A Phase 1 Study of Mixed Bacteria Vaccine (MBV) in Patients With Tumors Expressing NY-ESO-1 Antigen

Study Overview
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Brief Summary
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This was a phase 1, open-label, multiple dose, single-arm study. The mixed bacteria vaccine (MBV) was administered at a starting dose of 250 EU (1 µL) and escalated in each subject to a dose inducing the desired pyrogenic effect, defined as a body temperature of 38°C to 39.5°C. The primary objective was to determine the safety profile of MBV in subjects with malignant tumors that expressed the NY-ESO-1 antigen and to identify the dose that induced the desired pyrogenic effect. Secondary objectives were to evaluate the immunological effects and tumor response of subjects following vaccination.

Detailed Description
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Subjects in Cohort 1 were enrolled to receive MBV subcutaneously at a starting dose of 250 EU (1 µL; dose level 1) administered twice weekly. In the absence of a dose-limiting toxicity (DLT), the MBV dose was escalated in each subject to the MBV dose that elicited the desired pyrogenic effect, or up to the maximum dose of 547,000 EU (dose level 8). Once the desired pyrogenic effect was observed, subjects received MBV twice weekly for 4 doses at the pyrogenic dose level. Subjects in Cohort 2 were enrolled to receive MBV at the pyrogenic dose level (determined to be 60,800 EU [dose level 6]) twice weekly for 6 weeks. Vaccinations were injected intralesionally if possible and subcutaneously if intralesional injection was not possible. If a fever of 39.5°C to 40°C was observed, the subject's dose was reduced to dose level 5 (20,300 EU [81 μL]). Subjects were observed at the clinic for up to 6 hours following each vaccination, with vital signs measured hourly. At baseline and throughout the study, subjects were assessed for NY-ESO-1-specific humoral and cellular immunity, chemistry, hematology, and cytokine analysis (interleukin [IL]-1, IL-6, interferon [IFN]-γ, and tumor necrosis factor [TNF]-α). Safety was monitored continuously throughout the study.

Official Title
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A Phase 1 Study of Mixed Bacteria Vaccine (MBV) in Patients With Tumors Expressing NY-ESO-1 Antigen.

Conditions
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Melanoma, Sarcoma, Gastrointestinal Stromal Tumor (GIST), Head and Neck Cancer, Transitional Cell Carcinoma, Prostate Cancer, Ovarian Carcinoma, Esophageal Cancer, Breast Cancer

Intervention / Treatment
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* Biological: Mixed bacterial vaccine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed metastatic melanoma, head and neck cancer, transitional cell carcinoma, sarcoma, gastrointestinal stroma tumor (GIST) or prostate cancer. Tumor expression of NY-ESO-1 by reverse transcriptase and polymerase chain reaction (RT-PCR) analysis, preferably, or immunohistochemistry. Expected survival of at least 6 months. Karnofsky performance status ≥ 70%. Fully recovered from surgery. Declined, intolerated or completed standard therapy defined as follows for each tumor entity: Melanoma - resistance or intolerance to dacarbazine. Sarcoma - resistance or intolerance to anthracyclines and to one platinum-containing chemotherapy regimen, no indication for irradiation. GIST - failure or intolerance of imatinib and sunitinib. Head and neck cancer - no indication for irradiation, resistance or intolerance to platinum-containing chemotherapy. Transitional cell carcinoma - resistance or intolerance to cisplatin combined with gemcitabine. Prostate cancer- failure of antihormonal treatment and resistance or intolerance to docetaxel. Ovarian carcinoma - failure of standard chemotherapy consisting of a platinum agent combined with a taxane and of an anthracycline. Esophageal cancer - failure of standard chemotherapy consisting of a platinum agent. Breast cancer- failure or intolerance of standard first-, second- and third-line chemotherapy consisting of a taxane and anthracycline. No indication or resistance to standard antihormonal treatment. No indication or resistance to human epidermal growth factor receptor (HER)-2-neu targeted therapy. No indication or resistance to irradiation and/or surgery. Within the last 2 weeks prior to study day 1, vital laboratory parameters must have been within the normal range, except for the following laboratory parameters, which must have been within the ranges specified: Absolute neutrophil count (ANC): ≥ 1,000/mm3 Platelet count: ≥ 75,000/mm3 Alanine aminotransferase (ALT): ≤ 5 x upper limit of normal (ULN) Aspartate aminotransferase (AST): ≤ 5 x ULN Total bilirubin: ≤ 2.5 x ULN Creatinine: ≤ 2 mg/dL Age ≥ 18 years. Able and willing to give written informed consent. Exclusion Criteria: Clinically significant heart disease (New York Heart Association Class III or IV). Other serious illnesses, e.g., serious infections requiring antibiotics or bleeding disorders. Subjects with serious intercurrent illness requiring hospitalization. Known human immunodeficiency virus positivity. Chemotherapy, radiation therapy or immunotherapy within 4 weeks prior to first dose of study agent (6 weeks for nitrosoureas). Known autoimmune disease (rheumatoid arthritis, systemic lupus erythematosus), as these conditions might have interfered with the evaluation of the induced immune response. Subjects with vitiligo or melanoma-associated hypopigmentation were not excluded. Chronic use of immunosuppressive drugs such as systemic corticosteroids. Other malignancy within 3 years prior to entry into the study, except for treated non-melanoma skin cancer and cervical carcinoma in situ. Mental impairment that may have compromised the ability to give informed consent and comply with the requirements of the study. Lack of availability for immunological and clinical follow-up assessments. Participation in any other clinical trial involving another investigational agent within 4 weeks prior to first dosing of study agent. Pregnancy or breastfeeding. Women of childbearing potential: Refusal or inability to use effective means of contraception.

