AlloStim® Immunotherapy Dosing Alone or in Combination With Cryoablation in Metastatic Colorectal Cancer

Study Overview
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Brief Summary
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This is a single center, open label dose frequency escalation study of CryoVax®. personalized anti-tumor vaccine protocol combining the cryoablation of a selected metastatic lesion with intra-lesional immunotherapy with AlloStim®. The in-situ (in the body) cancer vaccine step combines killing a single metastatic tumor lesion by use of cryoablation in order to cause the release of tumor-specific markers to the immune system and then injecting bioengineered allogeneic immune cells (AlloStim®) into the lesion as an adjuvant in order to modulate the immune response and educate the immune system to kill other tumor cells where ever they reside in the body.

Detailed Description
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Colorectal cancer (CRC) ranks as the third most common cancer worldwide. Metastasis is the main reason of death in CRC patients. The current drugs used to treat colorectal cancer provide important treatment options for patients, their limitations including drug resistance, poor efficacy and severe side effects. Development of new therapeutic strategies for KRAS mutant as well as BRAF mutant tumors are therefore highly needed in order to offer a new category of drug (immunotherapy). This study targets the population of mCRC patients that have progressed after two lines of chemotherapy and are not eligible for targeted therapies. The study will assess six different dosing schedules. A standard 3 plus 3 study design will be used. The starting frequency for each dosing schedule will be escalated in subsequent groups of patients. The study will evaluate safety of increased frequency of AlloStim® dosing and anti-tumor effect of the new proposed dose and frequency schedule.

Official Title
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In-Situ Cancer Vaccine: Phase IIA, Open-Label Study to Assess the Safety of AlloStim® Immunotherapy Alone and in Combination With Cryoablation as Third Line Therapy for Metastatic Colorectal Cancer

Conditions
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Colorectal Cancer Metastatic

Intervention / Treatment
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* Biological: AlloStim
* Procedure: Cryoablation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult males and female subjects aged 18-80 years at screening visit Pathologically confirmed diagnosis of colorectal adenocarcinoma Presenting with metastatic disease: Primary can be intact or previously resected Metastatic lesion(s) in liver must be non-resectable Extrahepatic disease acceptable At least one liver lesion able to be visualized by ultrasound and determined to be safely assessable for percutaneous cryoablation Previous treatment failure of two previous lines of active systemic chemotherapy: Previous chemotherapy must have included an oxaliplatin-containing (e.g. FOLFOX) and an irinotecan-containing (e.g. FOLFIRI) regimen with or without bevacizumab administered in adjuvant setting or for treatment of metastatic disease If KRAS wild type, must have at least one prior anti-EGFR therapy Treatment failure can be due to disease progression or toxicity Disease progression on second line therapy must be documented radiologically and must have occurred during or within 30 days following the last administration of treatment for metastatic disease ECOG performance score: 0-1 Adequate hematological function: Absolute granulocyte count ≥ 1,200/mm3 Platelet count ≥ 100,000/mm3 PT/INR ≤ 1.5 or correctable to <1.5 at time of interventional procedures Hemoglobin ≥ 9 g/dL (may be corrected by transfusion) Adequate Organ Function: Creatinine ≤ 1.5 mg/dL Total bilirubin ≤ 1.5 times upper limit of normal (ULN) Alkaline phosphatase ≤ 2.5 times ULN Aspartate aminotransferase (AST) or (SGOT) ≤ 2.5 times ULN Alanine aminotransferase (ALT) or (SGPT) ≤ 2.5 times ULN EKG without clinically relevant abnormalities Female subjects: Not pregnant or lactating Patients with child bearing potential must agree to use adequate contraception Study specific informed consent in the native language of the subject. Exclusion Criteria: Bowel obstruction or high risk for obstruction Moderate or severe ascites requiring medical intervention Clinical evidence or radiological evidence of brain metastasis or leptomeningeal involvement Symptomatic asthma or COPD Pulmonary lymphangitis or symptomatic pleural effusion (grade ≥ 2) that results in pulmonary dysfunction requiring active treatment or oxygen saturation <92% on room air Bevacizumab (Avastin®) treatment within 6 weeks of scheduled cryoablation procedure Regorafenib prior to the Study Period Taking anticoagulant medication for concomitant medical condition (unless can be safely discontinued for invasive cryoablation, biopsy and intratumoral injection procedures) Prior allogeneic bone marrow/stem cell or solid organ transplant Chronic use (> 2 weeks) of greater than physiologic doses of a corticosteroid agent (dose equivalent to > 5 mg/day of prednisone) within 30 days of the first day of study drug treatment Topical corticosteroids are permitted Prior diagnosis of an active autoimmune disease (e.g., rheumatoid arthritis, multiple sclerosis, autoimmune thyroid disease, uveitis). Well controlled Type I diabetes allowed Prior experimental therapy History of blood transfusion reactions Known allergy to bovine products Progressive viral or bacterial infection All infections must be resolved and the subject must remain afebrile for seven days without antibiotics prior to being placed on study Cardiac disease of symptomatic nature History of HIV positivity or AIDS Concurrent medication known to interfere with platelet function or coagulation (e.g., aspirin, ibuprofen, clopidogrel, or warfarin) unless such medications 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 and biopsy procedures History of severe hypersensitivity to monoclonal antibody drugs or any contraindication to any of the study drugs Psychiatric or addictive disorders or other condition that, in the opinion of the investigator, would preclude study participation. Subjects that lack ability to provide consent for themselves

