Safety Study of Intratumoral Injection of Clostridium Novyi-NT Spores to Treat Patients With Solid Tumors That Have Not Responded to Standard Therapies

Study Overview
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Brief Summary
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This protocol will examine the safety of intratumoral administration of Clostridium Novyi-NT spores in patients with treatment-refractory solid tumor malignancies. This investigational study will measure anti-tumor activity of C. novyi-NT administered intratumoral in patients with treatment-refractory solid tumor malignancies.

Official Title
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Phase I Safety Study of Intratumoral Injection of Clostridium Novyi-NT Spores in Patients With Treatment-refractory Solid Tumor Malignancies

Conditions
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Solid Tumor Malignancies

Intervention / Treatment
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* Biological: Clostridium novyi-NT spores


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of an advanced solid tumor malignancy. There must be a target tumor which is measureable, palpable or clearly identifiable under ultrasound or radiographic guidance and amenable to percutaneous injection of C. novyi-NT spores. The targeted lesion must have a longest diameter ≥ 1 cm and ≤ 12 cm and be measurable as defined by RECIST 1.1 criteria. The target lesion must not be located in either the thoracic, abdominal or pelvic cavities or in the brain. There must be no clinical, no functional, and no radiographic evidence of bone involvement at the site of the target lesion. History of prior treatment with at least one line of systemic anticancer therapy, when an approved systemic therapy is available, and no curative option is available for continued treatment. At least 4 weeks have elapsed since the completion of major surgery, and the patient has fully recovered from this surgery and any post-surgical complications. Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less. Patient is at least 18 years of age. Patient is capable of giving informed consent. Patient of childbearing potential (defined by the clinical sites' standards) is using adequate birth control measures (e.g., barrier method with spermicide; intrauterine device; implantable or injectable hormonal contraceptives; surgical sterilization) for the duration of the study and will continue to use such precautions for 12 months after receiving treatment. Patient has no significant valvular heart disease (trace or mild valvular stenosis or regurgitation is allowed). Patient is able to stay within 45 minutes driving time of an emergency room for 28 days after doing. The patient has a caregiver for 28 days after dosing. Exclusion Criteria: Positive pregnancy test. Serum creatinine level > 1.5 x the upper limit of normal (ULN), chronic renal failure requiring hemodialysis or peritoneal dialysis. Patient has any of the following hematologic parameters: Platelet count equal to or less than 100,000/mm3 Hemoglobin less than 9.0 g/dL Absolute neutrophil count (ANC) less than 1,000 /mm3 Oxygen saturation (Sp02) of less than 95% on room air. Mean arterial blood pressure (BP) of less than 70 mmHg. Glasgow Coma Score (GCS) of less than 15. Treatment with an investigational drug within the past 30 days or 5 half-lives of that drug, whichever is shorter. Documented primary brain malignancy or brain metastases. Clinically significant ascites or clinical evidence or history of portosystemic hypertension or cirrhosis. Laboratory evidence of hepatic dysfunction indicated by any of the following: Bilirubin ≥ 1.5 x the ULN Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) above 2.5X the ULN Alkaline phosphatase above 2.5X the ULN International normalized ratio (INR) greater than 1.3 Patient has a foreign body which in the opinion of the treating investigator could be difficult to manage in case of infection (e.g. prosthetic hip). Clinically significant pleural effusion. Clinically significant pericardial effusion, circumferential pericardial effusion, or any effusion greater than 1.0 cm at any location around the heart. Need for ongoing treatment with an immunosuppressive agent. History of solid organ transplantation (with the exception of a corneal transplant > 3 months prior to screening). History of an ischemic insult in the previous 12 months (myocardial infarction, cerebral vascular accident, ischemic tissue from injury, transient ischemic attack. History of a significant medical illness deemed by the PI or local investigators as unsuitable for the trial. For example: i. Symptomatic congestive heart failure ii. Psychiatric Illness/social situation that may make study dangerous iii. Unstable angina pectoris Asplenia. Antibiotic allergies that would preclude treatment for a C. novyi-NT infection. Treatment with antibiotics within 2 weeks (14 days) of dosing. Active and clinically significant systemic or localized infection.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

