations. 
• Updated section 9.7 to note new PK collection 
information. 
• Revised the Schema. 


Protocol IT-01 Version Amendment 6 
Intensity Therapeutics’ Confidential Information                                                Page 4 of 212 
• Section 13.1 moved PT, PTT, INR to hematology 
from chemistry. 
• Provided more detail on exploratory endpoint 
RECIST modification section 13.2. 
• Updated PK section 13.3 for improved clarity. 
• Made minor wording and other changes to 
improve the consistency and clarity. 
 
Amendment 1 
12-Dec-2016 
The protocol was updated based on feedback from the 
US FDA and Canada’s Health Canada.   
• The starting dose was reduced to 5 mL from the 
proposed 7.5 mL.  
• The DLT criteria were modified and the DLT 
window was extended to 28 Days from 14 days, 
• Inclusion criteria were modified to require more 
stringent hemoglobin, platelet and coagulation 
parameters for subjects with deep tumors, 
• Additional safety background information was 
included in a number of sections, 
• Delayed tumor biopysing for at least the first 20 
subjects i.e.,10 superficial, and 10 deep tumors 
until the SSC reviews study safety data, 
• Expanded the descriptions in section 6 and the 
schema diagram to better clarify and specify the 
criteria for initiation of all cohorts after A1. 
• Added new section 9.12 to describe conditions 
for the discontinuation of study drug due to 
adverse events. 
• Added new section 10.2 to describe the 
management of selected adverse events. 
• Made minor wording and other changes to 
improve the consistency and clarity of the 
protocol. 
Original 
protocol 
October 5, 2016  
 
 
RATIONALE for Amendment 1:  The regulatory agencies sought to improve clarity on i) escalation 
within or initiation of new cohorts, ii) how adverse events would be managed (including drug or 
immune related AEs), iii) patient stopping procedures, iv) imaging of injection of tumors to improve 
necrosis monitoring of injected tumors, v) reducing bleeding risk as well as drug extravasation and 
vi) remove section inconsistencies.   
 
RATIONALE for Amendment 2:  In an effort to facilitate appropriate patient selection, recruitment 
and to support enrollment, the entry criteria have been modified.  The additional changes made 
improve the clarity and consistency of the protocol with its corresponding manuals and other 
ancillary documents. Changes to section 6 cohort A1 were as a result of dosing the sentinel patient. 
 


Protocol IT-01 Version Amendment 6 
Intensity Therapeutics’ Confidential Information                                                Page 5 of 212 
RATIONALE for Amendment 3.  These changes were made per request by and in agreement with 
FDA. 
 
RATIONALE for Amendment 4.  Several adjustments from the steering committee were 
implemented via administrative letters.  This amendment seeks to incorporate these changes plus 
include the most recent steering committee recommendations on new cohorts (combinations and 
higher dose cohort EC2).  Additional minor changes were made to improve the clarity and 
consistency of the protocol. 
 
RATIONALE for Amendment 5.  Fifty-five patients have been treated and the safety has been 
reviewed for the monotherapy and combination with pembrolizumab arms.  There has been only 1 
event that qualified for a technical DLT, which was a grade 3 abdominal pain, which was reviewed 
by the SSC and felt not to be dose limiting.  Side effects have been mainly low-grade pain at the 
injection site, and the pharmacokinetics support minimal exposure to the cytotoxic agents in the 
formulation.  We have therefore decided to simplify the dosing, to a fixed maximal amount of 
175mL.  Retreatment has also provided benefit.  As a result, Sponsor will add a periodic 
maintenance dose of INT230-6.  To capture the potential treatment benefit, the response criteria was 
amended to focus on iRECIST.  This criteria was first introduced to capture the unique response 
pattern seen with immunotherapy.  This study has demonstrated increases in tumor volume at the 
first scan which sometimes are associated with decreased contrast uptake.  We see an influx of 
immune cells on the 1 month tumor biopsy.  Sponsor therefore chose to focus on the iRECIST 
principles for assessing response.  Safety data was reviewed by the Study Steering Committee and 
supported initiation of the phase 2 portion of the protocol with the combination of pembrolizumab 
and INT230-6.  Additional minor changes were made to improve the clarity and consistency of the 
protocol.  In collaboration with the National Cancer Institute Sponsor conducted research in murine 
cancer models combining INT230-6 with CTLA-4 antibodies.  Sponsor’s published results show 
strong synergy of the combination with tumor growth inhibition and survival.  Amendment 4 
discussed an outline of the cohort with a CTLA-4 antibody (cohort FEC).  This amendment defines 
the specifics of the dosing and the CTLA-4 antibody being used in cohort FEC (ipilimumab). 
 
RATIONALE for Amendment 6.  The primary goal for Amendment 6 is to simplify the INT230-6 
dose calculation and ensure patients enrolled are likely to benefit from study drug.  70 patients have 
been treated in IT-01 as of December 31, 2020.  After SSC determination of safety in subjects 
receiving the fixed dose regimen and adequate characterization of the pharmacokinetics, we have 
removed the PK sampling.  In addition, blood biomarker sampling has been discontinued while we 
focus on the tumor associated biomarkers. A new exclusion criterion was added to exclude subjects 
that have a tumor(s) > 15 cm (in longest diameter). Further, treatment plan for subjects with tumors 
that are 9 to 15 cm should be discussed with and approved by the medical monitor. 
 
 
 


Protocol IT-01 Version Amendment 6 
Intensity Therapeutics’ Confidential Information                                                Page 6 of 212 
INVESTIGATOR’S AGREEMENT 
 
I have read the IT-01 protocol and agree to conduct the study as outlined.  I agree to maintain the 
confidentiality of all information received or developed in connection with this protocol. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
Date 
 
 


Protocol IT-01 Version Amendment 6 
Intensity Therapeutics’ Confidential Information                                                Page 7 of 212 
PROCEDURES IN CASE OF EMERGENCY 
 
Table 1: 
Emergency Contact Information 
Role in Study 
Name 
Address and Telephone number 
Responsible Physicians 
Ian B. Walters, MD 
Syed Mahmood, MD 
61 Wilton Road 
Westport, CT 06880 
Office Phone Number:  
Dr. Walters: (O) 203-221-7378 
Dr. Walters: (C) 510-406-1911 
Dr. Mahmood (O) 203-293-4224 
Dr. Mahmood (C) 646-541-0149 
Office Fax Number:  
203-557-3023 
Email:  
iwalters@intensitytherapeutics.com 
smahmood@intensitytherapeutics.com 
Drug Safety Physician 
Syed Mahmood, MD 
See above 
SAE Contact 
ProPharma 
Fax: 919-844-6948 
clinicalsafety@propharmagroup.com 
 


Protocol IT-01 Version Amendment 6 
Intensity Therapeutics’ Confidential Information                                                Page 8 of 212 
2. 
SYNOPSIS 
Name of Sponsor Company: 
Intensity Therapeutics, Inc., Westport, CT 
Name of Trial Management Company: 
Catalyst Clinical Research, LLC, Wilmington, NC (Catalyst) 
Name of Investigational Product: 
INT230-6 
Name of Active Ingredient: 
INT230-6 is supplied in a frozen, single use 10mL or 30 mL amber vial.  Each vial contains: 
Cisplatin (CIS) 0.5mg/mL 
Vinblastine Sulfate (VBL) 0.1mg/mL 
Sodium 2-hydroxybenzoylaminooctanoate (SHAO) 10mg/mL (as free acid) 
 
Title of Study:  
A Phase 1/2 Safety Study of Intratumorally Administered INT230-6 in Adult Subjects with Advanced 
Refractory Cancers 
Study center(s): University of Southern California (USC), Princess Margaret Hospital (PMH), Fox 
Chase Cancer Center (FCCC), Johns Hopkins University (JHU), University of Massachusetts 
Worcester (UMass), Columbia University (CU), Houston Methodist (HM) 
Principal Investigator: Lillian Siu (PMH) 
Investigators: Anthony El-Khoueiry (USC), Anthony Olszanski (FCCC), Nilofer Azad (JHU), Giles 
Whalen (UMass), Matthew Ingham (CU), Luis Camacho (HM) 
Studied period (years):  
First subject enrolled: May 25, 2017 
Estimated date last subject completed: July 2024 
Phase of development: 1/2 
 
Objectives:  
Primary: 
• The primary objective is to assess the safety and tolerability of multiple intratumoral doses 
of INT230-6 in subjects with advanced or recurrent malignancies.  This will be assessed by 
the rate of > grade 3 Adverse Events (AEs) attributed to INT230-6 and not the underlying 
disease 
Secondary: 
• Assess the preliminary efficacy of INT230-6 by measuring the disease control rate 
(CR+PR+PD) as assessed by iRECIST 
• Characterize the pharmacokinetic profile of multiple doses the three INT230-6 components 
(CIS, VBL, and SHAO) after single and then multiple IT tumor site injections 


Protocol IT-01 Version Amendment 6 
Intensity Therapeutics’ Confidential Information                                                Page 9 of 212 
• To characterize the overall safety profile of INT230-6 
Exploratory: 
• Characterize tumor response in injected and non-injected sites 
• Evaluate various tumor and anti-tumor immune response biomarkers that may correlate 
with tumor response 
• Evaluate overall response by iRECIST 
• Characterized the pharmacodynamics (PD) profile of the INT230-6 formulation in subject  
treated and untreated tumors 
• To assess the progression free and overall survival in subjects receiving INT230-6 
Methodology:  
This is a clinical study of a new investigational treatment that uses a novel drug product called 
“INT230-6" to treat advanced cancers.  INT230-6 is a fixed ratio, multi-agent formulated drug product 
designed specifically for intratumoral (IT) injection.  This study will determine the safety of 
administering a fixed volume of INT230-6 per cm3 of tumor into superficial, followed by multiple 
deep tumors.  A sentinel subject will be enrolled at the lowest dose and followed for 4 weeks prior to 
escalating or adding additional subjects.  Gradual intra-subject dose escalation will be done to increase 
the total amount of drug delivered to enable large tumors to be fully dosed at the proposed drug to 
tumor ratios.  Once escalation dosing cohorts are complete, if no MTD is obtained, then set a fixed 
total dose of INT230-6 to be used for all dosings.  Using fixed doses INT230-6 treatment shall consist 
of an induction phase for certain cohorts along with a maintenance regimen.  INT230-6 will also be 
tested in combination with additional agents such as checkpoint antibodies in escalation or fixed 
dosing. 
 
Dose escalation  
There are 6 cohorts of subjects in the escalation portion of the protocol where INT230-6 dosing is 
increased over 5 doses.  These escalation cohorts are (A, B1, EA, EC, EC2 and DEC).  Enrollment in 
these cohorts is closed. 
Cohort 1 (A) was a superficial tumor cohort starting at up to 5.0 mL of total dose with a low tumor 
load (1:4 ratio of drug to tumor).   
Cohort 2 (B1) was a deep tumor cohort starting at up to 5.0 mL and escalates the total dose and 
maximal dose per any one tumor.   
Cohort 3 (EA) explored administration in superficial tumors every 2 weeks.   
Cohort 4 (EC) explored administration in both superficial and deep tumors every 2 weeks at a higher 
drug load (1:2 ratio) and will escalate the total dose and maximal dose per any one tumor.   
Cohort 5 (EC2) explored administration in both superficial and tumors every 2 weeks at an 
intermediate drug load (1:3 ratio) and will escalate the total dose and maximal dose per any one tumor.   
Cohort 6 (DEC) combined pembrolizumab and escalating doses of INT230-6 and includes a safety 
lead-in cohort that doses INT230-6 in superficial tumors. 


Protocol IT-01 Version Amendment 6 
Intensity Therapeutics’ Confidential Information                                                Page 10 of 212 
 
 
Fixed Dose INT230-6 
There are 4 cohorts that use a maximum total fixed dose of INT230-6 of 175 mL for all 5 induction 
doses and along with maintenance doses.  The maintenance dose is an INT230-6 dose given every 9 
weeks +/- 10 days up to a maximum total dose amount of 175 mL.  The fixed dose cohorts are EC3, 
DEC2, FEC and potentially GEC and each follows the Q2 week INT230-6 dosing schedule at drug 
load to tumor volume ratio of 1:3 into both superficial and deep tumors for tumor types defined in the 
appropriate supplement.   
Cohort 7 (EC3) explores administration of INT230-6 monotherapy for any tumor type.   
Cohort 8 (DEC2) combines a fixed dose of pembrolizumab with the same INT230-6 dosing regimen of 
EC3 as outlined in Supplement A.   
Cohort 9 (FEC) combines a fixed dose of ipilimumab with the same INT230-6 dosing regimen of EC3 
as outlined in Supplement A.   
Future Cohort 10 (G cohort) combines INT230-6 with other molecules.   
Additional cohorts can be added depending on review of safety data by the Study Steering Committee.  
All cohorts and decisions to escalate the dose and introduce new subject populations will be governed 
by the Study Steering Committee (SSC).   
 
Expansion cohorts 
The SSC reviewed the safety and any available biologic and/or tumor measurement data, a decision to 
open expansion cohorts of 10-16 subjects with a single tumor type was made.  These groups will allow 
for better point estimates of the safety and preliminary efficacy in a homogenous population. 
Number of subjects (planned):  
The sample size (estimated to be between 100 and 175 subjects) during dose escalation cannot be 
precisely determined but depends on the observed toxicity.  In expansion cohorts, up to 16 subjects 
will be treated at fixed doses in a tumor type, to provide preliminary assessment of tumor response, in 
addition to safety assessment. 
Diagnosis and main criteria for inclusion:  
Key Inclusion Criteria  
1. The participant (or legally acceptable representative if applicable) provides written informed 
consent for the trial.   
2. Men and Women > 18 years of age on the day of signing consent. 
3. Have an Eastern Cooperative Oncology Group (ECOG) performance status < 2; (for 
pembrolizumab and ipilimumab combinations please see supplements DEC/DEC2 and 
FEC for ECOG criteria). 
4. Populations: INT230-6 will be injected into deep or superficial tumors for subjects with 
histologically or cytologically confirmed advanced or metastatic cancers; (for pembrolizumab 


Protocol IT-01 Version Amendment 6 
Intensity Therapeutics’ Confidential Information                                                Page 11 of 212 
and ipilimumab combinations please see supplements DEC/DEC2 and FEC for 
Populations). 
5. Includes subjects with loco-regional disease that have relapsed/recurred within 6 months of 
chemo-radiation and who have no standard of care.  
6. Subjects with metastatic disease who have failed one or more approved standard therapies, or 
have no alternate approved therapy available. Failure of all approved therapies that have a 
modest or marginal impact on survival is not required as long as the treating physician believes 
that treatment on study is appropriate for the subject and documents that the subject elects to 
defer the approved therapies. 
Note:  There is no limit on the number of prior therapies that a patient (subject) may 
have received prior to enrollment in any cohort. 
7. Subjects must have measurable disease by iRECIST 1.1 criteria including one target tumor for 
injection by the local site investigator/radiology.  Superficial tumors must have one tumor 
greater than or equal to 1.0 cm, deep tumors greater than or equal to 1.0 cm (as measured by 
caliper (for non-injected tumors only) or image guidance).  Lesions situated in a previously 
irradiated area are considered measurable if progression has been demonstrated in such lesions. 
8. Subjects must have a minimum of one injectable lesion as determined by the investigator (for 
superficial tumors) or radiologist (deep tumors). 
9. Prior chemotherapy or immunotherapy (tumor vaccine, cytokine, or growth factor given to 
control the cancer: systemic or IT) must have been completed at least 4 weeks prior to dosing 
(with the exception of kinase inhibitors or other short half-life drugs, a 2 week washout is 
acceptable prior to treatment) and all adverse events have either returned to baseline or 
stabilized. 
Note:  Subjects who have received prior platinum therapy are eligible irrespective of 
their response. 
10. Prior systemic radiation therapy (either IV, intrahepatic or oral) completed at least 4 weeks 
prior to study drug administration; (for ipilimumab combination please see supplement FEC 
exclusion criteria). 
11. Prior focal radiotherapy completed at least 2 weeks prior to study drug administration. 
12. Prior major treatment-related surgery completed at least 4 weeks prior to study drug 
administration. 
13. No prior primary or metastatic brain or meningeal tumors unless clinically and radiographically 
stable as well as off steroid therapy for at least 2 months. 
14. Life expectancy ≥8 weeks; (for ipilimumab combination please see supplement FEC 
inclusion criteria). 
15. A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at 
least one of the following conditions applies:  
a. Not a woman of childbearing potential (WOCBP)  
b. A WOCBP subject who may become pregnant or who are sexually active with a partner 
and who could become pregnant agrees to use an effective form of barrier contraception 
during the study and for at least 180 days in monotherapy; (for pembrolizumab and 


Protocol IT-01 Version Amendment 6 
Intensity Therapeutics’ Confidential Information                                                Page 12 of 212 
ipilimumab combinations please see supplements DEC/DEC2 and FEC for 
pregnancy criteria). (Male subjects must agree to use contraception and refrain from 
sperm donation during the study for 180 days after administration of study drug.) 
16. Have adequate organ function as defined by the below screening laboratory values that must 
meet the following criteria: 
a. WBC ≥2000/μL (≥2 x 109/L). 
b. Neutrophils ≥1000/μL (≥1 x 109/L); (for pembrolizumab and ipilimumab combinations 
please see supplements DEC/DEC2 and FEC for neutrophil criteria). 
c. For subjects with planned superficial only injections: PT, PTT/aPTT, and INR 
≤1.5 × ULN, Platelets ≥70x103/μL (≥ 70 x 109/L), Hemoglobin ≥8 g/dL  
d. Creatinine within the institution’s laboratory upper limit of normal or calculated creatinine 
clearance >50 ml/min; (for pembrolizumab combination please see supplements 
DEC/DEC2 for creatine criteria). 
e. ALT (SGOT)/AST (SGPT) ≤2.5 x ULN without, and ≤ 5 x ULN with hepatic metastases. 
f. Bilirubin ≤2 x ULN (except subjects with Gilbert’s syndrome, who must have total 
bilirubin <3.0 mg/dL (<52 µmol/L); (for pembrolizumab and ipilimumab combinations 
please see supplements DEC/DEC2 and FEC for bilirubin criteria). 
g. For subjects with planned deep tumor injections:  PT, PTT/aPPT, and INR within 
normal limits; Platelet count ≥100,000/μL; hemoglobin ≥ 9 g/dL.  
Note: ALT (SGPT) =alanine aminotransferase (serum glutamic pyruvic transaminase); 
AST (SGOT) =aspartate aminotransferase (serum glutamic oxaloacetic transaminase); 
ULN=upper limit of normal. 
1 Criteria must be met without erythropoietin dependency and without packed red blood 
cell (pRBC) transfusion within last 2 weeks.  
17. Additional criteria for combination arms can be found in the appropriate supplements. 
  
Key Exclusion Criteria 
Subjects who exhibit any of the following conditions at Screening will not be eligible for 
admission into the study: See DEC/DEC2, FEC, or potentially GEC supplements for 
additional criteria specific to those cohorts. 
1. History of severe hypersensitivity reactions to cisplatin or vinblastine or other products of the 
same class. 
2. Other prior malignancy, except for adequately treated basal or squamous cell skin cancer or 
superficial bladder cancer, or any other cancer from which the subject has been disease-free for 
at least 2 years. 
3. Subjects with tumors >15 cm (in longest diameter). Treatment plan for subjects with tumors 
that are 9 to15 cm must be discussed with and approved by the medical monitor. 
4. Underlying medical condition that, in the Principal Investigator’s opinion, will make the 
administration of study drug hazardous or obscure the interpretation of toxicity determination 
or adverse events. 
5. Concurrent medical condition requiring the use of immunosuppressive medications, or 
systemic corticosteroids (topical steroids are permitted); systemic corticosteroids must be 


Protocol IT-01 Version Amendment 6 
Intensity Therapeutics’ Confidential Information                                                Page 13 of 212 
discontinued at least 4 weeks prior to dosing. Inhaled or intranasal corticosteroids (with 
minimal systemic absorption) may be continued if the subject is on a stable dose. Non-absorbed 
intra-articular steroid injections will be permitted; or use of other investigational drugs (drugs 
not marketed for any indication) within 30 days prior to study drug administration. Use of 
steroids as prophylactic treatment for subjects with contrast allergies to diagnostic imaging 
contrast dyes will be permitted. 
6. For deep tumor cohorts, subjects who require uninterrupted anticoagulants of any type, on daily 
aspirin therapy or NSAIAs.  
7. Use of other investigational drugs (drugs not marketed for any indication) within 28 days prior 
to study drug administration. 
Pregnancy Exclusion: 
A WOCBP who has a positive urine pregnancy test (e.g., within 72 hours) prior to treatment.  If 
the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be 
required. 
NOTE: For specific inclusion/exclusion criteria relating to a potential combination, please refer 
to the combination specific supplement. 
Investigational product, dosage and mode of administration:  
INT230-6 administered intratumorally, a fixed combination of cisplatin, vinblastine and SHAO 
Duration of treatment:  
In A1 and B1 cohorts, subjects received injections monthly for up to 5 doses of INT230-6 (4 months). 
In E cohorts, injections are given every 2 weeks for up to 5 doses.  Cohorts EC3, DEC2, FEC and 
potentially GEC will utilize the once every 2 weeks dosing for 5 doses followed by maintenance 
dosing once every 9 weeks +/- 10 days until CR, PD or 2 years, whichever is first.  Given the short 
half-life of the components of INT230-6, safety follow up post the last dose of treatment is 28 days for 
monotherapy cohorts.  Subjects are followed regularly until progression and/or start of subsequent 
anti-cancer therapy.  Afterwards subjects will transition to a less frequent survival follow up.  The total 
expected duration of the study is 5 years.  
Reference therapy, dosage and mode of administration:  
NA 
Criteria for evaluation: 
Efficacy: 
Since this is a locally administered product, it allows for multiple efficacy analyses.  The primary 
efficacy measure will be disease control rate (CR+PR+SD) as assessed by iRECIST.  Since immune 
system activation is expected from preclinical studies, the trial will collect samples from the peripheral 
blood and from tumors to look at markers of activation.  Furthermore, observing tumor shrinkage in 
non-injected bystander tumors would also indicate potential immune activation.   In order to take the 
whole picture into account, the exploratory endpoints will look at overall tumor response, time to 
progression and overall survival.   
 
Safety: 


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Assessment of safety will be determined by ongoing review of clinical laboratory tests (blood and 
urine sampling for clinical laboratory parameters), pregnancy testing, Eastern Cooperative Oncology 
Group (ECOG) performance status, physical examination including vital sign measurements, any  
needed or completed electrocardiogram (ECG), and adverse events.  
 
Pharmacokinetic: 
Individual subject PK profiles will be tabulated following the intratumoral administration of INT230-6.  
Sponsor expects that the PK profiles of three analytes SHAO/CIS/VIN given intratumorally may have 
significant inter-subject variability.  This variability is due to the expected release kinetics into the 
blood stream following intratumoral dosing of INT230-6 via a) absorption into the tumor’s blood 
vasculature and b) from release from tumor microenvironment over time.  Final analysis of the PK at 
the doses given indicates that only 5% of the active ingredients for a given dose are present in the 
blood.  The concentration is very consistent and have a meaningful dose response.  As a result, the 
SSC determined that PK sample collection is no longer necessary at these dose levels in Amendment 6.  
 
Statistical methods: 
Safety Analyses: All recorded adverse events will be listed and tabulated by system organ class, 
preferred term, and dose and coded according to version 19.1 of MedDRA. The incidence of adverse 
events will be tabulated and reviewed for potential significance and clinical importance. Vital signs 
and clinical laboratory test results will be listed and summarized by dose. Any significant physical 
examination findings and results of clinical laboratory tests will be listed. ECG listings will be 
evaluated by the investigator and abnormalities, if present, will be listed.  
 
Adverse Events will be summarized for all reported data and by study period: a) up to and including 28 
days post last dose of initial treatment, and b) from first dose of re-initiation of treatment, for subjects 
who re-initiate study therapy while in follow-up, up to 28 days post-dose of the last re-treatment dose 
for all monotherapy cohorts.  Please see cohort supplements for combination follow up. 
 
Efficacy Analyses: In order to perform preliminary evaluation of anti-tumor activity, injected tumor 
response (ITR), bystander tumor response (BTR) overall objective response (ORR), and disease 
control rate (DCR) will be tabulated by frequency distribution overall and by tumor type.  
For DCR in each expansion cohort, an exact binomial 95% confidence interval will be determined by 
Clopper-Pearson method. Median time to response and duration of response will be summarized for 
those subjects with confirmed responses, using Kaplan-Meier method; PFS will be similarly 
summarized. Individual tumor measurements, tumor burden and % changes in tumor burden will be 
listed. Changes in tumor burden will be presented graphically.  
With 16 subjects treated in an expansion cohort, at a fixed dose and tumor type, the 90% confidence 
interval for a disease control rate would be (3.4% to 36%) if 2 subjects (12.5%) had a response, (5.3% 
to 42%) if 3 (19%) subjects had a response, (9.0% to 48%) if 4 (25%) subjects had a response, and 
(13.2% to 54.8%) if 5 (31%) subjects had a response.  
 


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Pharmacokinetic Analyses:  
A final PK analysis section will be included in the final clinical study report.  The release kinetics of 
each analyte is not expected to be uniform across subjects.  Sponsor shall assess the blood 
concentrations of the three analytes for each subject at the first cycle.  Sponsor shall correlate the 
systemic measurement (Cmax, AUC) of the 3 analytes to measured markers of systemic toxicity (in 
particular renal and blood – the known toxicities of the two active agents; cisplatin & vinblastine).   
Human plasma will be analyzed for the concentration of vinblastine and SHAO using validated 
LC/MS/MS methods, and for cisplatin using a validated ICP-MS method.  For pharmacokinetic 
profiling platinum drugs, total platinum levels in subject plasma or urine are routinely determined by 
spectroscopy methods as a surrogate.  Thus an ICP-MS method will be developed for this study to 
measure total platinum in human samples as a surrogate for cisplatin.  
In addition, scatter plots of Cmax and AUC(TAU) versus INT230-6 dose volume will be provided for 
the first dosing.  Dose proportionality per subject normalized to tumor volume will be assessed, by 
estimating the slope of linear regression of SHAO/CIS/VIN log(Cmax) on log(dose) and of 
log(AUC(TAU)) on log(dose) based on a power model. Point estimates and 90% confidence intervals 
for the dose proportionality parameter (slope of the linear regression) will be calculated for Cmax and 
AUC (TAU). Summary statistics for trough (Cmin) concentrations will be tabulated by dose and study 
cycle. Plots of Cmin vs. cycle will be assessed for Cohorts A1, B1 versus E Cohorts provided by dose.  
For D and F cohorts refer to the appropriate supplements.  Pharmacokinetic concentrations from sparse 
samples will be listed and may be used in combination with other studies for exposure-response or 
population pharmacokinetic modeling, which will be part of a separate report.  The SSC will evaluate 
whether PK sample collection can be stopped after a certain number of patients have been treated in 
cohort DEC2 and cohort FEC. 
 
Exploratory Biomarkers (Immune Function and others) Analyses: Summary statistics for immune 
function and other exploratory markers, such as but not limited to flow cytometry outcomes, cytokines, 
quantitative immunoglobulins, quantitative inflammatory infiltrates, T-cell repertoire and their changes 
(or percent changes) from baseline will be tabulated by cycle visit and dose to assess 
pharmacodynamic effects. In addition, the time course of biomarker outcomes will be investigated 
graphically, by summary plots (i.e., box plots) or individual subject plots over time. Possible 
associations between changes in biomarker measures of interest and pharmacokinetic exposure will be 
explored. Possible associations of various biomarkers measures (baseline value or change from 
baseline) with clinical outcome (e.g., tumor response) may will be explored based on data availability, 
using response-evaluable subjects, to assess explore predictive markers in tumors. Methods such as, 
but not limited to, logistic regression may be used to explore such associations. Measures from 
markers based on optional samples, e.g., tumor-based markers may be similarly presented, depending 
on data availability. 
Administrative interim analyses on safety and efficacy or on PK, and selected biomarkers may be 
provided at several times prior to completion of the study in order to facilitate program decisions and 
to support study presentations or publications. 
 
 
 


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TABLE OF CONTENTS 
 
 
1. 
TITLE PAGE ................................................................................................................ 1 
2. 
SYNOPSIS ................................................................................................................... 8 
TABLE OF CONTENTS ............................................................................................................... 16 
3. 
INTRODUCTION AND RATIONALE..................................................................... 24 
3.1. 
Background ................................................................................................................. 24 
3.2. 
Systemic chemotherapy .............................................................................................. 24 
3.3. 
Local administration of cytotoxic agents .................................................................... 25 
3.4. 
Immunotherapy ........................................................................................................... 25 
3.5. 
Drug Product INT230-6 .............................................................................................. 25 
3.6. 
Rationale for IT-01 Study Design............................................................................... 26 
3.6.1. 
Preclinical data with INT230-6 in cell lines ............................................................... 26 
3.6.2. 
Preclinical data with INT230-6 in vivo models .......................................................... 26 
3.6.3. 
Checkpoint blockade .................................................................................................. 28 
3.7. 
Prior Experience with Similar Investigational agents ................................................ 32 
3.8. 
Nonclinical Program for INT230-6 ............................................................................ 33 
3.9. 
Starting Dose Selection Method and Dose Escalation ............................................... 34 
3.10. 
Nonclinical Pharmacokinetics .................................................................................... 35 
4. 
STUDY OBJECTIVES .............................................................................................. 37 
4.1. 
Research Hypothesis ................................................................................................... 37 
4.2. 
Primary Objective ....................................................................................................... 37 
4.3. 
Secondary Objectives ................................................................................................. 37 
4.4. 
Exploratory Objectives ............................................................................................... 37 
5. 
OVERVIEW OF STUDY DESIGN ........................................................................... 38 
5.1. 
Dose Escalation .......................................................................................................... 38 
5.1.1. 
A. SUPERFICIAL TUMORS at 1:4 ratio: Dosing once per 28 days, Cohort A1 ..... 38 
5.1.2. 
B. DEEP TUMORS AT 1:4 ratio: Dosing once per 28 days Cohort B1 .................... 39 
5.1.3. 
C. SUPERFICIAL TUMORS AT 1:4 ratio: Every two-week dosing, Cohort EA .... 40 
5.1.4. 
D. SUPERFICAL and/or DEEP TUMORS every 2 weeks 1:2 ratio (Cohort EC) and 1:3 
ratio (Cohort EC2) ...................................................................................................... 40 
5.1.5. 
DEC Safety Cohort. COMBINATION WITH ANTI-PD-(L)1 agent(s): ................... 42 
5.2. 
Fixed Dose .................................................................................................................. 42 


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5.2.1. 
E. SUPERFICAL and/or DEEP TUMORS (cohort EC3) Monotherapy of INT230-642 
5.2.2. 
DEC2 Cohorts. COMBINATION WITH ANTI-PD-1 agent(s): see Supplement A for 
details on each PD-1 agent. ........................................................................................ 43 
5.2.3. 
FEC Cohorts. COMBINATION WITH ANTI-CTLA4 agent(s): see Supplement B for 
protocol details for INT230-6 combinations with anti-CTLA-4 agent(s). ................. 43 
5.2.4. 
GEC Cohorts.  Cohorts containing the letter “G” dose INT230-6 with agents other than 
PD-(L)1 or CTLA-4 antibodies. ................................................................................. 43 
5.3. 
Long Term Follow up ................................................................................................. 44 
5.4. 
Survival Follow-up Period .......................................................................................... 44 
5.5. 
Injection Procedure ..................................................................................................... 44 
6. 
STUDY POPULATION ............................................................................................. 47 
6.1. 
Inclusion Criteria ........................................................................................................ 47 
6.2. 
Exclusion Criteria ....................................................................................................... 49 
7. 
ASSIGNMENT TO STUDY ...................................................................................... 50 
8. 
DOSAGE AND ADMINISTRATION ....................................................................... 51 
8.1. 
Investigational Product ............................................................................................... 51 
8.2. 
Non-Investigational Product ....................................................................................... 51 
8.3. 
Physical Description of Study Drug ........................................................................... 51 
8.4. 
Packaging and Labeling .............................................................................................. 51 
8.5. 
Ordering Study Drug .................................................................................................. 52 
8.6. 
Storage ........................................................................................................................ 52 
8.7. 
Study Drug Preparation and Administration .............................................................. 52 
8.8. 
Drug Accountability ................................................................................................... 53 
8.9. 
Dose Adjustments ....................................................................................................... 54 
8.10. 
Incomplete Dosing ...................................................................................................... 54 
8.11. 
Dose Delay.................................................................................................................. 54 
8.12. 
Permanent Discontinuation of Study Drug Due to Adverse Events ........................... 54 
8.13. 
Destruction of Study Drug .......................................................................................... 55 
8.14. 
Return of Study Drug.................................................................................................. 55 
9. 
TOXICITY AND MANAGEMENT .......................................................................... 56 
9.1. 
Dose Escalation .......................................................................................................... 56 
9.1.1. 
Dose-limiting Toxicity................................................................................................ 56 
9.1.2. 
Stopping Rules for Dose-limiting Toxicity During Dose Escalation ......................... 56 
9.2. 
Possible Toxicities ...................................................................................................... 57 


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9.2.1. 
Management of select AEs ......................................................................................... 58 
9.3. 
Stopping Rules for Clinical Deterioration .................................................................. 58 
10. 
COMPLIANCE .......................................................................................................... 60 
11. 
CONCOMITANT THERAPY ................................................................................... 61 
11.1. 
Treatment of Isolated Tumors .................................................................................... 62 
12. 
STUDY EVALUATIONS .......................................................................................... 63 
12.1. 
Study Procedures by Visit .......................................................................................... 63 
12.1.1. 
Overview..................................................................................................................... 63 
12.1.2. 
Screening Period ......................................................................................................... 63 
12.1.3. 
Treatment Period ........................................................................................................ 67 
12.1.3.1. 
Cycle 1 ........................................................................................................................ 67 
12.1.3.2. 
Cycles/Doses 2 - 5 ...................................................................................................... 68 
12.1.4. 
Follow-up Period ........................................................................................................ 75 
12.1.5. 
Study Participation...................................................................................................... 75 
12.1.6. 
Discontinuation of Subjects from Treatment .............................................................. 76 
12.1.7. 
Safety Evaluations ...................................................................................................... 76 
12.2. 
Efficacy Evaluations ................................................................................................... 77 
12.2.1. 
Primary Efficacy Parameter ........................................................................................ 77 
12.2.2. 
Additional Efficacy parameters .................................................................................. 77 
12.2.3. 
Exploratory Biomarkers of Immune Response........................................................... 78 
12.3. 
Pharmacokinetic Evaluations...................................................................................... 79 
12.3.1. 
Sample Collection Volumes and Timepoints ............................................................. 79 
13. 
ADVERSE EVENT REPORTING ............................................................................ 80 
13.1. 
Definitions .................................................................................................................. 80 
13.1.1. 
Safety Reporting for Adverse Events ......................................................................... 81 
13.2. 
Serious Adverse Events .............................................................................................. 82 
13.3. 
Rapid Notification of Serious Adverse Events ........................................................... 83 
13.3.1. 
Reporting Responsibility ............................................................................................ 83 
13.3.2. 
Reporting Procedures.................................................................................................. 83 
13.4. 
Overdose ..................................................................................................................... 84 
13.5. 
Pregnancy ................................................................................................................... 84 
13.5.1. 
Reporting of Pregnancy .............................................................................................. 85 
13.6. 
Other Safety Considerations ....................................................................................... 85 
14. 
STATISTICAL METHODS ....................................................................................... 86 


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14.1. 
Sample Size Determination ........................................................................................ 86 
14.2. 
Study populations ....................................................................................................... 86 
14.2.1. 
All Enrolled Population .............................................................................................. 86 
14.2.2. 
All Treated Population ................................................................................................ 86 
14.2.3. 
Pharmacokinetic Data Set ........................................................................................... 86 
14.2.4. 
Response Evaluable Data Set ..................................................................................... 86 
14.2.5. 
Exploratory Biomarker (Immune Function and others) Data Set ............................... 86 
14.2.6. 
Retreatment Population .............................................................................................. 87 
14.3. 
Statistical Considerations............................................................................................ 87 
14.3.1. 
Demographics and Baseline Characteristics ............................................................... 87 
14.3.2. 
Extent of Exposure ..................................................................................................... 87 
14.3.3. 
Tumor Response. ........................................................................................................ 87 
14.3.4. 
Concomitant Medication ............................................................................................ 87 
14.3.5. 
Safety .......................................................................................................................... 87 
14.4. 
Efficacy ....................................................................................................................... 90 
14.4.1. 
Pharmacokinetic Parameters ....................................................................................... 90 
14.4.2. 
Exploratory Biomarkers (Immune Function and others) ............................................ 90 
15. 
ETHICAL ASPECTS ................................................................................................. 92 
15.1. 
Ethics and Good Clinical Practice .............................................................................. 92 
15.2. 
Confidentiality Regarding Study Subjects.................................................................. 92 
15.3. 
Institutional Review Board/Independent Ethics Committee/Review Ethics Board ... 92 
15.4. 
Informed Consent ....................................................................................................... 93 
16. 
ADMINISTRATIVE REQUIREMENTS .................................................................. 95 
16.1. 
Protocol Amendments ................................................................................................ 95 
16.2. 
Monitoring Procedures ............................................................................................... 96 
16.3. 
Investigational Site Training....................................................................................... 96 
16.4. 
Recording of Data and Retention of Documents ........................................................ 96 
16.4.1. 
Study Drug Records .................................................................................................... 97 
16.4.2. 
Case report Forms ....................................................................................................... 98 
16.5. 
Auditing Procedure ..................................................................................................... 98 
16.6. 
Publication of Results ................................................................................................. 98 
16.7. 
Disclosure and Confidentiality ................................................................................... 99 
16.8. 
Discontinuation of Study ............................................................................................ 99 
16.9. 
Data Management ....................................................................................................... 99 


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16.9.1. 
Data Collection ........................................................................................................... 99 
16.9.2. 
Database Management and Quality Control ............................................................... 99 
17. 
REFERENCES ......................................................................................................... 101 
18. 
APPENDICES .......................................................................................................... 102 
18.1. 
Appendix 1: iRECIST .............................................................................................. 102 
19. 
SUPPLEMENTAL COMBINATION COHORTS .................................................. 106 
List of Tables 
Table 1: 
Emergency Contact Information................................................................................... 7 
Table 2: 
Abbreviations and Specialist Terms ........................................................................... 21 
Table 3: 
Animal PK .................................................................................................................. 36 
Table 4: 
Cohort A1 0.25 mL/cm3 tumor ................................................................................... 39 
Table 5: 
Cohort B1 0.25 mL/cm3 tumor ................................................................................... 39 
Table 6:      Cohort EA injection every 2 weeks in superficial tumors .......................................... 40 
Table 7a: 
Cohort EC Every 2 weeks in Superficial and Deep tumors........................................ 41 
Table 8: 
INT230-6 Dosing calculations .................................................................................... 42 
Table 9: 
Dose Modification and Toxicity Management Guidelines for AEs Associated with 
INT230-6 using CTCAEv4.03.................................................................................... 58 
Table 10: Screening Procedural Outline ..................................................................................... 66 
Table 11: Schedule of events every 28 day dosing   ................................................................... 70 
Table 12: Schedule of events every 14 day dosing (monotherapy E cohorts) ............................ 72 
Table 13: Schedule Follow up Period ......................................................................................... 74 
Table 14: Tumor Biopsy and Genetic Sample collection ........................................................... 79 
Table 15: Time-point (TP) iResponse Time Point Response (TPR) ........................................ 103 
Table 16: iRECIST Best Overall Response (BOR) .................................................................. 104 
List of Figures 
Figure 1: 
Leakage from the intratumoral injection site of the preparations with and without the 
SHAO penetration enhancer. ...................................................................................... 27 
Figure 2: 
Comparison of dispersion following one-time, intratumoral injection of 75 or 225 µL 
for 90 seconds of drug only with ink compared to INT230-6/ink. ............................. 27 
Figure 3: 
Activity of INT230-6 in Colon26 model, results of different treatment groups with and 
without intact T-cells. ................................................................................................. 28 
Figure 4: 
Tumor Growth Inhibition Curves Combining INT230-6 with Checkpoint Inhibitors30 
 
