Increased Frequency of AlloStim(TM) Dosing in Combination With Cryoablation in Metastatic Breast Cancer Patients

Study Overview
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Brief Summary
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This phase I/II study is designed to compare different treatment schedules of a personalized anti-cancer vaccine protocol which combines the cryoablation of a selected metastatic lesion with intra-tumor immunotherapy. The cryoablation causes the tumor to release tumor-specific antigens into the surrounding environment. The injection of bioengineered allogeneic immune cells, AlloStim(TM), into the lesion is designed to modulate the immune response and educate the immune system to kill other tumor cells.

Detailed Description
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The study will assess three different dosing schedules. A standard 3 plus 3 study design will be used. The starting dose for each dosing schedule will be escalated in subsequent groups of patients. The study will evaluate safety of increased frequency of AlloStim (TM) dosing and anti-tumor effect of the new proposed dose and frequency schedule.

Official Title
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In-Situ Cancer Vaccine: Phase I/IIb, Open-Label Study to Assess Safety of AllostimTM in Combination With Cryoablation in Metastatic Breast Cancer Previously Treated With an Anthracycline, a Taxane and Capecitabine

Conditions
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Metastatic Breast Cancer

Intervention / Treatment
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* Biological: AlloStim
* Procedure: Cryoablation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Women w/ histologically/cytologically confirmed breast carcinoma Documented progressive metastatic disease not amenable to curative surgery/radiotherapy Age ≥18 and ≤70 years Prior treatments that included capecitabine and both an anthracycline and a taxane drug and resistant to taxane therapy ER+ patients: minimum cumulative dose of anthracycline (≥ 180 mg/m² of doxorubicin or ≥ 300 mg/m² of epirubicin) or resistance to anthracycline, capecitabine and anti-hormonal therapy Resistance is defined as tumor progression while receiving treatment or progression within 4 months of the last dose in the metastatic setting, or recurrence within 12 months in the neoadjuvant/adjuvant setting Post-menopausal ER+ and/or PR+ must have received at least 2 lines of prior anti-estrogen therapy, which includes an aromatase inhibitor Her2+ patients: at least 1 Her2+ targeted regimen containing trastuzumab alone or with pertuzumab/lapatinib. Trastuzumab/pertuzumab must have been discontinued at least 4 weeks before treatment Prior radiation therapy completed >4 weeks before treatment Measurable disease according to revised RECIST v.1.1 guidelines with at least 1 lesion deemed to be safely accessible for serial biopsy ECOG <2 Adequate hematological function Absolute granulocyte count ≥ 1,500/mm3 Platelet count ≥ 100,000/mm3 PT/INR ≤ 1.5 INR correctable to ≤ 1.5 or a PT/PTT correctable to normal limits. Patients receiving anti-coagulation treatment with agent such as warfarin/heparin may participate. For patients on warfarin, INR should be monitored weekly prior to any intervention to assure INR is stable. Heparin/warfarin must be withheld before biopsy Hemoglobin ≥ 9 g/dL (may be corrected by transfusion) Adequate organ function Creatinine ≤ 1.5 mg/dL Total bilirubin ≤ 1.5 times ULN Alkaline phosphatase≤2.5 times ULN (≤5 times normal if liver involvement) Aspartate aminotransferase (AST/SGOT) ≤ 5.0 times ULN Alanine aminotransferase (ALT/SGPT) ≤ 5.0 times ULN EKG without clinically relevant abnormalities Pre-menopausal with child bearing potential subjects must use adequate contraception Informed consent in the native language of the subject Exclusion Criteria: Peritoneal carcinomatosis Moderate-large ascites accumulation requiring/likely to require paracentesis Clinical/radiological evidence of brain metastasis/leptomeningeal involvement Pulmonary lymphangitis/symptomatic pleural effusion (grade ≥ 2) that results in pulmonary dysfunction requiring active treatment History of 2nd primary malignancy, except: bilateral breast carcinoma, in situ carcinoma of the cervix, adequately treated non-melanomatous carcinoma of the skin, and other malignancy treated at least 5 years with no evidence of recurrence >3 prior chemotherapy regimens for metastatic disease History of severe hypersensitivity to monoclonal antibody drugs/any contraindication to study drugs Pregnant or breast feeding Any serious, concurrent uncontrolled medical disorder Prior hepatectomy, liver chemoembolization, liver cryoablation/ radiofrequency ablated Symptomatic pulmonary disease Bevacizumab (Avastin®) within 3 weeks of accrual Prior allogeneic bone marrow/stem cell or solid organ transplant Chronic use (> 2 weeks) of greater than physiologic doses of corticosteroid agent (dose equivalent to > 10 mg/day of prednisone) within 30 days of the first day of study treatment. Topical and inhaled corticosteroids are permitted Concomitant active autoimmune disease Prior experimental therapy/cancer vaccine treatment Current immunosuppressive therapy, including: cyclosporine, antithymocyte globulin, or tacrolimus within 1 month of study entry History of blood transfusion reactions Known allergy to bovine products Know allergy to murine products Progressive viral/bacterial infection. All infections must be resolved and the patient must remain afebrile for 7days without antibiotics prior to enrollment Cardiac disease of symptomatic nature or cardiac ejection fraction < 45% History of HIV positivity or AIDS Psychiatric/addictive disorders or other condition that, in the opinion of the investigator, would preclude study participation Concurrent medication known to interfere with platelet function or coagulation (e.g., aspirin, ibuprofen, clopidogrel, or warfarin) unless can be discontinued for an appropriate time period based on the drug half-life and known activity (e.g., aspirin for 7 days) prior to cryoablation procedure Use of low molecular weight heparin preparations unless can be discontinued 8 hours prior to cryoablation