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: Dosing Schedule A<br>The priming step with ID injections of AlloStim on Days 0, 7, and 14 The vaccination step with cryoablation and IT (intratumoral) injection of AlloStim on Day 21 The activation step with IV infusion of AlloStim on Day 28 The booster step with two IV booster infusions of AlloStim on Days 56 and 84 Protocol follow-up procedures continue until day 112. Efficacy evaluation will continue monthly for each subject until death or loss to follow-up | Biological: AlloStim<br>* AlloStim is an activated living CD4+ Th1 memory cell derived from the blood of normal blood donors and intentionally mismatched to the recipient. AlloStim is bioengineered to express high levels of Type 1 inflammatory cytokines (such as interferon-gamma, TNF-alpha, GM-CSF) and immunomodulatory molecules such as CD40L. AlloStim has CD3/CD28-coated microbeads attached to assure activation upon infusion.<br>* Other names: CryoVax;Procedure: Cryoablation<br>* Percutaneous partial cryoablation of a single metastatic tumor lesion in the liver. The procedure is conducted under CT or ultrasound image-guidance<br>|
| Experimental: Dosing Schedule B<br>The priming step with ID injections of AlloStim on Days 0, 3 and days 7 and 10 The vaccination step with cryoablation and IT (intratumoral) injection of AlloStim on Day 14 The activation step with IV infusion of AlloStim on Day 21 The booster step with two IV booster infusions of AlloStim on Days 49 and 77 Protocol follow-up procedures continue until day 105. Efficacy evaluation will continue monthly for each subject until death or loss to follow-up | Biological: AlloStim<br>* AlloStim is an activated living CD4+ Th1 memory cell derived from the blood of normal blood donors and intentionally mismatched to the recipient. AlloStim is bioengineered to express high levels of Type 1 inflammatory cytokines (such as interferon-gamma, TNF-alpha, GM-CSF) and immunomodulatory molecules such as CD40L. AlloStim has CD3/CD28-coated microbeads attached to assure activation upon infusion.<br>* Other names: CryoVax;Procedure: Cryoablation<br>* Percutaneous partial cryoablation of a single metastatic tumor lesion in the liver. The procedure is conducted under CT or ultrasound image-guidance<br>|
| Experimental: Dosing Schedule C<br>The priming step with ID injections of AlloStim on Days 0, 3, 7, 10 and day 14 IV AlloStim on Day 21 The booster step with two IV booster infusions of AlloStim on Days 49 and 77 Protocol follow-up procedures continue until day 105. Efficacy evaluation will continue monthly for each subject until death or loss to follow-up | Biological: AlloStim<br>* AlloStim is an activated living CD4+ Th1 memory cell derived from the blood of normal blood donors and intentionally mismatched to the recipient. AlloStim is bioengineered to express high levels of Type 1 inflammatory cytokines (such as interferon-gamma, TNF-alpha, GM-CSF) and immunomodulatory molecules such as CD40L. AlloStim has CD3/CD28-coated microbeads attached to assure activation upon infusion.<br>* Other names: CryoVax;Procedure: Cryoablation<br>* Percutaneous partial cryoablation of a single metastatic tumor lesion in the liver. The procedure is conducted under CT or ultrasound image-guidance<br>|
| Experimental: Dosing Schedule D (reducing dose)<br>The priming step with ID injections of AlloStim on Days 0, 3, 7, 10 and day 14 IV AlloStim on Day 21 The booster step with two IV booster infusions of AlloStim on Days 49 and 77 Protocol follow-up procedures continue until day 105. Efficacy evaluation will continue monthly for each subject until death or loss to follow-up Protocol follow-up procedures continue until day 105. Efficacy evaluation will continue monthly for each subject until death or loss to follow-up | Biological: AlloStim<br>* AlloStim is an activated living CD4+ Th1 memory cell derived from the blood of normal blood donors and intentionally mismatched to the recipient. AlloStim is bioengineered to express high levels of Type 1 inflammatory cytokines (such as interferon-gamma, TNF-alpha, GM-CSF) and immunomodulatory molecules such as CD40L. AlloStim has CD3/CD28-coated microbeads attached to assure activation upon infusion.<br>* Other names: CryoVax;Procedure: Cryoablation<br>* Percutaneous partial cryoablation of a single metastatic tumor lesion in the liver. 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 (Part 1) (whether a Dose Limiting Toxicity (DLT) has occurred) | Three patients are enrolled at each frequency schedule in the absence of dose limiting toxicity (DLT).Two types of toxicity are assessed for determination of whether a Dose Limiting Toxicity (DLT) has occurred. An acute dose limiting toxicity (ADLT) is assessed within 48h of a dose administration. Cumulative dose limiting toxicity (CDLT) is assessed during the complete Safety Evaluation Period. | Window is defined from baseline until 28 days after the last dose administration (Safety Evaluation Period) | 
| To evaluate the anti-tumor effect of AlloStim combined with cryoablation at the new proposed dose and frequency schedule (Part 2) | Subjects at the new proposed dose and frequency schedule will be monitored for radiological, pathological and immunological response | 28 days after last dose administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To assess change from baseline in Health-Related Quality of Life (HRQoL) | Health-Related Quality of Life (HRQoL) will be measured using the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30) | From enrollment to 28 days after last dose administration | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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colorectal cancer, KRAS mutant, BRAF mutant, metastatic, liver metastasis, AlloStim®, cryoablation, cancer vaccine, immunotherapy, MSI-S