 


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List of Abbreviations and Definitions of Terms 
The following abbreviations and specialist terms are used in this study protocol. 
Table 2: 
Abbreviations and Specialist Terms  
Abbreviation or Specialist Term 
Explanation 
AE 
Adverse event 
APC 
Antigen-presenting cells 
ALT 
Amino Alanine Transferase 
AST 
Aspartate Aminotransferase 
AUC 
Area under the curve 
BOR 
Best overall response 
BP 
Blood Pressure 
BTR 
Bystander tumor response 
BUN 
Blood Urea Nitrogen 
cc or cm3 
Cubic centimeter 
Cmax 
Maximum blood concentration of an analyte 
CIS 
Cisplatin 
CR 
Complete response 
CRF or eCRF 
Case report form or electronic case report form 
CT 
Computed tomography 
CTA 
Clinical trial agreement 
CTCAE 
Common Terminology Criteria for Adverse Events 
DC 
Dendritic cells 
DCF 
Data clarification form 
DCR 
Disease control rate 
dL 
Deciliter 
DLT 
Dose-limiting toxicity 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
Electronic data capture 
EOT 
End of Trial 
FDA 
Food and Drug Administration 
FDG-PET 
Fluorodeoxyglucose - positron emission tomography 
FIH 
First in human 
GCP 
Good clinical practices 


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Abbreviation or Specialist Term 
Explanation 
GLP 
Good laboratory practices 
GMP 
Good manufacturing practices 
HIPPA 
Health Information Portability and Accountability Act 
HMGB1 
High Mobility Box Group 1 
HR 
Heart Rate 
ICF 
Informed consent form 
ICH 
International Council on Harmonization 
IFN 
Interferon 
IP 
Intraperitoneal 
IRB/IEC 
Institutional review board/independent ethics committee 
irAE 
Immune related adverse event 
iCPD 
iRECIST confirmed progressive disease 
iRECIST 
immune Response Evaluation Criteria in Solid Tumors 
iUPD 
iRECIST unconfirmed progressive disease 
IT 
Intratumoral  
ITR 
Injected tumor response 
IV 
Intravenous 
LDH 
Lactic Acid Dehydrogenase 
mAb 
Monoclonal antibody 
MeDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
mL 
Milliliter 
MRI 
Magnetic resonance imaging 
MSI-CRC 
Microsatellite Instable Colorectal Cancer 
MTD 
Maximum-tolerated dose 
NCI 
National Cancer Institute 
NE 
Not evaluable 
ng 
Nanogram 
NSAIA 
Non Steroidal Anti-inflammatory Agent 
ORR 
Objective response rate 
PBMC 
Peripheral blood mononuclear cell 
PD 
Progressive disease 
PD-1 
Programmed death-1 


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Abbreviation or Specialist Term 
Explanation 
PFS 
Progression free survival 
PK 
Pharmacokinetic 
PMH 
Princess Margaret Hospital 
PR 
Partial response 
PVG 
Pharmacovigilance 
RB 
Rose Bengal 
REB 
Review ethics board 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA 
Ribonucleic acid 
SAE 
Serious adverse event 
SC 
Subcutaneous 
SCID 
Severely compromised Immune deficient 
SD 
Stable disease 
SHAO 
8-((2-hydroxybenzoyl)amino)octanoate (sodium salt form) 
SLD 
Sum of longest diameters 
SNP 
Single nucleotide polymorphism 
SOP 
Standard operating procedures 
SSC 
Study Steering Committee 
TBD 
To be determined 
TCR 
T-cell receptor 
TEAE 
Treatment-emergent adverse event 
TNF 
Tumor necrosis factor 
ULN 
Upper Limit of Normal 
UM 
University of Miami 
USC 
University of Southern California 
VBL 
Vinblastine Sulfate or Vinblastine 
WOCBP 
Women of childbearing potential 
WHODD 
World Health Organization Drug Dictionary 


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3. 
INTRODUCTION AND RATIONALE 
3.1. 
Background 
This trial is a phase 1/2 safety study of intratumorally administered INT230-6 in adult subjects with 
Advanced Refractory Cancers.  This trial is an adaptive open label exploration of INT230-6.  The 
trial enrolls any advanced cancer subjects with an accessible tumor for injection who have failed or 
are not a candidate for approved therapies.  The trial will be governed by a Study Steering 
Committee (SSC) who will review the data and help to adapt the protocol to minimize the number of 
subjects need for each stage.  Since administration of the investigational material is direct to the 
tumor, biopsies of the tumor before and during treatment will enable assessment of immunologic 
effects in the tumor and help to understand possible pharmacodynamic effects.   
In the phase 1 portion INT230-6 was given in escalating amounts to the subject by increasing the 
number of tumors injected, increasing the total volume per tumor injected and increasing the 
concentration by tumor.  Many of these escalations were done with intra-subject increases.  The 
drug components are well known, but this combination and mode of administration had not been 
delivered before, therefore the trial sought to begin with tumors that are superficially palpable to 
establish safety data before progressing to tumors which required imaging guidance.   The central 
objective of the phase 1 portion of the study was to characterize the safety and tolerability of 
INT230-6 alone and in combination with other therapeutic agents.  The SSC has reviewed the safety 
and preliminary efficacy data from subjects in the phase 1 portion of the study. The SSC 
recommended initiation of phase 2 expansion cohorts of subjects.   
In the phase 2 expansion cohort portion of the study, the objective will be to characterize INT230-
6’s effect on the disease control rate as monotherapy and in combination with other drugs. Given the 
mechanism of action, Sponsor expects measurement of both the injected tumor responses as well as 
any bystander (untreated) tumor responses will be straightforward.   
Cisplatin (as an IV product) is considered an irritant at concentrations <0.5 mg/mL.  Vinblastine 
sulfate is considered a vesicant when dosed IV at 1 mg/mL.  In Sponsor’s local tolerance toxicology 
study both 2 and 5 mL of INT230-6 were injected directly in 3 different tissue types of healthy dogs 
(subcutaneously, intraperitoneal and intrahepatic) over 8 days.  There were no gross or microscopic 
vessication observations due to INT230-6 in any tissues when given locally.  The current status of 
the safety aspects of the drug product and this study, including clinical adverse events, can be found 
in the investigator’s brochure.  Please refer to the latest version of the investigator’s brochure for 
safety information. 
 
3.2. 
Systemic chemotherapy 
Systemic chemotherapy has formed the mainstay of the treatment of solid tumors from 1980s and 
onward offering the ability to kill rapidly dividing cells.  Many cytotoxic agents have components of 
their mechanism that involve immune activation (Galluzzi_2015 (1)). Yet when tumors are 
shrinking during the course of treatment, there is little evidence of a memory immune effect that is 
maintained.  There are several hypotheses for this observation.  While chemotherapy may be pro-
inflammatory, there are many anti-inflammatory signals in the tumor microenvironment 
(checkpoints, regulatory cells, etc.).  Recent approaches have combined chemotherapy with 
checkpoint inhibition to see if this aspect could yield a more robust immune effect (Rizvi_2016 (2)).  
Also, systemic administration of these agents results in impairment of bone marrow function.  It is 


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also speculated that the kinetics of tumor cell death are slower than the kinetics of the innate 
immune system. In other words, the innate system clears tumor antigens faster than they can be 
processed by the adaptive immune system (Obeid_2007 (3)).  However, given the number of tumors 
that remain sensitive to chemotherapy, this approach continues to be utilized and efforts to minimize 
impact on normal tissues are being studied. 
 
3.3. 
Local administration of cytotoxic agents 
In an effort to spare subjects from the side effects of systemically administered chemotherapy, 
researchers have delivered drugs directly to the tumor.  In animal models (typically localized 
disease), this has shown some promise.  However, in multiple clinical trials in advanced cancer 
patients, these approaches have failed to show superior outcomes compared to systemically 
administered drugs (Lammers_2006 (4)).  This is likely due to the poor diffusive and dispersive 
ability of these prior intratumoral formulations.  For the most part cytotoxic agents are hydrophilic 
and do not disperse throughout the tumor.  Research by the Sponsor indicates that intratumoral 
delivery of aqueous solutions are ejected from the tumor.  In addition, since many cancer cells could 
be circulating or residing in small amounts in other tissues, localized approaches often fail to treat 
the full extent of the disease.  IV administration can disperse drug broadly via the bloodstream; 
however, given systemic effects, only low drug doses ultimately reach the tumor and even less is 
taken up by the cancer cells.  Typically, cytotoxic drugs require active transport to enter cells, a 
process mediated by receptors.   Receptor transport is slow and efflux pumps within cancer cells 
often remove the drugs.  As a result of negative trials, registrational efforts for intratumoral delivery 
approaches of cytotoxic agents has been largely abandoned. 
 
3.4. 
Immunotherapy 
The concept of cancer immunotherapy has been around for many years, but its use is limited to a 
few settings (BCG in bladder and high dose IL-2 in melanoma).  In the 2000’s with the discovery of 
checkpoints and their role in suppressing anti-tumor immunity research on cancer treatments 
incorporating the immune system accelerated.  CTLA4 antibodies demonstrated that by blocking 
cancer’s negative signal, a proportion of metastatic melanoma patients could achieve a long-lasting 
response off of treatment.  Response to these treatments seemed to require an inflamed tumor and/or 
a high mutational burden in order for effect use of checkpoint inhibitors (Snyder_2014 (5)).  Further 
improvement on this concept was seen with the discovery of anti-PD-1 antibodies which seem to be 
more selective in activating the immune system and more capable of promoting an immune response 
than CTLA4 molecules.  Anti-PD-1 therapy has seen promising activity in a variety of tumor types 
and has been approved for use in melanoma, lung, urothelial, hepatocellular, gastric, cervical, 
hematologic, microsatellite unstable, and renal cancers (Pembrolizumab_Package_Insert (6)).  Yet 
many patients still do not respond to immunotherapy treatment.  Some improvement in melanoma 
can be seen if both approaches are given simultaneously (anti-CTLA4 combined with anti-PD1).   
 
3.5. 
Drug Product INT230-6 
INT230-6 is multi-component, new drug product specially formulated for intratumoral 
administration.  The technology used in the product facilitates dispersion of drugs throughout the 


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Intensity Therapeutics’ Confidential Information                                                Page 26 of 212 
tumor and diffusion into cancer cells.  INT230-6 is comprised of a cell permeation enhancer 
molecule with two, potent anti-cancer payloads (cisplatin and vinblastine) in fixed ratio. The 
enhancer is not covalently bound to the drugs.  Typically, the permeability of cancer cell membranes 
is more fluid than healthy cells (Sok_2002 (7)).  Thus, the presence of the enhancer allows for 
increased passive diffusion of the therapeutic agents into the cancer cells.  Both cisplatin and 
vinblastine function inside the cell.  Vinblastine acts by binding to tubulin leading to 
depolymerization of the microtubule and mitotic arrest.  This interrupts the cell cycle and stops 
replication of the cell (Vinblastine_Package_Insert (8)).  Cisplatin has a proposed mechanism of 
action that introduces a defect in the DNA, causing DNA damage and ultimately apoptosis 
(Dasari_2014 (9)).  Once the two molecules diffuse into the cell, the permeation enhancer is diluted 
from the drugs, which remain in higher concentration within the cell.  The combination of tubulin 
inhibition and cell apoptosis cause significant cell death throughout the injected tumor.  Data 
generated by the Sponsor show increased influx of dendritic and T-cells into the tumor.  The result is 
a robust CD8 response that clears the remaining live tumor cells.  Results from studies 
(Walters_2015 (10)) also show a CD4/CD8 memory response is also induced that can protect treated 
animals against re-exposure to the same cancer cell line.  This approach offers patients the potential 
for a targeted and generally nontoxic therapy – one that kills a large portion of the injected tumors - 
stimulates a systemic immune response to clear the tumor that eliminates distal tumor cells and 
prevents recurrences.   
 
3.6. 
Rationale for IT-01 Study Design 
3.6.1. 
Preclinical data with INT230-6 in cell lines 
INT230-6 has been studied in vitro with multiple patient derived and cancer cell lines.  In Caco-2 
monolayer studies, INT230-6 has demonstrated the ability to diffuse drugs through the membrane 
without disruption of the cell surface architecture.  The drugs also penetrate into the nucleus.  A 
critical ratio of enhancer to drug ratio is required to achieve this transport.  In addition, Sponsor 
studied the release of LDH by cells treated with INT230-6.  Results showed that when the drugs 
enter the cell, the membrane integrity is intact and LDH is not released (Intensity_in_vitro_e237 
(11)).  INT230-6 thus has strong dose dependent, growth inhibition of tumor cells. 
3.6.2. 
Preclinical data with INT230-6 in vivo models 
Intratumoral drug dispersion of formulations in tumors with and without cell penetration enhancers 
was evaluated using BxPc3 pancreatic tumor xenographs.  A butterfly needle was placed into the 
center of a tumor (>500 mm3).  Various amounts of either INT230-6 (N=8) or aqueous cisplatin 
(drug) (N=6) preparation with 3 drops of India Ink (~150 μL/10mL in each preparation) were 
injected over 90 seconds using metered pump at drug dose to tumor volume ratios of approximately 
1:11 or 1:5. The needle was left in the tumor for an additional 30 seconds following injection. After 
euthanasia, tumors were removed, dissected, then fixed and sliced for Haemotoxylin and Eosin 
(H&E) staining.  
The intratumorally dosed cisplatin without the enhancer showed substantial leakage from the 
injected tumors into the interstitial space between the tumor and skin. The injected INT230-6 
appeared to be fully absorbed into the tumor (Figure 1 ). INT230-6 plus ink dispersed throughout 
the tumor as seen in (Figure 2 ); however, drug without the penetration enhancer was poorly 
absorbed into the tumor and almost no ink is observed to be absorbed within the tumor. This 


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Intensity Therapeutics’ Confidential Information                                                Page 27 of 212 
advantage in dispersion (using measured dispersion diameters) for the INT230-6 preparation was 
highly significant (p<0.005) when compared to the cisplatin/vehicle group. 
Figure 1: 
Leakage from the intratumoral injection site of the preparations with and without the 
SHAO penetration enhancer. 
 
 
Figure 2: 
Comparison of dispersion following one-time, intratumoral injection of 75 or 225 µL 
for 90 seconds of drug only with ink compared to INT230-6/ink. 
 
INT230-6 demonstrated reduction in tumor burden that was statistically superior to no treatment 
controls in immune competent BALB/C mouse models.  Sponsor, in collaboration with the National 
Cancer Institute (NCI), investigated the impact on INT230-6 on promoting a T-cell response.  
Colon-26/CT26/4T1 studies all reveal strong anti-tumor activity of INT230-6.  Key features include 
the ability to reduce tumor burden from baseline in the majority of animals, high rates of complete 
responses that are dependent on CD8 T-cell activity, an ability to shrink and in some cases clear 
distal untreated tumors, and the ability to induce long term immunity which is co-dependent on CD4 
and CD8 T-cells.  Biopsies of tumors over time indicate recruitment of dendritic cells and 
lymphocytes to the tumor within 10 days of treatment (Bloom_2015 (12)) Walters_2015 (10)).  
Presumably these are facilitating antigen presentation of tumor antigens expressed by intact tumor 
cells that are no longer replicating and are undergoing cell death.  Sponsor suggests that antigen 
processing is occurring with evidence of cross priming.  Mice, given colon cancer SC using 
Sponsor’s technology achieved a complete response.  Animals rechallenged with a 4T1 breast 
cancer inoculation in the absence of any new treatment became more resistant to this challenge than 
naïve animals with no drug therapy.  There are publications in the literature of shared antigens 


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Intensity Therapeutics’ Confidential Information                                                Page 28 of 212 
between different tumor types (Bright_2014 (13)).  Further experiments indicate that responses in 
the injected tumors are partially due to enhanced cytotoxicity during the first week after treatment, 
but in part due to presence of CD8 T-cells.   When CD8 T-cells are depleted prior to treatment 
animals see regression of their tumors initially then regrowth with no complete responders.  These 
results compare to 80% complete responders if CD8 T-cells are present (see Figure 3 ). 
 
Figure 3: 
Activity of INT230-6 in Colon26 model, results of different treatment groups with 
and without intact T-cells. 
 
Panel A 
 
   Panel B 
 
         Panel C  
          Panel D 
Depletion study results; depletion prior to treatment with INT230-6 - (Panel A) IgG control i.e., no 
depletion 8/10 complete responses, (Panel B) CD4 cell depletion 7/10 complete responses, (Panel C) 
CD8 cell depletion 0/10 complete responses, or (Panel D) dual CD4/CD8 cell depletion 0/10 
complete responses.  
 
Multiple preclinical studies support consecutive injections (up to 5 daily injections in a cycle) into 
the same nodule (approximately 300mm3).  In addition, studies support repeating the treatment cycle 
after a period of rest yields improved efficacy outcomes without an increase toxicity.  In fact, there 
was some weight loss in the first cycle that resolved and nearly non-existent in subsequent cycles.  A 
preclinical study showed that after 3 days of injection 75% of a tumor became necrotic while the 
animals continued to be injected without additional complications.  The Sponsor believes that the 
totality of preclinical data demonstrating no observed or increased toxicity with significantly 
increased efficacy justifies in the protocol using tumor injection with multiple cycles of tumor 
reinjection. 
 
3.6.3. 
Checkpoint blockade 
Nature has created checkpoints on the immune system to regulate the activity of the immune cells. 
These pathways are crucial for self-tolerance to prevent the immune system from attacking healthy 
cells indiscriminately. Large pharmaceutical companies such as Merck, Roche, AstraZeneca, Pfizer 
and Bristol Myers Squibb (BMS) have developed new types of anti-cancer anti-body drugs with the 
ability to modify and block the checkpoints on the immune system.  These large molecules are the 
current immunotherapy that have shown long term durable responses in patients.   
However, these checkpoint molecules have shown success in only some types of cancers – often those 
that are the most mutated.  Sales of these drugs are currently in the billions of dollars. Approved 


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Intensity Therapeutics’ Confidential Information                                                Page 29 of 212 
checkpoint inhibitors block CTLA4 and PD-1 and PD-L1; however, many more targets are in clinical 
development.  
Our belief was that our products would be synergistic with checkpoint inhibitors.  We along with our 
partners at the National Cancer Institute conducted experiments to demonstrate that our lead drug 
INT230-6 is synergistic with these new checkpoint blockage drugs.  Results show strong benefit in 
regressing tumors with the combination of INT230-6 and checkpoint inhibitors and improving 
survival.  The data from the combination of INT230-6 with both anti-PD-1 or CTLA-4 antibodies in 
a dual tumor (metastatic) cancer mouse cancer model.  The data was generated by our partners at the 
National Cancer Institute and under our CRADA.   
 
 


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Figure 4: 
Tumor Growth Inhibition Curves Combining INT230-6 with Checkpoint 
Inhibitors 
a) Illustration of INT230-6 and anti-PD-1 treatment regimen (top). (26 (1x10 6 )  were inoculated into 
the right flank (day - 14).  Contralateral tumors were inoculated 11 days after primary tumors (day -
3). Primary tumors were treated with INT230-6 (50 µl / 400 mm3 tumor, 5 sequential days) starting 
on day 0. Average primary tumor volume on Day 0 was 290mm3 and average contralateral tumor 
volume was 42mm3• Anti-PD-1 treatment (100µg) was given on day 0, 3, 7 and 10. b) Kaplan-Meier 
plot (below illustration) and individual responses of c) treated (ipsilateral) (middle) and d) 
contralateral flank (bottom) are shown of vehicle (black), anti-PD-1 (purple), INT230-6 (red) and 
anti-PD-1+ INT230-6 (blue) treatment as well as contralateral tumor only control (orange, n = 10 / 
group). Fractions (e.g., 3/10) indicate the number of mice that completely lost tumor that the indicated 
flank. Log-rank test was significantly different between vehicle and INT230-6 (p < 0.0001), vehicle 
and anti-PD-1 + INT230-6 (p < 0.0001), anti-PD-1 and INT230-6 (p < 0.01) and anti-PD-1 and anti-
PD-1 + INT230-6 (p < 0.0001). Two-way ANOVA with Sidak's multiple comparison test of growth 
curves showed that untreated contralateral tumors only were significantly different (p < 0.0001) from 
all groups on secondary site. Furthermore, vehicle was significantly different (p < 0.0001) from 
INT230-6 and INT230-6+anti -PD-1 on day 8 and 11 on the primary site. Vehicle was significantly 
different (p < 0.05) from INT230-6+anti-PD-1 on day 11 on the secondary site. INT230-6 was 
significantly different anti-PD-1 or INT230-6+anti-PD-1 on day 16 (p < 0.01) and day 18 (p < 0.001) 
on the primary tumor site. INT230-6 was significantly different (p < 0.01) from INT230-6 + anti-PD-
1 on day 18 on the contralateral site. Anti-PD-1 was significantly different (p < 0.0001) from INT230-
6+ anti-PD-1 on day 8 and 11 at the primary site only. e) Illustration of INT230-6 and anti-CTLA-4 
treatment regimen (top). C26 (l x106) tumor cells w ere inoculated into the right flank (day -15). 
Contralateral tumors were inoculated 7 days after primary tumors (day - 8). Primary tumors were 
treated with INT230-6 (50 µl/400 mm3) tumor, 5 sequential days) starting on day 0. Average primary 
tumor volume on day 0 was 250mm3 and average contralateral tumor volume was 60 mm. Anti-
CTLA-4 treatment (100 µg) was given on day 0, 3 and 6. f) Kaplan-Meier plot (below illustration) 
and individual responses of g) treated (ipsilateral) (middle) and h) contralateral flank (bottom) are 
shown of vehicle (black), anti -CTLA-4 (purple), INT230-6 (red) and anti-CTLA-4+ INT230-6 (blue) 
treatment as well as contralateral tumor only control (orange, n = 10/group). Fractions (e.g., 4/10) 
indicate the number of mice that completely lost tumor in the indicated flank. Log-rank test was 
significantly different between vehicle and all other groups (p < 0.0001), INT230- 6 and anti-CTLA-
4+ INT230-6 (p < 0.0001) and anti-CTLA-4 and anti-CTLA-4+ INT230-6 (p < 0.0001). All 
experiments were performed twice. Two-way ANOVA with Sidak's multiple comparison test of 
growth curves showed that untreated contra-later tumors were significantly different (p < 0.0001) 
from all other groups on the contralateral site. Vehicle was significantly different (p < 0.0001) from 
INT230-6, antl-CTLA-4 and antl-CTLA-4+ INT230-6 on day 6 and 8 at the primary (ipsilateral) site. 
Vehicle was significantly different from antl-CTLA-4 (day 8: p < 0.0001) and antl-CTLA-4+ 
INT230-6 (day 6: p < 0.001, day 8: p < 0.0001) at the contralateral site. INT230-6 was significantly 
different from antl-CTlA-4 at the primary site (day 8: p < 0.05, day 10: 0.001) and secondary site 
(day 8: p < 0.01, day 9: p < 0.001, day 10: p < 0.0 001). INT23o-6 was significantly different from 
antl-CTLA-4 + INT230-6 at the contralateral site only (day 6: p < 0.05, day 8- 10: p < 0.0001). Anti-
CTLA-4 was significantly different from an tl-CTLA-4 + INT230-6 at the primary site (day 8: p < 
0.01, day 9: p < 0.05, day 10: p < 0.0001) and at the secondary site (day 6: p < 0.05). 
 
 
 


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Intensity Therapeutics’ Confidential Information 
3.7. 
Prior Experience with Similar Investigational agents 
Companies have recently reported results from locally administered (IT) products.  These 
companies report that local administration of their products is able to demonstrate distal 
responses through presumed immune activation.  These IT approaches claim good safety 
of the procedure and translation from preclinical models to the clinical setting. 
The firm Oncosec has developed a DNA plasmid which expresses IL-12 by in vivo 
electroporation (i.e., intratumoral needle placement with electric current). Immunosec 
performed a phase 1 study in melanoma which revealed that in 10 patients (53%) there 
was evidence of a systemic response resulting in either stable disease or objective 
regression of untreated bystander tumors. In addition, in three of these patients (15%), all 
of the distant tumors regressed completely in either the absence of any other systemic 
antitumor therapy (two patients) or after treatment with dacarbazine (one patient).  In 
vivo electroporation was associated with minimal systemic toxicity. No hematologic 
abnormalities were observed. The most frequent adverse event related to treatment was 
transient pain during the electroporation procedure (13 patients had grade 1 and eleven 
had grade 2 pain) and bleeding around the treatment site (13 patients had grade 1 and 11 
grade 2 hemorrhage).  A dose-proportional increase in IL-12 protein expression 
compared with pretreatment was seen in all patients with no significant IL-12 spillage 
into circulation and a correlative increase in tumor levels of IFN-gamma. The 
experimental regimen was found to be safe and well tolerated, with minimal systemic 
toxicity and with transient pain associated with the administration (Daud_2016 (14)). 
Provectus has developed an intralesional (IL) formulation of Rose Bengal (RB), an inert 
dye. In preclinical studies, utilizing an OVA-expressing B16 melanoma murine model, 
Provectus found that intratumoral RB treatment led to increased tumor- specific T-cells 
with memory characteristics. Intratumoral RB therapy also increased antigen-specific T-
cell proliferation and enhanced tumor regression. In addition, IL RB facilitated dendritic 
cells (DCs) infiltrating lymph nodes draining from tumor. Incubation of melanoma cells 
with RB led to necrosis and the release of High Mobility Group Box 1 (HMGB1), which 
activated DCs. The blockade of HMGB1 significantly reduced the antigen-presenting 
ability of DCs. Subsequently they performed a pilot clinical study in melanoma patients. 
Intratumoral RB led to tumor regression in both RB-injected and un-injected tumors, 
associated with an increase in circulating T-cells. Increased tumor-specific response was 
found from those circulating T-cells of 5 out of 7 tested patients after IL RB treatment. 
HMGB1 levels in patient sera were also elevated (Liu_2016 (15)).  Broadly, Provectus 
demonstrated response rates of approximately 50% in the injected melanoma tumors, and 
some bystander responses (33% CR+ PR) which correlated with injected tumor responses 
(Thompson_2015 (16)). 
Based on a comparison of Sponsor’s murine data, Sponsor expects INT230-6 will be 
more potent than either approach of Oncosec or Provectus.  INT230-6 acts by inducing 
direct tumor cell death due to potent agents.  In addition, INT230-6 attracts inflammatory 
cells to the tumor microenvironment.  Sponsor’s preclinical program, although not with a 
direct comparison to these other therapies, INT230-6 showed the ability to regress large 


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Intensity Therapeutics’ Confidential Information                                                   Page 33 of 212 
(>300m3) tumors as well as more pronounced effects on bystander untreated tumors 
(Intensity_E238 (18)). 
On October 27, 2015 the U.S. Food and Drug Administration (FDA) approved the first 
intratumorally dosed oncolytic virus therapy, talimogene laherparepvec (T-VEC, or 
Imlygic®). The agency approved T-VEC for the treatment of some patients with 
metastatic melanoma that cannot be surgically removed.  The approval was based on the 
results of a multicenter phase III clinical trial of patients with metastatic melanoma 
lesions in the skin and lymph nodes.  Substantially more patients in the trial treated with 
T-VEC had a decrease in the size of their skin and lymph node lesions that lasted at least 
6 months compared with patients treated with granulocyte macrophage colony-
stimulating factor. 
The treatment appears to work by directly killing cancer cells and stimulating an immune 
response against tumors, the trial investigators believe. Findings from the trial were 
published (Andbaka_2015(17)).  In the international phase III trial, called OPTiM, 436 
patients with unresectable stage IIIB to IV melanoma were randomly assigned to receive 
either T-VEC or GM-CSF. T-VEC was injected directly into the tumors, and subsequent 
doses were administered 3 weeks after the first dose, then once every 2 weeks. GM-CSF 
was administered subcutaneously every day for 14 days, in 28-day cycles.  The durable 
response rate, which was measured as an objective response to therapy that lasted for at 
least 6 months, was significantly higher in patients who received T-VEC (16.3 percent) 
than in those who received GM-CSF (2.1 percent). T-VEC also improved median overall 
survival, which was 23.2 months in the T-VEC arm and 18.9 months in the GM-CSF 
arm. 
 
3.8. 
 Nonclinical Program for INT230-6  
Sponsor sought guidance from FDA for a proposed nonclinical program during a pre-
IND meeting held in August 2014 to enable an IND submission.  Sponsor recognized the 
possibility of local and systemic exposures if INT230-6 injections via absorption in tumor 
blood vessels or seepage from the tumor.  Sponsor and FDA agreed on a nonclinical 
program consisting of 3 studies.  
• a non-GLP dose range finding study in rats 
• a non-GLP local tolerability study in dogs 
• a GLP study in rats 
The non-GLP rat study was to determine systemic toxicity using both intraperitoneal (IP) 
and intravenous (IV) administration of INT230-6.  The objectives of the study were a) to 
evaluate the effects of various dose volumes and regimens of INT230-6 on local and 
systemic toxicity; b) to assess systemic exposure; and c) to compare IP vs IV dosing.  
The non-GLP study would serve to determine the conditions most appropriate for a GLP 
study to characterize systemic toxicity in rats and determine the human starting dose. The 
non-GLP rat study successfully characterized the range of toxicities of INT230-6 and 
confirmed (per the vinblastine label) that IP administration in rats does represent systemic 


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Intensity Therapeutics’ Confidential Information                                                   Page 34 of 212 
exposure comparable to IV administration.  Thus, Sponsor conducted only IV 
administration for the pivotal (GLP-compliant) toxicology study of INT230-6 to enable 
higher dosages and exposures to be characterized for systemic toxicity evaluation. The rat 
was the most suitable species to evaluate systemic exposure because it is a sensitive 
model for all relevant endpoints except for emesis, which could have significantly 
disrupted the toxicology assessment if carried out in a larger species (e.g., dog). 
The GLP compliant rat study confirmed that administration of INT230-6 did not result in 
any new or previously unreported systemic toxicity.  Toxicities observed were consistent 
for either cisplatin or vinblastine.  The GLP study was conducted using once-weekly 
dosing for 3 weeks at three dose volumes.  This regimen exceeds the proposed clinical 
starting regimen of once monthly.  A 6-week non-dosing observation period enabled 
evaluations of recoveries, and satellite animals characterized plasma exposures to all 
three analytes after the first and last doses. 
Furthermore, the sponsor conducted a local tolerability toxicology study in dogs to assess 
local tolerance effects of human-scale dosages of INT230-6 in the event that a physician 
missed the targeted tumor and injected healthy tissue or that the drug (or components) 
partially seeped from a superficial or deep body tumor into the surrounding tissue. 
Plasma exposures were also assessed. There were 3 treatment groups in the study: 5 mL 
of vehicle/dose, 2 mL of INT230-6/dose and 5 mL of INT230-6/dose, with each animal 
dosed on Day 0 subcutaneous, Day 3 intraperitoneal and Day 8 intrahepatic (IH).  Other 
than injection site reactions attributed to extravasation from the IP dosing site, there were 
no observed clinical, macroscopic or histopathological observations or effects on 
surrounding healthy tissue in any INT230-6 treated dog groups for SC, IP or IH dosing 
attributable to the formulation. 
 
3.9. 
Starting Dose Selection Method and Dose Escalation 
FDA agreed to a protocol that used 1/10 of the STD10 to set the starting dose.  The STD10 
in the rat pivotal study was approximately 7.5 mL/kg1.  As a result, 1/10 of the rat STD10 
is 0.75 mL/kg, which equates on a body surface area basis to a human dose of 7.3 mL/60 
kg subject2. Therefore, Sponsor proposed that the maximum permissible starting dose for 
the first-in-human (FIH) trial be up to 5.0 mL per subject. The target dose per tumor of 
INT230-6 for the first cohort was 0.25 mL per cm3 of the tumor’s volume (i.e., 1:4 
loading dose).  This drug dose volume to tumor volume ratio has consistently shown to 
saturate large tumors in pharmacology testing and resulted in anti-tumor activity in 
multiple preclinical models.  An injected or to-be-injected tumor’s volume was 
determined using the ellipsoid calculation method (
) using 
the imaging technique available at the site (e.g., CT, ultrasound, or MRI).  In Amendment 
6, Sponsor is implementing a method to set INT230-6 dose for an individual tumor based 
on longest diameter. 
 
1 The actual value for 7.5 mL/kg IV was 12.9%.   
2 (0.75 ÷ 6.2 = 0.121 mL/kg, or 7.3 mL for a 60 kg person (60 x 0.121). 


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The total injected volume and the maximum per any one tumor was escalated in the 
phase 1 portion of the study.   As noted above, the toxicology program showed that 
INT230-6 administered IV resulted in no new toxicities.  Only events expected for either 
vinblastine or cisplatin were observed.  Please refer to the IB for further information. 
To date, doses of INT230-6 up to 172 mL have been well tolerated. Following the phase 
1, the SSC made a recommendation to increase dose levels of INT230-6 to 175 mL 
maximum dose. This regimen was submitted to the health authorities prior to activation 
of the fixed dose cohorts in Amendment 5.  Theoretically the total amount of cisplatin 
and vinblastine administered intratumorally using INT230-6 could be considerably safer 
than the approved or MTD of IV administered cisplatin/vinblastine.  If the agents are 
reduced/degraded or bound up while in the tumor microenvironment or inside the cancer 
cells the lesser toxicities effects could be expected.  (Vinblastine binds to a cell’s tubulin 
and cisplatin to the cell DNA.  Should these processes occur within the cancer cells of the 
tumors, then systemic exposure would be reduced and corresponding morbidity due to 
the drugs decreased).  Cohort EC has delivered doses of vinblastine in some subjects that 
have exceeded the typical IV dose, without any drug related grade 3 or higher AE’s in 
those subjects. 
 
3.10. 
Nonclinical Pharmacokinetics 
PK data from IV administration of INT230-6 in male and female rats for each main 
component in INT230-6 is reported in Table 3 below.  Plasma was analyzed for the 
concentration of vinblastine and SHAO using validated LC/MS/MS methods, and for 
cisplatin using a validated ICP-MS method.  For pharmacokinetic studies, total platinum 
levels in subject plasma and urine are routinely determined by spectroscopy methods as a 
surrogate for platinum drugs.  An ICP-MS method (Frontage Laboratories BTM-1942-
R2) was developed for this study to measure total platinum in rat study samples.  This 
document thus reports the ICP-MS measured total platinum values (obtained from plasma 
samples using method BTM-1942-R2) as cisplatin.  The results of these analyses were 
used for toxicokinetic analyses. 
 
 


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Table 3: 
Animal PK
 
 
 
Study  
Day 0 
Study 
 Day 0 
Study  
Day 14 
Study  
Day 14 
 
Variable 
Male 
Female 
Male 
Female 
Cisplatin   
AUClast (ng*h/mL) 
54,500 
58,200 
83,700 
67,900 
5 mL/kg of INT230-6 Bolus 
C0 (ng/mL) 
4150 
9010 
14100 
12600 
 
T1/2 (h) 
53† 
50† 
69† 
63† 
 
Cl (mL/min/kg) 
0.663 
0.633 
0.398 
0.503 
 
Vss (L/kg) 
2.61 
2.25 
2.02 
2.28 
*Note that total platinum is measured after cisplatin administration. Cisplatin, decay 
monoexponentially with a half-life of about 20 to 30 minutes following bolus 
administrations of 50 or 100 mg/m2 doses. Monoexponential decay and plasma half-lives 
of about 0.5 hour are also seen following 2-hour or 7-hour infusions of 100 mg/m2.  
 
 
Study  
Day 0 
Study 
 Day 0 
Study  
Day 14 
Study  
Day 14 
 
Variable 
Male 
Female 
Male 
Female 
SHAO  
AUClast (ng*h/mL) 
51,500 
55,200 
87,000 
71,000 
5 mL/kg of INT230-6 Bolus 
C0 (ng/mL) 
155,000 
171,000 
252,000 
213,000 
 
T1/2 (h) 
4.7† 
3.3† 
3.7 
4.2 
 
Cl (mL/min/kg) 
16.2† 
15.1† 
9.57 
11.7 
 
Vss (L/kg) 
0.132† 
0.205† 
0.089 
0.123 
 
 
 
Study  
Day 0 
Study 
 Day 0 
Study  
Day 14 
Study  
Day 14 
 
Variable 
Male 
Female 
Male 
Female 
Vinblastine  
AUClast (ng*h/mL) 
78.1 
63.1 
197 
148 
5 mL/kg of INT230-6 Bolus 
C0 (ng/mL) 
43.6 
36.2 
70.0 
46.5 
 
T1/2 (h) 
2.7† 
2.6† 
6.0 
5.8 
 
Cl (mL/min/kg) 
80.8† 
102† 
40.2 
53.7 
 
Vss (L/kg) 
18.1† 
21.8† 
14.4 
19.3 
† 
= Value is considered to be an approximation 
Dose-related toxicity is therefore most likely to occur during treatment or within 14 days 
following treatment, however the DLT window shall be extended to 28 days. 


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4. 
STUDY OBJECTIVES 
4.1. 
Research Hypothesis 
INT230-6 when administered intratumorally (IT) to one or more tumors will safely 
reduce tumor burden, control disease, and promote an immune response against the 
cancer. 
 
4.2. 
Primary Objective 
The primary objective is to assess the safety and tolerability of multiple IT doses of 
INT230-6 in subjects with advanced or recurrent malignancies.  This will be assessed by 
the rate of grade 3 or higher adverse events attributed to INT230-6 and not the underlying 
disease. 
 
4.3. 
Secondary Objectives 
The secondary objectives are to: 1) Assess the preliminary efficacy of INT230-6 by 
measuring the disease control rate (CR+PR+SD) as assessed by iRECIST; 2) characterize 
the pharmacokinetic profile of multiple doses of the three INT230-6 components (CIS, 
VBL, and SHAO) after single and then multiple IT tumor site injections. 3) characterize 
the overall safety of the INT230-6. 
 
4.4. 
Exploratory Objectives 
The exploratory objectives are to: 1) Characterize tumor response in injected and non-
injected sites; 2) Evaluate various tumor and anti-tumor immune response biomarkers 
that may correlate with tumor response; 3) Evaluate overall response by iRECIST; 4) 
Characterize the pharmacodynamics (PD) profile of the INT230-6 formulation in subject 
blood and treated and untreated tumors; 5) To assess the progression free and overall 
survival in subjects receiving INT230-6. 
 