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dosing Schedule A<br>the priming step with ID injection of AlloStim on Days 0, 7, and 14; the ablation step with cryoablation and intra-tumor injection of AlloStim on Day 21; the activation step with an IV infusion of AlloStim on Day 28; the booster step with intravenous booster infusion of AlloStim on Days 56 and 84; Protocol follow-up procedures continue until day 168 and at investigator discretion thereafter. | Biological: AlloStim<br>* AlloStim is derived from the blood of normal blood donors and is intentionally mismatched to the recipient.<br>* Other names: Personalized anti-tumor vaccine;Procedure: Cryoablation<br>* Percutaneous ablation of a single metastatic tumor lesion usually in liver or bone. The procedure is conducted under CT or ultrasound image-guidance.<br>|
| Experimental: Dosing Schedule B<br>the priming step with ID injection of AlloStim on Days 0 and 3 and an additional ID injection of AlloStim on Days 7 and 10; the ablation step with cryoablation and intra-tumor injection of AlloStim on Day 14; the activation step with an IV infusion of AlloStim on Day 21; the booster step with intravenous booster infusion of AlloStim on Days 49 and 77. Protocol follow-up procedures continue until day 168 and at investigator discretion thereafter. | Biological: AlloStim<br>* AlloStim is derived from the blood of normal blood donors and is intentionally mismatched to the recipient.<br>* Other names: Personalized anti-tumor vaccine;Procedure: Cryoablation<br>* Percutaneous ablation of a single metastatic tumor lesion usually in liver or bone. The procedure is conducted under CT or ultrasound image-guidance.<br>|
| Experimental: Dosing Schedule C<br>the priming step with ID injection of AlloStim on Days 0 and 3 and an additional ID injection of AlloStim on Days 7 and 10; the ablation step with cryoablation and intra-tumor injection of AlloStim on Day 14, and intra-tumor injection of AlloStim again into the same cryoablated lesion on Day 17; the activation step with an IV infusion of AlloStim on Day 21; the booster step with intravenous infusion of AlloStim on days 49 and 77. Protocol follow-up procedures continue until day 168 and at investigator discretion thereafter. | Biological: AlloStim<br>* AlloStim is derived from the blood of normal blood donors and is intentionally mismatched to the recipient.<br>* Other names: Personalized anti-tumor vaccine;Procedure: Cryoablation<br>* Percutaneous ablation of a single metastatic tumor lesion usually in liver or bone. The procedure is conducted under CT or ultrasound image-guidance.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To determine the safety of increased frequency of dosing | Three patients are enrolled at each frequency schedule in the absence of dose limiting toxicity (DLT). A DLT is defined as any allergic or autoimmune toxicity or other study drug related toxicity Grade 3 or higher during the DLT assessment window. | Window is defined as the time required receiving two doses of AlloStim IV push plus 28 days follow-up | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Health-Related Quality of Life | Health-Related Quality of life will be measured using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) and its supplementary breast cancer questionnaire (QLQ-BR23). | From enrollment to 90 days after last dose administration. | 
| Evaluate the anti-tumor effect of Allostim combined with cryoablation at the new proposed dose and frequency schedule. | Each treatment schedule will be monitored for radiological, pathological, and immunological response. These assessments will be compared between three treatment schedules. | 90 days after last dose administration |