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Clostridium novyi-NT spores

Luis A Diaz, MD

This study will include a one time intravenous (IV) infusion of Clostridium novyi-NT (C. novyi-NT) spores to treat solid tumors which have not responded to standard therapy.

Investigators at the SKCCC have developed a bacterial strain (C. novyi-NT) that can infect tumors and destroy them, but does not grow in normal tissues. In animal experiments, a single intravenous injection of these bacteria can cause dramatic regression of many tumors, and the tumors do not recur in approximately (\~) 30% of the animals.

This is a phase I dose escalation study using a single dose of Clostridium novyi-NT spores in patients with treatment-refractory solid tumor malignancies. The overall objective of this study is to determine the safety and document any preliminary evidence of anti-tumor activity in this patient population.

One Time Injection of Bacteria to Treat Solid Tumors That Have Not Responded to Standard Therapy

Phase I Safety Study of Clostridium Novyi-NT Spores in Patients With Treatment-Refractory Solid Tumor Malignancies

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Neoplasm Metastasis

Chordoma

Immunomodulating Agents

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.

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.

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

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

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

To determine the DLTs of C. novyi-NT in humans with treatment-refractory solid tumor malignancies when administered as a single IT injection.

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.

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.

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.

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.

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.

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.

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.

BioMed Valley Discoveries, Inc

An Adverse Event (AE) was any new untoward medical occurrence or worsening of a pre-existing medical condition in a clinical investigation subject administered an investigational medicinal product, even if it did not have a causal relationship with that product. Any unfavorable or unintended sign, symptom, or disease temporally associated with the use of the study agent, whether or not it was considered study agent-related was considered an AE.

Cohort 1

Cohort 2

Cohort 3

Cohort 4

Cohort 5

Cohort 6

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Brent Kreider

All TEAEs

Related TEAEs

CTCAE Grade 1 TEAEs

CTCAE Grade 2 TEAEs

CTCAE Grade 3 TEAEs

Life-Threatening TEAEs

Deaths

Serious TEAEs

The safety data set included all patients who received any amount of C. novyi-NT, the investigational medicinal product (IMP). Patients were included in the safety analysis according to the dose of IMP received.

Number of Patients With Treatment-emergent Adverse Events (TEAE)

Patient with any AEs qualified as DLTs

Patient with Gas gangrene qualified as DLTs

Patient with Sepsis qualified as DLTs

The safety data set included all patients who received any amount of C. novyi-NT, IMP. Patients were included in the safety analysis according to the dose of IMP received.

Number of Patients With Adverse Events Qualified as Dose Limiting Toxicities (DLTs)

Patient 1, Month 1

Patient 1, Month 2

Patient 2, Month 1 and Month 2

Patient 3, Month 1

Patient 4, Month 1

Patient 4, Month 2

Patient 5, Month 1

Patient 6, Month 1

Patient 6, Month 2

Patient 7, Month 1

Patient 8, Month 1

Patient 9, Month 1

Patient 10, Month 1

Patient 11, Month 1

Patient 11, Month 2

Patient 12, Month 1

Patient 12, Month 2

Patient 12, Month 4

Patient 12, Month 8

Patient 13, Month 1

Patient 13, Month 2

Patient 14, Month 1

Patient 14, Month 2

Patient 15, Month 1

Patient 16, Month 1

Patient 16, Month 2

Patient 17, Month 1

Patient 17, Month 2

Patient 17, Month 4

Patient 17, Month 8

Patient 18, Month 1

Patient 18, Month 2

Patient 19, Month 1

Patient 19, Month 2

Patient 20, Month 1

Patient 20, Month 2

Patient 21, Month 1, Month 2, Month 4

Patient 22, Month 1

Patient 22, Month 2

Patient 23, Month 1

Patient 23, Month 2

Patient 24, Month 1

The efficacy data set or full analysis set consisted of all patients in the safety population who had both a baseline tumor assessment and at least one post-baseline tumor assessment. Patients were included in the analysis according to the dose of IMP received.

Percentage Change in Tumor Size From Baseline of the Target Injected Lesion, Measured by Computed Tomography (CT) Scans or Magnetic Resonance Imaging (MRI) Scans

Month 1, Complete Response

Month 1, Partial Response

Month 1, Stable Disease

Month 1, Progressive Disease

Month 1, Unknown

Month 2, Complete Response

Month 2, Partial Response

Month 2, Stable Disease

Month 2, Progressive Disease

Month 2, Unknown

Month 4, Complete Response

Month 4, Partial Response

Month 4, Stable Disease

Month 4, Progressive Disease

Month 4, Unknown

Month 8, Complete Response

Month 8, Partial Response

Month 8, Stable Disease

Month 8, Progressive Disease

Month 8, Unknown

Number of Patients With RECIST Assessment on the Injected Lesion

Number of Patients With Overall RECIST Response

Scheduled, Screening

Scheduled, Day -1 to Day 0

Scheduled, Day 1

Scheduled, Day 2

Scheduled, Day 3

Scheduled, Day 4

Scheduled, Day 5

Scheduled, Day 7

Scheduled, Month 2

The safety data set included all patients who received any amount of C. novyi-NT, the IMP. Patients were included in the safety analysis according to the dose of IMP received.

Note: Two patients had positive C.novyi culture at Screening due to contamination, and one patient in Cohort 4 had positive C. novyi culture on Day 3 due to contamination.

Positive Blood Cultures-Number of Patients With Presence of C. Novyi-NT

Number of Patients With Cytokine Responses Analyzed

Number of Patients With Systemic Tumor Antigen Specific T-cell Responses

Number of Patients With Local Tumor-specific T-cell Responses

Patients received only single dose of C. novyi-NT spores (Cohort 1: 1 x 10\^4 spores) as an intratumoral (IT) injection, per protocol (pp).

Patients received only single dose of C. novyi-NT spores (Cohort 2: 3 x 10\^4 spores) as an IT injection, pp.

Patients received only single dose of C. novyi-NT spores (Cohort 3: 10 x 10\^4 spores) as an IT injection, pp.

Patients received only single dose of C. novyi-NT spores (Cohort 4: 30 x 10\^4 spores) as an IT injection, pp.

Patients received only single dose of C. novyi-NT spores (Cohort 5: 100 x 10\^4 spores) as an IT injection, pp.

Patients received only single dose of C. novyi-NT spores (Cohort 6: 300 x 10\^4 spores) as an IT injection, pp.

Overall Study

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
One Time Injection of Bacteria to Treat Solid Tumors That Have Not Responded to Standard Therapy	NCT00358397	Tumors	Clostridium nov...	18 Years -	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Safety Study of Intratumoral Injection of Clostridium Novyi-NT Spores to Treat Patients With Solid Tumors That Have Not Responded to Standard Therapies	NCT01924689	Solid Tumor Mal...	Clostridium nov...	18 Years -	BioMed Valley Discoveries, Inc
Safety Study of Intratumoral Injection of Clostridium Novyi-NT Spores to Treat Patients With Solid Tumors That Have Not Responded to Standard Therapies	NCT01924689	Solid Tumor Mal...	Clostridium nov...	18 Years -	BioMed Valley Discoveries, Inc

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