 


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5. 
OVERVIEW OF STUDY DESIGN 
5.1. 
Dose Escalation 
This is a FIH Phase 1/2, open label, non-randomized study. Subjects will have refractory, 
advanced cancers and will have failed or not be a candidate for standard of care. 
Investigators will have the option to continue INT230-6 based upon safety, local 
tolerability, and tumor response.  The phase 1 portion of the study was divided into up to 
escalating dose cohorts for administration of INT230-6 and for cohorts A1, B1, EA, EC 
follows a 3+3+3 design. 
Certain cohorts employed a subject safety lead in e.g., Cohorts A, EA, DEC, FEC, etc. 
cohort to estimate the rate of DLTs.  A rate of DLTs <33% is desirable.  The DLT 
observation window is 28 days. If less than 2 out of the first 6 subjects would have 
experienced a DLT, then additional subjects with different tumor types could have been 
enrolled to better define the safety in the different tumor types.  If 2 subjects would have 
experienced a DLT, then an additional 6 subjects could have been enrolled and followed 
for a 28 Day DLT window.  If > 3 subjects would have experienced a DLT, the safety 
data would have been reviewed by the SSC and a lower dose of INT230-6 would have 
been explored.  No DLTs were observed in the phase 1 portion of the study. 
The first 6 cohorts used an intrapatient dose escalation in the amounts noted per tables 4, 
5, 6, 7.  Dose escalation occurred by an increase in the amount and number of tumors that 
can be injected in a single subject, or by opening new cohorts at higher total drug 
exposure.   
5.1.1. 
A. SUPERFICIAL TUMORS at 1:4 ratio: Dosing once per 28 days, Cohort A1 
Cohort A1 – Superficial tumors included cutaneous and subcutaneous tumors. Nodal 
tumors were included if they were visible and palpable.  Examples of such cancers are 
melanoma, head and neck, breast, and lymphomas. A sentinel subject could have had up 
to 3 naïve, superficial tumors injected at Cycle1, Day 0, for a total of 5.0 mL of INT230-
6.  Depending on the extent of superficial disease, it may not have been possible to inject 
the maximum amount for a given subject. After the sentinel subject was on treatment for 
28 days (i.e., up to 3 tumors injected on day 0 and 28 days follow up), if there were no 
DLTs, upon agreement from the SSC, more subjects could have been enrolled into 
Cohort A1, and received monthly injections as per the schedule on Days 0, 28, 56, 84 and 
112 (n=2-9).  Cohort A1 continued until at least 3 subjects could have had the 
opportunity to complete at least 56 days or 3 DLTs would have occurred.  If 1 DLT was 
observed in the first 3 subjects, an additional 3 subjects at this dose level could have been 
added.  If there was 1 more DLT in the first 6 subjects, 3 more would have been added.  
If a third dose-limiting toxicity was observed in any dose level, even if < 9 subjects are 
enrolled, enrollment in that dose level would have been discontinued and a lower dose 
level or intermediate dose level would have been explored.  A rate of DLTs that exceeds 
33% is unacceptable for this population.  There were no DLTs in this cohort. 
Efforts were made to avoid injecting INT230-6 into necrotic tissue. Redosing was 
permitted using ultrasound guidance to ensure proper needle placement. In any subject, if 
no DLTs were observed after 28 days of follow up, the subject could have received 


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injections into up to 5 superficial tumors (cycle 2).  If no DLTs were observed after 28 
days of follow-up, the subject could have received superficial injections into any 
superficial tumors monthly on days 56, 84 and 112 (total of 5 cycles).   
For each injection day, there was a limit to the total volume of administration, a limit on 
the maximum number of tumors (cycles 1-2 but not cycles 3-5) that could have been 
injected, and a limit on the maximum volume that could be injected into the largest 
tumor. This information is highlighted in the following schedule (Table 4). Note that the 
injection volume on subsequent cycles could have declined as the tumor size changes 
over time. 
Table 4: 
Cohort A1 0.25 mL/cm3 tumor  
Cycle 1 
Cycle 2 
Cycle 3-5 
maximum dose 
5.0 mL 
Up to 10 mL 
Up to 15 mL 
maximum number of tumors injected 
up to 3 
up to 5 
No limit 
maximum volume for largest tumor 
Up to 5.0 mL 
Up to 10 mL 
Up to 15 mL 
 
5.1.2. 
B. DEEP TUMORS AT 1:4 ratio: Dosing once per 28 days Cohort B1  
Cohort B1 was initiated and followed the same schedule as Cohort A1, but also allowed 
injections in deep tumors with image guidance (Table 5 ). Deep tumors were defined as 
those that lie within the body such as in an organ and are not able to be felt by touch.  
Tumors in the pancreas, liver, colon, lung and stomach are examples of deep tumors.  
Note that a sentinel subject in this cohort could have received a single injection totaling 
up to 5.0 mL into a naïve, deep tumor (subjects; n=1); if no DLTs were observed, this 
subject could have received injections into up to 3 deep or superficial tumors 28 days 
later. Efforts were made to avoid injecting INT230-6 into necrotic tissue.  Redosing was 
performed using CT or ultrasound guidance.  If no DLTs were observed, the same subject 
could have received deep or superficial injections into any 5 tumors monthly on days 56, 
84 and 112 (total 5 cycles).   
After the sentinel subject was on treatment for 28 days (i.e., up to 1 injection and 28 days 
follow up) and upon agreement from the Study Steering Committee (SSC), more subjects 
could have received monthly injections as per the schedule on Days 0, 28, 56, 84 and 112 
(n=2).  Note that the injection volume on subsequent cycles could have declined as the 
tumor size changes over time.   
 Table 5: 
Cohort B1 0.25 mL/cm3 tumor  
Cohort B1 Superficial + Deep 
Cycle 1 
Cycle 2 
Cycle 3-5 
maximum dose 
5.0 mL 
Up to 15 mL 
Up to 30 mL 
maximum number of tumors injected 
1 
Up to 3 
Up to 5 
maximum volume for largest tumor 
5.0 mL 
Up to 10 mL 
Up to 15 mL 


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Depending on the extent of disease, it might not have been possible to inject the 
maximum amount for a given subject.  Cohort B1 continued until at least 3 subjects had 
the opportunity to complete at least three doses or if 3 DLTs had occurred.  If 1 DLT was 
seen in the first 3 subjects, an additional 3 subjects at this dose level could have been 
added.  If there was 1 more DLT in the first 6 subjects, 3 more could have been added. If 
≥3 DLTs were seen in up to 9 subjects, the SSC would have paused accrual and reviewed 
the data.  If a third DLT was observed in any dose level in any cohort, even if < 9 patients 
were enrolled, enrollment in that dose level would have been discontinued and a lower 
dose level or intermediate dose level in that Cohort would have been explored.  A rate of 
DLTs that exceeds 33% is unacceptable for this population.  There were no DLTs in this 
cohort. 
 
5.1.3. 
C. SUPERFICIAL TUMORS AT 1:4 ratio: Every two-week dosing, Cohort EA  
Cohort EA design is described in Table 6.  
Table 6:      Cohort EA injection every 2 weeks in superficial tumors 
Cohort EA superficial  
Cycle 1 
Cycle 2 
Cycle 3-5 
maximum dose 
Up to 20 mL 
Up to 20 mL 
Up to 30 mL 
maximum number of tumors injected 
Up to 3 
Up to 5 
No Limit 
maximum volume for largest tumor 
10 mL 
Up to 10 mL 
Up to 20 mL 
Cohorts EA was initiated and continued until at least 3 subjects had the opportunity to 
complete at least three cycles or 3 DLTs would have occurred.  If 1 DLT was seen in the 
first 3 subjects, an additional 3 subjects at this dose level would have been added.  If 
there is 1 more DLT in the first 6 subjects, 3 more would have been added.  If ≥3 DLTs 
were seen in up to 9 subjects, the SSC would have paused accrual and reviewed the data.  
If a third dose-limiting toxicity was observed in any dose level in any cohort, even if < 9 
subjects are enrolled, enrollment in that dose level would have discontinued and a lower 
dose level or intermediate dose level in that Cohort would have been explored.  A rate of 
DLTs that exceeds 33% is unacceptable for this population. There were no DLTs in this 
cohort. 
 
5.1.4. 
D. SUPERFICAL and/or DEEP TUMORS every 2 weeks 1:2 ratio (Cohort EC) 
and 1:3 ratio (Cohort EC2) 
Cohort EC was similar to Cohort EA but with a higher loading dose of INT230-6 (50% 
injection to tumor volume i.e., 0.50 mL/cm3 tumor) (Table 7a) and a higher total dose 
escalation. Cohort EC2 (Table 7b) had higher drug volumes at a lower drug loading (1:3) 
per tumor compared with EC.  


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Table 7a: 
Cohort EC Every 2 weeks in Superficial and Deep tumors 
Cohort EC Superficial 
and/or Deep Tumors 
Dose 1     
(C1, D0 / 
Day 0) 
Dose 2      
(C1, D14 
/ Day 14) 
Dose 3     
(C2, D0 / 
Day 28) 
Dose 4      
(C2, Day 14 
/ Day 42) 
Dose 5    
(C3, D0 / 
Day 56) 
Total volume (mL) 
30 
60 
120 
120 
120 
Maximum volume for any 
one tumor (mL) 
Up to 15 
Up to 30 Up to 60 Up to 80 
Up to 100 
Maximum number of deep 
tumors allowed to be 
injected* 
2 
4 
6 
6 
6 
Maximum drug to tumor 
ratio** 
1:2 
1:2 
1:2 
1:2 
1:2 
Table 7b           Cohort EC2 
Cohort EC2 Superficial 
and Deep Tumors 
Dose 1     
(C1, D0 / 
Day 0) 
Dose 2      
(C1, D14 
/ Day 14) 
Dose 3     
(C2, D0 / 
Day 28) 
Dose 4      
(C2, Day 14 
/ Day 42) 
Dose 5    
(C3, D0 / 
Day 56) 
Total volume (mL) 
100 
130 
160 
190 
220 
Maximum volume for any 
one tumor (mL) 
Up to 60 
Up to 
100 
Up to 120 Up to 140 
Up to 160 
Maximum number of deep 
tumors allowed to be 
injected* 
2 
4 
6 
6 
6 
Maximum drug to tumor 
ratio** 
1:3 
1:3 
1:3 
1:3 
1:3 
 
*There was no limit to the number of superficial tumors allowed to be injected 
provided the total dose was not exceeded. 
**Could have been lower than 1:2 (case of EC) or 1:3 (case of EC2) if the tumor 
size exceeded 2 to 3 times the maximal volume to be administered. (e.g., a 60 cc 
tumor on dose 1 received the max 15mL or 1:4, but on dose 2 could receive 30 
mL or 1:3). 
Cohort EC was initiated and continued until at least 3 subjects had the opportunity to 
complete at least three cycles or 3 DLTs had occurred.  If 1 DLT was seen in the first 3 
subjects, an additional 3 subjects at this dose level would have been added.  If there was 1 
more DLT in the first 6 subjects, 3 more would have been added.  If ≥3 DLTs were seen 
in up to 9 subjects, the SSC would have paused accrual and reviewed the data.  If a third 
dose-limiting toxicity was observed in any dose level in any cohort, even if < 9 subjects 
were enrolled, enrollment in that dose level would have discontinued and a lower dose 
level or intermediate dose level in that Cohort would have been explored.  A rate of 
DLTs that exceeds 33% is unacceptable for this population.  There were no DLTs in this 
cohort. 
Cohort EC2 was initiated and continued until at least 6 subjects had the opportunity to 
complete at least three cycles or 4 DLTs had occurred.  If 2 DLTs were seen in the first 6 




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maximum dose to achieve the 1:3 target ratio.  The total dose is to be divided up and injected 
into as many tumors as feasible, with the aim to treat as many visible tumors as possible 1to 3 
times during the course of the induction treatment.  After the 5 doses, subjects continue to the 
maintenance phase where they can repeat injecting new lesions or previously injected lesions 
with up to 175mL once every 9 weeks.  Treatment should continue until patient’s tumors 
disappear (CR), confirmed progression (iCPD) or 2 years whichever is first. 
5.2.2. 
DEC2 Cohorts. COMBINATION WITH ANTI-PD-1 agent(s): see Supplement A 
for details on each PD-1 agent. 
DEC cohorts were initiated and are a combination of INT230-6 plus an anti-PD-1 
therapy. The subject population (tumor types) and other details for this group of subjects 
is defined in Supplement A.  
5.2.3. 
FEC Cohorts. COMBINATION WITH ANTI-CTLA4 agent(s): see Supplement 
B for protocol details for INT230-6 combinations with anti-CTLA-4 agent(s). 
Cohort FEC was initiated and is a combination of INT230-6 plus an anti-CTLA4 therapy. 
The subject population (tumor types) and other details for this group of subjects is 
defined in Supplement B. 
5.2.4. 
GEC Cohorts.  Cohorts containing the letter “G” dose INT230-6 with agents 
other than PD-(L)1 or CTLA-4 antibodies.  
The subject population (tumor types) and other details for this potential group of subjects 
will be defined in a future Supplement C. 
 
Study Steering Committee 
The Study Steering Committee is comprised of the majority of study investigators plus 
representatives from the Sponsor.  The SSC will review safety data regularly in an 
ongoing basis on all subjects.  Decisions to increase the number of subjects in a cohort, to 
increase the loading concentration injected into the tumors, and the decision to begin 
treating deep tumors will require agreement from this committee.  The SSC will review 
the data on any sentinel subjects and facilitate the decision to recruit more subjects.   
 
Expansion Groups 
The SSC has reviewed the safety and any available biologic and/or tumor measurement 
data from phase 1, and recommended opening expansion groups of 10-16 subjects with  
single tumor types.  These groups allow for better point estimates of the safety and 
preliminary efficacy in a homogenous population of subjects. These groups try to 
optimize drug exposure (i.e., maximum injection volume and drug load) to facilitate the 
optimal tumor destruction potential. 
 


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5.3. 
Long Term Follow up 
Subjects who completed therapy, including treatment with or without retreatment, 
treatment with maintenance, or discontinued treatment for any reason other than clinical 
or radiological progression will enter the Long Term Follow up period.  Subjects will be 
evaluated every 8 weeks for one year (until Amendment 5), and every 9 weeks 
(Amendment 6).  During this Long Term Follow up Period, if a subject progresses or 
receives an intervening anti-cancer therapy, the subject will then enter the Survival 
Follow up Period.   
Subjects who discontinue treatment due to clinical or radiological progression or 
Withdraw Consent from study treatment(s) will not enter Long Term Follow up, but will 
enter survival follow up as outlined below. 
5.4. 
Survival Follow-up Period 
Following completion of the treatment and long-term follow-up, as applicable, all 
subjects will be followed for survival.  After that initial assessment of all study subjects, 
any surviving subjects will have their survival status assessed approximately every 3 
months by either a telephone or in-person contact until study completion or termination 
by the Sponsor.  With the exception of noting the first use of subsequent anti-cancer 
therapies, no other data (e.g., subsequent therapies, performance status etc.) beyond 
survival will be collected during these calls/visits. 
 
5.5. 
Injection Procedure 
For all injections, proper precautions to prevent bleeding will be followed per the 
institutional guidelines for anti-coagulants for this patient population. The risk of the 
procedure should be similar to a biopsy.  Greater precautions should be taken when 
injecting deep tumors. Subjects cannot be on aspirin or NSAIAs.  Anticoagulants must be 
held with proper washout period prior to injection and not re initiated until the physician 
is confident that there have been no bleeding complications from the procedure.     
 
Cohort A1, EA: 
 
Superficial Tumors 
The minimum tumor size must be > 1.0 cm in diameter on Day 0.  An eligible superficial 
tumor is defined as one that has not been previously irradiated, and has had at least 4 
weeks to heal after any surgery or open biopsy.  Note superficial tumors that have been 
irradiated previously but have evidence of active tumor growth, can be considered. 
Superficial tumor injection: A sentinel subject with accessible and eligible superficial 
tumors in the skin, subcutaneous tissues, and/or lymph nodes will receive up to 3 IT 
injections into different tumors that are considered the most troublesome (defined as the 
largest that are without confounding factors to permit local toxicity assessment and 


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which are causing the greatest morbidity (acknowledging that this is a subjective 
assessment).  The largest tumor should be targeted first). 
After IT injections, the sentinel subject was monitored for at least 6 hours post-injection 
with vital signs, physical exams including close examination of the injection site and 
surrounding tissues for any untoward reactions, safety labs, and adverse events (see 
Table 11 for  28 day dosing and Table 12 for 14 day dosing).  If there were no safety 
concerns, the subject would have been discharged to return to the clinic on Day 1 for the 
same safety follow up as on Day 0.  The subjects would have been admitted to the 
hospital for observation if deemed medically necessary.  This subject would have 
returned for safety evaluations on Days 7 and 14.  On Day 14 or day 28 (cohort 
dependent) the subject was evaluated for additional IT injections into superficial tumors.  
If the subject had no persistent adverse events greater than Grade 2 (NCI CTCAE v 4.03) 
that could reasonably be attributed to the IT injection or the components of INT230-6, the 
subject could have received repeat injections in up to 5 tumors on day 28, and on 
subsequent cycles any number tumors chosen by the investigator. 
After this first subject completed at least 28 days of follow up without persistent ≥Grade 
3 (NCI CTCAE v 4.03) adverse events that could reasonably be attributed to INT230-6, 
additional subjects were enrolled in this cohort.   
Note: On subsequent cycles, previously injected or new tumors could have been treated.  
Data from animals suggest re-injecting the same tumors leads to better tumor control.  
Ultimately the decision to re-inject the same tumors was made by the treating physician. 
The total number of additional tumors that were readily injectable were considered.  
Ultrasound was used for needle placement to avoid injecting areas of necrosis. 
 
Cohorts B1, EC, EC2, EC3, DEC, DEC2, FEC, GEC 
 
All Tumor Types Including Deep Tumors 
Subjects having previously identified deep tumors observed using ultrasound, CT scan, 
MRI or PET/CT technologies will be eligible for treatment of their deep tumors provided 
the inclusion and exclusion criteria are met. The procedure will be done with ultrasound- 
or CT scan-, directed IT injection into deep tumors of at least 1.0 cm in diameter.  Most 
troublesome tumors are defined as the largest that are without confounding factors, such 
as an unclear window to approach the tumor, unclear path for the needle which avoids 
major structures, scarring, proximity to large vessels, large areas of necrosis, inability to 
ascertain a local toxicity assessment.  Most troublesome tumors are causing the greatest 
morbidity (acknowledging that this is a subjective assessment).  The technical feasibility 
will be assessed by an interventional radiologist during the screening process to 
determine if the subject can be treated with this approach and what the most suitable 
tumors are for injection.  The largest tumor should be targeted first with the least amount 
of puncture wounds. Rex Medical deep tumor injection device (QuadraFuse) can be used 
to enable proper dispersion of the drug product throughout the different quadrants of 


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large tumors (device to be provided by the Sponsor).  See PK and Biomarker Manual and 
Injection Manual for further information. 
After IT injections, the sentinel subject in cohort B1 (any others are to be designated by 
the SSC) was monitored for at least 6 hours post-injection with vital signs, physical 
exams including close examination of the injection site and surrounding tissues for any 
untoward reactions, safety labs, and adverse events (see Table 12).  If there were no 
safety concerns, the subject was discharged to return to the clinic on Day 1 for the same 
safety follow up as on Day 0. The subject would have been admitted to the hospital for 
observation if deemed medically necessary.   
Subjects will return for safety evaluations on Days 7 and 14 for cohort B1 and weekly for 
all E cohorts.  On Day 14 for all E cohorts, and Day 28 for cohort B1, subjects will be 
evaluated for additional IT injections.  If the subjects have no persistent adverse events 
greater than Grade 2 (NCI CTCAE v 4.03) that can reasonably be attributed to the IT 
injection or the components of INT230-6, the subjects can receive repeat injections.  
Over the course of the induction phase, investigators should attempt, if safe, to dose as 
many tumors as possible at least 2 or 3 times at the proper dose as noted in Table 8. 
It is not necessary to inject each tumor on each of the 5 induction dosing sessions.  For 
subjects who received 3 injections at the proper dose (from Table 8) in a given tumor 
prior to completion of 5 dosing sessions decisions regarding further treatment should be 
discussed with the Medical Monitor. 
Note: On subsequent cycles, previously injected or new tumors may be treated.  Data 
from animals suggest re-injecting the same tumors leads to better tumor control. The 
treating physician will ultimately decide which tumors will be injected, taking into 
consideration the response of the injected tumor(s) and the number of additional tumors 
that can be readily injected.  Ultrasound or CT guidance may be used for needle 
placement to avoid injecting areas of necrosis.  
 
Methodology:  
INT230-6 will be injected into the periphery of the accessible and deep body tumors 
through the smallest and shortest gauge needle as possible to reach the entire depth of the 
tumor. For deep body tumors, ultrasonography or CT guidance at physician’s choice will 
be used to place the needle into the tumor. The needle will be moved throughout the 
tumor with a pullback technique (distal, middle and proximal) if possible and be removed 
after each injection or when all tumors have been injected (see Injection Manual for more 
details).  


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6. 
STUDY POPULATION 
See supplements for further details on population specifics for DEC, DEC2, FEC cohorts 
or potentially GEC cohort. 
6.1. 
Inclusion Criteria  
1. The participant (or legally acceptable representative if applicable) provides written 
informed consent for the trial.   
2. Men and Women > 18 years of age on the day of signing consent. 
3. Have an Eastern Cooperative Oncology Group (ECOG) performance status < 2; (for 
pembrolizumab and ipilimumab combinations please see supplements DEC/DEC2 
and FEC for ECOG criteria). 
4. Populations: INT230-6 will be injected into deep or superficial tumors for subjects with 
histologically or cytologically confirmed advanced or metastatic cancers; (for 
pembrolizumab and ipilimumab combinations please see supplements DEC/DEC2 
and FEC for Populations). 
5. Includes subjects with loco-regional disease that have relapsed/recurred within 6 months 
of chemo-radiation and who have no standard of care.  
6. Subjects with metastatic disease who have failed one or more approved standard 
therapies, or have no alternate approved therapy available. Failure of all approved 
therapies that have a modest or marginal impact on survival is not required as long as the 
treating physician believes that treatment on study is appropriate for the subject and 
documents that the subject elects to defer the approved therapies. 
Note:  There is no limit on the number of prior therapies that a patient (subject) 
may have received prior to enrollment in any cohort. 
7. Subjects must have measurable disease by iRECIST 1.1 criteria including one target 
tumor for injection by the local site investigator/radiology.  Superficial tumors must have 
one tumor greater than or equal to 1.0 cm, deep tumors greater than or equal to 1.0 cm (as 
measured by caliper (for non-injected tumors only) or image guidance).  Lesions situated 
in a previously irradiated area are considered measurable if progression has been 
demonstrated in such lesions. 
8. Subjects must have a minimum of one injectable lesion as determined by the investigator 
(for superficial tumors) or radiologist (deep tumors). 
9. Prior chemotherapy or immunotherapy (tumor vaccine, cytokine, or growth factor given 
to control the cancer: systemic or IT) must have been completed at least 4 weeks prior to 
dosing (with the exception of kinase inhibitors or other short half-life drugs, a 2 week 
washout is acceptable prior to treatment) and all adverse events have either returned to 
baseline or stabilized. 
Note:  Subjects who have received prior platinum therapy are eligible irrespective 
of their response. 
 


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10. Prior systemic radiation therapy (either IV, intrahepatic or oral) completed at least 4 
weeks prior to study drug administration; (for ipilimumab combination please see 
supplement FEC exclusion criteria). 
11. Prior focal radiotherapy completed at least 2 weeks prior to study drug administration. 
12. Prior major treatment-related surgery completed at least 4 weeks prior to study drug 
administration. 
13. No prior primary or metastatic brain or meningeal tumors unless clinically and 
radiographically stable as well as off steroid therapy for at least 2 months. 
14. Life expectancy ≥8 weeks; (for ipilimumab combination please see supplement FEC 
inclusion criteria). 
15. A female participant is eligible to participate if she is not pregnant, not breastfeeding, and 
at least one of the following conditions applies:  
a. Not a woman of childbearing potential (WOCBP)  
b. A WOCBP subject who may become pregnant or who are sexually active with a 
partner and who could become pregnant agrees to use an effective form of barrier 
contraception during the study and for at least 180 days in monotherapy; (for 
pembrolizumab and ipilimumab combinations please see supplements 
DEC/DEC2 and FEC for pregnancy criteria). (Male subjects must agree to use 
contraception and refrain from sperm donation during the study for 180 days after 
administration of study drug.) 
16. Have adequate organ function as defined by the below screening laboratory values that 
must meet the following criteria: 
a. WBC ≥2000/μL (≥2 x 109/L). 
b. Neutrophils ≥1000/μL (≥1 x 109/L); (for pembrolizumab and ipilimumab 
combinations please see supplements DEC/DEC2 and FEC for neutrophil 
criteria). 
c. For subjects with planned superficial only injections: PT, PTT/aPTT, and INR 
≤1.5 × ULN, Platelets ≥70x103/μL (≥ 70 x 109/L), Hemoglobin ≥8 g/dL  
d. Creatinine within the institution’s laboratory upper limit of normal or calculated 
creatinine clearance >50 ml/min; (for pembrolizumab combination please see 
supplements DEC/DEC2 for creatine criteria). 
e. ALT (SGOT)/AST (SGPT) ≤2.5 x ULN without, and ≤ 5 x ULN with hepatic 
metastases. 
f. Bilirubin ≤2 x ULN (except subjects with Gilbert’s syndrome, who must have total 
bilirubin <3.0 mg/dL (<52 µmol/L); (for pembrolizumab and ipilimumab 
combinations please see supplements DEC/DEC2 and FEC for bilirubin 
criteria). 
g. For subjects with planned deep tumor injections:  PT, PTT/aPPT, and INR within 
normal limits; Platelet count ≥100,000/μL; hemoglobin ≥ 9 g/dL.  
Note: ALT (SGPT) =alanine aminotransferase (serum glutamic pyruvic 
transaminase); AST (SGOT) =aspartate aminotransferase (serum glutamic 
oxaloacetic transaminase); ULN=upper limit of normal. 


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1 Criteria must be met without erythropoietin dependency and without packed red 
blood cell (pRBC) transfusion within last 2 weeks.  
17. Additional criteria for combination arms can be found in the appropriate supplements. 
 
6.2. 
Exclusion Criteria 
Subjects who exhibit any of the following conditions at Screening will not be eligible for 
admission into the study: See DEC/DEC2, FEC, or potentially GEC supplements for 
additional criteria specific to those cohorts. 
18. History of severe hypersensitivity reactions to cisplatin or vinblastine or other products of 
the same class. 
19. Other prior malignancy, except for adequately treated basal or squamous cell skin cancer 
or superficial bladder cancer, or any other cancer from which the subject has been 
disease-free for at least 2 years. 
20. Subjects with tumors >15 cm (in longest diameter). Treatment plan for subjects with 
tumors that are 9 to15 cm must be discussed with and approved by the medical monitor. 
21. Underlying medical condition that, in the Principal Investigator’s opinion, will make the 
administration of study drug hazardous or obscure the interpretation of toxicity 
determination or adverse events. 
22. Concurrent medical condition requiring the use of immunosuppressive medications, or 
systemic corticosteroids (topical steroids are permitted); systemic corticosteroids must be 
discontinued at least 4 weeks prior to dosing. Inhaled or intranasal corticosteroids (with 
minimal systemic absorption) may be continued if the subject is on a stable dose. Non-
absorbed intra-articular steroid injections will be permitted; or use of other 
investigational drugs (drugs not marketed for any indication) within 30 days prior to 
study drug administration. Use of steroids as prophylactic treatment for subjects with 
contrast allergies to diagnostic imaging contrast dyes will be permitted. 
23. For deep tumor cohorts, subjects who require uninterrupted anticoagulants of any type, 
on daily aspirin therapy or NSAIAs.  
24. Use of other investigational drugs (drugs not marketed for any indication) within 28 days 
prior to study drug administration. 
Pregnancy Exclusion: 
A WOCBP who has a positive urine pregnancy test (e.g., within 72 hours) prior to 
treatment.  If the urine test is positive or cannot be confirmed as negative, a serum 
pregnancy test will be required 
 
NOTE: For specific inclusion/exclusion criteria relating to a potential combination, 
please refer to the combination specific supplement 


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7. 
ASSIGNMENT TO STUDY 
The investigative site will contact Catalyst for treatment assignment once a subject is 
determined to be eligible for enrollment. Subjects who meet all eligibility requirements 
will be assigned to a treatment group as determined by Catalyst. Once assigned, numbers 
for screen failures, non-treated, non-evaluable, or discontinued subjects will not be re-
used. 
 


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8. 
DOSAGE AND ADMINISTRATION 
8.1. 
Investigational Product 
An investigational product, also known as investigational medicinal product in some 
regions, is defined as follows: A pharmaceutical form of an active substance or placebo 
being tested or used as a reference in a clinical study, including products already with a 
marketing authorization but used or assembled (formulated or packaged) in a way 
different from the authorized form, or used for an unauthorized indication, or when used 
to gain further information about the authorized form. The investigational product should 
be stored in a secure area according to local regulations. It is the responsibility of the 
investigator to ensure that investigational product is only dispensed to study subjects. The 
investigational product must be dispensed only from official study sites by authorized 
personnel according to local regulations. In this protocol, investigational product(s) is: 
INT230-6, an anti-PD1 (pembrolizumab), CTLA-4 antibody (ipilimumab), or other drug. 
 
8.2. 
Non-Investigational Product 
Other medications used in the study as support or rescue medication for preventative, 
diagnostic, or therapeutic reasons, as components of the standard of care for a given 
diagnosis, are considered non-investigational products.  In this protocol, non-
investigational products are local anesthesia, anti-emetics (if prescribed by the 
investigator) and sedation. 
 
8.3. 
Physical Description of Study Drug 
INT230-6 is supplied in a frozen single use 10 mL or 30 mL amber vial.  Each vial 
contains: 
 
Name of Active Ingredients: 
Cisplatin, (cis-diamminedichloroplatinum - CIS) 0.5mg/mL and  
Vinblastine Sulfate (VBL) 0.1 mg/mL 
 
Name of Important Excipients: 
Sodium 2-hydroxybenzoylaminooctanoate (SHAO) 10 mg/mL (of free acid). 
 
8.4. 
Packaging and Labeling 
The study drug will be packaged and labeled according to current good manufacturing 
practices (GMP). Details of the packaging and labeling of clinical supplies may be found 
in the Pharmacy and Drug Product Labeling Manual. 


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8.5. 
Ordering Study Drug 
Clinical supplies may be requested by completing the Clinical Supplies Request Form 
and faxing it or e-mailing the form to the Sponsor with a copy to Catalyst. 
 
8.6. 
Storage 
Sterile INT230-6 has demonstrated that when stored frozen for 2 years at -20°C all three 
main ingredient substances comprising the drug product retain approximately ~100% of 
their T=0 concentrations upon thaw.  Long term stability studies are in process.  
Confirmation of the drug product’s stability for use beyond 24 months shall be provided 
prior to use for drug product batches older than 24 months.  
INT230-6 vials must be stored at a temperature of approximately -20°C (-15°C to -25°C 
is acceptable) and should be protected from light. Recommended safety measures for 
preparation and handling of INT230-6 include laboratory coats and gloves. After 
INT230-6 has been removed from the freezer, the total storage time (at room 
temperature) is not to exceed 4 hours. 
Care must be taken to assure sterility of the prepared solution as the product does not 
contain any anti-microbial preservative or bacteriostatic agent.  
The product storage manager should ensure that the study drug is stored in accordance 
with the environmental conditions (temperature, light, and humidity) as determined by 
the sponsor. If concerns regarding the quality or appearance of the study drug arise, do 
not dispense the study drug and contact the sponsor immediately. 
 
8.7. 
Study Drug Preparation and Administration 
INT230-6 is to be administered as an intratumoral injection.  Each 10 mL or 30 mL vial 
of INT230-6 must be thawed to room temperature prior to use.  (See Injection and Dosing 
Manual Section 2.1 for determining the number of vials to thaw for each subject session 
for each cohort).  Heating of the INT230-6 vials is not permitted.  Thaw by placing the 
vials needed for dosing on a bench at room temperature. After one hour gently shake the 
vials to assure that any particulates that may be visible go into solution.  INT230-6 must 
be dosed within 1 to 4 hours following removal from the freezer assuring that the vial is 
at room temperature at time of preparation.  Injection of tumors must be performed under 
ultrasound, endoscopic or CT guidance. The extent of necrosis in the tumor should be 
assessed prior to re-injecting the same tumor. 
If dosing into superficial tumors, prepare a standard syringe and sufficiently sized 22 
gauge (or finer e.g. 23, 24 gauge) needle of proper length for the size of the tumor.  (See 
below for dosing deep tumors).  Remove the foil overseal from the vial and place the 
needle into the rubber stopper.  Draw the appropriate drug volume for the tumor to be 
dosed into the syringe at either the 0.25 mL per cm3 of tumor or 0.5 mL per cm3 of tumor 


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ratio (depending on the cohort to be dosed).  Use a fractionating technique to assure that 
the dose of INT230-6 is administered to each quadrant of the tumor.  If known, dose into 
the proliferating portion of the tumor rather than into any necrotic areas.  Administer the 
entire dose throughout the tumor (moving the needle throughout the tumor as outlined 
per the Injection Manual) gently pushing the plunger.  Prior to withdrawing the needle 
from the tumor, count to 30 to assure time for the INT230-6 formulation to thoroughly 
diffuse throughout the tumor.   If tumor is superficial with potential for ulceration (e.g. 
melanoma), please cover with an occlusive dressing which can be removed in 48 hrs.   
For dosing into deep tumors note Sponsor shall provide a special syringe (see PK and 
Biomarker Manual and Injection Manual for further intratumoral deep tumor dosing 
information).  Note: it takes approximately 1 mL to prime the tubing for the injection 
device. 
Care must be taken to maintain the sterility of the INT230-6 solution as the product does 
not contain any anti-microbial preservative or bacteriostatic agents.  Do not reinsert the 
needle into the vial after the subject has been dosed.  Use a fresh, clean drawing needle if 
more material from the vial is to be used.  
Anti-PD1and anti CTLA4 therapy will be prepared as directed in the relevant 
Supplements 
Training videos have been prepared by the Sponsor for: 
25. Drug Preparation 
26. Dosing Superficial Tumors 
27. Deep Tumor Dosing 
It is expected that research staff who are involved in any of the above activities (drug 
preparation, labelling or dosing) view the videos and that training is documented prior to 
involvement in such activities. 
 
8.8. 
Drug Accountability 
Sponsor will provide the study drug supply. All study drug(s) will be supplied to the 
Investigator by Sponsor or its designee. Study drug supplies must be kept in an 
appropriate, secure locked area and stored in accordance with the conditions specified on 
the labels (approximately -20°C). The Investigator or designated study person must 
maintain an accurate record of dispensing the study drug in a Drug Accountability Log, a 
copy of which must be given to Sponsor at the end of the study. The Drug Accountability 
Log will record the study drugs received, dosages prepared, time prepared, doses 
dispensed, and doses and/or vials destroyed. The Drug Accountability Log will be 
reviewed by the field monitor during site visits and at the completion of the study. 
 


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8.9. 
Dose Adjustments 
Intrasubject dose reductions for the management of toxicities are not permitted unless 
discussed with and approved by the Sponsor Medical Monitor. 
 
8.10. 
Incomplete Dosing 
Depending on the technique used for injection, it is possible that a single tumor will not 
allow for the full volume of administration. Every effort should be made to deliver the 
total dose, across the permitted number of tumors. Depending on the overall tumor 
burden this may not be possible, in which case it should be recorded in the CRF.  If the 
tumor shrinks after one or more injections, the total volume declines, less total drug can 
be given, this will be recorded in the CRF. 
 
8.11. 
Dose Delay 
Delay of up to 14 days are permitted for treating on the next cycle for safety reasons.  If 
the delay is greater than 2 weeks, then the subject should come off study unless discussed 
with and approved by the medical monitor.  These delays are not intended for 
administrative type/scheduling issues due to holidays, weather, etc.  The visit windows in 
Table 10 should be used in such circumstances.  If, in the case of such delay it is beyond 
the allowed visit window, approval via a Protocol Waiver Form from Sponsor Medical 
Monitor should be obtained prior to the visit occurring. 
 
8.12. 
Permanent Discontinuation of Study Drug Due to Adverse 
Events  
INT230-6 should be permanently discontinued for a subject due to the occurrence of 
any of the following AEs that have not resolved prior to the next treatment 
• Any CTC Grade ≥3 immunologic related event that persists >1week despite 
treatment per institutional guidelines 
• CTC Grade 4 neutropenia > 7 days or neutropenic fever 
• Persistent ≥ CTC Grade 3 anemia despite growth factor support 
• Platelets < 70,000 for superficial tumors, <100, 000 for deep tumors 
• ≥ CTC Grade 3 elevation in liver enzymes 
• ≥ CTC Grade 4 neuropathy 
• Creatinine >1.5mg/dl 
• Any anaphylactic type reactions 
• ≥ Grade 3 nausea or vomiting that persists despite maximal supportive care  


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• Any AE, laboratory abnormality, or intercurrent illness which, in the judgement 
of the Investigator, presents a substantial clinical risk to the subject with 
continued treatment 
 
8.13. 
Destruction of Study Drug 
If study drugs (those supplied by the sponsor or sourced by the investigator) are to be 
destroyed on site, it is the investigator’s responsibility to ensure the destruction of drug is 
according to applicable regulations, guidelines and institutional procedures. Appropriate 
records of the disposal must be maintained at all times. The unused study drugs can only 
be destroyed after being inspected and reconciled by the responsible Sponsor Study 
Monitor. 
 
8.14. 
Return of Study Drug 
Study drug will not be returned. All unused and/or partially used study drug may be 
destroyed on site providing the site has an applicable standard operating procedure on 
file. 
 


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9. 
TOXICITY AND MANAGEMENT 
9.1. 
Dose Escalation  
Cohorts A1, B1, EA, EC, EC2, DEC escalated doses.  Cohorts EC3, DEC2, FEC start out 
with a fixed total dose for each treatment session. For doses within Cohorts EC3, DEC2, 
FEC, investigators may decide to treat certain tumors on one visit and then treat 
additional tumors on subsequent visits that may involve an increase of INT230-6 dose 
given.  This section describes the management of the potential toxicities. 
9.1.1. 
Dose-limiting Toxicity 
A DLT is defined as a > Grade 3 study drug-related adverse event (using NCI CTCAE 
Version 4.03) occurring during the first dose (DLT window extends up to 28 days after 
dosing), excluding: 
• Grade 3 adverse event of tumor injection reaction (defined as local pain, 
irritation, or rash localized at sites of known or suspected tumor) that resolves 
with supportive care measures within 48 hours 
• Grade 3 or 4 nausea or vomiting that is adequately treated with supportive 
care and that resolve within one to two days 
• Any bleeding that is self-limiting from or near the site of injection and 
resolves within 24 hours with non-invasive measures and without the need for 
transfusion 
• Grade 3 or 4 electrolyte abnormalities that correct to below grade 3 with 
standard measures within 48 hours 
A DLT will be considered related to study drug unless there is a clear, well-documented, 
alternative explanation for the toxicity. Delayed DLTs are adverse events that meet the 
criteria of DLTs that occur after Cycle 1.  If >1 member of a cohort should have a DLT 
for Doses 2 -5, then the SSC will determine how accrual shall proceed for that cohort. 
 
Intrasubject dose escalation 
Any events of > Grade 3 that are considered study drug-related after cycle 1 for a subject 
will be reviewed by the SSC to assess if alterations in dosing levels and or frequency are 
needed for that subject.  If more than one member of a cohort should have a > Grade 3 
event for cycles 2 to 5, then the SSC will determine how accrual should proceed for that 
cohort. 
All adverse events that meet DLT criteria must be reported to the pharmacovigilance 
services vendor (ProPharma) within 24 hours of the study site being made aware of the 
event using the rapid notification procedures described in Section 13.3.2. 
9.1.2. 
Stopping Rules for Dose-limiting Toxicity During Dose Escalation 
Cohorts in the dose escalation portion will be expanded up to 9 subjects in the case of 1 
or 2 DLTs.  More than two DLTs in a dose escalation expanded cohort (N=9) will exceed 


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the MTD. At the time a third DLT is observed in any dose level in any cohort, even if < 9 
subjects are enrolled, enrollment in that dose level will be discontinued and a lower dose 
level or intermediate dose level in that Cohort will be explored.  Any delayed DLTs will 
be evaluated on a case-by-case basis.  The SSC will provide additional oversight and will 
be reviewing safety on an ongoing basis and may make adjustments to this criterion 
based on the data. 
Subjects who are tolerating a study drug dose level that is being reviewed due to DLTs 
that occurred in other subjects will not be automatically precluded from continued dosing 
during this safety review and will be allowed to continue dosing for as long as it is 
tolerated unless the safety review mandates dose reduction. After safety analysis by the 
Investigators and Sponsor (with FDA and IRB notification), a decision will be made 
whether to resume enrollment and continue dosing at the current dose or initiate a new 
cohort of subjects at a lower INT230-6 dose.  
 
