A Study of Ad-RTS-hIL-12 With Veledimex in Subjects With Breast Cancer

Study Overview
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Brief Summary
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This is a single-arm, phase Ib/II study to examine the safety, tolerability and preliminary efficacy of one cycle of Ad-RTS-hIL-12 immunotherapy in women with advanced breast cancer and pre-study SD or PR after completion of a minimum 12 week course of standard first- or second-line chemotherapy. The patient population will include patients with locally advanced or metastatic breast cancer of all subtypes.

Detailed Description
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Subjects who have PD or a CR after the standard chemotherapy are not eligible for the study. Following entry into the trial, patients will go on a treatment holiday from chemotherapy and enter an immunotherapy phase of treatment. Continuation of HER2-targeted antibody therapy is permitted during this immunotherapy phase for women with HER2+ disease. Scans will be conducted at 6 and 12 weeks after the start of Ad-RTS-hIL-12 immunotherapy to determine tumor response. Radiographic PD at week 6 must be confirmed at least 4 weeks later, either at week 12 or earlier if clinically necessitated.

Official Title
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A Single-arm, Open-label Study of Ad-RTS-hIL-12 + Veledimex Following First-, Second-, or Third-Line Standard Treatment in Subjects With Locally Advanced or Metastatic Breast Cancer

Conditions
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Metastatic Breast Cancer

Intervention / Treatment
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* Biological: Ad-RTS-hIL-12
* Drug: Veledimex


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female, age ≥ 18 years Histologically-confirmed, locally advanced or metastatic adenocarcinoma of the breast Achievement of SD or PR after a minimum of 12 weeks of pre-study first- or second-line standard chemotherapy Presence of at least 2 measurable lesions Standard treatment interrupted, except if anti-HER2 therapy All treatment-related or radiation-related toxicities resolved to Grade 1 or lower Submission of copies of tumor measurements and scans Life expectancy > 12 weeks ECOG performance status of 0 to 1 Adequate bone marrow function Adequate liver function Adequate renal function Female subjects and their male partners must agree must agree to use a highly reliable method of birth control Able to swallow oral medication Willing to comply with study procedures Exclusion Criteria: Metastatic breast cancer patients currently on hormonal therapy as first- or second-line are not permitted Prior radiation therapy encompassing > 25% of bone marrow Any congenital or acquired condition leading to compromised ability to generate an immune response Immunosuppressive therapy Use of systemic immunosuppressive drugs Requirement for continual immune suppression Major surgery within 4 weeks of study treatment An active, second potentially life-threatening cancer Presence of brain or subdural metastases Any signs and/or symptoms of brain metastases must be stable for ≥ 4 weeks Radiographic stability should be determined by comparing contrast-enhanced CT or MRI scans at screening to scans obtained by the same method at least 4 weeks earlier Presence or documented history of any of the following autoimmune conditions: Inflammatory bowel disease Rheumatoid arthritis, systemic progressive sclerosis (scleroderma), systemic lupus erythematosus, autoimmune vasculitis Motor neuropathy considered of autoimmune origin Presence of meningeal carcinomatosis Use of any medications that induce, inhibit, or are substrates of CYP450 3A4 History or evidence of cardiac disease as indicated by any of the following: Congestive heart failure greater than NYHA Class II Unstable angina or new-onset angina (begun within the last 3 months), or myocardial infarction within the 6 months prior to enrollment Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy Congenital long QT syndrome or taking drugs known to prolong the QT interval Current use of any drugs with a known risk of causing torsades de pointes Evidence or history of thromboembolic, venous, or arterial events within the past 3 months Evidence or history of bleeding diathesis or coagulopathy International normalized ratio (INR) and activated partial thromboplastin time (aPTT) > 1.5 x ULN, in subject who is not therapeutically anticoagulated. History of malabsorption syndrome or other condition that would interfere with enteral absorption Presence of active clinically serious infection Diagnosis of infection with HIV or chronic infection with hepatitis B or C Any other unstable or clinically significant concurrent medical condition Pregnant or breast-feeding Use of any investigational, non-United States Food and Drug Administration (US FDA) approved drug Participation in any other clinical trial Presence of any condition which makes the patient unsuitable

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ad-RTS-hIL-12 + Veledimex<br>Intratumoral injection of Ad-RTS-hIL-12 in combination with veledimex | Biological: Ad-RTS-hIL-12<br>* Approximately 1.0x10^12 viral particles (vp) per injection<br>* Other names: INXN-2001;Drug: Veledimex<br>* 7 oral doses of veledimex<br>* Other names: INXN-1001 (activator ligand);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Composite measure of safety and tolerability of Ad-RTS-hIL-12 immunotherapy following a first-or second-line standard treatment in HER2-negative subjects, or together with a first- or second-line anti-HER2 antibody therapy in HER2-positive subjects | Composite measure of safety and tolerability based on lab parameters, vitals, physical examination data and deaths, SAEs, and AEs resulting in patient discontinuation. Toxicity stopping rules when applicable will be determined based on a clinical assessment made by the SRC. | 2.5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression rate at 12 weeks after the start of one cycle of Ad-RTS-hIL-12 immunotherapy |  | 2.5 years | 
| Overall response rate (ORR), defined as the rate of complete response (CR) plus the rate of partial response (PR) at 12 weeks following the start of Ad-RTS-hIL-12 immunotherapy |  | 2.5 years | 
| Disease control rate (DCR), defined as the proportion of subjects who have a complete response (CR), partial response (PR), or stable disease (SD) at 12 weeks following the start of one cycle of Ad-RTS-hIL-12 immunotherapy |  | 2.5 years | 
| Number of subjects whose baseline tumor status (stable disease or partial response) improves to partial response or better at 12 weeks following the start of Ad-RTS-hIL-12 immunotherapy |  | 2.5 years | 
| Comparison of radiographic tumor responses by irRC with RECIST |  | 2.5 years | 
| Impact of treatment on serum immune biomarkers such as cytokines, chemokines, soluble receptors and antibodies to tumor antigens |  | 2.5 years |