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
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>Subjects received MBV at a starting dose of 250 EU (dose level 1) twice weekly, with intrasubject dose escalations for each subsequent administration in the absence of a DLT until the desired pyrogenic effect was observed. The maximum possible dose to be investigated was 547,000 EU (dose level 8). | Biological: Mixed bacterial vaccine<br>* MBV was administered twice weekly by subcutaneous injection in Cohort 1 and by intralesional (preferred) or subcutaneous (if intralesional not possible) injection in Cohort 2. In Cohort 1, the MBV starting dose was 250 EU (dose level 1) with possible intrasubject escalations up to 547,000 EU (dose level 8). In Cohort 2, all subjects received MBV at a fixed dose of 60,800 EU (dose level 6).<br>* Other names: MBV;|
| Experimental: Cohort 2<br>Subjects received MBV twice weekly at the fixed dose (60,800 EU [dose level 6]) that was determined to be the pyrogenic dose level in Cohort 1. | Biological: Mixed bacterial vaccine<br>* MBV was administered twice weekly by subcutaneous injection in Cohort 1 and by intralesional (preferred) or subcutaneous (if intralesional not possible) injection in Cohort 2. In Cohort 1, the MBV starting dose was 250 EU (dose level 1) with possible intrasubject escalations up to 547,000 EU (dose level 8). In Cohort 2, all subjects received MBV at a fixed dose of 60,800 EU (dose level 6).<br>* Other names: MBV;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Analysis of treatment-emergent adverse events (TEAEs) reported from clinical laboratory tests, physical examinations, and vital signs from pre-treatment through 4 weeks after the last dose of study treatment. | Up to 3 months | 
| Number of Participants With Pyrogenicity at Each Dose Level Tested in the Intrasubject Dose Escalation Performed Over a Dose Range of 250 to 547,000 EU | Intrasubject dose escalation performed over a dose range of 250 to 547,000 EU until achievement of the desired pyrogenic effects (i.e., body temperature increase to 38°C to 39.5°C). Of note, the median pyrogenic dose was 60,800 EU. | Weeks 1 through 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Serum NY-ESO-1-specific Immune Responses | Serum NY-ESO-1-specific immune responses evaluated by humoral immunity (antibodies measured by ELISA), cellular immunity (CD8+ T-cell and CD4+ T-cell measured by ELISPOT), and cytokine activation (measured by ELISA) from pre-treatment through 4 weeks after the last dose of study treatment. [Note: CD = cluster of differentiation; IFN =interferon; IL = interleukin; TNF = tumor necrosis factor] | Up to 3 months | 
| Number of Participants With Best Overall Tumor Response | Tumor responses evaluated using computed tomography and categorized according to RECIST version 1.0 at pre-treatment and 4 weeks after the last dose of study treatment. Per RECIST v1.0 for target lesions and assessed by MRI: Complete Response (CR): Disappearance of all target lesions [no evidence of disease]; Partial Response (PR): ≥ 30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD): ≥ 20% increase in the sum of the longest diameter of target lesions; Stable Disease (SD): small changes that do not meet above criteria. | Up to 3 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MBV, Mixed Bacterial Vaccine, NY-ESO-1