9.2. 
Possible Toxicities 
Based on the safety experience in the first 70 patients, the most common treatment 
associated adverse event is injection site pain.  Other constitutional adverse events 
(nausea, vomiting, decreased appetite and anorexia) have also been reported.   
Additional theoretical toxicities that could be affected by INT230-6, which may or may 
not be increased with the combination of immune activating agents, such as hematologic, 
cardiovascular, hepatic, musculoskeletal, and other systems, and may include the 
following: 
• Allergic reaction/hypersensitivity: Fever, chills, shakes, itching, rash, hyper- 
or hypotension, and difficulty breathing. It is likely that most injection-related 
adverse events will occur within the first 24 hours after the injection and may 
be treated by supportive treatment as indicated. 
• Injection procedure:  Pain during and after the injection, bleeding, infection, 
tumor ulceration and edema. The needle utilized for this is the same or smaller 
size than what is typically used for a biopsy.  All attempts at using a single 
injection point for each tumor are suggested.  Additionally, injection volumes 
of liquid into the tumor should provide some back pressure to help reduce the 
potential for bleeding.  The Quadrafuse device has been used for injection of 
deep tumors and has a low rate of hemorrhage as a complication.   
• Other potential adverse effects of INT230-6: Fatigue, anemia, leukopenia, 
hyponatremia, other laboratory abnormalities (including increases in gamma-
glutamyl transferase (GGT), aspartate aminotransferase (AST) and alanine 
aminotransferase (ALT), lipase, creatinine), nausea or vomiting, decreased 
appetite, weight loss, muscle aches, chills, dizziness, and urinary retention. 
• Adverse effects associated with IV Cisplatin and Vinblastine are less likely 
given the dose used in this study: Renal damage, visual disturbances, hearing 
loss/tinitis, peripheral neuropathy, sensory loss/numbness, tingling, areflexia 


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and difficulty walking, xerostomia or xerosis, dehydration, dysgeusia, 
alopecia, thrombocytopenia, other blood abnormalities (low magnesium, 
calcium, potassium), bleeding, dark urine, chest pain or heart attack, sweating, 
depression, muscle cramps, pain including headaches. 
• Extravasations: There are no reports of simultaneous extravasations of CIS 
and VBL so guidance on countermeasures does not exist.  Also watch closely 
for any toxicities when given intradermally for skin tumors. 
 
9.2.1. 
Management of select AEs 
The following table describes potential AEs and the management suggestions for 
INT230-6.  The investigator should use good medical judgement in determining the 
optimal care for his or her subjects. 
Table 9: 
Dose Modification and Toxicity Management Guidelines for AEs 
Associated with INT230-6 using CTCAEv4.03  
General instructions: 
1. 
For situations where INT230-6 has been withheld, INT230-6 can be resumed 
after AE has been reduced to baseline or Grade 1  
2. 
For severe and life-threatening AEs, INT230-6 should be permanently 
discontinued 
AEs 
Action taken to INT230-6 
AE management  
Monitor and follow-up  
Allergic reaction or 
hypersensitivity 
Hold drug if Grade > 3 
Follow the package insert for 
CIS and VBL, these AEs 
usually can be managed with 
by administration of 
epinephrine, corticosteroids, 
and antihistamines.   
You may consider a 
rechallenge with INT230-6 if 
grade <2 and resolves with 
minimal treatment.   
Typical cytotoxic effects 
including fatigue, nausea, 
vomiting, anorexia, 
decreased appetite 
Hold drug if Grade > 3 
Supportive care as per 
institutional guidelines 
Consider using anti-emetic 
premedication on next 
INT230-6 dose 
Local reactions 
Hold drug if Grade > 3 
apply heat packs, 
subcutaneous hyaluronidase 
Consider prophylactic 
antihistamines and low dose 
corticosteroids on next 
INT230-6 dose 
Injection pain 
Hold drug if Grade > 3 
Pain control medications as 
prophylaxis and for 
treatment as per institutional 
standard 
Consider prophylactic pain 
medication prior to 
subsequent injections. If 
Grade 3 or higher, do not 
increase INT230-6 dose 
9.3. 
Stopping Rules for Clinical Deterioration 
Accumulating evidence indicates that the emergence of objective responses to agents that 
activate anti-tumor immune responses follows delayed kinetics of weeks or months, and 
can be preceded by initial apparent radiological progression, or appearance of new 


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tumors or some enlarging tumors while certain target tumors are regressing (“mixed 
response”). It is thus reasonable to allow for these possibilities and continue to treat the 
subject until progression is confirmed and found to be advancing and continuing at the 
next imaging assessment. These considerations should be balanced by clinical judgment 
as to whether the subject is clinically deteriorating and unlikely to receive any benefit 
from continued treatment. Such deterioration will be assessed to have occurred after a 
clinical event that, in the Investigator’s opinion, is attributable to disease progression, is 
unlikely to reverse with continued study treatment and therefore indicates that the subject 
is not benefiting from study treatment and cannot be managed by the addition of 
supportive care (such as bisphosphonates and/or bone directed radiotherapy, thoracentesis 
or paracentesis of accumulating effusions). The decision to continue or stop treatment 
should be discussed with the Sponsor Medical Monitor and will be documented in the 
study records. 
Examples of events that may, in the Investigator’s opinion, indicate a lack of clinical 
benefit include, but are not limited to, the following: 
• Performance status decrease of at least 2 points from baseline 
• Skeletal related events defined by the following: 
− Pathologic bone fracture in the region of cancer involvement 
− Cancer related to bone surgery  
− Spinal cord or nerve root compression 
• Bladder outlet or urethral obstruction 
• Development of new central nervous system (CNS) metastases 
• Subjects that develop new CNS metastases in the setting of improving 
baseline disease may have focal radiation, resection, or other local curative 
procedures performed after consultation with the Medical Monitor. 
If continued study therapy is deemed to offer the subject potential benefit, subjects may 
be allowed to restart study therapy after recovery from symptoms related to the procedure 
performed (i.e., local edema) and steroid dosing at < 10 mg prednisone/day or equivalent, 
after recovery to baseline or grade 1. 
Subjects that have locally curative procedures while on study drug and subsequently 
develop new CNS metastases at a subsequent imaging assessment should discontinue 
study therapy and enter the follow-up period. 
Any setting where the initiation of new anti-neoplastic therapy has been deemed 
beneficial to the subject even in the absence of any such documented clinical events. 


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10. 
COMPLIANCE 
The Investigator or their designated study personnel will maintain a log of all study drugs 
received, dispensed, destroyed, and returned. Drug supplies will be inventoried and 
accounted for throughout the study.  
The Investigator and the study personnel will ensure that each subject receives the 
calculated dose of the study drug based on tumor volume, as in section 5.2. 
 


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11. 
CONCOMITANT THERAPY 
All medications taken within 14 days before the administration of study drug and all 
concomitant therapy administered during the study will be recorded on the relevant case 
report form (CRF), along with the reason for therapy use. 
1. The use of local anesthesia and /or sedatives as well as anti-emetics to facilitate the 
injection procedure is permitted. 
2. Inhaled or intranasal corticosteroids (with minimal systemic absorption) may be 
continued if the subject is on a stable dose. Non-absorbed intra-articular steroid injections 
will be permitted. Systemic corticosteroids required for the control of injection reactions 
must be tapered and be at non-immunosuppressive doses (< 10 mg/day of prednisone or 
equivalent) for at least 2 weeks before the next study drug administration. The use of 
steroids as prophylactic treatment for subjects with contrast allergies to diagnostic 
imaging contrast dyes will be permitted (other cases can be discussed with the medical 
monitor to allow higher doses for clear medical indications). 
3. Use of new herbal remedies, other marketed anti-cancer chemo/immunotherapy drugs, or 
investigational drugs (drugs not marketed for any indication) is not permitted. 
4. New chemotherapy or immunotherapy is not permitted. 
5. Palliative/therapeutic therapies (e.g., focal radiotherapy for pain, thoracocentesis or 
paracentesis for comfort) may be administered after consultation with the Medical 
Monitor. Palliative radiation will not be delivered to injected tumor sites while on study. 
6. Various growth factors are permitted as per ASCO guidelines after the 28 day DLT 
window. 
7. The use of live vaccines while on study is prohibited. The use of any killed or attenuated 
vaccines for the prevention of influenza is permitted at any time without a study drug 
washout interval. The use of other killed or attenuated vaccines for the prevention of 
infectious diseases may be permitted on a case-by-case basis and must be discussed with 
the medical monitor prior to its use. A washout interval prior to and post vaccination may 
be required in these instances. Any vaccinations administered while on study must be 
documented in the subject’s medical records and recorded in the CRF. 
All subjects should be maintained on the same concomitant medications 
throughout the study period, as medically feasible. Any new concomitant 
medications prescribed for the subject or changes to dosing/schedule of 
concomitant medications should be recorded on the appropriate CRF page. The 
addition of a new concomitant medication for which there is a concern that it may 
not be permitted should be first reviewed with the Sponsor Medical Monitor. 
8. No concomitant medication information will be collected following subject 
discontinuation from the study except for concomitant medication use associated with 
study drug-related adverse events or adverse events that lead to discontinuation from 
study and start of next anti-cancer therapy. Additional information for combination arms 
can be found in the appropriate supplements. 
 


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11.1. 
Treatment of Isolated Tumors 
Treatment of isolated/symptomatic tumors by local surgery or radiation therapy is 
permitted for palliative or potentially curative management at any time beyond Cycle 2. 
All interventions should be discussed in advance with the Sponsor Medical Monitor. 
Palliative radiation will not be delivered to injected tumor sites while on study. 
 


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12. 
STUDY EVALUATIONS 
12.1. 
Study Procedures by Visit 
12.1.1. 
Overview 
The study is divided into periods (Screening, Treatment, Long Term Follow-up and 
Survival Follow up) with associated evaluations and procedures that must be performed 
at specific time points. The Time and Events Schedules Table 10, Table 11  ( every 28 
day dosing) and Table 12 (every 14 day dosing cohorts) summarize the frequency and 
timing of efficacy, safety, and other study measurements.  
As soon as the subject is considered for this study and before performing any study 
procedures, the subject will have the study explained to him/her and will be asked to give 
written informed consent and HIPAA authorization. Informed consent/HIPAA 
authorization must be obtained before any procedures that do not form a part of the 
subject’s normal standard of care. Baseline imaging (within 28 days) and ECG as part of 
the subject’s previous routine care (performed within 14 days) of first dose need not be 
repeated. 
All subjects (withdrawn or completed) should have final evaluations and procedures 
performed. 
12.1.2. 
Screening Period 
Subjects will be evaluated for entry criteria during the Screening Period within 28 days 
before administration of study drug. The following procedures and evaluations will be 
completed for each subject before Day 0 and before inclusion in the study: 
• Informed consent/HIPAA may be obtained < 28 days before receiving study 
drug, and before any Screening procedures are performed; 
• Review of Inclusion/Exclusion criteria; 
• Medical history (to include collection of prior medications administered to the 
subject during the Screening Period, prior and concurrent medical conditions, 
and baseline signs and symptoms).  Additional information on diagnosis 
confirmation and stage and tumor-specific therapy history will also be 
collected; 
• Screening signs and symptoms: Note: Clinical adverse events occurring after 
signing informed consent/HIPAA authorization, but before study drug 
administration are to be recorded on the Medical History/Current Medical 
Conditions CRF;  Serious Adverse Events that occur after signing Informed 
Consent  must be reported according to the safety reporting procedures and 
recorded in the eCRF; 
• Vital sign measurements including temperature, O2 Saturations, heart rate, and 
resting blood pressure; 
• Height; 


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• Weight; 
• Complete physical examination (including examination of skin, head, eyes, 
nose, throat, neck, joints, lungs, heart, abdomen [including liver and spleen], 
lymph nodes, and extremities). A brief neurological examination should also 
be performed to rule out potential brain involvement; 
• ECOG performance status; 
• Clinical laboratory tests: 
• Hematology: Complete blood count (CBC) with differential (including 
absolute lymphocyte count) and direct platelet count (see Section 12.1.7) 
using ~5 mL of blood.  Coagulation: PT, PTT/aPTT, INR3; 
• Chemistry (using ~5 mL of blood):  
Alanine aminotransferase 
Creatine phosphokinase 
Phosphorus 
Albumin 
Creatinine 
Potassium 
Alkaline phosphatase 
Gamma-glutamyl 
transpeptidase  
Glucose  
Lactate dehydrogenase 
Sodium 
Aspartate aminotransferase 
Amylase 
Thyroid Stimulating Hormone,  
Total bilirubin 
Bicarbonate 
Lipase 
Total protein 
Calcium 
 
Triglycerides 
Chloride 
Low density lipoprotein 
Urea (or blood urea nitrogen) 
Cholesterol (total) 
Magnesium 
Uric acid 
• Electrolytes (including sodium, phosphorous, potassium, chloride, and bicarbonate); 
• Urinalysis: Gross examination including specific gravity, protein, glucose, and blood.  
Urine microscopic analysis is mandatory with all other lab tests; 
• Serum or urine pregnancy test (for all women of childbearing potential; pregnancy 
test must be negative to continue); 
• 12-lead Electrocardiogram (ECG); 
• Tumor imaging (CT/MRI or PET/CT of chest/abdomen/pelvis) and any other known 
sites of involvement (i.e. brain) within 28 days of first dose. The same imaging 
modality technique should be used throughout the protocol; 
 
3 INR should be measured only for those subjects taking warfarin, blood collection may require a separate draw  


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• Peripheral blood samples will be collected prior to initiation of study therapy. These 
samples will be analyzed for SNP. Prior to Amendment 6, blood samples were 
analyzed for flow cytometry parameters, cytokine panel, and quantitative 
immunoglobulins as outlined in Section 12.2.3; 
• Prior concomitant medications; 
• Interventional radiology assessment for deep tumors to assess feasibility and 
determine which tumors are best for injection.  
 


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Table 10: 
Screening Procedural Outline 
Procedure 
Screening 
visit 
Notes 
Informed Consent 
X 
  
Inclusion/Exclusion criteria 
X 
All criteria should be assessed at screening and confirmed 
prior to first dose 
Medical History 
X 
Including malignancy diagnosis and summary of tumor 
specific therapy 
Oncology and/or Interventional 
Radiology 
X 
Assess feasibility for intratumoral injection and determine 
which tumors are most appropriate for injection 
Physical Examination 
X 
  
Physical Measurements 
X 
Height and Weight; Body Surface Area 
Brief Neurological Exam 
X 
 
Vital Signs and O2 sat 
X 
Including BP, HR, Temperature and O2 saturation.  Obtain at 
screening and within 4 hours of the first dose 
ECG 
X 
Within 14 days prior to first dose 
ECOG Performance Status 
X 
Within 14 days prior to first dose 
Prior Medications 
X 
All prior medications to treat the neoplasm 
Concomitant Medications 
X 
Within 14 days prior to first dose 
Adverse Events Assessment 
X 
Clinical adverse events occurring after signing informed 
consent/HIPAA authorization, but before study drug 
administration are to be recorded on the Medical 
History/Current Medical Conditions CRF.  AEs meeting the 
definition of Serious must be reported according to the SAE 
reporting requirements. 
Laboratory Tests 
X 
CBC w/differential, coagulation and chemistry panel (for full 
list of labs see Section 12.1.2)  Urinanalysis with 
microscopic evaluation if dipstick is abnormal.  Within 14 
days prior to first dose.  (INR only for subjects taking 
warfarin) 
Pregnancy Test (WOCBP only) 
X 
 Serum or urine 
Screening/Baseline Tumor 
Assessment 
X 
CT, MRI or PET/CT of Head and Neck, Chest, Abdomen, 
and all other known sites of disease (i.e. Brain) within 28 
days prior to first dose.  At screening, all tumors >1 cm in 
diameter are to be reported with an estimate number of the 
number of tumors <1 cm recorded as well. 
Enrollment 
X 
  
Genetic Testing 
X 
See Table 14  
 


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Intensity Therapeutics’ Confidential Information                                                   Page 67 of 212 
12.1.3. 
Treatment Period 
The Treatment Period of the study is divided into 28 day cycles with associated evaluations and 
procedures that must be performed at specific time points (see Table 11) every 28 day dosing and 
Table 12 every 14 day dosing). Subjects who meet selection criteria may start INT230-6 
treatment within 28 days of screening. Subjects will receive injections of INT230-6 every 14 or 
28 days based on their Cohort assignment.  INT230-6 will also be dosed every 9 weeks +/- 10 
days in the cohorts specifying maintenance dosing (EC3, DEC2, FEC and potentially GEC).  
Results of assessments must be reviewed before administering the next dose. The maximum 
duration of study therapy to be administered to an individual subject in this study is 2 years (up 
to maximum of 4 months of initial treatment plus maintenance therapies for certain cohorts as 
well as Follow up and Survival Follow up). 
Every effort should be made to schedule visits within the protocol-specified windows. For 
injection delays (i.e., by 1 to 13 days) or missed doses, see Section 8.11 for administration 
details. A subject who is withdrawn from the study before the completion of the first cycle for a 
reason other than a DLT will be replaced. 
12.1.3.1. Cycle 1 
A cycle is defined as 28 days. Dose 1 (Cycle 1 Day 0) 1 will begin with the first IT injection of 
INT230-6 (Day 0) and will continue through to completion of evaluations by Day 28. For 
cohorts A1 and B1 subjects will be dosed every 28 days for a total of 5 cycles (Days 0, 28, 56, 84 
and 112) with a response assessment every 2 months for the first year and then every 3 months 
until progression. In "E" Cohorts, subjects will be dosed every 14 days for a total of 3 cycles 
(Days 0, 14, 28, 42, and 56). 
During Cycle 1 Day 0, the following evaluations will be performed as indicated in Table 11 for 
28 day dosing and in Table 12 for 14 day dosing.  Results will be recorded on the CRF: 
• Physical Exam: A full physical Exam will be performed on Day 0.  A Targeted 
physical examination (including measurement of vital signs as well as pulmonary, 
heart, abdomen, and skin assessments) will be conducted at all subsequent visits; 
• Vital sign measurements to include temperature, pulse, O2 saturation and resting 
blood pressure as defined in the Time and Events Schedule (Table 11 for every 28 
day dosing and Table 12 for every 14 day dosing).  Vital signs will be obtained before 
injection and then 15, 30, 60 post injection.  In addition,180 and 360 minutes post 
injection vital signs are collected at C1D0.   
• Weight; 
• Assessment of signs and symptoms; 
• Adverse Event Assessment; 
• ECG; 
• ECOG performance status; 
• Serum sample for pharmacokinetics is eliminated in Amendment 6.Clinical 
laboratory tests (local laboratories; Hematology (using ~5 mL of blood), coagulation 


Protocol IT-01 Version Amendment 6 
Intensity Therapeutics’ Confidential Information                                                   Page 68 of 212 
and clinical chemistry laboratories (using ~5 mL of blood) must be performed and 
reviewed before dosing. Labs do not need to be repeated if obtained within 72 hours 
of starting treatment). This includes a CBC with differential and Chemistry as 
outlined in Section 12.1.2; 
• Any new > Grade 3 laboratory abnormality such as liver function test elevations, 
electrolyte fluctuation, or hematologic deterioration should be assessed for potential 
risk to continued dosing. In the event of uncertainty, the Sponsor Medical Monitor 
should be contacted; 
• Urinalysis;  
• Serum or urine pregnancy test to be performed locally (for all women of childbearing 
potential; pregnancy test must be negative before study drug administration to 
continue); 
• CT/MRI Brain screening: CT/MRI Brain, only if clinically indicated by the 
development of new symptoms that suggest new CNS involvement;  
• Tumor imaging (CT/MRI or PET/CT chest/abdomen/pelvis) to be conducted only if 
imaging has not occurred within previous 29 days;  
• US/CT measurements of injected tumor; 
• Response assessment and documentation; 
• Cryopreserved peripheral blood mononuclear cells (PBMCs) and serum. Collection 
eliminated in Amendment 6. 
• Tumor and blood samples that are available after completion of designated analyses 
may be used in the future for identification of potential predictive and/or 
pharmacodynamic markers. These assessments will provide exploratory insights into 
the immunomodulatory activity of INT230-6.; 
• Concomitant medications; 
• INT230-6 injections (after all other evaluations for the visit according to the Time 
and Events (Table 12) have been completed except for the post injection vital signs);  
• Over 20 subjects have received INT230-6 more than 3 times into both superficial and 
deep tumors, with more than 10 subjects having had multiple deep tumor injections.  
The SSC reviewed the subject safety on February 8th, 2019 and authorized initiation 
of biopsies from both superficial and deep tumors; On Cycle 1 Day 0, an on-study 
biopsy of an injected tumor is mandatory prior to INT230-6 injection.  If possible, a 
biopsy of one (1) bystander tumor selected and taken by the attending physician; 
however, if risk is too high to such bystander tumor, then the biopsy should not be 
taken.  The SSC shall review periodically to determine whether subject biopsies can 
continue to be taken. 
12.1.3.2. Cycles/Doses 2 - 5 
INT230-6 injections (after all other evaluations for the visit according to the Time and Events 
Table have been completed except for the post-injection vital signs).  During cycles 4 and 5 there 


Protocol IT-01 Version Amendment 6 
Intensity Therapeutics’ Confidential Information                                                   Page 69 of 212 
is no scheduled dosing of INT230-6 for patients being dosed every 14 days (E cohort, may apply 
to combination cohorts, see supplement for specific schedules). 
• Physical Exam: A Targeted physical examination will be conducted at all visits; 
• Vital sign measurements to include temperature, pulse, O2 saturation and resting 
blood pressure.  On the day of each injection, vital signs will be obtained before 
injection and then 15, 30 and 60 minutes post injection;  
• Weight; 
• ECOG performance status; 
• Any new > Grade 3 laboratory abnormality such as liver function test elevations, 
electrolyte fluctuation, or hematologic deterioration should be assessed for potential 
risk to continued dosing. In the event of uncertainty, the Sponsor Medical Monitor 
should be contacted.;  
• Hematology with differential; 
− Coagulation  
• Clinical chemistry; as outlined in Section 12.1.2.  
• First tumor imaging (CT/MRI chest/abdomen/pelvis) should be done at 12 weeks +/- 
10 days from the date of the first baseline scan (Cycle 1, D0) with repeat scans every 
9 weeks +/- 10 days thereafter until end of study or confirmed progression whichever 
occurs first;  
• Urinalysis; 
• Serum or urine pregnancy test to be performed locally (for all women of childbearing 
potential; pregnancy test must be negative before study drug administration to 
continue); 
• Response assessment and documentation; 
• On Cycle 2 Day 0 only, an on-study biopsy of an injected tumor is mandatory and if 
possible a biopsy of one (1) bystander tumor selected and taken prior to dosing by the 
attending physician; however if the risk is too high to take a biopsy from a bystander 
tumor, then a biopsy should not be taken.  The SSC shall review safety periodically to 
determine whether additional subject biopsies can continue to be taken; 
• Tumor samples that are available after completion of designated analyses may be 
used in the future for identification of potential predictive and/or pharmacodynamic 
markers. These assessments will provide exploratory insights into the 
immunomodulatory activity INT230-6; 
• Concomitant medications and AE assessment; 
 
 


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Table 11: 
Schedule of events every 28 day dosing   
 
Cycle1 (+/- 1 Day) 
Cycle 2-5 (+/- 1 Day) 
Maintenance 
Procedure 
Day 0 dosing 
Day 1 
Day 7 
Day 14 
Day 0 
dosing 
Day 7 
Day 14 
 
INT230-6 dosing  
every 9 weeks +/- 10 days 
repeat every 28 days for each cycle 
 
Safety Assessments 
Physical Examination 
X 
 
Targeted Physical Examination2 
 
X 
X 
X 
X 
X 
X 
X 
Weight3 
X 
 
 
 
X 
 
 
X 
Vital Signs4 
X 
X 
X 
X 
X 
X 
X 
X 
Assessment of Signs and Symptoms 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory Tests5 
X 
X 
X 
X 
X 
X 
Pregnancy test6 
X 
X 
X 
ECOG Performance status7 
X 
X 
X 
X 
X 
X 
X 
X 
US/CT of injected tumor8 
X 
X 
X 
Tumor imaging (CT/MRI 
chest/abdomen/pelvis)9, 10, 11 
X11 
 
 
 
X9, 10 
 
 
 
Additional blood or radiographic measures 
clinically indicated12 
X 
X 
X 
Clinical Drug Supplies 
X 
X 
 
Dispense Study Treatment 
X 
X 
 
Vital Status 
 
 
 
 
 
 
 
 
On study biopsy13 
X 
X 
 
PBMS and Serum Sample 
 
 
 
X 
X 
 
 
 


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Intensity Therapeutics Confidential Information  
 
 
Table 11: 
Schedule of events every 28 day dosing   
 
Cycle1 (+/- 1 Day) 
Cycle 2-5 (+/- 1 Day) 
Maintenance 
Procedure 
Day 0 dosing 
Day 1 
Day 7 
Day 14 
Day 0 
dosing 
Day 7 
Day 14 
 
INT230-6 dosing  
every 9 weeks +/- 10 days 
repeat every 28 days for each cycle 
Serum sample for pharmacokinetics 
X 
X 
X 
 
X 
X 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
 
Footnotes are shown after Table 13


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Intensity Therapeutics Confidential Information 
Table 12: 
Schedule of events every 14 day dosing (monotherapy E cohorts) 
Cycle1 (+/- 1 Day) 
 
Cycle 2 (+/- 1 Day) 
Cycle 3 (+/- 1 Day) 
Maintenance 
Procedure 
Day 0 
dosing 
Day 
1 
Day 
7 
Day 
14 
Day 
21 
Day 0 
dosing 
 
Day 
7 
Day 
14 
Day 
21 
Day 
0 
Day 
7  
Day 
14 
 
Every 9 weeks +/- 10 days 
 
Safety Assessments 
Physical Examination  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Targeted Physical Examination2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight3 
X 
 
 
 
 
X 
 
 
 
X 
 
 
X 
Vital Signs4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assessment of Signs and 
Symptoms 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory Tests5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test6 
X 
X 
 
X 
X 
 
X 
 
X 
ECOG Performance status7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
US/CT of injected tumor8 
X 
X 
 
X 
X 
 
X 
 
X 
Tumor imaging (CT/MRI 
chest/abdomen/pelvis)9, 10, 11 
X11 
 
 
 
 
 
 
 
 
 
 
X9, 10 
Additional blood or radiographic 
measures clinically indicated12 
X 
 
 
 
 
X 
 
 
 
X 
 
 
X 
Clinical Drug Supplies 
X 
X 
 
X 
X 
 
X 
 
X 
Dispense Study Treatment 
X 
X 
 
X 
X 
 
X 
 
X 


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Table 12: 
Schedule of events every 14 day dosing (monotherapy E cohorts) 
Cycle1 (+/- 1 Day) 
 
Cycle 2 (+/- 1 Day) 
Cycle 3 (+/- 1 Day) 
Maintenance 
Procedure 
Day 0 
dosing 
Day 
1 
Day 
7 
Day 
14 
Day 
21 
Day 0 
dosing 
 
Day 
7 
Day 
14 
Day 
21 
Day 
0 
Day 
7  
Day 
14 
 
Every 9 weeks +/- 10 days 
Vital Status 
 
 
 
 
X 
On study biopsy13 
X 
 
X 
 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Anti-Cancer medications 
 
 
 
 
 
 
 
 
 
 
 
 
X 
  ECG14 if medically indicated 
X 
 
 
 
 
Footnotes are shown after Table 13 


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Intensity Therapeutics Confidential Information  
 
 
 Table 13: 
Schedule Follow up Period 
 
End of Treatment1,  
Long Term 
Follow Up 
(every 9 weeks 
from last 
cycle) 
End of Follow 
Up  
(Subject has PD 
and moves to 
Survival FU) 
Survival Follow 
Up 
Targeted PE2 
X 
X 
X 
 
Weight3 
 
 
 
 
Vital signs4 
X 
X 
X 
 
Assessment of SXS 
X 
X 
 
 
Adverse Events 
X 
X 
 
 
Laboratory Tests5 
X 
 
 
 
Pregnancy test6 
X 
 
 
 
ECOG7 
X 
 
 
 
Tumor imaging9 10 
 
X 
X 
 
Additional blood or 
radiologic assessment11, 
as applicable12 
X 
X 
 
 
Vital status 
 
 
 
X 
Con meds 
X 
X 
X 
 
Report any subsequent 
anti-cancer therapy 
 
 
X 
X 
1 EOT visit to be completed when a subject withdraws from treatment and is not going to proceed to additional cycles of 
treatment. 
2 Physical examination to be conducted and any new or worsening signs and symptoms are to be recorded. 
3 Height/weight to be taken at baseline must be collected at these times as well, and then only repeat weights at the start of each 
cycle. 
4 O2 saturation and resting blood pressure.  On the day of each injection, vital signs will be obtained before injection and then 15, 
30 and 60 minutes post injection.  In addition, for cycle 1, vital signs will be collected at 180 and 360 minutes, including O2 
saturation, and resting blood pressure.   
5  CBC with Differential, Chemistry and Urinalysis as outlined in Section 12.1.2.   Grade 3 laboratory abnormality should be 
assessed for potential risk to continued dosing.  In the event of uncertainty, the Sponsor medical monitor should be contacted.> 
Grade 3 laboratory abnormality should be assessed for potential risk to continued dosing.   
6 Serum or urine pregnancy testing must be performed for woman of childbearing potential and found to be negative before 
dosing. 
7 ECOG performance status to be assessed before each injection. 
8 Measurements used to guide placement of the needle for injection.   
9 The same technique (CT/MRI or PET/CT) used at screening should be used throughout the study. 
10 Investigators will assess tumor response using CT/MRI or PET/CT measurements.   Assessments should occur 12 weeks +/- 
10 days from the first dose (Cycle 1, D0) and then every 9 weeks +/- 10 days for every image thereafter.   
11 Tumor imaging only needs to be collected if it has not occurred within the last 29 days. 
12 Serum based disease markers if appropriate will be collected at the same timepoints as tumor imaging. Other imaging to be 
collected as clinically indicated (i.e., brain scans, etc.).  
13 Subjects must consent to fresh repeat biopsies of tumors taken prior to dosing on days 0 and 28 (day 0 in cycle 2) during the 
course of the study at injection sites are mandatory unless cleared by the Sponsor medical monitor. Additionally, 1 biopsy of an 
untreated bystander tumor that is readily accessible without the need for general anesthesia should be taken by the attending 
physician if possible; however, if risk too high such bystander biopsy should not be taken.  The post-dose biopsy sample must 
be taken from the same lesion(s) that were collected at pre-dose (C1D0). If there is an issue that precludes the ability to 
biopsy the same pre-dose lesion at the later timepoint (C2D0), please inform the Medical Monitor and attempt to biopsy 
from the pre-dose lesions during a subsequent visit. 
14 Baseline ECG to be done and repeated only if medically indicated throughout the study.


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12.1.4. 
Follow-up Period 
Follow-up visits will be conducted after completion of the Treatment Period (induction and maintenance for 
those cohorts with maintenance treatment) or as indicated in Section 5.4.  Patients who receive all 5 
treatment doses or discontinue treatment for any reason except Disease Progression, or Withdrawal of 
consent should enter Long Term Follow up Period.  These patients are to be evaluated every 9 weeks 
including scans until disease progression or they receive an intervening anti-cancer medication.  After 
documented disease progression or receipt of an intervening anti-cancer medication, patients will enter 
Survival Follow up.  During this time, patients will be contacted every 3 months for patient status (phone call 
or clinic visit).  For subjects who discontinue treatment due to progression, follow-up should be completed 
approximately every 3 months as noted below (survival follow up). Completion of subsequent follow-up 
visits will depend on the status of the subject at the end of treatment. All subjects will be followed from the 
last visit until progression, initiation of a new therapy, or the duration of the study (4 years), whichever 
occurs first.  
Following completion of the treatment and follow-up periods, all subjects will be followed for survival after 
completion of treatment phases and through the follow up period of the protocol.  Subjects will have their 
survival status assessed approximately every 3 months by either a telephone, in-person contact, or chart 
review until study completion or termination by the Sponsor.  No other data (e.g., subsequent therapies, 
performance status etc.) beyond survival will be collected during these calls/visits. 
12.1.5. 
Study Participation 
Each subject will have their study participation documented, including the number of cycles completed, the 
duration of the Follow-up Period, and if discontinuing from the study, the reason for discontinuation.  At the 
end of each cycle, the subject continuation status for each subject will be documented on the CRF. 
If for any reason, either study treatment or observations were discontinued, the reason will be recorded.  The 
primary reasons for discontinuation will be documented: 
• Adverse event(s) 
• Protocol violation 
• Disease progression (clinical or radiological) 
• Subject withdrew consent 
• Subject is lost to follow-up 
• Death 
• Other 
Subjects who discontinue from the study should be followed until resolution and/or stabilization of any 
adverse event.  All subjects who discontinue from the study should complete Follow-up Visits to be 
monitored for 28 days following the last dose of INT230-6 for the occurrence of study drug-related adverse 
events or other clinically significant adverse event.  Subjects who are unable to complete the follow-up visits 
should be contacted at least once within 28 days following the last dose INT230-6. 
 
 
 
 


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12.1.6. 
Discontinuation of Subjects from Treatment 
Subjects MUST discontinue investigational product (and non-investigational product at the discretion of the 
investigator) for any of the following reasons: 
• Withdrawal of informed consent (subject’s decision to withdraw for any reason) 
• Any clinical adverse event (AE), laboratory abnormality or intercurrent illness which, in the 
opinion of the investigator, indicates that continued participation in the study is not in the best 
interest of the subject 
• Pregnancy 
• Termination of the study by Sponsor 
• Loss of ability to freely provide consent through imprisonment or involuntarily incarceration 
• for treatment of either a psychiatric or physical (e.g., infectious disease) illness 
• Inability to comply with protocol 
• Discretion of the investigator 
• Disease progression or clinical deterioration as defined in Section 9.3   
• Dosing delays greater than the maximum allowed dosing delays as defined in Section 8.11.  All 
subjects who discontinue should comply with protocol specified follow-up procedures as outlined 
in Section 12.1.4.  The only exception to this requirement is when a subject withdraws consent for 
all study procedures or loses the ability to consent freely (i.e., is imprisoned or involuntarily 
incarcerated for the treatment of either a psychiatric or physical illness). 
12.1.7. 
Safety Evaluations 
The following evaluations will be performed during the study to measure the safety and tolerability of 
INT230-6: clinical laboratory tests (blood and urine sampling for clinical laboratory parameters see below), 
pregnancy testing, ECOG performance status, physical examinations including vital sign measurements, 
ECG, and the incidence and severity of treatment-emergent adverse events.  
Hematology 
Hematology analyses will consist of the following tests:  
Hemoglobin 
Mean cell volume 
Hematocrit 
Mean cell hemoglobin 
Red blood cell count 
Mean cell hemoglobin concentration 
 
Platelet count 
White blood cell count (total and differential) 
Coagulation; PT, PTT/aPTT, INR 
 
Clinical Chemistry 


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Clinical chemistry analyses will consist of the following tests:  
Alanine aminotransferase 
Creatine phosphokinase 
Phosphorus 
Albumin 
Creatinine 
Potassium 
Alkaline phosphatase 
Gamma-glutamyl 
transpeptidase  
Glucose  
Lactate dehydrogenase 
Sodium 
Aspartate aminotransferase 
Amylase 
Thyroid Stimulating Hormone 
Total bilirubin 
Bicarbonate 
Lipase 
Total protein 
Calcium 
 
Triglycerides 
Chloride 
Low density lipoprotein 
Urea (or blood urea nitrogen) 
Cholesterol (total) 
Magnesium 
Uric acid 
Urinalysis 
Urinalysis with microscopic analysis will be performed by the clinical laboratory. Analytes will include: pH, 
glucose, ketones, blood, and protein.  If abnormalities are noted on any of the dipstick results, microscopic 
analysis will be performed. 
12.2. 
Efficacy Evaluations 
 
Measured qualitatively (present only at screening), absent, progression, stable, and unevaluable. 
12.2.1. 
Primary Efficacy Parameter 
The primary efficacy parameter is disease control rate (CR + PR + SD), as assessed using iRECIST 
(Appendix 1 Section 18.1).  Per iRECIST criteria, up to 5 target tumors are identified at baseline and 
followed., In this study, a target tumor is a single injected tumor identified at baseline or post baseline, and 
up to 10 target tumors will be followed.  Please refer to the Statistical Analysis Plan for tumor definitions.  
Subject to PI discretion, cohorts EC3, DEC2, FEC and potentially GEC may have any number of tumors 
injected during a given session.  Record as many tumor measurements in the CRF as possible.   
Evaluation of individual injected tumors will take place at every visit, with overall response (Complete, 
Partial, Stable, Progressive, Not Evaluable) adjudicated for each.  ITR calculation could include original 
target tumors, bystander tumors that become injected, and new measurable lesions that are injected.   
12.2.2. 
Additional Efficacy parameters 
An additional efficacy parameter is the injected tumor response (ITR) and bystander tumor response (BTR) 
rate, defined as either the number of injected or non-injected bystander tumors with confirmed CR or PR, 
divided by the total number of injected or bystander tumors identified at baseline.  Tumor response status 
will be assessed using iRECIST response categories for tumors that have not been injected (as detailed in 
Section 18.1).  Up to 9 bystander tumors will be identified at baseline and followed.  Evaluation of individual 
bystander tumors will take place at every visit, with overall response (Complete, Partial, Stable, Progressive, 


Protocol IT-01 Version Amendment 6 
 
 
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Intensity Therapeutics Confidential Information 
Not evaluable) adjudicated for each.  BTR calculation will only include bystander tumors that are not 
injected at that visit.   
An exploratory analysis will combine all efficacy measures (injected and bystander) to calculate an overall 
response rate (ORR) using iRECIST criteria, with the modification to allow more than 5 target tumors in the 
calculation of sum of diameters. The ORR will be based on the number of subjects with confirmed CR or 
PR, divided by the total number of subjects with measurable disease at baseline.   
 
12.2.3. 
Exploratory Biomarkers of Immune Response 
Additional sample collections efficacy may be performed to measure the impact of INT230-6 upon the 
potency of the immune response and evaluate biomarkers that may ultimately be associated with beneficial 
clinical responses (refer to PK and Biomarker Manual for additional information on biopsies). 
Samples (including serum and PBMCs) for evaluation of cytokines, lymphocyte phenotype (by flow 
cytometry), quantitative immunoglobulins, disease-related biomarkers (or antibody responses to selected 
antigens), cellular immune responses to tumor antigens, and a panel of recall non-tumor antigens may be 
assessed. 
Available slides and tissue samples from tumor biopsies collected before enrollment in this study may also 
be examined for tumor markers and inflammatory infiltrates. 
Readily accessible tissue from the research-related biopsies will be collected at baseline and then on study 
(refer to PK and Biomarker Manual for additional information).  Tissue samples from these tumor biopsies, 
as well as from any other clinically indicated and consented biopsies conducted during the study will be 
collected, to assess morphology and the presence or absence of inflammatory infiltrates, and their cellular 
characterization. 
Additional sample collections and analyses may be performed at selected study sites with a site-specific 
amendment.  All samples collected for these exploratory analyses will be stored and may be used for 
subsequent research relevant to tumor immune response. 
Blood biomarkers collections have been eliminated in Amendment 6. 
The following table is a summary of the samples to be collected.  
 
