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INT230-6 injections every 28 days for 5 sessions into only superficial tumors, low starting dose, low concentration per tumor.

Completed

INT230-6 injections every 28 days for 5 sessions into deep tumors, low starting dose, low drug concentration per tumor

Completed

INT230-6 injections every 2 weeks for 5 sessions into superficial tumors, medium starting dose, low drug concentration per tumor

Completed

INT230-6 injections every 2 weeks for 5 sessions into superficial or deep tumors, moderately high starting dose, high drug concentration per tumor

Completed

INT230-6 injections every 2 weeks for 5 sessions into superficial or deep tumors, high starting dose, moderate drug concentration per tumor, higher number of tumors to be treated per session than EC

Completed

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

INT230-6 injections every 2 weeks for 5 sessions 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.

Completed

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

Completed

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

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.

The drug is stored frozen and must be dosed at room temperature.

The drug dose to be administered is set by the tumor volume of the target lesions - not the subject's body surface area

INT230-6

The anti-PD-1 antibody will be added concomitantly with INT230-6 as noted in cohort DEC and DEC2

anti-PD-1 antibody

The anti-CTLA-4 antibody will be added concomitantly with INT230-6 as noted in cohort FEC

anti-CTLA-4 antibody

Ian B. Walters, M.D.

Lillian Siu, M.D., FRCP

Anthony El-Khoueiry, M.D.

Anthony J. Olszanski, M.D., RPh

Nilofer Azad, M.D.

Giles F Whalen, M.D.

Matthew Ingham, M.D.

Luis Camacho, M.D.

This study evaluates the intratumoral administration of escalating doses of a novel, experimental drug, INT230-6. The study is being 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 plans to test INT230-6 in combination with anti-PD-1 and anti-CTLA-4 antibodies.

INT230-6 is comprised of a 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 demonstrates 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 seeks 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 seeks to understand whether tumor regression can be achieved and patient outcomes improved.

There were 6 cohorts in the escalation portion of the protocol. Five dosed INT230-6 alone and one was combined with pembrolizumab. Cohorts A and B1 treated superficial tumors at a 1:4 ratio of drug to tumor with a low tumor load once per month. Cohort EA was similar to cohort A with INT230-6 every 2 weeks. Cohort EC escalated the total and maximal dose per any one tumor to a ratio of 1:2 \& dosed every two weeks. Cohort EC2 explored a drug load ratio of 1:3 and escalated the dose per tumor further. Cohort DEC combined INT230-6 with a fixed amount of pembrolizumab.

On-going, non-escalation cohorts include 1) monotherapy INT230-6 cohort (EC3) dosed every two weeks 2) INT230-6 in a combination with pembrolizumab (DEC2) and 3) INT230-6 in combination with ipilimumab (FEC). Other specific regimens or combinations of INT230-6 may be designated by the Study Steering Committee.

There is no masking and all patients will receive INT230-6 treatments.

A Phase 1/2 Safety Study of Intratumorally Dosed INT230-6

A Phase 1/2 Safety Study of Intratumorally Administered INT230-6 in Adult Subjects With Advanced Refractory Cancers

Characterize response in non-injected lesions (up to 5) using length (cm) as the key parameter for measurement.

Evaluate various tumor and anti-tumor immune response biomarkers from blood, tumor tissue that may correlate with tumor response. Flow and tissue panels may include Live-Dead, CD3, CD4, CD8, FoxP3, Ki-67, ICOS, DAPI, PD-1, LAG-3, TIM-3, CTLA-4 and analysis of blood serum cytokine such as Th1/Th2, IFN-γ, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12 p70, IL-13, and TNF-α.

Evaluate overall response by iRECIST including survival

The primary objective is to assess the safety and tolerability of single and multiple intratumoral doses of INT230-6 in subjects with advanced or recurrent malignancies. This will be assessed by the rate of ≥ grade 3 AE's attributed to INT230-6 and not the underlying disease.

All recorded adverse events will be listed and tabulated by system organ class, preferred term, and dose and coded according to the most current version of MedDRA. The incidence of adverse events will be tabulated and reviewed for potential significance and clinical importance.

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.

Assess the preliminary efficacy of INT230-6 by measuring the disease control rate (CR+PR+SD) as assessed by iRECIST.

Assess INT230-6's effect on tumors by measuring the length, width and height (centimeters) of injected tumors during the dosing and afterward.

Characterize the peak plasma profile for the three INT230-6 components after single and then multiple IT tumor site injections for safety purposes. This has been completed.

Characterize the pharmacokinetic AUC profile of each of the three INT230-6 components for AUC after single IT tumor site injection for safety purposes. This has been completed.

Characterize the half life of each of the three INT230-6 components after single and multiple IT tumor site injections for safety purposes. This has been completed.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
A Phase 1/2 Safety Study of Intratumorally Dosed INT230-6	NCT03058289	Breast Cancer Head and Neck C... Squamous Cell C... Lymphoma Pancreatic Canc... Liver Cancer Colon Cancer Lung Cancer Bile Duct Cance... Chordoma of Sac... Sarcoma	INT230-6 anti-PD-1 antib... anti-CTLA-4 ant...	18 Years -	Intensity Therapeutics, Inc.
A Phase 1/2 Safety Study of Intratumorally Dosed INT230-6	NCT03058289	Breast Cancer Head and Neck C... Squamous Cell C... Lymphoma Pancreatic Canc... Liver Cancer Colon Cancer Lung Cancer Bile Duct Cance... Chordoma of Sac... Sarcoma	INT230-6 anti-PD-1 antib... anti-CTLA-4 ant...	18 Years -	Intensity Therapeutics, Inc.

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