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: Clostridium novyi-NT spores<br> | Biological: Clostridium novyi-NT spores<br>* Phase 1 study: It will be an escalating dose design, with no intracohort escalation. The first cohort dose will begin at 1 x 10(4) spores/kg and will escalate by tripling through 5 cohorts up to 100 x 10(4) spores/kg.<br>* Other names: anaerobic bacteria;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Treatment-emergent Adverse Events (TEAE) | To determine the safety profile of C. novyi-NT in humans with treatment-refractory solid tumor malignancies when administered as a single IT injection. CTCAE: Common Terminology Criteria for Adverse Events | From screening until follow-up visit (up to 12 months) | 
| Number of Patients With Adverse Events Qualified as Dose Limiting Toxicities (DLTs) | To determine the DLTs of C. novyi-NT in humans with treatment-refractory solid tumor malignancies when administered as a single IT injection. | From screening until follow-up visit (up to 12 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage Change in Tumor Size From Baseline of the Target Injected Lesion, Measured by Computed Tomography (CT) Scans or Magnetic Resonance Imaging (MRI) Scans | To document preliminary anti-tumor activity of the injected lesion after administering a single IT injection of C. novyi-NT in humans with treatment-refractory solid tumor malignancies. Response and progression was evaluated using the international criteria proposed by the RECIST 1.1. Objective responses were measured by serial CT or MRI scans of the injected lesion and sites of metastatic involvement. Overall response, based on CT/MRI scan results, was based on observation of measurable and non-measurable disease as compared to baseline and nadir in target and non-target tumors per RECIST 1.1. Change from baseline is presented. | At screening, at follow up (at 1, 2, 4, and 8 months (±2 days) after dosing) | 
| Number of Patients With RECIST Assessment on the Injected Lesion | To document preliminary anti-tumor activity of the injected lesion after administering a single IT injection of C. novyi-NT in humans with treatment-refractory solid tumor malignancies. The evaluation of anti-tumor activity included a response for the injected lesion. Response and progression was evaluated using the international criteria proposed by the RECIST 1.1. Objective responses were measured by serial CT or MRI scans of the injected lesion and sites of metastatic involvement. Overall response, based on CT/MRI scan results, was based on observation of measurable and non-measurable disease as compared to baseline and nadir in target and non-target tumors per RECIST 1.1. | At follow up (at 1 and 2, 4, and 8 months (±2 days) after dosing) | 
| Number of Patients With Overall RECIST Response | To document preliminary anti-tumor activity of an overall response after administering a single IT injection of C. novyi-NT in humans with treatment-refractory solid tumor malignancies. The evaluation of anti-tumor activity included an overall response. | At follow up (at 1 and 2, 4, and 8 months (±2 days) after dosing) | 
| Positive Blood Cultures-Number of Patients With Presence of C. Novyi-NT | To study the presence of circulating C. novyi-NT spores after administration as a single IT injection to humans with treatment-refractory solid tumor malignancies. | At Screening, at Days -1 to 0, at Days 1, 2, 3, 4, 5, 7, at follow up (at 2 months (±2 days) after dosing) | 
| Number of Patients With Cytokine Responses Analyzed | The host immune and inflammatory response to C. novyi-NT spores was measured in routine blood sampling over the course of the study. The following table presents the data for the patients who had analyzable cytokine data. This table was included to simply indicate the number of patients who participated in the cytokine response analysis. | 2 years | 
| Number of Patients With Systemic Tumor Antigen Specific T-cell Responses | The host immune and inflammatory response to C. novyi-NT spores was measured in routine blood sampling over the course of the study. Release of T-cell cytokines and effector molecules (interferon [IFN]-γ , Granzyme B, and tumor necrosis factor [TNF]-α) from the patient's own peripheral blood mononuclear cells (PBMCs) treated with allogenic tumor cell line lysates were quantified by Enzyme-Linked Immunosorbent Spot (ELISPOT) assays. A positive response was defined as a frequency that is significantly (p <0.05, two-tailed t-test) greater than the mean of control no-antigen wells and detectable (i.e., >1:100,000). No patients were analyzed for Cohort 1 and Cohort 2 based on the original study protocol. | 2 years | 
| Number of Patients With Local Tumor-specific T-cell Responses | The host immune and inflammatory response to C. novyi-NT spores was measured in routine blood sampling over the course of the study. Immunostaining for tumor infiltrating cells was analyzed independently by 2 investigators. Respective counting of 3 slides per patient between 5 to 20 fields of vision at 200x were scored using the modified ALLRED scoring method. Respective counts were averaged in each case. Pre and post treatment needle biopsies from injected and non-injected tumors were stained for the presence of tumor infiltrating immune cells. No patients were analyzed for Cohort 1 and Cohort 2 based on the original study protocol. | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Phase 1, Metastatic Disease, Solid Tumor, Malignancy, Metastases, Clinical Trial, Hypoxia, Necrosis, Intratumoral, Locally advanced cancer, Immunotherapy, Sarcoma, Chordoma, Bacteriolytic