 


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Table 14: 
Tumor Biopsy and Genetic Sample collection 
Blood biomarkers collections have been eliminated in Amendment 6. 
Collection timing 
Tumor Biopsy 
Whole Blood  
Gene Expression 
Whole Blood  
SNP 
Screening 
 
X 
X 
Cycle 1, Day 0 (prior to 
treatment) 
X1 
 
 
Cycle 2, Day 0  
(prior to treatment)  
X1 
 
 
 
1Following the completion of 20 subjects through at least 3 treatment cycles each with a minimum of 10 subjects having had deep 
tumors injections and review by the SSC of the safety, a biopsy may to be taken immediately prior to injection of INT230-6 (refer 
to PK and Biomarker Manual for additional information).  Safety of biopsying to be reviewed after 5 subjects by SSC. As of this 
amendment, safety has been demonstrated, and all subjects will have tumor biopsies. 
 
12.3. 
Pharmacokinetic Evaluations 
12.3.1. 
Sample Collection Volumes and Timepoints 
PK sampling has been discontinued in Amendment 6.  The SSC has eliminated dose escalation in 
Amendment 5.  Most recent PK data shows that only 5% of the active ingredients for a given dose are 
present in the blood and the concentrations show a meaningful dose response.  As a result, the SSC 
determined that PK sample collection is no longer necessary in Amendment 6.  A final PK analysis section 
will be included in the final clinical study report.   


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13. 
ADVERSE EVENT REPORTING 
Clinical adverse events occurring after signing informed consent/HIPAA authorization, but before study drug 
administration are to be recorded on the Medical History/Current Medical Conditions CRF. 
 
13.1. 
Definitions 
An adverse event is any undesirable sign, symptom, clinically significant laboratory abnormality, or medical 
condition occurring after starting study treatment, even if the event is not considered to be study drug-related. 
Each adverse event is to be reported on an Adverse Event CRF page.  Adverse events are graded using the 
Cancer Therapy Evaluation Program (CTEP) CTCAE, Version 4.03.  If CTCAE grading does not exist for 
an adverse event, the severity of mild (1), moderate (2), severe (3), life-threatening (4), and death related to 
an adverse event (5) will be used. Information about all adverse events, whether volunteered by the subject, 
discovered by Investigator questioning, or detected through physical examination, laboratory testing, or other 
means, will be collected, and recorded on the Adverse Event CRF page and followed as appropriate. Adverse 
event monitoring should be continued until adverse event resolution/stabilization (whichever is later).  
Medical conditions/diseases present before the injection of study drug are only considered adverse events if 
they worsen after receiving any study drug.  Clinical events occurring before the administration of study drug 
but after signing the ICF and providing HIPAA authorization are to be recorded on the Medical 
History/Current Medical Conditions CRF page.  All laboratory values are to be reviewed by the Investigator 
and abnormal values will be graded according to CTCAE Version 4.03 and reported in the study report. 
A laboratory abnormality is considered an adverse event if it results in: 
• discontinuation from study drug, 
• necessitates therapeutic medical intervention, 
• if the Investigator assesses the abnormality as an adverse event, or 
• any laboratory test that is clinically significant or meets the definition of a SAE 
It is expected that wherever possible, the clinical, rather than the laboratory term would be used by the 
reporting investigator (e.g., anemia versus low hemoglobin value).  These adverse events will be recorded on 
the Adverse Events CRF page and will include all signs, symptoms, or diagnosis associated with them. 
As far as possible, each adverse event will also be described by: 
1. Description 
2. Duration (start and end dates) 
3. CTCAE Grade 1 through 5 or severity if CTCAE is not available 
4. Relationship to the study drug - related or not related 
5. Relationship to the dosing procedure – related or not related 
6. Action(s) taken with study drug 
7. Whether event was serious 
8. Whether event is ongoing (i.e., not resolved). 
 


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Relationship to Study Drug 
The relationship of each adverse event to study drug will be defined as “not related” or “related”.  The 
Investigator is responsible for determining the study drug relationship for each adverse event that occurs 
during the study.  Assessments are to be recorded on the appropriate CRF page. 
 
Not related 
The temporal relationship of the clinical event to study drug administration makes a causal relationship 
unlikely, or other drugs, therapeutic interventions or underlying conditions provide a sufficient explanation 
for the observed event. 
 
Related 
The temporal relationship of the clinical event to study drug administration makes a causal relationship 
possible, and other drugs, therapeutic interventions or underlying conditions do not provide a sufficient 
explanation for the observed event. 
 
Action(s) Taken 
The actions taken with study drug in response to an adverse event are described.  One or more of these are to 
be selected: 
− No action taken 
− Study drug permanently discontinued due to this adverse event 
− Study drug temporarily interrupted 
− Study drug dosage adjusted 
13.1.1. 
Safety Reporting for Adverse Events 
All adverse events or other clinically relevant adverse events occurring up to 28 days after administration of 
the last dose of study drug will be collected for subjects continuing in the study. 
For subjects who discontinue from the study within 28 days after the administration of the last dose of study 
drug: 
• Study drug-related adverse event information will be collected and should be followed to 
resolution/stabilization 
• Adverse events that lead to the discontinuation should be followed to resolution/stabilization 
• A telephone contact for the safety update would be acceptable if the subject cannot manage an 
office visit 
• Only study drug-related serious or other clinically significant adverse events will be collected for 
all subjects > 28 days after the administration of the last dose of study drug. 
 
A nonserious adverse event is an AE not classified as serious. 


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The collection of nonserious AE information should begin at initiation of study drug (day 0) and should 
conclude 28 days after last dose of study drug.  Nonserious AEs should be followed to resolution or 
stabilization, or reported as SAEs if they become serious (see Section 13.2).  Follow-up is also required for 
nonserious AEs that cause interruption or discontinuation of study drug, or those that are present at the end 
of study treatment as appropriate.  All identified nonserious AEs must be recorded and described on the 
nonserious AE page of the CRF. 
 
13.2. 
Serious Adverse Events  
A serious adverse event is defined in general as an untoward (unfavorable) adverse event which: 
1. is fatal or life-threatening (defined as an event in which the subject was at risk of death at the time of 
the event; it does not refer to an event which hypothetically might have caused death if it were more 
severe); 
2. requires or prolongs hospitalization; 
3. is significantly or permanently disabling or incapacitating; 
4. constitutes a congenital anomaly or a birth defect; or 
5. may jeopardize the subject and may require medical or surgical intervention to prevent one of the 
outcomes listed above.  (Examples of such events include, but are not limited to, intensive treatment 
in an emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do 
not result in hospitalization.) 
 
Suspected transmission of an infectious agent (e.g. any organism, virus or infectious particle, pathogenic or 
non-pathogenic) via the study drug is a SAE. 
Although pregnancy, overdose (greater than 50% more than the intended dose) and cancer are not always 
serious by regulatory definition, these events must be reported to the Sponsor within 24 hours (See 
Section 13.5 for reporting pregnancies). 
NOTE: Progressive disease is not considered a SAE. 
The following hospitalizations are not considered SAEs in Sponsor clinical studies: 
• a visit to the emergency room or other hospital department < 24 hours, that does not result in 
admission (unless considered "important medical event" or event life threatening) 
• elective surgery, planned prior to signing consent 
• admissions as per protocol for a planned medical/surgical procedure 
• routine health assessment requiring admission for baseline/trending of health status (e.g. routine 
colonoscopy) 
• medical/surgical admission for purpose other than remedying ill health state and was planned 
prior to entry into the study.  Appropriate documentation is required in these cases. 


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• admission encountered for another life circumstance that carries no bearing on health status and 
requires no medical/surgical intervention (e.g., lack of housing, economic inadequacy, care-giver 
respite, family circumstances, administrative). 
• Hospitalizations occurring under the following circumstances are not considered serious adverse 
events: admission to a hospice for respite care; hospitalizations planned before entry into the 
clinical study; hospitalization for elective treatment of a condition unrelated to the studied 
indication or its treatment; hospitalization on an emergency, outpatient basis that does not result 
in admission (unless fulfilling the criteria above); hospitalization as part of the normal treatment 
or monitoring of the studied indication; or hospitalization to facilitate the work up of a Grade 1 
adverse event, including overnight hospitalization following study drug administration for 
nonmedical reasons. 
 
13.3. 
Rapid Notification of Serious Adverse Events 
13.3.1. 
Reporting Responsibility 
Any serious adverse event occurring in a subject after he/she has provided informed consent and HIPAA 
authorization, and while receiving study treatment; or during the 28 days following study drug 
administration; or within 28 days of the last visit for screen failures must be reported. 
The timeframe for reporting after discontinuation of study drug may be extended if there is a strong 
suspicion that the study drug has not yet been eliminated or the pharmacodynamic effects of the study drug 
persist beyond 28 days.  All serious adverse events must also be reported for the timeframe in which the 
study drug interferes with the standard medical treatment given to a subject. 
The investigator should collect any SAE occurring after these time periods that is believed to be related to 
study drug or protocol-specified procedure.  A SAE report should be completed for any event where doubt 
exists regarding its status of seriousness. 
If the investigator believes that a SAE is not related to study drug, but is potentially related to the conditions 
of the study (such as withdrawal of previous therapy, or a complication of a study procedure), the 
relationship should be specified in the narrative section of the SAE Report Form. 
Each serious adverse event must be reported by the Investigator to Propharma (SAE Reporting FAX 919-
844-6948), or designee, within 24 hours of learning of its occurrence, even if it is not felt be related to study 
drug. Serious adverse events occurring after 28 days from the last dose of INT230-6 must be reported if 
deemed related to study drug.  The report must include the adverse event term, subject identifier, attribution, 
description, concomitant medication used to treat the adverse event, and any other relevant information.  
Follow-up information about a previously reported serious adverse event must also be reported to Sponsor 
within 24 hours of receiving the information.  Sponsor, or its designee, may contact the Investigator to obtain 
further information about a reported serious adverse event.  If warranted, an Investigator Alert may be issued 
to inform all Investigators involved in any study with the same study drug that a serious adverse event has 
been reported. 
13.3.2. 
Reporting Procedures 
The Investigator must complete the Serious Adverse Event Report Form in English, assess the causal 
relationship to study drug, and send the completed form to the SAE Reporting FAX Number (919-844-


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6948) within 24 hours, to Sponsor or its designee.  The study monitor will review the Serious Adverse Event 
Report Form and the supporting source documents during monitoring visits. 
Follow-up information should be sent to the same SAE Reporting Fax Number that received the original 
Serious Adverse Event Form, within 24 hours of the time the information is known.  Either a new Serious 
Adverse Event Report Form is faxed (indicating that the information is a follow-up), or the original form 
may be re-faxed (with the new information highlighted and a new date provided).  The follow-up report 
should describe whether the serious adverse event has resolved or is continuing, if and how it was treated, 
and whether the subject continued or permanently discontinued study participation.  The form(s) and FAX 
confirmation sheet(s) must be retained in the investigational site study file. 
The Investigator is responsible for informing the Institutional Review Board/Independent Ethics 
Committee/Review Ethics Board (IRB/IEC/REB) of the serious adverse event and providing them with all 
relevant initial and follow-up information about the event.  Sponsor or designee will communicate serious 
adverse events to the study sites as required by regulatory authorities. 
SAEs must be recorded on the Sponsor SAE Report Form; pregnancies on a Sponsor Pregnancy Surveillance 
Form.  These original Sponsor Forms are to remain on site.  SAEs, whether related or not related to study 
drug, and pregnancies must be reported to Sponsor within 24 hours via confirmed facsimile (fax) 
transmission, or scanned and reported via electronic mail to: 
 
SAE Email Address:  clinicalsafety@propharmagroup.com 
SAE Facsimile Number: 919-844-6948 
 
If only limited information is initially available, follow-up reports are required.  (Note: Follow-up SAE 
reports should include the same investigator term(s) initially reported.)  If an ongoing SAE changes in its 
intensity or relationship to study drug or if new information becomes available, a follow-up SAE report 
should be sent within 24 hours to the Sponsor using the same procedure used for transmitting the initial SAE 
report.  
All SAEs should be followed to resolution or stabilization. 
 
13.4. 
Overdose 
An overdose is defined as the accidental or intentional injection of any excessive dose of INT230-6 (for this 
study it is defined as >50% of the intended dose).  
Any overdose must be recorded in the trial medication section of the CRF.  In the event of overdose of INT230-6, 
subjects should receive appropriate advice and supportive medical care by the investigator or his/her designee and 
be followed-up accordingly.  For monitoring purposes, any case of overdose – whether or not associated with an 
AE (serious or non-serious) – must be reported to the Sponsor in an expedited manner. 
 
13.5. 
Pregnancy 
Pregnancy testing must be performed in all women of childbearing potential throughout the study as 
specified in the Time and Event Schedule table, and the results of all pregnancy tests (positive or negative) 


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are to be recorded on the CRF.  All women of childbearing potential must have a negative pregnancy test 
before each INT230-6 injection.  If the pregnancy test is positive, the subject must not receive INT230-6 and 
must not continue in the study.  The subject will be followed to determine the outcome of the pregnancy. 
Females of non-childbearing potential are defined as females with functioning ovaries with a documented 
history of tubal ligation or hysterectomy or females who are post-menopausal, as defined by 12 months of 
spontaneous amenorrhea with an appropriate clinical profile, e.g., age appropriate, > 45 years, in the absence 
of hormone replacement therapy.  In questionable cases, a blood sample for follicle stimulating hormone and 
estradiol will be obtained to confirm childbearing potential. 
In addition, all women of childbearing potential should be instructed to contact the Investigator immediately 
if they suspect they might be pregnant (e.g., missed or late menstrual period) at any time during the study 
Treatment Period part of the study or during the 60-day period following their last dose of study drug. 
Male subjects should contact the Investigator immediately if they suspect they may have fathered a child 
during the study Treatment Period part of the study or during the 180-day period following their last dose of 
study drug.  When possible, partner’s pregnancies should be followed (to term) to determine the outcome. 
13.5.1. 
Reporting of Pregnancy 
If, following initiation of the investigational product, it is subsequently discovered that a study subject or a 
female partner of a male study participant is pregnant or may have been pregnant at the time of 
investigational product exposure, including during at least 6 half-lives after product administration, the 
investigational product will be permanently discontinued for the female study participant in an appropriate 
manner.  Protocol required procedures for study discontinuation and follow-up must be performed on the 
subject unless contraindicated by pregnancy (e.g. x-ray studies).  Other appropriate pregnancy follow-up 
procedures should be considered if indicated. 
Pregnancies should be reported to Propharma but will not be considered as SAEs.  They will be 
tracked to determine the final outcome of the fetus.  Propharma Pregnancy Questionnaire and 
Outcome forms will be used for this function. If the pregnancy ends in an unfavorable manner (i.e., 
miscarriage, birth defect, etc.), the investigator is responsible for determining if the outcome met SAE 
criteria. 
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal outcome and, 
where applicable, offspring information must be reported on the Pregnancy Surveillance Form.  Infants 
should be followed for a minimum of 8 weeks. 
 
13.6. 
Other Safety Considerations 
Any significant worsening noted during interim or final physical examinations, electrocardiograms, x-rays, 
and any other potential safety assessments, whether or not these procedures are required by the protocol, 
should also be recorded as a nonserious or serious AE, as appropriate, and reported accordingly. 
 


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14. 
STATISTICAL METHODS 
14.1. 
Sample Size Determination 
The sample size (estimated to be between 100 and 175 subjects) during dose escalation and expansion cannot 
be precisely determined but depends on the observed toxicity.   
There are 6 cohorts of subjects in the escalation portion of the protocol where INT230-6 dosing is increased 
over 5 doses.  These escalation cohorts are (A1, B1, EA, EC, EC2 and DEC). 
There are potentially 4 fixed dose cohorts (EC3, DEC2, FEC and G) that use a maximum total fixed dose of 
INT230-6 of 175 mL for all 5 induction doses as well as a maintenance dose.  In EC3, DEC2 and FEC 
expansion cohorts, 10-16 subjects will be treated at fixed INT230-6 doses in a tumor type, to provide 
additional safety information and preliminary assessment of tumor response within a disease indication.  G 
cohort will be a combination of fixed dose INT230-6 with other molecules.  With 16 subjects treated in an 
expansion cohort, at a fixed dose and tumor type the 90% confidence interval for an objective response rate 
would be (5.3% to 42%) if 3 (19%) subjects had a response, (9.0% to 48%) if 4 (25%) subjects had a 
response and (13.2% to 54.8%) if 5 (31%) subjects had a response.  
 
14.2. 
Study populations 
14.2.1. 
All Enrolled Population 
All subjects who sign informed consent form will be included.  Subject disposition will be tabulated using 
this data set. 
14.2.2. 
All Treated Population 
All subjects who receive at least 1 dose or any partial dose of INT230-6.  This population will be used for 
safety analyses, and primary efficacy analyses. 
14.2.3. 
Pharmacokinetic Data Set 
All available concentration-time data from subjects who receive INT230-6 will be reported.  All available 
derived PK parameter values will be included in the PK data set and reported, but only subjects with 
adequate PK profiles will be included in the summary statistics and statistical analysis. PK sampling has 
been eliminated in Amendment 6. 
14.2.4. 
Response Evaluable Data Set 
Response evaluable subjects will be defined as all subjects who receive at least one dose of INT230-6, have a 
baseline tumor assessment with measurable disease, and one of the following: 1) at least one on-treatment 
tumor evaluation, 2) clinical progression, or 3) death prior to the first on-treatment tumor evaluation. 
14.2.5. 
Exploratory Biomarker (Immune Function and others) Data Set 
All subjects who receive at least one dose of INT230-6 and have at least one measurement for a specific 
marker will be included in the data set for that marker.  All treated subjects with at least one baseline 
measurement will be included in predictive analyses; treated subjects with baseline measurement and at least 
one on treatment measurement will be included in pharmacodynamic assessments. Blood biomarker 
sampling has been eliminated in Amendment 6. 


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14.2.6. 
Retreatment Population 
For cohorts A1, B1, EA, EC, EC2, DEC, those subjects who have completed treatment and have not started 
any subsequent anti-cancer therapy were eligible for retreatment.  Subjects who qualified for re-initiation of 
treatment were evaluated for safety and efficacy based on availability of data.   
 
14.3. 
Statistical Considerations 
Please refer to the Statistical Analysis Plan (SAP). 
14.3.1. 
Demographics and Baseline Characteristics 
Subject demographics and baseline characteristics including age, sex, race, ethnicity, weight, baseline 
disease diagnosis, and medical conditions will be summarized by dose level using descriptive statistics. 
14.3.2. 
Extent of Exposure 
The dose of INT230-6 taken by subjects will be summarized by total dose and number of tumors injected. 
Additional parameters will be summarized, such a reason for study drug interruption and number of tumors 
with drug exuded.  A by-subject listing of treatment exposure will be generated. 
Combination study drugs for cohorts 7 and higher will also be summarized.  Details will be provided in the 
statistical analysis plan.   
14.3.3. 
Tumor Response. 
The primary efficacy endpoint of disease control rate (DCR), defined as the sum of complete, partial and 
stable disease responses divided by the total number of subjects in the efficacy population, will be 
determined per iRECIST criteria for fixed dose and expansion cohorts.  DCR will be tabulated by overall and 
by tumor type. Exploratory analysis will be conducted by cohort, Phase 1 cohorts (monotherapy and PD-1), 
Phase 2 cohorts (monotherapy, PD-1 and CTLA-4), Phase 1 and 2 cohorts (monotherapy and PD-1), tumor 
types, study visit, number of INT230-6 doses, number of cycles of INT230-6 (i.e., retreatment), and number 
of prior lines of therapy.  Since iRECIST methods were not implemented at the time of dose escalation, DCR 
for these cohorts will be analyzed per RECIST v1.1.    
For DCR, exact binomial 95% confidence intervals will be determined by Clopper-Pearson method. Median 
time to response and duration of response will be summarized for those subjects with confirmed responses, 
using Kaplan-Meier method; Progression free survival (PFS) will be similarly summarized. Individual tumor 
measurements, tumor burden and % changes in tumor burden will be listed. Changes in tumor burden will be 
presented graphically. 
14.3.4. 
Concomitant Medication 
Concomitant medications will be coded using the World Health Organization Drug Dictionary (WHODD). 
Concomitant medications will be summarized.  Tabulation will be made with respect to the proportion of 
subjects taking at least 1 concomitant medication for each preferred term during the study.  A listing of 
concomitant medications by subject will be provided. 
14.3.5. 
Safety 
The primary objective is to assess the safety and tolerability of multiple intratumoral doses of INT230-6 in 
subjects with advanced or recurrent malignancies.  This will be assessed by the rate of > grade 3 AEs 


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attributed to study drugs (INT230-6 and others per the appropriate protocol supplement), and study 
procedure, and not the underlying disease.   
Safety Analyses:  
All recorded adverse events will be listed and tabulated by system organ class, preferred term, and coded 
according to version 19.1 of Medical Dictionary for Regulatory Activities (MedDRA). The incidence of 
adverse events will be tabulated and reviewed for potential significance and clinical importance. Vital signs 
and clinical laboratory test results will be listed and summarized. Any significant physical examination (PE) 
findings and results of clinical laboratory tests will be listed. Electrocardiogram (ECG) listings will be 
evaluated by the investigator and abnormalities, if present, will be listed.  
Adverse Events will be summarized for all reported data and by study period: a) up to and including 28 days 
post last dose of initial treatment, and b) from first dose of re-initiation of treatment, for subjects who re-
initiate study therapy while in follow-up, up to 28 days post-dose of the last re-treatment dose.  In order to 
better estimate MTD or toxicity frequency of some events of interest, logistic regression or constrained 
Bayesian estimation may be used to model frequency by INT230-6 dose level for each population arm or 
across population arms when combination of different population arms is deemed appropriate. 
The following safety parameters will be evaluated: 
Adverse Events 
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a pre-existing 
medical condition in a subject or clinical investigation subject administered an investigational (medicinal) 
product and that does not necessarily have a causal relationship with this treatment.  An AE can therefore be 
any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or 
disease temporally associated with the use of investigational product, whether or not considered related to the 
investigational product.  Adverse events can be spontaneously reported or elicited during open-ended 
questioning, examination, or evaluation of a subject.  (In order to prevent reporting bias, subjects should not 
be questioned regarding the specific occurrence of one or more AEs.) 
Following the subject’s written consent to participate in the study, all SAEs, whether related or not related to 
study drug, must be collected, including those thought to be associated with protocol-specified procedures.  
All SAEs must be collected that occur within 28 days of discontinuation of dosing.  The investigator should 
collect any SAE occurring after these time periods that is believed to be related to study drug or protocol-
specified procedure.  A SAE report should be completed for any event where doubt exists regarding its status 
of seriousness.  If the investigator believes that a SAE is not related to study drug, but is potentially related to 
the conditions of the study (such as withdrawal of previous therapy, or a complication of a study procedure), 
the relationship should be specified in the narrative section of the SAE Report Form. 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) to 
categorize a system organ class and a preferred term for each adverse event.  The number of subjects who 
experienced at least 1 adverse event, study drug related adverse event, severe (Grade 3 or above) adverse 
event, serious adverse event, and the number of subjects withdrawn due to adverse events will be 
summarized.  For each system organ class and preferred term, summaries will be made with respect to the 
number and proportion of subjects having at least 1 occurrence of an adverse event during the study, using 
the worst grade reported within a subject.  The incidence of adverse events will be presented overall, by 
system organ class and preferred term, intensity (based on NCI CTCAE Version 4.03), and additional 
grouping by severity and relationship to study drug.  Individual listings of adverse events will be provided. 
DLTs and study drug-related Grade >2 adverse events will be listed individually. 


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Physical Examination 
Abnormal PE findings with onset prior to first dose of study drug will be recorded as medical history. Any 
abnormal or clinically significant findings on or after dosing will be recorded as an adverse event. Clinical 
significance will be determined by the Principal Investigator at each site. 
Individual medical/surgical history will be listed by subject. Individual abnormal or clinically significant PE 
findings after dosing will be recorded as an adverse event and listed separately with AEs. 
 
Vital Signs 
Vital sign measurements and change from baseline will be summarized.  Vital signs include weight, systolic 
blood pressure (SBP), diastolic blood pressure (DBP), body mass index (BMI, derived), heart rate, oxygen 
saturation, and temperature. Individual vital sign measurements will be listed. 
 
ECGs 
ECG data will be read and interpreted locally. Summary statistics of ECG overall interpretation will be 
displayed.  Per subject ECG test results at will be listed. 
Abnormal clinically significant ECG findings on or after informed consent will be recorded as an adverse 
event and displayed with AEs. 
 
Clinical Laboratory Tests 
Clinical laboratory values will be summarized in SI units.  Severity grades will be programmatically 
calculated using standard American Medical Association’s (AMA) laboratory normal ranges [AMA Manual 
of Style, AMA 2009] and the quantitative NCI CTCAE 4.03 criteria (when available for a specific laboratory 
abnormality). Laboratory values considered to be normal by CTCAE criteria, meaning they do not qualify as 
Grade 1-4, will be assigned a severity grade of 0.  
Summary statistics of numerical laboratory test results and changes of test results from baseline will be 
reported for hematology, coagulation, serum chemistry, and urinalysis at each scheduled time point. For 
values with categorical results, the frequency and percentage of each result category will be tabulated at each 
scheduled time point. Shift tables will also be included reporting change from baseline category (low, 
normal, high) to post-dose category (low, normal, high).  Abnormal laboratory values that lead to a change in 
subject management or that are considered to be of clinical significance will be reported as an adverse event 
(serious adverse event if relevant) and summarized by SOC/PT and according to severity in the appropriate 
AE tables.  Clinical significance will be determined by the Principal Investigator at each site. 
Pregnancy test results will be displayed in a listing. 
 
ECOG Performance Status 
ECOG performance status will be summarized using descriptive statistics. ECOG performance status per 
subject during the trial will also be listed. 
 


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14.4. 
Efficacy  
14.4.1. 
Pharmacokinetic Parameters 
The release kinetics of each analyte is not expected to be uniform across subjects. Sponsor shall assess the 
blood concentrations of the three analytes for each subject at the first cycle. Sponsor shall correlate the 
systemic measurement [maximum plasma drug concentration (Cmax), area under the curve (AUC)] of the 3 
analytes to measured markers of systemic toxicity [in particular renal and blood – the known toxicities of the 
two active agents; cisplatin (CIS) & vinblastine (VBL]. Human plasma will be analyzed for the concentration 
of VBL and 8-((2-hydroxybenzoyl)amino)octanoate (sodium salt form) (SHAO) using validated LC/MS/MS 
methods, and for cisplatin using a validated ICP-MS method. For pharmacokinetic profiling platinum drugs, 
total platinum levels in subject plasma or urine are routinely determined by spectroscopy methods as a 
surrogate. Thus, an ICP-MS method is developed for this study to measure total platinum in human samples 
as a surrogate for cisplatin.  
In addition, scatter plots of Cmax and AUCTAU versus INT230-6 dose volume will be provided for the first 
cycle. Dose proportionality per subject normalized to tumor volume will be assessed, by estimating the slope 
of linear regression of SHAO/CIS/VIN log(Cmax) on log(dose) and of log(AUCTAU) on log(dose) based on 
a power model. Point estimates and 90% confidence intervals for the dose proportionality parameter (slope 
of the linear regression) will be calculated for Cmax and AUCTAU. Summary statistics for trough [minimum 
plasma drug concentration Cmin)] concentrations will be tabulated by dose and study cycle. Plots of Cmin 
vs. cycle will be assessed for cohorts by combining A1, B1 versus E Cohorts and grouping subjects by 
similar dose volumes of INT230-6. Pharmacokinetic concentrations from sparse samples will be listed, and 
may be used in combination with other studies for exposure-response or population pharmacokinetic 
modeling, which will be part of a separate report.  
Administrative interim analyses of pharmacokinetic may be provided at various times during the study in 
order to support program decisions or publications.  PK sampling has been eliminated in Amendment 6. 
14.4.2. 
Exploratory Biomarkers (Immune Function and others) 
The pharmacodynamic effects based on the immunomodulatory activity of INT230-6 on selected immune 
cell populations (for example, T-cell repertoire and their changes (or percent changes) on flow cytometry) 
and soluble factors in blood (cytokines), exploratory immune function markers including flow cytometry 
markers, humoral and cellular immune responses to tumor antigens (quantitative immunoglobulins, 
quantitative inflammatory infiltrates, when available) and a panel of recall non-tumor antigens will be 
assessed by summary statistics for outcomes from these markers and their changes (or percent changes) from 
baseline tabulated.  In addition, the time course of biomarker outcomes will be conveyed graphically, by 
summary plots (i.e., box plots) or individual subject plots over time.  Possible associations between changes 
in biomarker measures of interest and pharmacokinetic exposure will be explored.  Possible associations of 
various biomarkers measures (baseline value or change from baseline) with clinical outcome (e.g., tumor 
response) may will be explored based on data availability, using response-evaluable subjects, to assess 
predictive markers in tumors. Methods such as, but not limited to, logistic regression may be used to explore 
such associations. Measures from markers based on optional samples, e.g., tumor-based markers may be 
similarly presented, depending on data availability.  
Potential associations of various biomarker measures (baseline value or change from baseline) with clinical 
outcome (e.g., tumor response or disease control) will be explored e.g., for expression levels of PD-L1 
protein measured by immunohistochemistry techniques in tumor sections at baseline may be explored based 
on data availability, using response-evaluable subjects, to explore assess potential predictive effects of these 


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markers.  Methods such as, but not limited to, logistic regression may be used to further assess such 
associations. 
Measures from markers based on optional samples, e.g., tumor-based markers may be similarly presented, 
depending on data availability.  
Administrative interim analyses of biomarker data may be provided at various times during the study (e.g., 
for the initial and the additional study cohorts) in order to support program decisions or publication. Blood 
biomarker assessments have been eliminated in Amendment 6. 
 


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15. 
ETHICAL ASPECTS 
15.1. 
Ethics and Good Clinical Practice  
This study must be carried out in compliance with the protocol and in accordance with Sponsor and site 
SOPs.  These are designed to ensure adherence to Good Clinical Practice (GCP), as described in the 
International Conference on Harmonization (ICH) Harmonized Tripartite Guidelines for GCP 1996 and in 
accordance with the ethical principles underlying European Union Directive 2001/20/EC and the United 
States Code of Federal Regulations, Title 21, Part 50 (21CFR50) and Title 21, Part 312 (21CFR312). 
The protocol and any amendments and the subject informed consent will receive Institutional Review 
Board/Independent Ethics Committee/Review Ethics Board (IRB/IEC/REB) approval/favorable opinion 
before initiation of the study.  Study personnel involved in conducting this study will be qualified by 
education, training, and experience to perform their respective tasks.  This study will not use the services of 
study personnel where sanctions have been invoked or where there has been scientific misconduct or fraud 
(e.g., loss of medical license, debarment). 
All potential serious breaches must be reported to Sponsor immediately. A serious breach is a breach of the 
conditions and principles of GCP in connection with the study or the protocol, which is likely to affect, to a 
significant degree, the safety or physical or mental integrity of the subjects of the study or the scientific value 
of the study. 
 
15.2. 
Confidentiality Regarding Study Subjects 
Investigators must assure that the privacy of subjects, including their personal identity and all personal 
medical information, will be protected at all times, as required by law. In CRFs and other study documents 
submitted to Sponsor or its designee, subjects will be identified by their initials, subject number, date of 
birth, and gender. 
Personal medical information may be reviewed and/or copied for research, quality assurance, and/or data 
analysis. This review may be conducted by the study monitor, properly authorized persons on behalf of 
Sponsor, an independent auditor, IRBs/IECs or regulatory authorities. Personal medical information will 
always be treated as confidential. 
 
15.3. 
Institutional Review Board/Independent Ethics Committee/Review Ethics 
Board 
Before implementing this study, the protocol, the proposed ICF, and other information provided to subjects 
must be reviewed by an IRB/IEC/REB. A signed and dated statement that the protocol, and ICF, subject 
recruitment materials/process (e.g., advertisements), and any other written information to be provided to 
subjects have been approved by the IRB/IEC must be given to Sponsor before study initiation. The name and 
occupation of the chairperson and the members of the IRB/IEC (preferred) or the IRB’s Health and Human 
Safety Assurance number must be supplied to Sponsor or its designee. Any amendments to the protocol 
which need formal approval, as required by local law or procedure, will be approved by this committee. The 
IRB/IEC will also be notified of all other administrative amendments (i.e., administrative changes). 
The investigator or sponsor should also provide the IRB/IEC with a copy of the Investigator Brochure or 
product labeling, information to be provided to subjects and any updates. 


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The investigator or sponsor should provide the IRB/IEC with reports, updates and other information (e.g. 
expedited safety reports, amendments and administrative letters) according to regulatory requirements or 
institution procedures. 
 
15.4. 
Informed Consent 
Investigators must ensure that subjects, or, in those situations where consent cannot be given by subjects, 
their legally acceptable representatives, are clearly and fully informed about the purpose, potential risks, and 
other critical issues regarding clinical studies in which they volunteer to participate. 
The Investigator, or designee, will explain to each subject (or legally authorized representative) the nature of 
the research study, its purpose, the procedures involved, the expected duration of subject participation, 
alternative treatment, potential risks and benefits involved, and any discomfort which may occur during the 
subject’s participation in the study. Each subject will be informed that participation in the study is voluntary 
and that he/she may withdraw from the study at any time and that withdrawal of consent will not affect 
his/her subsequent medical treatment or relationship with the treating physician. 
This informed consent should be given by means of a standard written statement, written in nontechnical 
language. The subject should read and consider the statement before signing and dating it and should be 
given a copy of the signed document. No subject can enter the study and no study-related procedures can be 
done before his/her informed consent has been obtained. 
The ICF must be submitted by the Investigator with the protocol for IRB/IEC approval. Sponsor supplies a 
proposed ICF template that complies with regulatory requirements, includes all elements required by ICH, 
GCP and applicable regulatory requirements, and is considered appropriate for the study. The sample 
informed consent form will adhere to the ethical principles that have their origin in the Declaration of 
Helsinki. Any changes to the proposed ICF suggested by the Investigator must be agreed to by Sponsor or its 
designee before submission to the IRB/IEC, and a copy of the approved version must be provided to the 
Sponsor study monitor after IRB/IEC approval. 
 
Investigators must: 
1. Provide a copy of the consent form and written information about the study in the language in which 
the subject is most proficient prior to clinical study participation. The language must be non-technical 
and easily understood. 
2. Allow time necessary for subject or subject's legally acceptable representative to inquire about the 
details of the study. 
3. Obtain an informed consent signed and personally dated by the subject or the subject's legally 
acceptable representative and by the person who conducted the informed consent discussion. 
4. Obtain the IRB/IEC’s written approval/favorable opinion of the written informed consent form and 
any other information to be provided to the subjects, prior to the beginning of the study, and after any 
revisions are completed for new information. 
5. If informed consent is initially given by a subject’s legally acceptable representative or legal 
guardian, and the subject subsequently becomes capable of making and communicating their 
informed consent during the study, then consent must additionally be obtained from the subject. 


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6. Revise the informed consent whenever important new information becomes available that is relevant 
to the subject's consent. The investigator, or a person designated by the investigator, should fully 
inform the subject or the subject's legally acceptable representative or legal guardian, of all pertinent 
aspects of the study and of any new information relevant to the subject's willingness to continue 
participation in the study. This communication should be documented. 
 
The consent form must also include a statement that Sponsor and regulatory authorities have direct access to 
subject records. 
Subjects unable to give their written consent (e.g., stroke subjects, or subjects with severe dementia) may 
only be enrolled in the study with the consent of a legally acceptable representative. The subject must also be 
informed about the nature of the study to the extent compatible with the subjects’ understanding, and should 
they become capable, personally sign and date the consent form as soon as possible. The explicit wish of a 
subject unable to give his or her written consent, who is capable of forming an opinion and assessing this 
information to refuse participation in, or to be withdrawn from, the clinical study at any time should be 
considered by the investigator. 
The rights, safety, and well-being of the study subjects are the most important considerations and should 
prevail over interests of science and society. 
 


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16. 
ADMINISTRATIVE REQUIREMENTS 
16.1. 
Protocol Amendments 
Any change or modification to this protocol requires a written protocol amendment that must be approved by 
Sponsor before implementation. Amendments significantly affecting the safety of subjects, the scope of the 
investigation, or the scientific quality of the study require additional approval by the IRB/IEC of all centers 
and, in some countries, by the regulatory authority. A copy of the written approval of the IRB/IEC must be 
given to the Sponsor study monitor, or their designee. Examples of amendments requiring such approval are: 
1. Increase in drug dosage or duration of exposure of subjects, or any significant increase in the 
number of subjects under study; 
2. Significant change in the study design (e.g., addition or deletion of a control group); 
3. Increase in the number of procedures to which subjects are exposed; or 
4. Addition or deletion of a test procedure intended to improve safety monitoring. 
 
These requirements for approval should in no way prevent any immediate action from being taken by the 
Investigator or by Sponsor in the interests of preserving the safety of all subjects included in the study. If an 
immediate change to the protocol is felt by the Investigator to be necessary and is implemented by him/her 
for safety reasons, Sponsor should be notified and the IRB/IEC for the center should be informed within 1 
working day. Any significant deviation must be documented in the CRF. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) prior to obtaining 
IRB/IEC approval/favorable opinion, as soon as possible the deviation or change will be submitted to: 
− IRB/IEC for review and approval/favorable opinion 
− Sponsor 
− Regulatory Authority(ies), if required by local regulations 
− Documentation of approval signed by the chairperson or designee of the IRB(s)/IEC(s) must 
be sent to Sponsor. 
 
If an amendment substantially alters the study design or increases the potential risk to the subject: (1) the 
consent form must be revised and submitted to the IRB(s)/IEC(s) for review and approval/favorable opinion; 
(2) the revised form must be used to obtain consent from subjects currently enrolled in the study if they are 
affected by the amendment; and (3) the new form must be used to obtain consent from new subjects prior to 
enrollment. 
If the revision is an administrative letter, investigators must inform their IRB(s)/IEC(s). Amendments 
affecting only administrative aspects of the study do not require formal protocol amendments or IRB/IEC 
approval; however, the IRB/IEC for each center must be kept informed of such administrative changes. 
Examples of administrative changes not requiring formal protocol amendments and IRB/IEC approval that 
can be treated as administrative amendments include, but are not limited to: 
1. Changes in the staff used to monitor studies (e.g. Sponsor staff versus a contract research 
organization); and 


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2. Minor changes (within regulatory guidelines) in the packaging or labeling of study drug. 
 
16.2. 
Monitoring Procedures 
Before study initiation, at a site initiation visit or at an Investigator’s meeting, a Sponsor representative will 
review the protocol, CRFs, and other study documents with the Investigators and their staff. During the 
study, the Sponsor Study Monitor, or designee, will visit the site regularly to check the completeness of 
subject records, accuracy of entries on the CRFs, adherence to the protocol and to GCP, progress of 
enrollment, and also to ensure that study drug is being stored, dispensed, and accounted for according to 
specifications. 
The Investigator must give the study monitor access to relevant hospital or clinical records to confirm their 
consistency with the CRF entries. No information in these records about the identity of the subjects will 
leave the study center. Sponsor monitoring standards require full verification for the presence of informed 
consent, HIPAA authorization, adherence to the inclusion/exclusion criteria, documentation of serious 
adverse events, and recording of efficacy and safety variables. Additional checks of the consistency of source 
data with the CRFs are performed according to the study-specific monitoring plan. 
Representatives of Sponsor must be allowed to visit all study site locations periodically to assess the data 
quality and study integrity. On site they will review study records and directly compare them with source 
documents, discuss the conduct of the study with the investigator, and verify that the facilities remain 
acceptable. 
In addition, the study may be evaluated by Sponsor internal auditors and government inspectors who must be 
allowed access to CRFs, source documents, other study files, and study facilities. Sponsor audit reports will 
be kept confidential. 
The investigator must notify Sponsor promptly of any inspections scheduled by regulatory authorities, and 
promptly forward copies of inspection reports to Sponsor. 
 
16.3. 
Investigational Site Training 
Sponsor and its contracted study management company, Catalyst, will provide quality investigational staff 
training prior to study initiation. Training topics will include but are not limited to: GCP, AE reporting, study 
details and procedure, electronic CRFs, study documentation, informed consent, deep tumor dosing 
procedures and enrollment of WOCBP. 
 
16.4. 
Recording of Data and Retention of Documents 
All information required by the protocol should be provided; any omissions or corrections should be 
explained. All CRFs should be completed and available for collection within a timely manner, preferably no 
more than 10 days after the subject’s visit (except for the last visit of the last subject, which should be 
completed in a timely manner, preferably within 5 working days), so that the study monitor may check the 
entries for completeness, accuracy and legibility, ensure the CRF is signed by the Investigator and transmit 
the data to Sponsor or its designee. 


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The CRF will be completed by the authorized study site personnel. Electronic queries will be used to 
communicate eligible discrepant data with the study sites. 
The Investigator must maintain source documents for each subject in the study. All information on CRFs will 
be traceable to these source documents, which are generally maintained in the subject’s file. The source 
documents will contain all demographic and medical information, including laboratory data, ECGs, etc., and 
also a copy of the signed informed consent/HIPAA authorization, which should indicate the study number 
and title of the study. 
Essential documents, as listed below, will be retained by the Investigator for the maximum period required to 
comply with national and international regulations, or institutional procedures, or for the period specified by 
the sponsor, whichever is longer. Sponsor will notify the Investigator(s)/institution(s) when study-related 
records are no longer required to be retained. The Investigator agrees to adhere to the document retention 
procedures by signing the protocol. The investigator must contact Sponsor prior to destroying any records 
associated with the study. 
If the investigator withdraws from the study (e.g., relocation, retirement), the records shall be transferred to a 
mutually agreed upon designee (e.g., another investigator, IRB). Notice of such transfer will be given in 
writing to Sponsor. 
Essential documents include: 
1. Signed protocol and all amendments; 
2. IRB/IEC approvals for the study protocol and all amendments; 
3. All source documents and laboratory records; 
4. CRF copies; 
5. Subjects’ ICF/HIPAA authorization; and 
6. Any other pertinent study documents. 
16.4.1. 
Study Drug Records 
It is the responsibility of the investigator to ensure that a current disposition record of investigational product 
(those supplied by the sponsor) is maintained at each study site where study drug is inventoried and 
dispensed. Records or logs must comply with applicable regulations and guidelines and should include: 
− amount received and placed in storage area 
− amount currently in storage area 
− label ID number or batch number 
− amount dispensed to and returned by each subject, including unique subject identifiers 
− amount transferred to another area/site for dispensing or storage 
− non-study disposition (e.g. lost, wasted) 
− amount destroyed at study site, if applicable 
− amount returned to the sponsor 
− retain samples for bioavailability/bioequivalence, if applicable 


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− dates and initials of person responsible for Investigational Product (IP) 
dispensing/accountability, as per the Delegation of Authority Form. 
The sponsor will provide forms to facilitate inventory control if the investigational site does not have an established 
system that meets these requirements. 
16.4.2. 
Case report Forms 
An investigator is required to prepare and maintain adequate and accurate case histories designed to record 
all observations and other data pertinent to the investigation on each individual treated or entered as a control 
in the investigation. Data reported on the CRF that are derived from source documents must be consistent 
with the source documents or the discrepancies must be explained. 
Electronic CRFs will be prepared for all data collection fields except for fields specific to SAEs and 
pregnancy, which will be reported on the SAE form and Pregnancy Surveillance form, respectively. Spaces 
may be left blank only in those circumstances permitted by study-specific CRF completion guidelines 
provided by the sponsor. 
The confidentiality of records that could identify subjects must be protected, respecting the privacy and 
confidentiality rules in accordance with the applicable regulatory requirement(s). The investigator will 
maintain a signature sheet to document signatures and initials of all persons authorized to make entries 
and/or corrections on CRFs. 
The completed CRF, must be promptly reviewed, signed, and dated by a qualified physician who is an 
investigator or sub-investigator electronically through the Sponsor’s electronic data capture tool.  
Each individual electronically signing electronic CRFs must meet Sponsor training requirements and must 
only access the Sponsor electronic data capture tool using the unique user account provided by the sponsor. 
User accounts are not to be shared or reassigned to other individuals. 
 
16.5. 
Auditing Procedure 
In addition to the routine monitoring procedures, Sponsor, or its designees, may conduct audits of clinical 
research activities in accordance with internal SOPs to evaluate compliance with the principles of GCP. 
Sponsor, its designee, or a regulatory authority may wish to conduct an inspection (during the study or after 
its completion). If an inspection is requested by a regulatory authority, the Investigator will inform Sponsor 
immediately that this request has been made. 
 
16.6. 
Publication of Results 
Any formal presentation or publication of data collected from this study will be considered as a joint 
publication by the Investigator(s) and the appropriate personnel of Sponsor. Authorship will be determined 
by mutual agreement. For multicenter studies, it is mandatory that the first publication be based on data from 
all centers, analyzed as stipulated in the protocol by Sponsor statisticians, and not by the Investigators 
themselves. Investigators participating in multicenter studies agree not to present data gathered from one 
center or a small group of centers before the full, initial publication, unless formally agreed to by all other 
Investigators and Sponsor. 


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The data collected during this study are confidential and proprietary to the sponsor. Any publications or 
abstracts arising from this study require approval by the sponsor prior to publication or presentation and must 
adhere to the sponsor’s publication requirements as set forth in the approved clinical trial agreement (CTA). 
All draft publications, including abstracts or detailed summaries of any proposed presentations, must be 
submitted to the sponsor at the earliest practicable time for review, but at any event not less than 30 days 
before submission or presentation unless otherwise set forth in the CTA. Sponsor shall have the right to 
delete any confidential or proprietary information contained in any proposed presentation or abstract and 
may delay publication for up to 60 days for purposes of filing a patent application. 
Sponsor must receive copies of any intended communication in advance of submission (at least 30 working 
days for a journal submission and 15 days for an abstract or oral presentation). Sponsor will review the 
communications for accuracy (thus avoiding potential discrepancies with submissions to health authorities), 
verify that confidential information is not being inadvertently disclosed, and provide any relevant 
supplementary information. Authorship of communications arising from pooled data may include members 
from each of the contributing centers, as well as Sponsor personnel. 
 
16.7. 
Disclosure and Confidentiality 
By signing the protocol, the Investigator agrees to keep all information generated in connection with the 
study or provided by Sponsor or its designee in strict confidence and to request similar confidentiality from 
his/her staff and the IRB/IEC. Study documents provided by Sponsor (protocols, Investigators’ Brochures, 
CRFs, and other material) will be stored appropriately to ensure their confidentiality. Such confidential 
information may not be disclosed to others without direct written authorization from Sponsor, except to the 
extent necessary to obtain informed consent/HIPAA authorization from subjects who wish to participate in 
the study. 
16.8. 
Discontinuation of Study 
Sponsor reserves the right to discontinue study for any reason at any time. 
16.9. 
Data Management 
16.9.1. 
Data Collection 
Investigators must enter the information required by the protocol into the Electronic Data Capture (EDC) 
system.  The electronic CRF (eCRF) will be completed by the authorized study site personnel. An electronic 
version of the final eCRF book for each subject will be forwarded to the study sites for record keeping at the 
study site closure. 
16.9.2. 
Database Management and Quality Control 
Data items from the CRFs will be entered into the study database using data entry with verifications. 
Subsequently, the information entered into the database will be systematically checked by Data Management 
staff following Sponsor, or its designee, data management procedures. Obvious errors will be corrected by 
Sponsor personnel, or its designee. Other errors, omissions, or requests for clarification will be queried; 
queries will be returned to the study site for resolution.  After receipt in Data Management, the resolutions 
will be entered into the database. Quality control audits of all key safety and efficacy data in the database 
will be conducted as agreed upon by relevant team members. 


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Data will be entered into the EDC system by the authorized study site personnel. Electronic queries will be 
used to communicate eligible discrepant data with the study sites. 
When the database has been declared to be complete and accurate, the database will be locked. Any changes 
to the database after that time can only be made by joint written agreement of the Sponsor study team. 


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17. 
REFERENCES 
1. Galluzzi L, Buqué A, Kepp O, Zitvogel L, Kroemer G.  Immunological Effects of Conventional 
Chemotherapy and Targeted Anticancer Agents. Cancer Cell. 2015 Dec 14;28(6):690-714. 
2. Rizvi NA, Hellmann MD, Brahmer JR, et al.  Nivolumab in Combination With Platinum-Based 
Doublet Chemotherapy for First-Line Treatment of Advanced Non-Small-Cell Lung Cancer.  J Clin 
Oncol. 2016 Jun 27.  
3. Obeid,M,  Panaretakis,T,  Tesniere,A et al. Leveraging the Immune System during Chemotherapy: 
Moving Calreticulin to the Cell Surface Converts Apoptotic Death from ‘‘Silent’’ to Immunogenic.  
Cancer Res 2007; 67: (17) September 1, 2007. 
4. Lammers, T, Peshke, P, Kuhnlein, R et al.  Effect of Intratumoral Injection on the Biodistribution and 
the Therapeutic Potential of HPMA Copolymer-Based Drug Delivery Systems. Neoplasia 2006: 
8:10:788-795. 
5. Snyder A, Makarov V, Merghoub T, et al.  Genetic basis for clinical response to CTLA-4 blockade in 
melanoma.  Eur J Pharmacol. 2014 October 5; 0: 364–378.  
6. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/125514s034lbl.pdf 
7. Sok, M, Sentjurc, M, Schara, M et al.  Cell membrane fluidity and prognosis of lung cancer.  Ann 
Thorac Surg 2002;73:1567-1571 
8. Product monograph Vinblastine 
9. Dasari, S, and Tchounwou, PB Cisplatin in cancer therapy: molecular mechanisms of action. Eur J 
Pharmacology. 2014 October 5;0:364-378. 
10. Walters, I, Bender, L, Terabe, M et al. INT230-6, a novel intratumoral anticancer agent, is able to 
eradicate large established tumors and stimulate potent anti-tumor immunity.  Cancer Research 2015, 
Volume 75, Issue 15 Supplement Abstract 4295 
11. Bender, L. in vitro report study E237-ITN-02: Preliminary studies to determine the optimal 
procedures to investigate the interaction of penetration enhancers with selected antitumor agents.  
Data on file at Intensity Therapeutics. 
12. Bloom, A, Bender, L, Terabe, M et al. INT230-6 shows strong synergy with anti-PD-1 and can 
induce high complete response rates with T cell memory response in a colon cancer mouse model   
Journal for Immunotherapy of Cancer 2015, 3(Suppl 2):P352  
13. Bright, R, Bright, J. Byrne, J Overexpressed oncogenic tumor-self antigens. Human Vaccines & 
Immunotherapeutics 10:11, 3297--3305; November 2014.
 
 
14. Daud, A, DeConti, R,  Andrews, S et al.  Phase I Trial of Interleukin-12 Plasmid Electroporation in 
Patients with Metastatic Melanoma. J Clin Oncol 2016:26:5896-5903. 
15. Liu, L, Innamarato, PP, Kodumudi,K et al.  Oncotarget, 9247, May 2016. 
16. Thompson Poster from HemOnc Today Melanoma and Cutaneous Malignancies 2015 April 10-11 
New York. Trials in Progress: Intralesional PV-10 vs Systemic Chemotherapy for Treatment of 
Locally Advanced Cutaneous Melanoma" 
17. Andbacka, RH et. al, Talimogene Laherparepvec Improves Durable Response Rate in Patients With 
Advanced Melanoma.  J Clin Oncol. 2015 Sep 1;33(25):2780-8. doi: 10.1200/JCO.2014.58.3377. 
Epub 2015 May 26.  
18. Bender, L. Determination of the effects of IT-001 and IT-006 on the growth inhibitory activites of 
selected anticancer agents.  In vivo report e238 Colon26 data on file at Intensity Therapeutics. 


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18. 
APPENDICES 
18.1. 
Appendix 1: iRECIST  
18.1.1. 
iRECIST Response Assessment 
Overall response will also be assessed using iRECIST. Immunotherapeutics may result in infiltration of 
immune cells leading to transient increase in the size in malignant lesions, or undetectable lesions becoming 
detectable. The criteria are identical to those of RECIST 1.1 in many respects but have been adapted to 
account for instances where an increase in tumor burden, or the appearance of new lesions, does not reflect 
true tumor progression. 
Key differences are described below. All responses defined using iRECIST criteria are designated with a 
prefix. iRECIST time-point and best overall responses will be recorded separately. 
18.1.2. 
Confirming Progression 
Unlike RECIST 1.1, iRECIST requires the confirmation of progression and uses the terms iUPD 
(unconfirmed progression) and iCPD (confirmed progression). Confirmatory scans should be performed at 
least 4 weeks, but no longer than 8 weeks after iUPD. 
iCPD is confirmed if further increase in tumor burden, compared to the last assessment, is seen as evidenced 
by one or more of the following: 
• Continued increase in tumor burden (from iUPD) where RECIST 1.1 definitions of progression 
had been met (from nadir) in target, non-target disease or new lesions 
o Progression in target disease worsens with an increase of at least 5 mm in the 
absolute value of the sum 
o Continued unequivocal progression in non-target disease with an increase in tumor 
burden 
o Increase in size of previously identified new lesion (s) (an increase of at least 5 mm 
in the absolute value of the sum of those considered to be target new lesions) or 
additional new lesions. 
• RECIST 1.1 criteria are met in lesions types (target or non-target or new lesions) where 
progression was not previously identified, including the appearance of additional new lesions. 
If iUPD is not confirmed at the next assessment, then the appropriate response will be assigned (iUPD if the 
criteria are still met, but no worsening, or iSD, iPR or iCR if those criteria are met compared to baseline). As 
can be seen in Table 15 , the prior documentation of iUPD does not preclude assigning iCR, iPR, or iSD in 
subsequent time-point assessments or as best overall response (BOR) providing that iCPD is not documented 
at the next assessment after iUPD. 
18.1.3. 
New lesions 
New lesions should be assessed and measured as they appear using RECIST 1.1 criteria (maximum of 5 
lesions, no more than 2 per site, at least 10 mm in long axis (or 15 mm in short axis for nodal lesions), and 
recorded as New Lesions-Target (NLT) and New Lesion-Non-Target (NLNT) to allow clear differentiation 
from baseline target and non-target lesions. 
New lesions may either meet the criteria of NLT or NLNT to drive iUPD (or iCPD). However, the 
measurements of target lesions should NOT be included in the sum of measures of original target lesions 


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identified at baseline. Rather, these measurements will be collected on a separate table in the case record 
form. 
PD is confirmed in the New Lesion category if the next imaging assessment, conducted at least 4 weeks (but 
not more than 8 weeks) after iUPD confirms further progression from iUPD with either an increase of at least 
5 mm in the absolute value of the sum of NLT OR an increase (but not necessarily unequivocal increase) in 
the size of NLNT lesions OR the appearance of additional new lesions. 
Table 15: 
Time-point (TP) iResponse Time Point Response (TPR) 
Target Lesions 
Non-Target 
Lesions* 
New 
Lesions* No prior 
iUPD** Prior iUPD**; *** 
iCR 
iCR 
No 
iCR 
iCR 
iCR 
Non-iCR/Non- 
iUPD 
No 
iPR 
iPR 
iPR 
Non-iCR/Non- 
iUPD 
No 
iPR 
iPR 
iSD 
Non-iCR/Non- 
iUPD 
No 
iSD 
iSD 
iUPD with no 
change OR 
decrease from 
last TP 
iUPD 
with 
no 
change
 
O
R decrease from 
last TP 
Yes 
NA 
NLs confirms iCPD if NLs were previously identified and increase in 
size (≥5 mm in SOM for NLT or any increase for NLNT) or number. 
If no change in NLs (size or number) from last TP, remains iUPD 
iSD 
iUPD 
No 
iUPD 
Remains iUPD unless iCPD confirmed based in further increase in 
size of NT disease (need not meet RECIST 1.1 criteria for 
unequivocal PD) 
iUPD 
Non-iCR/Non- 
iUPD 
No 
iUPD 
Remains iUPD unless iCPD confirmed based on: 
o further increase in SOM of at least 5 mm, otherwise remains 
iUPD 
iUPD 
iUPD 
No 
iUPD 
Remains iUPD unless iCPD confirmed based on further increase in: 
o previously identified T lesion iUPD SOM ≥5 mm and / or 
o NT lesion iUPD (prior assessment - need not be unequivocal PD) 
iUPD 
iUPD 
Yes 
iUPD 
Remains iUPD unless iCPD confirmed based on further increase in: 
o previously identified T lesion iUPD ≥5 mm and / or 
o previously identified NT lesion iUPD (need not be unequivocal) 
and /or 
o size or number of new lesions previously identified 
Non- iUPD/PD 
Non-iUPD/PD 
Yes 
iUPD 
Remains iUPD unless iCPD confirmed based on 
o increase in size or number of new lesions previously identified 
* Using RECIST 1.1 principles. If no PSPD occurs, RECIST 1.1 and iRECIST categories for CR, PR and SD would be the 
same. ** in any lesion category. *** previously identified in assessment immediately prior to this TP. 


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All patients will have their iBOR from the start of study treatment until the end of treatment 
classified as outlined below. 
Table 16: 
iRECIST Best Overall Response (BOR) 
TPR1 
TPR2 
TPR3 
TPR4 
TPR5 
iBOR 
iCR 
iCR, 
iPR, 
iUPD, NE 
iCR, iPR, iUPD, NE 
iUPD 
iCPD 
iCR 
iUPD 
iPR, iSD, NE 
iCR 
iCR, iPR, iSD, iUPD, NE 
iCR, iPR, iSD, iUPD, iCPD, NE 
iCR 
iUPD 
iPR 
iPR, iSD, iUPD, NE 
iPR, iSD, iUPD, NE, iCPD 
iPR, iSD, iUPD, NE, iCPD 
iPR 
iUPD 
iSD, NE 
PR 
iPR, iSD, iUPD, NE 
iPR, iSD, iUPD, iCPD, NE 
iPR 
iUPD 
iSD 
iSD, iUPD, NE 
iSD, iUPD, iCPD, NE 
iSD, iUPD, ICPD, NE 
iSD 
iUPD 
iCPD 
Anything 
Anything 
Anything 
iCPD 
iUPD 
iUPD 
iCPD 
Anything 
Anything 
iCPD 
iUPD 
NE 
NE 
NE 
NE 
iUPD 
• 
Table assumes a randomised study where confirmation of CR or PR is not required. 
• 
NE = not evaluable that cycle. 
• 
Designation “I” for BOR can be used to indicate prior iUPD to aid in data interpretation. 
• 
For patients with non-target disease only at baseline, only CR or non-CR/non-PD can be assigned at each TPR but is not 
shown in the table for ease of presentation. 
18.1.4. 
Response and Stable Disease Duration (RECIST 1.1 and iRECIST) 
Response duration will be measured from the time measurement criteria for CR/PR or iCR/iPR 
(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 on study 
(including baseline). 
Stable disease duration will be measured from the time of start of treatment until the criteria for 
progression are met, taking as reference the smallest sum on study (including baseline). 
18.1.5. 
Methods 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. Assessments should be identified 
on a calendar schedule and should not be affected by delays in therapy. While on study, all 
lesions (including target, bystander, and non-target) recorded at baseline should have their actual 
measurements recorded at each subsequent evaluation, even when very small (e.g. 2 mm). If it is 
the opinion of the radiologist that the lesion has likely disappeared, the measurement should be 
recorded as 0 mm. If the lesion is believed to be present and is faintly seen but too small to 
measure, a default value of 5 mm should be assigned. For lesions which fragment/split add 
together the longest diameters of the fragmented portions; for lesions which coalesce, measure 
the maximal longest diameter for the “merged lesion”.    
Clinical Lesions. Clinical lesions will only be considered measurable when they are superficial 
and ≥10 mm as assessed using calipers (e.g. skin nodules). For the case of skin lesions, 
documentation by color photography including a ruler to estimate the size of the lesion is 
recommended. If feasible, imaging is preferred. 


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Chest X-ray. Chest CT is preferred over chest X-ray, particularly when progression is an 
important endpoint, since CT is more sensitive than X-ray, particularly in identifying new 
lesions. However, lesions ≥20 mm on chest X-ray may be considered measurable if they are 
clearly defined and surrounded by aerated lung. 
CT, MRI. CT is the best currently available and reproducible method to measure lesions selected 
for response assessment. This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm or less. When CT scans have slice thickness 
greater than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness. 
MRI is also acceptable in certain situations (e.g. for body scans). Other specialized imaging or 
other techniques may also be appropriate for individual case.4 For example, while PET scans are 
not considered adequate to measure lesions, PET-CT scans may be used providing that the 
measures are obtained from the CT scan and the CT scan is of identical diagnostic quality to a 
diagnostic CT (with IV and oral contrast). 
Ultrasound. Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. If new lesions are identified by ultrasound in the course of the study, 
confirmation by CT is advised. 
Endoscopy, Laparoscopy. The utilization of these techniques for objective tumor evaluation is 
not advised. However, they can be useful to confirm complete pathological response when 
biopsies are obtained or to determine relapse in trials where recurrence following complete 
response or surgical resection is an endpoint. 
Tumor Markers. Tumor markers alone cannot be used to assess objective tumor response. If 
markers are initially above the upper normal limit, however, they must normalize for a patient to 
be considered in complete response. 
Cytology, Histology. These techniques can be used to differentiate between PR and CR in rare 
cases if required by protocol (for example, residual lesions in tumor types such as germ cell 
tumors, where known residual benign tumors can remain). When effusions are known to be a 
potential adverse effect of treatment (e.g. with certain taxane compounds or angiogenesis 
inhibitors), 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 advised to differentiate between response or stable disease and progressive disease. 
 
 


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19. 
SUPPLEMENTAL COMBINATION COHORTS 
 
 


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19.1. 
SUPPLEMENT A : COMBINATION OF PEMBROLIZUMAB 
WITH INT230-6 ARM DEC AND DEC2 SPECIFIC 
INSTRUCTIONS 
 
 
 
 


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TABLE OF CONTENTS 
 
20. 
PEMBROLIZUMAB BACKGROUND ..................................................................111 
20.1. 
Pharmaceutical and Therapeutic Background ..........................................................111 
20.1.1. 
Pre-clinical and Clinical Trials .................................................................................112 
20.1.2. 
Justification for Dose ................................................................................................112 
20.2. 
Rationale for combination of Pembrolizumab and INT230-6 ..................................113 
20.3. 
Cohorts Objective: ....................................................................................................115 
20.4. 
Overview of DEC2 Study Design .............................................................................116 
20.5. 
Injection Procedure for INT230-6 ............................................................................117 
20.6. 
Inclusion Criteria ......................................................................................................117 
20.7. 
Exclusion Criteria .....................................................................................................119 
20.7.1. 
Medical Conditions ...................................................................................................119 
20.7.2. 
Meals and Dietary Restrictions .................................................................................121 
20.7.3. 
Contraception ............................................................................................................121 
20.7.4. 
Pregnancy .................................................................................................................122 
20.7.5. 
Use in Nursing Women ............................................................................................122 
20.7.6. 
Treatments Administered ..........................................................................................122 
20.8. 
Dose Modification ....................................................................................................129 
20.8.1. 
Intrapatient dose escalation .......................................................................................129 
20.8.2. 
Definition of Dose-limiting Toxicity ........................................................................129 
20.8.3. 
Dose modification and toxicity management for immune-related AEs 
associated with pembrolizumab ................................................................................131 
20.8.4. 
Dose modification and toxicity management of infusion-reactions related to 
pembrolizumab .........................................................................................................139 
20.8.5. 
Management of select INT230-6 potential AEs .......................................................140 
20.8.6. 
Other allowed dose interruption for pembrolizumab ................................................142 
21. 
CONCOMITANT THERAPY .................................................................................143 
21.1. 
Rescue Medications & Supportive Care ...................................................................144 
21.2. 
Discontinuation/Withdrawal Criteria ........................................................................144 
21.2.1. 
Discontinuation of pembrolizumab ..........................................................................144 
21.3. 
Permanent Discontinuation of INT230-6 Due to Adverse Events ...........................144 


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21.3.1. 
Timing of Dose Administration ................................................................................145 
21.3.2. 
Tumor Imaging and Assessment of Disease .............................................................145 
21.3.3. 
Initial Tumor Imaging ...............................................................................................145 
21.3.4. 
Tumor Imaging During the Study.............................................................................145 
21.3.5. 
End of Treatment and Follow-up Tumor Imaging ...................................................146 
21.3.6. 
iRECIST Assessment of Disease ..............................................................................146 
22. 
ADVERSE EVENTS, SERIOUS ADVERSE EVENTS AND OTHER 
REPORTABLE SAFETY EVENTS ........................................................................150 
22.1. 
Time Period and Frequency for Collecting AE, SAE and Other Reportable 
Safety Event Information ..........................................................................................150 
22.2. 
Events of Clinical Interest (ECI) ..............................................................................150 
22.3. 
Treatment of Pembrolizumab Overdose ...................................................................151 
22.4. 
Stopping Rules for Clinical Deterioration ................................................................151 
23. 
STATISTICAL ANALYSIS PLAN SUMMARY ...................................................153 
24. 
REFERENCES .........................................................................................................154 
 
LIST OF TABLES 
Table 17: Study Treatments ......................................................................................................123 
Table 18: DEC safety cohort dosing regimen ...........................................................................124 
Table 19: Schedule of events: INT230-6 dosing every 14 days for 5 doses (induction) 
with Pembrolizumab (PM) every 21 days +/- 3 days ...............................................125 
Table 20: Dose Modification and Toxicity Management Guidelines for Immune-
related AEs Associated with Pembrolizumab. ..........................................................132 
Table 21: Dose modification and toxicity management guidelines on pembrolizumab 
associated infusion reaction based on degree of toxicity ..........................................138 
Table 22: Dose Modification and Toxicity Management Guidelines for AEs 
Associated with INT230-6 using CTCAEv4.03 .......................................................141 
Table 23: Imaging and Treatment after First Radiologic Evidence of Progressive 
Disease ......................................................................................................................148 
 
 


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LIST OF FIGURES 
 
Figure 5: 
Synergy of INT230-6 with anti-PD-1 antibodies-in injected and uninjected 
lesions in murine models of cancer ..........................................................................115 
Figure 6: 
Schedule of dosing for both agents: ..........................................................................129 
Figure 7: 
Imaging and Treatment for Clinically Stable Participants Treated with 
INT230-6 plus pembrolizumab after First Radiologic Evidence of PD 
Assessed by the Investigator .....................................................................................149 
 
 
 


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23. 
STATISTICAL ANALYSIS PLAN SUMMARY 
Please see Section 14 of the main protocol. 
 


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24. 
REFERENCES 
1. 
Blank, C., et al., PD-L1/B7H-1 inhibits the effector phase of tumor rejection by T cell 
receptor (TCR) transgenic CD8+ T cells. Cancer Res, 2004. 64(3): p. 1140-5. 
2. 
Chemnitz, Jens M., Parry, Richard V., Nichols, Kim E., June, Carl H., Riley, James L., 
SHP-1 and SHP-2 Associate with Immunoreceptor Tyrosine-Based Switch Motif of 
Programmed Death 1 upon Primary Human T Cell Stimulation, but Only Receptor Ligation 
Prevents T Cell Activation. The Journal of Immunology.2004, 173: 945–954 
3. 
Curran, M.A., et al., PD-1 and CTLA-4 combination blockade expands infiltrating T cells 
and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc Natl Acad 
Sci U S A, 2010. 107(9): p. 4275-80. 
4. 
Disis, Mary L. Immune Regulation of Cancer. Journal of Clinical Oncology.2010; 28 
(29):4531-4538 
5. 
Dudley, Mark E., Wunderlich, John E.,Yang, James C., Sherry, Richard M., Topalian, 
Suzzane L., Restifo, Nicholas P., Royal, Richard E., Kammula, Udai, White, Don E.,  
Mavroukakis, Sharon A., et al. Adoptive Cell Transfer Therapy Following Non-
Myeloablative but Lymphodepleting Chemotherapy for the Treatment of Patients With 
Refractory Metastatic Melanoma. Journal of Clinical Oncology.2005; 0732-183 
6. 
Francisco, Loise M., Sage, Peter T., and Sharpe, Arlene H. The PD-1 pathway in tolerance 
and autoimmunity. Immunological Reviews.2010; 0105-2896 
7. 
Greenwald, Rebecca J., Freeman, Gordon J., and Sharpe, Arlene H. The B7 Family 
Revisited. Annual Reviews.2005; 23:515–48 
8. 
Hirano, F., et al., Blockade of B7-H1 and PD-1 by monoclonal antibodies potentiates 
cancer therapeutic immunity. Cancer Res, 2005. 65(3): p. 1089-96. 
9. 
Hunder NN, Wallen H, Cao J, Hendricks DW, Reilly JZ, Rodmyre R, et al. Treatment of 
metastatic melanoma with autologous CD4+ T cells against NY-ESO-1. N Engl J Med 
2008;358(25):2698-703 
10. 
Mathios D, Kim, J, Mangraviti, Phallen J, Park CK et al.  Anti-PD1 antitumor immunity is 
enhanced by local and abrogated by systemic chemotherapy in GBM.  Sci Transl Med 
2016;8(370) p1-22. 
11. 
Intensity 2018 ESMO poster 
12. 
Bloom, A, Bender, L, Terabe, M et al. INT230-6 shows strong synergy with anti-PD-1 
and can induce high complete response rates with T cell memory response in a colon 
cancer mouse model   Journal for Immunotherapy of Cancer 2015, 3(Suppl 2):P352  
13. 
Nomi, T., et al., Clinical significance and therapeutic potential of the programmed death-1 
ligand/programmed death-1 pathway in human pancreatic cancer. Clin Cancer Res, 2007. 
13(7): p. 2151-7. 
14. 
Okazaki T, Maeda A, Nishimura H, Kurosaki T, Honjo T. PD-1 immunoreceptor inhibits 
B cell receptor-mediated signaling by recruiting src homology 2-domain-containing 
tyrosine phosphatase 2 to phosphotyrosine. Proc Natl Acad Sci U S A 2001;98(24):13866-
71. 


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15. 
Parry, Richard V., Chemnitz, Jens M., Frauwirth, Kenneth A., Lanfranco, Anthony R., 
Braunstein, Inbal., Kobayashi, Sumire V., Linsley, Peter S., Thompson, 4 Craig B. and 
Riley, James L. CTLA-4 and PD-1 Receptors Inhibit T-Cell Activation by Distinct 
Mechanisms. MOLECULAR AND CELLULAR BIOLOGY, 2005; 0270-7306 
16. 
Pilon-Thomas, S., et al., Blockade of programmed death ligand 1 enhances the therapeutic 
efficacy of combination immunotherapy against melanoma. J Immunol, 2010. 184(7): p. 
3442-9.  
17. 
Riley, James L., PD-1 signaling in primary T cells. Immunological Reviews. 2009; 0105-
2896 
18. 
Shepard, Kelly-Ann., Fitz, Lori J., Lee, Julie M., Benander, Christina, George, Judith A., 
Wooter, Joe, Qiu, Yongchang, Jussif, Jason M., Carter, Laura L., Wood, Clive R., 
Chaudhary, Divya.  PD-1 inhibits T-cell receptor induced phosphorylation of the 
ZAP70/CD3 signalosome  and downstream signaling to PKC. FEBS Letters. 2004; 
0014-5793  
19. 
Spranger, S., et al., Mechanism of tumor rejection with doublets of CTLA-4, PD-1/PD-L1, 
or IDO blockade involves restored IL-2 production and proliferation of CD8(+) T cells 
directly within the tumor microenvironment. J Immunother Cancer, 2014. 2: p. 3.  
20. 
Strome, S.E., et al., B7-H1 blockade augments adoptive T-cell immunotherapy for 
squamous cell carcinoma. Cancer Res, 2003. 63(19): p. 6501-5. 
21. 
Weber, J., Immune checkpoint proteins: a new therapeutic paradigm for cancer--preclinical 
background: CTLA-4 and PD-1 blockade. Semin Oncol, 2010. 37(5): p. 430-9. 
22. 
Zhang, PDXuewu, Schwartz, Jean-Claude D., Guo, Xiaoling, Bhatia, Sumeena, Cao, 
Erhu,Chen, Lieping, Zhang, Zhong-Yin, Edidin, Michael A., Nathenson, Stanley G. Almo, 
Steven C. Structural and Functional Analysis of the Costimulatory Receptor Programmed 
Death-1. Immunity.2004; 337-347 
23. 
Seymour L, Bogaerts J, Perrone A, Ford R, Schwartz LH, Mandrekar S, et al. iRECIST: 
guidelines for response criteria for use in trials testing immunotherapeutics. Lancet 
Oncol. 2017 Mar;18(3):e143-e152. 
 
 
 


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25. 
SUPPLEMENT B : COMBINATION OF IPILIMUMAB WITH 
INT230-6 
TABLE OF CONTENTS 
 
25. 
SUPPLEMENT B : COMBINATION OF IPILIMUMAB WITH INT230-6..........156 
26. 
IPILIMUMAB BACKGROUND .............................................................................159 
26.1. 
Rationale for combination of Ipilimumab and INT230-6 .........................................159 
26.2. 
Cohort Objective: ......................................................................................................161 
26.3. 
Overview of Study Design ........................................................................................162 
26.4. 
Re-treatment with Ipilimumab and/or INT230-6 .....................................................163 
26.5. 
Injection Procedure for INT230-6 ............................................................................163 
26.6. 
Inclusion Criteria ......................................................................................................163 
26.7. 
Exclusion Criteria .....................................................................................................165 
26.7.1. 
Medical Conditions ...................................................................................................165 
26.7.2. 
Meals and Dietary Restrictions .................................................................................167 
26.7.3. 
Contraception ............................................................................................................167 
26.7.4. 
Pregnancy .................................................................................................................168 
26.7.5. 
Use in Nursing Women ............................................................................................168 
26.7.6. 
Treatments Administered ..........................................................................................168 
26.8.3. 
Dose modification and toxicity management for INT230-6 and Ipilimumab ..........179 
26.8.3.1. 
Dose modification and toxicity management for immune-related AEs 
associated with Ipilimumab ......................................................................................179 
26.8.3.2. 
Management of select INT230-6 potential AEs .......................................................180 
26.8.4. 
Other allowed dose interruption for Ipilimumab and/or INT230-6 ..........................182 
27. 
CONCOMITANT THERAPY .................................................................................183 
27.1. 
Rescue Medications & Supportive Care ...................................................................184 
27.2. 
Discontinuation/Withdrawal Criteria ........................................................................184 
27.2.1. 
Discontinuation of Ipilimumab .................................................................................184 
27.3. 
Permanent Discontinuation of INT230-6 Due to Adverse Events ...........................185 
27.3.1. 
Timing of Ipilimumab Dose Administration ............................................................186 
27.3.2. 
Tumor Imaging and Assessment of Disease .............................................................186 


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27.3.3. 
Initial Tumor Imaging ...............................................................................................186 
27.3.4. 
Tumor Imaging During the Study.............................................................................186 
27.3.5. 
End of Treatment and Follow-up Tumor Imaging ...................................................187 
27.3.6. 
iRECIST Assessment of Disease ..............................................................................187 
28. 
ADVERSE EVENTS, SERIOUS ADVERSE EVENTS AND OTHER 
REPORTABLE SAFETY EVENTS ........................................................................191 
28.1. 
Time Period and Frequency for Collecting AE, SAE and Other Reportable 
Safety Event Information ..........................................................................................191 
28.2. 
Events of Clinical Interest (ECI) ..............................................................................191 
28.3. 
Treatment of Ipilimumab Overdose ..........................................................................192 
29. 
STATISTICAL ANALYSIS PLAN SUMMARY ...................................................194 
30. 
APPENDICES ..........................................................................................................195 
30.1. 
APPENDIX 1: DESCRIPTION OF THE iRECIST PROCESS FOR 
ASSESSMENT OF DISEASE PROGRESSION .....................................................195 
30.1.1. 
iRECIST Response Assessment ...............................................................................195 
30.1.2. 
Confirming Progression ............................................................................................195 
30.1.3. 
New lesions ...............................................................................................................195 
30.1.4. 
Response and Stable Disease Duration (RECIST 1.1 and iRECIST) ......................197 
30.1.5. 
Methods of Measurement .........................................................................................197 
30.2. 
APPENDIX  2: IPILIMUMAB MANAGEMENT ALGORITHMS .......................199 
30.3. 
Appendix 3: Women of Childbearing potential; Definitions and methods of 
contraception .............................................................................................................209 
31. 
REFERENCES .........................................................................................................212 
LIST OF TABLES 
Table 24: Study Treatments ......................................................................................................169 
Table 25:   Screening Procedural Outline ....................................................................................171 
Table 26:  Schedule of events: INT230-6 dosing every 14 days (E cohorts) with 
Ipilimumab Q3weeks x 4 ..........................................................................................173 
Table 27: Cohort FEC: Schedule ..............................................................................................175 
Table 28: Dose Modification and Toxicity Management Guidelines for AEs 
Associated with INT230-6 using CTCAE v4.03 ......................................................181 
Table 29: Imaging and Treatment after First Radiologic Evidence of Progressive 
Disease ......................................................................................................................189 
Table 30: Time-point (TP) iResponse Time Point Response (TPR)Table ...............................196 
Table 31: iRECIST Best Overall Response (BOR) ..................................................................197 


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LIST OF FIGURES 
Figure 8: Synergy of INT230-6 with anti-CTLA-4 antibodies-in injected and uninjected 
lesions in murine models of cancer ..........................................................................160 
Figure 9: 
Schedule of dosing for both agents: ..........................................................................177 
Figure 10: Imaging and Treatment for Clinically Stable Participants Treated with 
INT230-6 plus Ipilimumab after First Radiologic Evidence of PD Assessed 
by the Investigator ....................................................................................................190 
 
 
 
 

SAP_001.pdf: 
Confidential 
STATISTICAL ANALYSIS PLAN
Protocol Title: A Phase 1/2 Safety Study of Intratumorally Administered INT230-6 in 
Adult Subjects with Advanced Refractory Cancers
Statistical Analysis Plan (SAP) Version: 3.1 
SAP Date: February 22, 2023 
Study Drug: INT230-6 
Phase of Study: Phase 1/2 
Protocol Number: IT-01
Protocol Version: Amendment 6.0 
Protocol Date: 23 MAR 2021 
Sponsor: Intensity Therapeutics, Inc.
CRO Preparing SAP: Catalyst Inc.


Intensity Therapeutics, Inc.
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Statistical Analysis Plan Version 3.1 
 
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Page 2 of 41 
SIGNATURE PAGE 
 
This document has been prepared, reviewed and approved by:
STUDY BIOSTATISTICIAN APPROVAL: 
----------------------------------------------
Lydia King 
Director, Biostatistics, 
Catalyst CR, Inc.
SPONSOR APPROVAL: 
-----------------------------------------------
Lewis H. Bender
President and CEO
Intensity Therapeutics, Inc. 
----- -------------------------------------------
L
i H B
d
-------------------------------------------------


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REVISIONS HISTORY LOG 
Changes to the approved SAP should be logged in this table. 
Version 
Revision 
Date** 
Author of 
Revision* 
Section(s) 
Modified 
Description and/or 
Reason(s) for Revision 
2.0 
04SEPT2020 LKing 
Synopsis 
Updated to make more 
succinct and less repetitive of 
protocol. 
Section 3 
Updated objectives and 
endpoints per Protocol 
Amendment 5 
Section 4.1 
Updated per Protocol 
Amendment 5 and to make 
more succinct.  Removed 
study schematic figure.  
Added table to summarize 
cohorts.   
Section 5 
Updated per Protocol 
Amendment 5 sample size 
estimates and informed 
consent documents. 
Section 6 
Defined the retreatment 
population 
Section 7.1 
Added convention to present 
tables by study part (Dose 
Escalation and Highest Dose), 
thereby creating table repeats 
for each study part.   
Section 7.5 
Updated list of subgroups for 
analysis. 
Section 7.6 
Added conventions to be used 
for missing dates. 
Section 8.4 
Added pembrolizumab and 
ipilimumab as combination 
study drugs 
Throughout 
Cosmetic editing.  Additional 
analyses added per sponsor 
requests and per Protocol 
Amendment 5. 
2.1 
21Dec2020 
Dtemplin 
Throughout 
Cosmetic editing 
Updated abbrevations table 
and list of tables 


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Section 9.3 
Added last treatment date to 
PFS censoring rule. 
Section 10.1 
Added related to pem or ipi to 
overall AE summary 
Section 12 
Removed association 
analysis. 
2.2 
23Feb2021 
PHealy 
Throughout 
Cosmetic editing and 
formatting 
 
 
 
Section 10.1 
Revised definition of 
treatment emergent adverse 
event to match protocol 
2.3 
22Aug2022 
07OCT2022 
PHealy 
LBender 
Throughout 
Editing and formatting based  
preparation for study closure. 
2.4 
29Nov2022 
PHealy 
Throughout 
Editing in response to 
Intensity review. 
3.0 
12Dec2022 
PHealy 
Throughout 
Editing in response to 
Intensity review. Particular 
focus regarding inability to 
utilize RECIST/iRECIST 
3.1 
22Feb2023 
LKing/Intensity Section 9.1 
Added efficacy analysis with 
response evaluable 
population.  Added new 
population – scan evaluable 
population. 
 
 
 
Section 9.2 
Updated censoring rule for 
OS.   
 
 
 
Section 10.1 
Clarified groups for 
maximum severity AE tables 
 
 
 
General 
Reference to SAP appendix 
with programming 
clarifications 
* Provide first initial and last name. 
** Update the last revision dates on the cover page and the header. 
 
 


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SYNOPSIS 
Sponsor: Intensity Therapeutics, Inc., Westport, CT 
 
Product: INT230-6 
Phase of development: Phase 1/2 
Protocol title: A Phase 1/2 Safety Study of Intratumorally Administered INT230-6 in Adult Subjects 
with Advanced Refractory Cancers 
Objectives: 
Primary:  
x 
The primary objective is to assess the safety and tolerability of multiple intratumoral (IT) doses 
of INT230-6 in subjects with advanced or recurrent malignancies. This will be assessed by the 
rate of  Grade 3 adverse events (AEs) attributed to INT230-6 or the treatment when combined 
with immunotherapies and not the underlying disease.  
Secondary:  
x 
Assess the preliminary efficacy of INT230-6 alone and when combined with immunotherapies 
by measuring the disease control rate (CR+PR+SD) as assessed by iRECIST 
x 
Characterize the pharmacokinetic profile of multiple doses of the three INT230-6 components 
(CIS, VBL, and SHAO) after single and then multiple IT tumor site injections  
x 
Characterize the overall safety profile of the INT230-6 
Exploratory: 
x 
Characterize tumor response in injected and non-injected sites 
x 
Evaluate various tumor and anti-tumor immune response biomarkers that may correlate with 
tumor response 
x 
Evaluate overall response by RECIST or iRECIST 
x 
Characterize the pharmacodynamics (PD) profile of the INT230-6 formulation in subject blood 
and treated and untreated tumors 
x 
To assess the progression free and overall survival in subjects receiving INT230-6 
Methodology:  
This is a clinical study of a new investigational treatment that uses a novel drug product called 
“INT230-6" to treat advanced cancers. INT230-6 is a fixed ratio, multi-agent formulated drug product 
designed specifically for IT injection. This study will determine the safety of administering a fixed 
volume of INT230-6 per cm3 of tumor into superficial, followed by multiple deep tumors alone or as a 
treatment combined with immunotherapies. A sentinel subject was enrolled at the lowest dose and 
followed for 4 weeks prior to escalating or adding additional subjects. Gradual intra-subject dose 
escalation was done to increase the total amount of drug delivered to enable large tumors to be fully 
dosed at the proposed drug to tumor ratios. Once escalation dosing cohorts was complete, and no MTD 
was obtained, then set a maximum total dose of 175 mL of INT230-6 was to be used for all dosings. In 
certain amendment INT230-6 treatment shall consisted of an induction phase for certain cohorts along 
with a maintenance regimen. INT230-6 was also tested in combination with checkpoint antibodies.  
 
Dose Escalation  
There are 6 cohorts of subjects in the escalation portion of the protocol where INT230-6 dosing is 
increased over 5 doses. These escalation cohorts are (A, B1, EA, EC, EC2 and DEC). The first (A) is a 
superficial tumor cohort starting at up to 5.0 mL of total dose with a low tumor load (1:4 ratio of drug 


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Page 6 of 41 
to tumor). The 2nd (B1) cohort is in deep tumors and starts with up to 5.0 mL and escalates the total 
dose and maximal dose per any one tumor. Cohort 3 (EA) will explore an every 2 week administration 
in superficial tumors. Cohort 4 (EC) follows the every 2 week schedule at a higher drug load (1:2 ratio) 
in both superficial and deep tumors and will escalate the total dose and maximal dose per any one 
tumor. Cohort 5 (EC2) follows the Q2 week schedule at an intermediate drug load (1:3 ratio) in both 
superficial and deep tumors and will escalate the total dose and maximal dose per any one tumor. The 
6th cohort (DEC) doses combinations of pembrolizumab and escalating doses of INT230-6 and 
includes a safety lead-in cohort that doses INT230-6 only into superficial tumors.  
 
Maximum Highest Dose of INT230-6  
There are 3 cohorts that use up to a maximum total dose of INT230-6 of 175 mL for all 5 induction 
doses as well as a maintenance dose. The maintenance dose is a single dosing session of INT230-6 
given every 9 weeks ± 10 days up to a maximum total dose amount of 175 mL. The maximum 175 mL 
dose cohorts were EC3, DEC2, and FEC, and each followed the Q2 week INT230-6 dosing schedule at 
drug load to tumor volume ratio of 1:3 into both superficial and deep tumors for tumor types defined in 
the appropriate supplement. Cohort 7 (EC3) dosed INT230-6 alone for any tumor type. The 8th cohort 
(DEC2) combined fixed dose of pembrolizumab with the same INT230-6 dosing regimen as EC3 as 
outlined in Protocol Supplement A. The 9th cohort (FEC) was a combination of a CTLA4 antibody, 
ipilimumab, with the same INT230-6 dosing regimen as EC3. A 10th cohort (G Cohort) was designed 
to be a combination of INT230-6 with another molecule.  However, no other cohort after FEC was 
added. All cohorts and decisions to escalate the dose and introduce new subject populations were 
governed by the Study Steering Committee (SSC).  
 
Expansion Cohorts  
DEC2 and FEC are expansion cohorts of 10-16 subjects with various tumor types. These groups 
allowed for better point estimates of the safety and preliminary efficacy in a homogenous population of 
INT230-6 combined with immune checkpoint inhibitor drugs. Decisions on expansion cohorts for 
monotherapy (e.g., for EC3) were possible; however, no such cohort was added.  
Number of subjects enrolled:  
The sample size was estimated to be between 100 and 175 subjects during dose escalation and 
expansion. The final enrollment consisted of 110 subjects two of whom participated in more than one 
cohort. 
Statistical methods: 
Safety Analyses: All recorded adverse events were listed and tabulated by system organ class, preferred 
term, dose and cohort and coded according to version 25.1 of Medical Dictionary for Regulatory 
Activities (MedDRA). The incidence of adverse events were tabulated and reviewed for potential 
significance and clinical importance. Vital signs and clinical laboratory test results were listed and 
summarized by cohort. Any significant physical examination (PE) findings and results of clinical 
laboratory tests were to be listed. Electrocardiogram (ECG) listings were to be evaluated by the 
investigator and abnormalities, if present, were to be listed.  
Adverse Events were summarized for all reported data and by study period: a) up to and including 
28 days post last dose of initial treatment.  
 
Efficacy Analyses:  The primary efficacy endpoint of disease control rate (DCR), defined as the sum of 
complete, partial and stable disease responses divided by the total number of subjects in the efficacy 
population, will be determined per criteria based on RECIST or iRECIST. DCR was tabulated overall 
and by subgroups of interest. 


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For DCR, exact binomial 95% confidence intervals will be computed using the Clopper-Pearson 
method. Median time to response and duration of response will be summarized for those subjects with 
responses, using the Kaplan-Meier method; overall survival (OS) will be similarly summarized. 
Individual tumor measurements, tumor burden, % changes in tumor burden, and progression free 
survival (PFS) will be listed.  
Changes in overall survival will be presented graphically for all monotherapy subjects, for 
monotherapy subjects receiving an INT230-6 dose volume over the course of their treatment less than 
or  of their incoming reported total tumor burden, with pembrolizumab, with ipilimumab and in 
all sarcoma types (collectively) for monotherapy and combined with iplimumab.  
 
Pharmacokinetic Analyses: The pharmacokinetic analyses described will be reported in a separate 
report. A brief summary of the results will be included in this CSR. The release kinetics of each analyte 
is not expected to be uniform across subjects. Sponsor shall assess the blood concentrations of the three 
analytes for each subject at the first cycle. Sponsor shall correlate the systemic measurement 
[maximum plasma drug concentration (Cmax), area under the curve (AUC)] of the 3 analytes to 
measured markers of systemic toxicity [in particular renal and blood – the known toxicities of the two 
active agents; cisplatin (CIS) & vinblastine (VBL)]. Human plasma will be analyzed for the 
concentration of VBL and 8-((2-hydroxybenzoyl)amino)octanoate (sodium salt form) (SHAO) using 
validated LC/MS/MS methods, and for cisplatin using a validated ICP-MS method. For 
pharmacokinetic profiling platinum drugs, total platinum levels in subject plasma or urine are routinely 
determined by spectroscopy methods as a surrogate. Thus an ICP-MS method will be developed for 
this study to measure total platinum in human samples as a surrogate for cisplatin.  
In addition, a separate pharmacokinetic report shall be prepared that showtime plots of plasma 
concentrations,  Cmax and AUCTAU versus INT230-6 dose volume will be provided for the first cycle. 
Dose proportionality per subject normalized to tumor volume will be assessed, by estimating the slope 
of linear regression of SHAO/CIS/VIN log(Cmax) on log(dose) and of log(AUCTAU) on log(dose) based 
on a power model. Point estimates and 90% confidence intervals for the dose proportionality parameter 
(slope of the linear regression) will be calculated for Cmax and AUCTAU. Summary statistics for trough 
[minimum plasma drug concentration Cmin] concentrations will be tabulated by dose and study cycle. 
Plots of Cmin vs. cycle will be assessed for cohorts by combining A1, B1 versus E Cohorts and grouping 
subjects by similar dose volumes of INT230-6. Pharmacokinetic concentrations from sparse samples 
will be listed, and may be used in combination with other studies for exposure-response or population 
pharmacokinetic modeling, which will be part of the separate report.  
 
Exploratory Biomarkers (Immune Function and others): The analyses regarding biomarkers to assess 
pharmacodynamic effects will be reported in separate report(s). A brief summary of the biomarker 
work shall be included in this CSR. 
Possible associations between changes in biomarker measures of interest and pharmacokinetic exposure 
were explored. Possible associations of various biomarkers measures (baseline value or change from 
baseline) with clinical outcome (e.g., tumor response) may be explored based on data availability. 
Administrative interim analyses such as ad hoc presentations or date for safety meetings may be 
provided at several times prior to completion of the study in order to facilitate program decisions and to 
support study presentations or publications. No formal interim analyses were conducted for this study. 
Any reports for exploratory biomarkers will be added as addendums to the SAP. 


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TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN ................................................................................................1 
SIGNATURE PAGE .......................................................................................................................2 
REVISIONS HISTORY LOG .........................................................................................................3 
SYNOPSIS ......................................................................................................................................5 
TABLE OF CONTENTS .................................................................................................................8 
LIST OF TABLES .........................................................................................................................10 
1. 
LIST OF ABBREVIATIONS.....................................................................................11 
2. 
INTRODUCTION ......................................................................................................13 
3. 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................13 
3.1. 
Research Hypothesis ...................................................................................................13 
3.2. 
Objectives and Endpoints ...........................................................................................13 
4. 
STUDY DESIGN .......................................................................................................18 
4.1. 
General Study Design and Plan ..................................................................................18 
4.1.1. 
Dose Escalation ..........................................................................................................19 
4.1.2. 
Highest Dose ...............................................................................................................20 
4.1.3. 
Expansion Cohorts ......................................................................................................21 
4.1.4. 
Long Term Follow up .................................................................................................21 
4.1.5. 
Survival Follow-up Period ..........................................................................................21 
4.2. 
Study Population .........................................................................................................21 
4.2.1. 
Selection of Study Population ....................................................................................21 
4.2.2. 
Subject Replacement ..................................................................................................22 
4.3. 
Randomization and Blinding ......................................................................................22 
4.4. 
Study Assessments......................................................................................................22 
4.5. 
Protocol Deviations ....................................................................................................22 
5. 
SAMPLE SIZE DETERMINATION .........................................................................22 
6. 
ANALYSIS POPULATIONS ....................................................................................22 
6.1. 
All Enrolled Population ..............................................................................................22 
6.2. 
All Treated Population ................................................................................................22 
6.3. 
Pharmacokinetic Population .......................................................................................23 
6.4. 
Response Evaluable Population ..................................................................................23 
6.5. 
Scan Evaluable Population .........................................................................................23 


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6.6. 
Exploratory Biomarker (Immune Function and others) Population ...........................23 
6.7. 
Retreatment Population ..............................................................................................23 
7. 
GENERAL STATISTICAL CONSIDERATIONS ....................................................23 
7.1. 
General Reporting Conventions .................................................................................24 
7.2. 
Interim Analyses .........................................................................................................25 
7.3. 
Multi-Center Studies ...................................................................................................25 
7.4. 
Multiple Comparisons / Multiplicity ..........................................................................26 
7.5. 
Examination of Subgroups .........................................................................................26 
7.6. 
Handling of Dropouts or Missing Data ......................................................................26 
7.7. 
Outlier Handling .........................................................................................................27 
7.8. 
Adjustments for Covariates ........................................................................................27 
8. 
SUMMARY OF STUDY POPULATION DATA .....................................................27 
8.1. 
Subject Disposition .....................................................................................................27 
8.2. 
Protocol Deviations ....................................................................................................28 
8.3. 
Demographics and Baseline Characteristics ...............................................................28 
8.4. 
Dosing and Extent of Exposure ..................................................................................28 
8.5. 
Prior and Concomitant Medications ...........................................................................29 
9. 
EFFICACY ANALYSES ...........................................................................................29 
9.1. 
Additional Efficacy Analysis ......................................................................................30 
9.2. 
Progression-Free Survival and Overall Survival ........................................................30 
10. 
SAFETY ANALYSES ...............................................................................................31 
10.1. 
Adverse Events ...........................................................................................................32 
10.2. 
Clinical Laboratory Evaluations .................................................................................34 
10.3. 
Vital Signs ..................................................................................................................34 
10.4. 
ECGs ...........................................................................................................................34 
10.5. 
Physical Examination .................................................................................................35 
11. 
CLINICAL PHARMACOLOGY ANALYSES .........................................................35 
12. 
OTHER ANALYSES .................................................................................................35 
12.1. 
Pharmacokinetic Analysis ..........................................................................................35 
12.2. 
Exploratory Biomarkers of Immune Response ...........................................................35 
12.3. 
Pharmacodynamic Analyses .......................................................................................35 
13. 
CHANGES IN THE STATISTICAL METHODS FROM THOSE STATED 
IN THE PROTOCOL .................................................................................................35 


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14. 
REFERENCES ...........................................................................................................36 
15. 
TABLES, FIGURES, LISTINGS ...............................................................................36 
APPENDIX 1. ................................................................................................................................37 
1. 
TOTAL TUMOR BURDEN (TTB) ...........................................................................37 
2. 
% DOSED TTB ..........................................................................................................37 
3. 
INJECTED TUMOR RESPONSE RATE (ITR) ........................................................37 
4. 
BYSTANDER TUMOR RESPONSE RATE (BTR) .................................................37 
5. 
PROGRESSION DEFINITION .................................................................................38 
6. 
IMPUTATION OF END DATE OF LAST PRIOR ANTI-CANCER 
THERAPY ..................................................................................................................38 
7. 
PEMBRO LISTINGS/RETREATED SUBJECTS.....................................................38 
8. 
IMPUTATION OF END DATE OF LAST PRIOR ANTI-CANCER 
THERAPY ..................................................................................................................38 
OTHER NOTES ............................................................................................................................39 
 
LIST OF TABLES 
Table 1: Abbreviations ...................................................................................................................11 
Table 2: Objectives and Endpoints ................................................................................................13 
Table 3: Dosing for Phase 1 Cohorts .............................................................................................18 
 
 
 
 


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1. 
LIST OF ABBREVIATIONS 
Table 1: Abbreviations 
Abbreviation 
Explanation 
AE 
Adverse event 
AUC 
Area under the concentration-time curve 
AUCĲau 
Area under the concentration-time curve over dosing interval tau 
BMI 
Body mass index 
BTR 
Bystander tumor response 
Ce3 
A contract research organization 
CIS 
Cisplatin 
Cmax 
Maximum plasma drug concentration 
Cmin 
Minimum plasma drug concentration 
CR 
Complete response 
CRO 
Contract research organization 
CSR 
Clinical study report 
DBP 
Diastolic blood pressure 
DCR 
Disease control rate 
DLT 
Dose-limiting toxicity 
DOR 
Duration of response 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
FIH 
First in human 
HR 
Heart rate 
iRECIST 
Immune Response Evaluation Criteria in Solid Tumors 
IT 
Intratumoral  
ITR 
Injected tumor response 
MedDRA 
Medical Dictionary for Regulatory Activities 
ORR 
Objective response rate 
PD 
Progressive disease 
PD 
Pharmacodynamics 
PD1 
Programmed death-1 


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Abbreviation 
Explanation 
PE 
Physical examination 
PFS 
Progression free survival 
PK 
Pharmacokinetic 
PR 
Partial response 
PT 
Preferred term 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAS 
Statistical Analysis System 
SAP 
Statistical Analysis Plan 
SBP 
Systolic blood pressure 
SD 
Stable disease 
SD 
Standard deviation 
SHAO 
8-((2-hydroxybenzoyl)amino)octanoate (sodium salt form) 
SOC 
System organ class 
SOD 
Sum of diameters 
SOP 
Standard operating procedure 
SSC 
Study steering committee 
TEAE 
Treatment-emergent adverse event 
TLF 
Tables, listings and figures 
TTB 
Total Tumor Burden 
TTR 
Time to response 
VBL 
Vinblastine sulfate or vinblastine 
WHODD 
World Health Organization Drug Dictionary 
 
 
 


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2. 
INTRODUCTION 
This statistical analysis plan (SAP) describes the planned analysis and reporting for Intensity 
Therapeutics, Inc. Protocol IT-01, entitled “A Phase 1/2 Safety Study of Intratumorally 
Administered INT230-6 in Adult Subjects with Advanced Refractory Cancers”. This is a 
Phase 1/2 trial to evaluate the safety, tolerability, and preliminary efficacy of INT230-6 in adult 
subjects with advanced refractory cancers. The research hypothesis of the study is that 
INT230-6, when administered intratumorally (IT) to one or more tumors at a sufficient loading 
to the subject’s total tumor burden (TTB), will safely reduce tumor burden and promote an 
immune response against the cancer allowing subjects to have an increase in survival.  
This SAP is intended to describe the planned analyses of the primary and secondary endpoints 
and other analyses mentioned in the protocol, as well as the presentation of study data to be 
included in the clinical study report (CSR) for Protocol IT-01. Additional analyses that were not 
mentioned in the protocol, but which are now planned, are also described. A discussion of the 
steps taken to prepare the data for analysis, such as study milestones, data partitioning and 
derived data, is provided. Examples of tables and figures that will be used to summarize the data 
are included in the companion document IT-01 Tables, Listings and Figures Shells. 
This SAP has been developed according to Ce3 SOP 700: Developing and Maintaining a 
Statistical Analysis Plan, and accordingly, this plan and any deviations from this plan must be 
finalized, approved, and placed on file before the study database is locked.  
3. 
STUDY OBJECTIVES AND ENDPOINTS 
3.1. 
Research Hypothesis 
INT230-6 when administered intratumorally (IT) to one or more tumors at an optimal dose to 
tumor volume ratio (i.e., greater than 1 mL per 4 cc of tumor) while treating a sufficient amount 
of the visible disease will safely reduce tumor burden, stabilize disease, promote an immune 
response against the cancer, and extend overall survival.   
3.2. 
Objectives and Endpoints 
Objectives and endpoints are described in Table 2. 
Table 2: Objectives and Endpoints 
Cohort 
Cohort 
Description 
Number 
Objective 
Endpoint 
A1 
B1  
EA 
EC 
EC2 
Dose 
Escalation, 
Monotherapy 
PRIMARY 
Safety and tolerability of 
multiple intratumoral 
doses of INT230-6 in 
subjects with advanced or 
recurrent malignancies 
Grade 3, 4, or 5 study 
drug-related adverse events  


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Cohort 
Cohort 
Description 
Number 
Objective 
Endpoint 
 
SECONDARY 
1) Assess the preliminary 
efficacy of INT230-6  
2) Characterize the 
pharmacokinetic profile 
of multiple doses of the 
three INT230-6 
components (CIS, VBL, 
and SHAO) after single 
and then multiple IT 
tumor site injections 
3) Characterize the 
overall safety of the 
INT230-6 
1) Disease Control Rate 
(CR+PR+SD) as defined by 
criteria based on RECIST 1.1 
2) Cmax, Cmin, Tmax, AUCTAU, 
Accumulation index 
3) Incidence and severity of 
treatment-emergent adverse 
events (TEAEs) 
Clinical laboratory results 
(hematology, chemistry, 
urinalysis) 
ECOG performance status 
Physical examination, including 
vital sign measurements 
ECG results 
 
EXPLORATORY 
1) Characterize tumor 
response in injected and 
non-injected sites  
2) Evaluate various tumor 
and anti-tumor immune 
response biomarkers that 
may correlate with tumor 
response  
3) Evaluate overall 
response by criteria based 
on RECIST or iRECIST 
4) Characterize the 
pharmacodynamics (PD) 
profile of the INT230-6 
formulation in subject 
blood and treated and 
untreated tumors 
5) To assess the 
progression free (PFS) 
and overall survival (OS) 
in subjects receiving 
INT230-6 and cancer 
subtype of sarcoma. 
 
1) Injected and Bystander 
tumor response rates to be 
conducted outside of this SAP. 
2) Biomarker results 
3) Response adjudicated as 
complete (CR), partial (PR), 
stable disease (SD), progressive 
disease (PD) or Not evaluable 
(NE); Best overall response and 
duration or response 
4) PD profile results 
5) PFS and OS as defined in 
Section 9.2 of this document 
EC3 
Highest set 
Dose, 
Monotherapy 
PRIMARY 
SECONDARY 
EXPLORATORY 
Objectives are the same as 
the above cohorts  
 


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Cohort 
Cohort 
Description 
Number 
Objective 
Endpoint 
DEC 
Dose 
Escalation, 
Combination 
Therapy 
PRIMARY 
Assess the safety and 
tolerability of INT230-6 
with pembrolizumab 
Grade 3, 4, or 5 study drug-
related adverse events 
attributed to the combination 
and not the underlying disease 
SECONDARY 
1) Characterize the 
overall safety of INT230-
6 combined with 
pembrolizumab 
2) Assess the injected 
tumor response 
3) Characterize the 
pharmacokinetic profile 
of multiple doses of the 
three INT230-6 
components (CIS, VBL, 
and SHAO) after single 
and then multiple IT 
tumor site injections. 
1) Incidence and severity of 
treatment-emergent adverse 
events (TEAEs) 
Clinical laboratory results 
(hematology, chemistry, 
urinalysis) 
ECOG performance status 
Physical examination, including 
vital sign measurements 
ECG results 
2) Injected Response Rates 
3) Cmax, Cmin, Tmax, AUCTAU, 
Accumulation index 
EXPLORATORY 
1) Characterize tumor 
response in injected and 
non-injected sites  
2) Evaluate various tumor 
and anti-tumor immune 
response biomarkers that 
may correlate with tumor 
response 
3) Characterize the 
pharmacodynamics (PD) 
profile of the INT230-6 
plus pembrolizumab in 
subject blood and in 
treated and untreated 
tumors 
4) Assess the overall 
survival in subjects 
receiving INT230-6 plus 
pembrolizumab meeting 
inclusion criteria. 
1) Bystander Response Rates, 
Objective Response Rates, Best 
Overall Response, Duration of 
Response 
2) Biomarker results 
3) PD profile results 
4) PFS and OS as defined in 
Section 9.2 of this document 
DEC2 
Highest 
INT230-6 
Dose, 
Combination 
Therapy 
PRIMARY 
Preliminary efficacy of 
INT230-6 combined with 
pembrolizumab 
Disease control rate (CR + PR 
+ SD) of multiple intratumoral 
doses of INT230-6 combined 
with pembrolizumab and 
assessed with criteria based on 
RECIST or iRECIST 
SECONDARY 
1) Characterize the 
overall safety of INT230-
1) Grade 3 or higher adverse 
events attributed to the 


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Cohort 
Cohort 
Description 
Number 
Objective 
Endpoint 
6 combined with 
pembrolizumab  
2) Assess the injected 
tumor response 
3) Characterize the 
pharmacokinetic profile 
of multiple doses of the 
three INT230-6 
components (CIS, VBL, 
and SHAO) after single 
and then multiple IT 
tumor site injections. 
combination and not the 
underlying disease 
Incidence and severity of 
treatment-emergent adverse 
events (TEAEs) 
Clinical laboratory results 
(hematology, chemistry, 
urinalysis) 
ECOG performance status 
Physical examination, including 
vital sign measurements 
ECG results 
2) Injected Tumor Response 
Rate 
EXPLORATORY 
1) Characterize tumor 
response in injected and 
non-injected sites 
2) Evaluate various tumor 
and anti-tumor immune 
response biomarkers that 
may correlate with tumor 
response 
3) Evaluate overall 
response by criteria based 
on RECIST  or iRECIST 
4) Characterize the 
pharmacodynamics (PD) 
profile of the INT230-6 
plus pembrolizumab in 
subject blood and in 
treated and untreated 
tumors 
5) To assess the 
progression free and 
overall survival in 
subjects receiving 
INT230-6 plus 
pembrolizumab meeting 
inclusion criteria. 
1) Injected and Bystander 
Response Rates; Objective 
response rates; Best overall 
response; Duration of Response 
2) Biomarker results 
3) Response adjudicated as 
complete (CR), partial (PR), 
stable disease (SD), progressive 
disease (PD) or Not evaluable 
(NE); Best overall response and 
duration or response 
4) PD profile results 
5) PFS and OS as defined in 
Section 9.2 of this document 
FEC 
Highest Dose, 
Combination 
Therapy 
PRIMARY 
Assess preliminary 
efficacy of multiple 
intratumoral doses of 
INT230-6 combined with 
the standard dose and 
schedule of Ipilimumab (3 
mg/kg Q3 wk for 4 doses) 
Disease control rate (CR + PR 
+ SD) based on RECIST or 
iRECIST 


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Cohort 
Cohort 
Description 
Number 
Objective 
Endpoint 
SECONDARY 
1) Characterize the 
overall safety of the 
combination 
2) Assess the preliminary 
efficacy of INT230-6 with 
Ipilimumab by measuring 
the injected and bystander 
tumor response 
3) Characterize the 
pharmacokinetic profile 
of multiple doses of the 
three INT230-6 
components cisplatin 
(CIS), vinblastine sulfate 
(VBL) and the cell 
penetration enhancer 
(SHAO) after single and 
then multiple IT tumor 
site injections 
1) Grade 3 or higher adverse 
events attributed to the 
combination and not the 
underlying disease 
Incidence and severity of 
treatment-emergent adverse 
events (TEAEs) 
Clinical laboratory results 
(hematology, chemistry, 
urinalysis) 
ECOG performance status 
Physical examination, including 
vital sign measurements 
ECG results  
2) Injected and Bystander 
Response Rates 
3) Cmax, Cmin, Tmax, AUCTAU, 
Accumulation index 
EXPLORATORY 
1) Characterize tumor 
response in injected and 
non-injected sites  
2) Evaluate various tumor 
and anti-tumor immune 
response biomarkers that 
may correlate with tumor 
response  
3) Evaluate overall 
response by criteria based 
on RECIST or iRECIST 
4) Characterize the 
pharmacodynamics (PD) 
profile of the INT230-6 
formulation in subject 
blood and treated and 
untreated tumors 
5) To assess the 
progression free (PFS) 
and overall survival (OS) 
in subjects receiving 
INT230-6. 
6) Explore the activity of 
the combination of 
IN230-6 with Ipilimumab 
compared to INT230-6 
alone in patients with the 
same tumor types such as 
sarcoma. 
1) Injected and Bystander 
tumor response rates  
2) Biomarker results 
3) Response adjudicated as 
complete (CR), partial (PR), 
stable disease (SD), progressive 
disease (PD) or Not evaluable 
(NE); Best overall response and 
duration or response 
4) PD profile results 
5) PFS and OS as defined in 
Section 9.2 of this document  
6) Subgroup analysis of 
efficacy endpoints 


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4. 
STUDY DESIGN 
4.1. 
General Study Design and Plan 
This is a first-in-human (FIH) Phase 1/2, open label, non-randomized study. Subjects will have 
refractory, advanced cancers and will have failed at least 1 therapy or not be a candidate for 
standard of care. Investigators will have the option to continue INT230-6 based upon safety, 
local tolerability, and tumor response.  
Table 3 provides details on the Phase 1 cohorts included in this study.  More details on dosing 
and injection can be found in the Study Protocol. 
Table 3: Dosing for Phase 1 Cohorts 
Study Part 
Cohort 
Tumor Type 
Tumor 
Ratio 
(Dose) 
Dosing 
Schedule 
Combination 
Drug 
Other 
Escalation 
A1 
Superficial 
1:4 
Once per 
28 days 
No 
Retreatment 
option after 
completing 
5 doses 
B1 
Superficial + 
Deep 
1:4 
Once per 
28 days 
No 
EA 
Superficial 
1:4 
Every 2 
weeks 
No 
EC 
Superficial 
and/or Deep 
1:2 
Every 2 
weeks 
No 
EC2 
Superficial 
and/or Deep 
1:3 
Every 2 
weeks 
No 
DEC 
Superficial 
and/or Deep 
1:3 
Every 2 
weeks 
Anti-PD1 
Phase 2/ 
Dose 
EC3 
Superficial 
and/or Deep 
1:3 
(Maximum 
175 mL) 
Every 2 
weeks for 5 
doses 
(Induction 
treatment) 
No 
Maintenance 
treatment 
every 9 
weeks after 
completing 
5 doses 
DEC2 
Superficial 
and/or Deep 
1:3 
(Maximum 
175 mL) 
Every 2 
weeks for 5 
doses 
(Induction 
treatment) 
Anti-PD1 
FEC 
Superficial 
and/or Deep 
1:3 
(Maximum 
175 mL) 
Every 2 
weeks for 5 
doses 
(Induction 
treatment) 
Anti-CTLA4 


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For purposes of analysis Cohorts A, B1, EA, EC are to be combined as one group as are cohorts 
EC2 and EC3. The A/B1,EA/EC population is defined as low loading monotherapy treatment, 
where low loading refers to a lesser potential for proper treatment of a subject’s total tumor 
burden due to dose volume restrictions on INT230-6 during escalation. Cohort EC2/EC3 is 
defined as high loading monotherapy treatment, where high loading refers to a greater potential 
for proper treatment of a subject’s total tumor burden due to meaningfully higher dose volume 
amounts allowed for INT230-6. 
4.1.1. 
Dose Escalation 
The Phase 1 portion of the study included the administration of escalating doses of INT230-6 in 
a 3+3+3 design for Cohorts A1, B1, EA, EC, EC2, and a 6+6 design for Cohort DEC and FEC. 
The SSC, comprised of the majority of study investigators plus representatives from the Sponsor, 
reviewed safety data regularly on an ongoing basis on all subjects. Decisions to increase the 
number of subjects in a cohort, to increase the concentration injected into the tumors, and the 
decision to begin treating deep tumors required agreement from this committee. The SSC 
reviewed the data on the sentinel subjects and facilitate the decision to recruit more subjects. 
After each escalation cohort, the SCC reviewed safety to determine escalation into the next 
cohort.  
The following dose escalation rules applied: 
x Cohorts A1, B1 
 A sentinel subject will be on treatment for 28 days 
 If there are no Dose-limiting toxicities (DLTs), upon agreement from SSC, more 
subjects can be enrolled 
 Cohort will continue until at least 3 subjects have completed at least 56 days (A1) 
or 3 doses (B1) or if 3 DLTs (A1, B1) have occurred 
 If 1 DLT is seen in the first 3 subjects, an additional 3 subjects at this dose level 
will be added 
 If there is one more DLT in the first 6 subjects, 3 more will be added 
 If  3 DLTs are seen in up to 9 subjects, the SCC will pause accrual and review 
the data 
 At the time a third DLT is observed in any dose level, even if < 9 subjects are 
enrolled, enrollment in that dose level will be discontinued and a lower dose level 
or intermediate dose level will be explored 
 A rate of DLTs that exceeds 33% is unacceptable for this population 
x Cohorts EA, EC 
 No sentinel subject required 
 Cohort will continue until at least 3 subjects have completed at least 3 cycles or 
3 DLTs have occurred 


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 If 1 DLT is seen in the first 3 subjects, an additional 3 subjects at this dose level 
will be added 
 If there is one more DLT in the first 6 subjects, 3 more will be added 
 If  3 DLTs are seen in up to 9 subjects, the SCC will pause accrual and review 
the data 
 At the time a third DLT is observed in any dose level, even if < 9 subjects are 
enrolled, enrollment in that dose level will be discontinued and a lower dose level 
or intermediate dose level will be explored 
 A rate of DLT’s that exceeds 33% is unacceptable for this population 
x Cohort EC2 
 No sentinel subject required 
 Cohort will continue until at least 6 subjects have completed at least 3 cycles or 
4 DLTs have occurred 
 If 2 DLTs are seen in the first 6 subjects, an additional 6 subjects at this dose level 
will be added. If  4 DLTs are seen in up to 12 subjects, the SSC will pause 
accrual and review the data 
 A rate of DLT’s that exceeds 33% is unacceptable for this population 
Cohort DEC will include a combination of INT230-6 plus an anti-PD-1 therapy. The SCC will 
determine the subject population (tumor type) and the dose for this group of subjects. See 
Supplement A of the Protocol for details on the PD-1 agent. 
4.1.2. 
Highest Dose 
Monotherapy Cohort EC3 and Combination Cohorts DEC2 and FEC shall use up to a maximum dose 
of INT230-6 of 175 mL with the number of tumors being dosed per session to be decided by the 
investigators. The dose being set by the subject’s tumor burden. After completing 5 doses of INT230-
6, a maintenance single treatment of INT230-6 by intratumoral injection of up to 175 mL should 
be given every 9 weeks ± 10 days into target tumors until either progressive disease, radiologic 
or biopsy confirmed complete response, or two years. Refer to the Study Protocol for details on 
combination drug dosing. Decisions to increase the number of subjects in a cohort, to change the 
INT230-6 dose into the tumors, and the decision as to which populations to include will require 
consensus from the SCC. 
Up to a maximum of 44 subjects will be enrolled in Cohort DEC2. Review of DLTs will continue for 
Cohort DEC2 with the following conventions: 
x If 2 subjects experienced a DLT, an additional 6 subjects will be entered and followed 
for a 28 day DLT window 
x If > 3 subjects experience a DLT, the safety data will be reviewed by the SSC to 
determine if a lower dose or lower loading ratio per tumor of INT230-6 could be 
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x If the DLT rate is excessive during enrollment of the additional 44 subjects, the SSC 
reviewed the data and determine how the INT230-6 dose will be decreased, and the 
number of additional patients enrolled on the study at the lower dose 
For Cohort FEC, up to 15 subjects could be recruited into each of the following cancer types: 
metastatic hepatocellular carcinoma (HCC), breast cancer (BC) and soft tissue sarcoma. The 
overall cohort will employ a 6 subject safety lead-in to evaluate safety and toxicities. The safety 
data will be reviewed by the SCC to determine whether expansion to the total of 45 subjects 
should be permitted. For the HCC subjects in Cohort FEC, the first accrued HCC subject shall be 
evaluated at Day 28. This sentinel HCC subject must receive two INT230-6 doses and 
1 ipilimumab dose prior to accruing the remainder of the HCC portion of the cohort. If there are 
more than 2 DLTs in the HCC cohort, the SSC will evaluate de-escalation of ipilimumab. 
4.1.3. 
Expansion Cohorts  
DEC2 and FEC are expansion cohorts of 10-16 subjects with various single tumor types. These 
groups will allow for better point estimates of the safety and preliminary efficacy in a 
homogenous population of INT230-6 combined with immune checkpoint inhibitor drugs. 
Decisions on expansion cohorts for monotherapy (e.g., for EC3) may be made at a later time. 
4.1.4. 
Long Term Follow up  
Subjects who complete a full course of treatment including those who receive retreatment or who 
have discontinued treatment for any reason other than clinical or radiological progression will 
enter the Long Term Follow up period. During this time, subjects will be evaluated every 
8 weeks for the first year and every 3 months thereafter. During this Long Term Follow up 
Period, if a subject progresses or receives an intervening anti-cancer therapy, the subject will 
then enter the Survival Follow up Period.  
Subjects who discontinue treatment due to clinical or radiological progression or are Lost to 
Follow up or Withdraw Consent will not enter Long Term Follow up, but will enter survival 
follow up as outlined below. 
4.1.5. 
Survival Follow-up Period 
Following completion of the treatment and long term follow-up, as applicable, all subjects will 
be followed for survival. After that initial assessment of all study subjects, any surviving subjects 
will have their survival status assessed approximately every 3 months by either a telephone or 
in-person contact until study completion or termination by the Sponsor. With the exception of 
noting the first use of subsequent anti-cancer therapies, no other data (e.g., subsequent therapies, 
performance status etc.) beyond survival will be collected during these calls/visits. 
4.2. 
Study Population 
4.2.1. 
Selection of Study Population 
Male and female subjects at least 18 years old who meet the inclusion and exclusion criteria as 
outlined in Protocol Section 6 will be enrolled in the study.  


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4.2.2. 
Subject Replacement 
Subjects withdrawn from the study prior to completion of the DLT-evaluable period for a reason 
other than a DLT will be replaced. 
4.3. 
Randomization and Blinding 
This is an open-label non-randomized study. 
4.4. 
Study Assessments 
Details of scheduled assessments are presented in the study Protocol, with clarifications in 
Administrative letters 7 and 8.  Tumor imaging occurred 12 weeks ± 10 days after first dose and 
every 9 weeks ± 10 days thereafter. 
4.5. 
Protocol Deviations 
No deviations from the protocol are anticipated. Any protocol deviations recorded will be 
categorized as major or minor prior to data release for the final analysis of the primary endpoint. 
A summary table of the major protocol deviations will be generated for both dose escalation and 
expansion stages. A listing of major protocol deviations will be provided, sorted by center and 
phase.summarized and listed. 
5. 
SAMPLE SIZE DETERMINATION 
The sample size was estimated to be between 100 and 175 subjects during dose escalation and 
expansion. The final enrollment consisted of 110 subjects two of whom participated in more than 
one cohort. Expansion cohorts may treat subjects in a specific tumor type (e.g., sarcoma that 
would include chordoma) to provide additional safety information and preliminary assessment of 
tumor response within a disease indication.  
With 16 subjects treated in an expansion cohort in a given tumor type, the 90% confidence 
interval for an objective response rate would be 5.3% to 42% if 3 (19%) subjects had a response, 
9.0% to 48% if 4 (25%) subjects had a response and 13.2% to 54.8% if 5 (31%) subjects had a 
response.  
6. 
ANALYSIS POPULATIONS 
6.1. 
All Enrolled Population  
All subjects who sign the informed consent form, meet all inclusion/exclusion criteria, and are 
assigned to a cohort will be included. Subject disposition will be tabulated using this data set.  
6.2. 
All Treated Population  
All subjects who receive at least 1 dose or any partial dose of INT230-6. This population will be 
used for safety analyses and primary efficacy analyses.  


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6.3. 
Pharmacokinetic Population  
All available concentration-time data from subjects who receive INT230-6 will be reported. All 
available derived Pharmacokinetic (PK) parameter values will be included in the PK data set and 
reported, but only subjects with adequate PK profiles will be included in the summary statistics 
and statistical analysis. Further information will be provided in the PK manual. PK sampling was 
eliminated in Protocol Amendment 6. Pharmacokinetic analysis will be presented separately as 
an addendum. 
6.4. 
Response Evaluable Population  
Response evaluable population (REP) is defined as all subjects who receive at least one dose of 
INT230-6, have a baseline tumor assessment with measurable disease, and one of the following: 
1) at least one on-treatment tumor evaluation, 2) clinical progression, or 3) death prior to the first 
on-treatment tumor evaluation. This population will be used for primary efficacy analyses. 
6.5. 
Scan Evaluable Population  
The Scan Evaluable Population (SEP) will be defined as all subjects who receive at least one 
dose of INT230-6, have a baseline tumor assessment with measurable disease, and at least one 
on-treatment tumor evaluation via a scan at two months or later post first dose. 
6.6. 
Exploratory Biomarker (Immune Function and others) Population  
All subjects who receive at least one dose of INT230-6, have a pre-dose and at least one 
post-dose measurement for a specific marker will be included in the data set for that marker. All 
treated subjects with at least one baseline measurement will be included in predictive analyses; 
treated subjects with baseline measurement and at least one on treatment measurement will be 
included in pharmacodynamic assessments. Blood biomarker sampling was eliminated in 
Protocol Amendment 6. Biomarker analysis will be presented separately as an addendum. 
6.7. 
Retreatment Population  
For Cohorts A1, B1, EA, EC, EC2, and DEC, those subjects who have completed treatment and 
have not started on any subsequent anti-cancer therapy will be eligible for retreatment. Prior to 
Study Protocol Amendment 5, three subjects had initiatied retreatment. This population 
assignment will no longer be applicable moving forward with the study. Given the few numbers, 
these three subjects will be described in the Clinical Study Report (CSR) with regards to safety 
and efficacy in the form of a case series and will also be included in summaries regarding their 
initial and subsequent treatment as applicable. No aggregate tables will be developed solely for 
this population.   
7. 
GENERAL STATISTICAL CONSIDERATIONS 
All analyses described below will be carried out using SAS® Version 9.4 or higher. Continuous 
variables (e.g., age) are summarized using descriptive statistics. Categorical variables (e.g., race) 
are summarized using counts and percentages. Percentages are calculated using the total number 
of subjects in each cohort. 


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7.1. 
General Reporting Conventions 
In this document, when describing tables to be generated, cohort groups will be referenced as 
being presented ‘by treatment’. The following data conventions are applied to all data 
presentations and summaries.  
Treatments  
x Cohorts A, B1, EA, EC are to be combined for analysis and defined as low loading 
monotherapy treatment, where low loading refers to a lesser potential for proper 
treatment of a subject’s total tumor burden due to dose volume restrictions on 
INT230-6 during escalation. 
x Cohorts EC2 and EC3 are to be combined for analysis purposes and defined as high 
loading monotherapy treatment, where high loading refers to a greater potential for 
proper treatment of a subject’s total tumor burden due to meaningfully higher dose 
volume amounts allowed for INT230-6. 
x Cohorts DEC and DEC2 are to be combined to define INT230-6 with pembrolizumab 
treatment 
x Cohort FEC is defined as the combination of INT230-6 with ipilimumab treatment. 
 Data will be described and summarized separately for low and high dose 
monotherapy cohort groups (A1/B1/EA/EC vs. EC2/EC3) and combination 
cohorts by treatment (DEC/DEC2 and FEC). 
 For assessments performed at defined time points, the data will be summarized 
and  reported for each time point. 
 Summary tables for continuous variables will contain the following statistics: N 
(number of subjects in the population); n (number of subjects with data); mean; 
standard deviation (SD); median; minimum; and maximum; 25th and 75th 
percentiles when applicable. Selected statistics may also include a 2-sided 95% 
normal approximation confidence intervals (CIs) on the mean. 
 Summary tables for categorical variables will include: N (number of subjects in 
the denominator); n (number of subjects in the numerator); and percent and will 
be presented in the format XX (XX.X%), where the percentage is in parentheses. 
Selected statistics also may include 2-sided 95% CIs for the percent based on the 
exact Clopper-Pearson methodology for binomial proportions.  
 Unless noted to the contrary, the denominator used for the calculation of 
percentages will be the number of subjects in the specified analysis population 
who are in the cohort being summarized. 
 Date variables are formatted as yyyy-MM-dd for presentation. Time is formatted 
in military time as HH:MM for presentation. 
 The baseline value for a given parameter is the last non-missing value prior to the 
first dose. A value is considered to be post-baseline if it is obtained after the first 
study drug administration.  


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 Change from baseline is calculated as (post-baseline result – baseline result). 
Percent change from baseline is calculated as (change from baseline/baseline 
results * 100). If either the baseline or post-baseline result is missing, the change 
from baseline and/or percent change from baseline is set to missing as well. 
 Data from study centers will be pooled for all analyses 
 Study Day is defined as calendar date – date of first treatment + 1 if the calendar 
date is on or after the date of first treatment, and calendar date – date of first 
treatment if the calendar date is before the date of first treatment 
 Measurements from unscheduled visits will be included in listings, but not 
summary tables 
 Missing data conventions for individual endpoints are described in detail below 
for the endpoints 
 Listings will be provided of all data collected in the electronic Case Report Form 
(eCRF) 
 Wherever possible, data will be decimal aligned 
 For continuous variables, use the following conventions for significant digits: 
mean (xx.x), median (xx.x), standard deviation (xx.xx), minimum (xx.x) and 
maximum (xx.x). If data results are less than 1, format decimal points to one more 
place than the measured value for all summary variables except format to two 
more places for standard deviations 
 Version 25.1 of MedDRA will be used for this study.  
 WHODRUG Enhanced Sep-2022 B3 will be used for this study. 
The accompanying table, listing, figures (TLF) document to this SAP provides the expected 
layout and titles of the tables, figures, and listings. Any changes to format, layout, titles, 
numbering, or any other minor deviation will not necessitate a revision to the SAP nor will it be 
considered a deviation from planned analyses. Only true differences in the analysis methods or 
data handling will necessitate such documentation.  Please refer to the SAP appendix for 
additional programming notes. 
7.2. 
Interim Analyses  
Administrative interim analyses on safety and efficacy or on PK, and selected biomarkers may 
be provided at several times prior to completion of the study in order to facilitate program 
decisions and to support study presentations or publications. No formal interim analyses are 
planned for this study. 
7.3. 
Multi-Center Studies 
This is a multi-center study. Given the small sample size of the study, no site effect will be 
considered in any statistical analysis. 


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7.4. 
Multiple Comparisons / Multiplicity 
No adjustments for multiple tests or multiple comparisons will be utilized. 
7.5. 
Examination of Subgroups 
Analysis endpoints of safety and efficacy variables may be further explored with the following 
subgroups:   
x Tumor ratio (1:4, 1:3, 1:2 or dose set by longest diameter formulas) 
x Dose schedule (every 2 weeks versus every 4 weeks) 
x Superficial tumor injection subjects versus deep tumor injection subjects 
x Tumor type (Sarcoma) 
x Status of prior treatment with platinum-based antineoplastics or vinca alkaloid 
therapies 
x Subjects with less than 2 tumors injected compared to those with 2 tumors 
x Tumor burden: subjects receiving  40% of tumor burden injected versus those 
receiving < 40% ; tumor burden is calculated based on EDC documentation of target, 
bystander, non-target, and new tumors. Subjects receiving   40% of baseline total 
tumor burden injected overall (during the course of therapy) and at first dose will be 
explored. For overall, the sum of all injection volumes will be used in the calculation.   
The subgroups to be analyzed for each endpoint are described in Section 8, Section 9, and 
Section 10. 
7.6. 
Handling of Dropouts or Missing Data 
Where individual data points are missing because of insufficient samples, dropouts, or other 
reasons, the data will be analyzed based on reduced denominators (e.g., using the response 
evaluable population). For survival analysis, dropouts without confirming events will be treated 
as censored. 
All missing and partial start dates will be queried for a value. If a complete start date cannot be 
obtained, the following imputation rules apply in order to calculate duration of adverse event, 
concomitant medication use, or prior cancer history endpoints: 
x Missing month and day 
 If the year of the incomplete start date is the same as the year of the date of study 
drug administration, then the missing month and day of the start date will be 
imputed to be the month and day of the start of study drug administration. 
 If the year of the incomplete start date is before the year of the date of study drug 
administration, December 31 will be assigned to the missing fields. 
 If the year of the incomplete start date is after the year of the date of study drug 
administration, January 1 will be assigned to the missing fields. 


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x Missing month only 
 If only the month is missing, the day will also be treated as missing, and both 
month and day will be replaced according to the above procedure. 
x Missing day only 
 If the month and year of the incomplete start date are the same as the month and 
year of the date of study drug administration, the start date of study drug will be 
assigned to the missing field (i.e., AEs will be assumed treatment-emergent, and 
medications will be assumed concomitant). 
 If the month and year of the incomplete start date are before the month and year 
of the date of study drug administration, the last day of the month will be assigned 
to the missing field. 
 If the month and year of the incomplete start date are after the month and year of 
the date of study drug administration, the first day of the month will be assigned 
to the missing field. 
If the stop date is complete and the imputed start date, when imputed as instructed above, is after 
the stop date, the start date will be imputed to equal the stop date. 
7.7. 
Outlier Handling 
Potential data entry errors manifested as outliers will be handled in the data management process 
through edit checks. 
7.8. 
Adjustments for Covariates 
There is no plan to adjust for any covariates. 
8. 
SUMMARY OF STUDY POPULATION DATA 
Tables related to the study population will be in Section 14.1 and listings in Section 16.2 of the 
TLF Shell Document and the CSR. 
8.1. 
Subject Disposition 
The total number of subjects enrolled and the total number of subjects in each analysis 
population will be provided by study part. Among subjects who received any study drug, 
frequency and percentage of subjects who completed treatment, prematurely discontinued and 
reasons for premature discontinuation, and reason for end of study will be tabulated. 
Separate listings will be provided for subject disposition, inclusion/exclusion eligibility, and 
analysis population assignment. The disposition listing will include informed consent date, first 
treatment, last treatment, treatment duration (days), reason for premature discontinuation from 
study drug treatment, date of study discontinuation, reason for study discontinuation, date of 
subsequent anti-cancer therapy, and, if applicable, date of death.   


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8.2. 
Protocol Deviations 
The number of protocol deviations per subject (mean, SD, median, minimum, and maximum), 
the number and percentage of subjects who presented at least one protocol deviation in each 
category, and the number and percentage of subjects who discontinued due to protocol violation 
will be summarized for each study part and overall.  
All major and minor protocol deviations will be listed. 
8.3. 
Demographics and Baseline Characteristics 
Descriptive statistics will be used to summarize demographics and baseline characteristics for the 
Safety Population. 
Subject demographics and baseline characteristics including age, sex, race, ethnicity, height, 
weight, and Eastern Cooperative Oncology Group (ECOG) performance status will be 
summarized by study part.  
Medical and surgical history/physical findings will be coded using MedDRA Version 25.1 and 
summarized by system organ class (SOC)/ preferred term (PT) and study part. Cancer history at 
screening will be summarized by diagnosis and stage for each study part. Previous anti-cancer 
therapy, prior cancer surgery, and prior radiation therapy will be summarized by study part and 
tumor type. Previous anti-cancer therapy will be further categorized as the number and 
percentage of subjects having any platinum-based antineoplastics, vinca alkaloid therapies, 
anti-PD-1 agents, or other prior anti-cancer therapies. These summaries will include summary 
statistics of prior regimens per subject, best overall response, number experiencing peripheral 
neuropathy (platinum-based antineoplastics only), and number resistant to the therapy 
(platinum-based antineoplastics and vinca alkaloids only).   
Duration on last prior therapy will be calculated as the earliest of Progression Date on prior 
therapy, Last Date on prior Treatment, or Date of IT-01 Screening less the earliest Treatment 
Initiation Date of Most Recent Prior Cancer Therapy, converted to months by dividing by 
30.4375. A separate tornado plot will present duration on last prior therapy vs. duration on 
INT230-6 for Cohorts A/B1/EA/EC, EC2/EC3, DEC/DEC2 and FEC.   
Listings will be provided for individual subject demographics and baseline medical and surgical 
history/physical findings, as well as cancer history at screening, previous anti-cancer therapy, 
prior cancer surgery and prior radiation. 
8.4. 
Dosing and Extent of Exposure 
The dose of INT230-6 administered to subjects will be summarized by total dose injected (mL), 
maximum dose injected into any one tumor (mL), number of tumors injected for each cohort and 
percent of total tumor burden injected. Drug leakage will also be listed. Subjects receiving study 
drug per protocol, subjects receiving partial or incomplete drug dose, and reasons for interruption 
will be summarized. Individual study drug administration records and deviations in 
administration will be listed, as well as the largest dose into any one tumor.  


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Pembrolizumab and ipilimumab administration will be summarized in a table and listing and will 
include total dose administered, dosing delays, reason for dosing delays, number and reasons of 
subjects permanently discontinuing drug, and number and reasons of infusion interruptions.    
8.5. 
Prior and Concomitant Medications 
Prior and concomitant medications will be coded using the World Health Organization Drug 
Dictionary (WHODD) Version Dec 2016. Prior and concomitant medications will be 
summarized by preferred term. A listing of prior and concomitant medications by subject will be 
provided. Non-drug treatments and procedures will be listed. 
9. 
EFFICACY ANALYSES 
Due to the method of action of the INT230-6 therapy observed over the course of the study, 
proper assessment utilizing RECIST or iRECIST was not possible. A response across all lesions 
using sum of diameters to assess efficacy over time using response criteria was not utilized. 
Thus, efficacy analyses will largely focus on the response of individual tumors (injected and 
bystander) as opposed to an overall tumor response, and any overall response will utilize the 
modified response criteria defined below. 
Efficacy analyses will be conducted on the All Treated Population (ATP) , the Response 
Evalauble Population (REP), and the Scan Evaluable Population (SEP).  RECIST 1.1 
assessments were not collected. Rather injected tumor response and non-injected tumor response 
utilizing some of the RECIST criteria were evaluated. Sponsor utilized RECIST principles with 
the injected and non-injected tumor measurements obtained. Efficacy will be determined based 
on a modified version of RECIST 1.1 criteria. Specifically, complete response (CR) and partial 
response (PR) will be defined for injected tumors followed per RECIST 1.1 utilizing target 
lesions. Progressive disease will be determined by clinical or radiological deterioration leading to 
the subject being taken off-treatment at the discretion of the investigator. Stable disease (SD) is 
defined as any adequate assessment not considered CR, PR, or progression. The appearance of a 
new lesion will not necessarily be considered progression and if possible will be assessed. Any 
post-baseline visit where a target lesion present at baseline was not assessed will result in a Not 
Evaluable (NE) assessment for that lesion. Data will be presented by treatment and, when 
indicated, by subgroups. 
The primary efficacy parameter is the disease control rate (DCR), defined as the number of 
subjects obtaining a best overall response of either CR, PR, or SD as described above divided by 
the total number of subjects in the analysis population. The DCR will be presented with 
accompanying 95% exact binomial confidence intervals for each study part for the ATP 
population, REP, SEP, and by subgroup.  
At baseline, lesions are classified as measurable or nonmeasurable per either RECIST 1.1 
guidelines, depending on the cohort. Baseline measurable lesions are further classified as target 
(injected) or bystander (non-injected), while non-measurable lesions are classified as non-target 
(non-target lesions are not eligible for injection). A sum of diameters (SOD) (longest for 
extranodal lesions and shortest for lymph nodes) will be calculated for all target lesions. Tumor 
volume (for target tumors with three dimensions) will also be calculated using the modified 


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ellipsoid method or by longest diameter if specified in an particular protocol amendment. 
Bystander lesions will be recategorized as target lesions once injected, but target lesions will 
always remain target lesions.   
9.1. 
Additional Efficacy Analysis 
Additional efficacy parameters include the duration of response (DOR), the injected tumor 
response (ITR), the bystander tumor response (BTR), progression free survival (PFS), and 
overall survival (OS).  These endpoints will be summarized by treatment (see section 7 for 
definition of each treatment) and subgroup.  Other than 1 listing reporting bystander tumors’ 
diameter that declined over time that declined (noted below), the bystander tumor response rate 
(BTR) analysis will be conducted separately from the SAP from collected radiographic data. 
DOR is defined as the time from first tumor assessment of CR, PR, or SD to the time of 
progressive disease or death due to any cause.  For responders with no death or progression, 
DOR will be censored on the last non-PD tumor assessment or follow-up call.   
The median DOR as obtained from Kaplan-Meier methods will be presented by treatment and 
subgroup and will include the median, 25th percentile, 75th percentile, and a 2-sided point-wise 
95% confidence interval.   
ITR will be based on the target tumors at the baseline visit; tumors that become target during the 
study will also be included in the ITR calculation at the time they are treated. The ITR is defined 
as the ratio of CR + PR in injected tumors / total number of injected tumors. Thus, bystander or 
non-target lesions dosed at later dates are not included in calculations for ITR. 
The ITR will be calculated based on the maximum likelihood estimator and summarized in 
tables. The estimate of ITR will be accompanied by 2-sided 95% exact binomial confidence 
intervals as determined by the Clopper-Pearson method and assessed at each study-specified 
timepoint where an assessment is performed. 
The BTR will follow the same definition as the ITR for bystander tumors. Note that bystander 
tumors that are injected on study will be included in the ITR calculation.  
Individual tumor assessments for target and bystander, non-target, and new lesions will be listed, 
with location, method of assessment, longest diameter, shortest diameter, depth, volume, and 
percent change from baseline included for each target and bystander tumor, as well as Total 
Tumor Burden at Baseline, Cumulative Dose, Percent TTB dosed, and dose category (< 40% 
YHUVXV per subject.   Another listing will be produced for the Abscopal effect of 
bystander tumors, defined as any bystander tumor with any decrease in tumor size at any point 
during the study, but before being injected with study drug. 
9.2. 
Progression-Free Survival and Overall Survival 
Progression free survival (PFS) and Overall Survival (OS) will be evaluated for the All Treated 
Population, the REP, and the SEP. PFS will be defined as the time (in months) from first dose of 
INT230-6 to either observation of clinical deterioration, removal from study, or occurrence of 
death due to any cause within 126 days (approximately 2 time intervals for tumor assessments) 
of the last tumor assessment. Progression date will be defined as the end of treatment date as 
captured per eCRF guidelines when the reason for end of treatment is either ‘Radiographic 


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deterioration’ or ‘Clinical deterioration.’ In subjects without a progression date or with a death 
date more than 126 days after the last tumor assessment, the PFS time will be censored on the 
date of last tumor assessment or last treatment date if the subject has no post-baseline tumor 
assessments. PFS analyses will consider tumor assessments after treatment discontinuation.  
OS will be defined as the time (in months) from first dose of INT230-6 to death. Subjects for 
whom death is not reported will be censored at the date of end of study. 
PFS and OS will be summarized in a listing. The median time to OS as obtained from Kaplan-
Meier methods will be tabulated by subgroup and will include the median, 25th percentile, 75th 
percentile, and a 2-sided point-wise 95% confidence interval. Hazard ratios may be determined 
between certain curves for the Kaplan Meier figures noted below. 
A Kaplan Meier figure of OS for the All Treated, REP, and SEP populations will be presented 
for each of the following:  
x a curve all treated monotherapy patients, a curve for subjects that received a dose to 
total tumor burden < 40% of tumor burden, a curve for those subjects that had a dose 
to total tumor burden  40%,  
x a curve for escalation cohort combining A1, B1, EA, EC, and a curve for escalation 
cohort combining EC2 and EC3,   
x a curve for sarcoma patients in the monotherapy cohort and a curve for monotherapy 
sarcoma patients having 40% of their total tumor burden treated, 
x a curve for the pembrolizumab DEC/DEC2 combined cohort for subjects, 
x a curve for all ipilimumab FEC cohort subjects,  
x a curve for the ipilimumab FEC sarcoma subjects, a curve for all monotherapy 
sarcoma patients and a curve for monotherapy sarcoma subjects having  40% of 
their total tumor burden treated will be included. 
10. 
SAFETY ANALYSES 
The primary safety objective is to assess the safety of INT230-6 in subjects with advanced or 
recurrent malignancies as determined by the rate of  Grade 3 AE’s attributed to INT230-6 and 
not the underlying disease. Safety and tolerability of INT230-6 will be assessed for the All 
Treated Population. Adverse events will be graded using the National Cancer Institute’s 
Common Terminology Criteria for Adverse Events Version 4.03. Dose limiting toxicities (DLT) 
for this study are defined DVD Grade 3 study drug-related adverse events occurring during the 
first dose (DLT window extends up to 28 days after dosing), with exceptions noted in 
Section 9.1.1 of the study Protocol.  
Subjects will be monitored throughout the treatment and follow-up period for occurrence of AEs. 
Additional safety parameters to be measured/assessed include PE findings, vital sign 
measurements, hematology, coagulation, serum chemistries, urinalysis, ECOG performance 
status, and ECG. 
Tables related to the safety analyses are located in Section 14.3 and listings in Section 16.2. 


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10.1. 
Adverse Events 
Adverse event summaries will be based on treatment-emergent adverse events (TEAEs), and will 
be presented by study part. TEAEs are defined as any non-serious AE or unrelated serious AE 
(SAE) that occurs during or after administration of the first dose of treatment through 28 days 
after the last dose, any non-serious AE or unrelated SAE that occurs during or after retreatment 
up to 28 days post-dose of the last re-treatment, any related SAE occurring after first dose of 
treatment without respect to date of last dose, or any event that is present at baseline but worsens 
in intensity. Adverse events will be summarized by treatment. Events worsening in severity will 
be considered new AEs. AEs recorded in the eCRF that began prior to treatment will be recorded 
and displayed as part of the medical history. 
All adverse events will be coded using Version 25.1 of MedDRA. Summaries of TEAEs will 
present data by System Organ Class (SOC) and preferred term (PT) in order of decreasing 
frequency of total SOC count, followed by decreasing frequency of total PT count. The 
following conventions will be followed in summarizing multiple occurrences of an adverse event 
for a certain assessment period when summarizing data from individual subjects: 
x Each subject will be counted only once within SOC or PT 
x The highest known severity within a body system or a PT will be assigned to the 
event 
x The strongest relationship within a body system or a PT will be assigned to the event. 
The denominator used for calculation of percentages will be the number of subjects in the All 
Treated population per cohort. 
An overall summary of treatment emergent adverse events (TEAEs) will include: 
x number and percentage of subjects with one or more TEAEs 
x number and percentage of subjects with one or more INT230-6 monotherapy TEAEs  
x number and percentage of subjects with one or more TEAEs for DEC and DEC2 
cohorts (not by individual drug agent) 
x number and percentage of subjects with one or more TEAEs for FEC cohort (not by 
individual drug agent) 
x number and percentage of subjects with one or more procedure-related TEAEs for 
INT230-6 monotherapy treatments (all monotherapy cohorts combined) 
x number and percentage of subjects with one or more related TEAEs for DEC and 
DEC2 cohorts (not by individual drug agent) 
x number and percentage of subjects with one or more related TEAEs for FEC cohort 
(not by individual drug agent) 
x number and percentage of subjects with one or more severe (Grade 3 or above) 
TEAEs 


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x number and percentage of subjects with one or more severe (Grade 3 or above) 
INT230-6 monotherapy treatment-related TEAEs (all monotherapy cohorts 
combined) 
x number and percentage of subjects with one or more severe (Grade 3 or above) 
related TEAEs for DEC and DEC2 cohorts (not by individual drug agent) 
x number and percentage of subjects with one or more severe (Grade 3 or above) 
related TEAEs for FEC cohort  (not by individual drug agent) 
x number and percentage of subjects with one or more serious adverse events (SAEs) 
x number and percentage of subjects with one or more INT230-6 monotherapy-related 
SAEs (all monotherapy cohorts combined) 
x number and percentage of subjects with one or more related SAEs for DEC and 
DEC2 cohorts 
x number and percentage of subjects with one or more related SAEs (for FEC cohort) 
x number of deaths (if any) 
x number and percentage of subjects with one or more TEAEs resulting in 
discontinuation from the study 
The frequency and percentage of TEAEs by SOC and PT for each treatment will be tabulated. 
The frequency and percentage of TEAEs by SOC/PT by maximum severity (Grade 1 - 5) will be 
presented by treatment. The frequency and percentage of Related TEAEs and of All TEAS 
(related or unrelated) by PT and by maximum severity will be presented for the following 
cohorts:  
x Overall Monotherapy 
x Monotherapy Cohorts A1/B1/EA/EC 
x Monotherapy Cohorts EC2/EC3 
x Combination Pembrolizumab Cohorts DEC/DEC2 
x Combination Ipilimumab Cohort FEC 
x Monotherapy Sarcoma Subjects  
x Combination Ipilimumab Cohort FEC Sarcoma Subjects 
x Note:Sarcoma includes chordoma. 
The number and percentage of TEAEs by SOC/PT considered related to study drug will be 
summarized. Number and percentage of subjects experiencing Grade 3 or higher TEAEs by 
SOC/PT will be summarized. Number and percentage of subjects experiencing Serious TEAEs 
by SOC/PT will be summarized. The frequency and percentage of TEAEs that lead to study 
discontinuation will be presented. If a subject moves from monotherapy to combination therapy 
treatment, the summary adverse events will be calculated based on the treatment at the time of 
the event. 


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A listing of all AEs data sorted by subject, including the verbatim term, MedDRA SOC and 
preferred term, duration of AE (calculated as Stop Date – Start Date + 1), Outcome, Severity, 
Relationship to Study Drug, Relationship to Dosing Procedure, Action Taken, Subject 
Discontinued Y/N, DLT Y/N, and SAE criteria, if relevant, will be provided. Additionally, 
individual AE records of SAEs, any deaths occurring during the study, AEs that led to 
discontinuation, Grade  3 AEs, and DLTs will be listed separately. 
10.2. 
Clinical Laboratory Evaluations 
Clinical laboratory values will be summarized in SI units. Severity grades will be 
programmatically calculated using standard American Medical Association’s (AMA) laboratory 
normal ranges [AMA Manual of Style, AMA 2009] and the quantitative NCI CTCAE 4.03 
criteria (when available for a specific laboratory abnormality). Laboratory values considered to 
be normal by CTCAE criteria, meaning they do not qualify as Grade 1 - 4, will be assigned a 
severity grade of 0. For laboratory tests without any CTCAE criteria, toxicity grades will be 
recorded as 99. 
Summary statistics of numerical laboratory test results and changes of test results from baseline 
will be reported by treatmentfor hematology, coagulation, serum chemistry, and urinalysis at 
each scheduled time point. For values with categorical results, the frequency and percentage of 
each result category will be tabulated at each scheduled time point by treatment. Shift tables will 
also be included reporting change from baseline category (low, normal, high) to post-dose 
category (low, normal, high) for cohorts and overall. Abnormal laboratory values that lead to a 
change in subject management or that are considered to be of clinical significance will be 
reported as an adverse event (serious adverse event if relevant) and summarized by SOC/PT and 
according to severity in the appropriate AE tables. Clinical significance will be determined by 
the Principal Investigator at each site. 
Individual test result records, including repeat assessments, and comments for hematology, 
coagulation, serum chemistry, and urinalysis will be displayed in listings. Laboratory values 
outside normal limits will be identified with flags for high, low, and normal limits in the listings. 
Pregnancy test results will be displayed in a listing. 
10.3. 
Vital Signs 
Vital sign measurements and change from baseline will be summarized by cohort, tumor type 
and study visit using descriptive statistics. Vital signs include weight, systolic blood pressure 
(SBP), diastolic blood pressure (DBP), body mass index (BMI, derived), heart rate, oxygen 
saturation, and temperature. Individual vital sign measurements will be listed. 
10.4. 
ECGs 
Summary statistics of ECG overall interpretation will be displayed by treatmentand study visit. 
Per subject ECG test results will be listed. 
Abnormal clinically significant ECG findings on or after informed consent will be recorded as an 
adverse event and displayed with AEs. 


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10.5. 
Physical Examination 
Abnormal PE findings with onset prior to first dose of study drug will be recorded as medical 
history. Any abnormal or clinically significant findings on or after dosing will be recorded as an 
adverse event. Clinical significance will be determined by the Principal Investigator at each site. 
Individual medical/surgical history will be listed by subject. Individual abnormal or clinically 
significant PE findings after dosing will be recorded as an adverse event and listed separately 
with AEs. 
11. 
CLINICAL PHARMACOLOGY ANALYSES 
Not Applicable. 
12. 
OTHER ANALYSES 
12.1. 
Pharmacokinetic Analysis 
PK analysis is detailed in the PK manual. Pharmacokinetic are out of the scope of this analysis 
plan and will be summarized separately. 
12.2. 
Exploratory Biomarkers of Immune Response 
Summary statistics for immune function and other exploratory markers, such as but not limited 
to flow cytometry outcomes, cytokines, quantitative immunoglobulins, quantitative 
inflammatory infiltrates, T-cell repertoire and their changes (or percent changes) from baseline 
will be tabulated by cycle visit and dose to assess pharmacodynamic effects. In addition, the time 
course of biomarker outcomes will be investigated graphically, by summary plots (i.e., box plots) 
or individual subject plots over time. Possible associations between changes in biomarker 
measures of interest and pharmacokinetic exposure will be explored.  
Measures from markers based on optional samples, e.g., tumor-based markers may be similarly 
presented, depending on data availability. Additional information can be found in the Biomarker 
Manual.   
Biomarker analyses are out of the scope of this analysis plan and will be summarized separately. 
12.3. 
Pharmacodynamic Analyses 
Pharmacodynamic analyses are out of the scope of this analysis plan and will be summarized 
separately. 
13. 
CHANGES IN THE STATISTICAL METHODS FROM THOSE 
STATED IN THE PROTOCOL 
None. 


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14. 
REFERENCES 
None. 
15. 
TABLES, FIGURES, LISTINGS 
Tables, listings and figures will be generated according to the companion document which 
details the layout of the output. Minor style deviation from specification defined in the shell 
document in the final production is permissible. 
 
 


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APPENDIX 1.  
The following information provides additional programming instructions to define important 
variables that are not available in the main SAP text. 
1. 
TOTAL TUMOR BURDEN (TTB) 
Step 1: If all 3 dimensions are reported, volume = (longest*shortest*depth*0.63) 
Step 2: If not all 3 dimensions are reported and longest diameter is reported, volume calculation 
is based on the longest diameter measurement. 
1. If .< longest < 1.5 cm, volume = 1 cm3 
2. If 1.5  longest  4 cm, volume = longest3/2 
3. If 4 < longest < 9 cm, volume = longest3/3 
4. If longest  9 cm, volume = longest3/4 
5. If shortest is only measurement reported, Diameter = shortest and follow step 2 tasks 1 to 
4 for volume calculations 
Step 3: Sum all calculated volume values across target and bystander tumors. 
2. 
% DOSED TTB 
Step 1. Calculate TTB of all of a patient’s bystander and target tumors reported in the database  
using the TTB formulas above.  
Step 2. Calculate patient’s cumulative dose of INT230-6  
Step 3. Calculate % Dosed TTB as (cumulative dose / Patient TTB) * 100. 
3. 
INJECTED TUMOR RESPONSE RATE (ITR) 
At a given visit, assess whether each injected tumor has achieved a PR or CR per RECIST 1.1. 
Count the total number of target (injected) tumors that achieve a PR or CR and divide by the 
total number of target tumors at that visit. This is the ITR. A PR is defined as a change  30% in 
tumor volume, a CR is defined as having no visible tumor. 
Note: for re-baselining retreated subjects that switch to a new cohort, the last assessment prior 
to the first retreatment is used as the baseline reference for determining PR. 
4. 
BYSTANDER TUMOR RESPONSE RATE (BTR) 
Follow the method for ITR, instead using bystander tumors. Note that if a bystander tumor is 
injected on study, this tumor can no longer by considered bystander after the date of injection 
and will be included in the ITR calculation from that injection date visit onward. This can cause 
the denominator to be dynamic over visits. 


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5. 
PROGRESSION DEFINITION 
Progression is defined as a patient who radiographically or clinically deteriorated as captured on 
any number of forms designating the patient is ending treatment or death. This includes the end 
of treatment form, end of maintenance form, follow-up form, and survival form. Note that typical 
RECIST 1.1 indications of progression such as an increase in sum of longest diameters of 20% 
or the presence of a new lesion are not considered progression for the purposes of PFS. 
6. 
IMPUTATION OF END DATE OF LAST PRIOR ANTI-CANCER 
THERAPY 
 If end date is completely missing, use IT-01 screening date 
 If year is present and end month is missing, use the min of (IT-01 screening date, 
last date of year) 
 If month is present and day is missing, use the min of (IT-01 screening date, last 
date of month) 
7. 
PEMBRO LISTINGS/RETREATED SUBJECTS 
Baseline listings (demographics, disposition, prior therapy, etc): the 2 retreated subjects should 
appear in the monotherapy listings only (we are already doing this – no change) 
 Study drug administration: the 2 subjects monotherapy administration of 
INT230-6 should appear in the monotherapy table/listing. The INT230-6 
administration that occurred during combination therapy should appear in the 
pembro table/listings. 
 Safety: events should appear in the cohort in which they occurred (we’re already 
doing this) 
 Other event-based outputs related to safety (labs, ECG, vital signs): similar to 
adverse events, these assessments should appear in the cohort in which they 
occurred for the 2 retreated subjects. 
8. 
IMPUTATION OF END DATE OF LAST PRIOR ANTI-CANCER 
THERAPY 
 If end date is completely missing, use IT-01 screening date 
 If year is present and end month is missing, use the min of (IT-01 screening date, 
last date of year) 
 If month is present and day is missing, use the min of (IT-01 screening date, last 
date of month) 


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OTHER NOTES 
 Footnote: “Subjects 004-002 and 002-009 were initially treated on monotherapy 
and were later retreated on combination therapy with pembrolizumab. Applicable 
events are presented in the display according to these patients corresponding 
regimen.” 
 Regarding 001-005’s follow-up status and time to event outcomes like DOR, I 
confirmed there are no other indications this patient came off treatment/study, so I 
think we’ll leave as is. It would be useful to include this in the delivery email in 
case the sponsor wonders what’s going on with this one patient who is likely an 
outlier. 
 


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ITR/BTR re-baselining 
Consider the below table for a hypothetical patient that had a baseline bystander tumor treated during the first treatment course and 
then later retreated. 
USUBJID 
VISIT 
Cohort 
TRLNKID 
Treated 
Tumor 
Class 
Baseline 
Flag 
BTR 
calculation 
ITR 
calculation 
Comments 
1001 
Screening 
EC 
BY-11 
N 
Bystander 
  
N 
N 
Pre-baseline but not most 
recent assessment. Not used 
at all. 
1001 
Screening 
EC 
BY-11 
N 
Bystander 
Y 
Y 
N 
Baseline for BTR calculation 
1001 
C2D0 
EC 
BY-11 
N 
Bystander 
  
Y 
N 
Tumor not yet treated so 
included in BTR calculation 
1001 
C4D0 
EC 
BY-11 
N 
Bystander 
Y 
Y 
Y 
Tumor not yet treated so 
included in BTR calculation 
AND also baseline for ITR 
calculation 
1001 
Repeat Assessment 
1 
EC 
BY-11 
Y 
Target 
  
N 
Y 
First treated visit. Tumor is 
now target and previous 
assessment is baseline for 
reference 
1001 
Repeat Assessment 
2 
EC 
BY-11 
Y 
Target 
Y 
N 
Y 
Considered for ITR on first 
treatment AND is baseline 
reference for Retreatment 
1001 
C2D0 Retreatment 
DEC 
BY-11 
Y 
Target 
  
N 
Y 
Included for Retreatment 
ITR calculation 
1001 
C4D0 Retreatment 
DEC 
BY-11 
Y 
Target 
  
N 
Y 
Included for Retreatment 
ITR calculation 
1001 
C6D0 Maintenance 
DEC 
BY-11 
Y 
Target 
  
N 
Y 
Included for Retreatment 
ITR calculation 
Important notes: 
-First Screening assessment is not included at all because there is a later screening assessment that can be used as baseline. 
-Subject is considered for BTR through C4D0. 
-Upon being treated as Repeat Assessment 1, subject is now considered for ITR. The last bystander measurement is used as baseline for ITR calculation on the 
first treatment course. 
-Patient is retreated in the 3rd to last row (C2D0 retreatment). ITR calculation is restarted for new cohort, using the last record from the EC cohort as baseline. 


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Dosed TTB 
Consider the following hypothetical patient’s baseline tumor burden for calculation of Dosed TTB. 
USUBJID 
Tumor Class 
TRLNKID 
Longest 
Diameter 
Shortest 
Diameter 
Depth 
(LD*SD*Depth*0.63) 
1001 
Target 
T-1 
4 
3 
3 
22.68 
1001 
Target 
T-2 
2 
1 
1.5 
1.89 
1001 
Bystander 
BY-11 
2 
1 
1 
1.26 
1001 
Bystander 
BY-12 
1.5 
1.2 
1 
1.134 
 
To find TTB, we would simply add the tumors’ individual LD*SD*D*0.63 calculations together: 22.68+1.89+1.26+1.134 = 26.964 
To calculate % dosed TTB , we add up the total dose received by the patient and divide it by the patient’s TTB. For example, if this 
patient received a total of 20 ml in T-1 and 1 ml in T-2 of INT230-6, the % dosed TTB would be (20mL + 2 mL) / (26.964 cc) * 
100 = ~81.5% 
Note that this example TTB calculation had all 3 measurements available (LD, SD, Depth) and so just uses Step 1 from the formula 
for TTB. Had less measurements been available, we would proceed to Step 2, calculate TTB as indicated, and sum them together in 
the same way.