AlloStim® In-Situ Vaccine in Pre-Treated Metastatic Colorectal Cancer

Study Overview
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Brief Summary
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This is a personalized anti-cancer vaccine protocol which includes an in-situ (in the body) cancer vaccine step which 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 due to a mutation in KRAS or BRAF. This is a Phase II/III, randomized, open-label, multicenter, controlled, two arm study designed to determine the efficacy in terms of OS and the safety of the InSituVax (AlloStim+ Cryoablation) personalized in-situ anti-cancer vaccine protocol (Treatment Arm) compared with Physician's Choice (PC) of Treatment + Cryoablation (Control Arm) in Metastatic Colorectal Cancer. Subjects are randomized 2:1 into the treatment or control arms.

Official Title
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A Phase II/III, Randomized, Open Label, Controlled, Two Arm Study Comparing Overall Survival of AlloStim® Combined With Cryoablation to a Physician's Choice Combined With Cryoablation in 3rd Line Treatment for Metastatic Colorectal Cancer

Conditions
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Metastatic Colorectal Cancer

Intervention / Treatment
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* Biological: AlloStim®
* Procedure: cryoablation
* Other: Physician's Choice (PC)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult males and female subjects aged 18 years or older at screening visit Pathological diagnosis of colorectal adenocarcinoma Metastatic disease with at least one lesion in liver Primary can be intact or resected Metastatic lesion(s) in liver non-resectable Extrahepatic disease acceptable KRAS/BRAF mutant disease or KRAS wild type w/previous anti-EGFR treatment At least one liver lesion able to be visualized by ultrasound and determined to be safely assessable for percutaneous cryoablation Previous treatment failure of at 2 previous lines of active systemic chemotherapy for metastatic disease: Previous chemotherapy must have included one line with oxaliplatin (e.g. FOLFOX) and a previous second line with irinotecan (e.g. FOLFIRI) with or without bevacizumab If KRAS wild type, at least one anti-EGFR therapy in first or second line Treatment failure can be due to disease progression or toxicity Disease progression on 2nd line therapy must be documented radiologically and have occurred during or within 30 days following the last administration of 2nd line chemotherapy 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 ULN, Alkaline phosphatase ≤ 2.5 times ULN, AST or SGOT ≤ 2.5 times ULN, ALT or SGPT≤2.5 times ULN EKG without clinically relevant abnormalities Female subjects: Not pregnant or lactating Subjects with child bearing potential must agree to use adequate contraception Study specific informed consent in the native language of the subject Exclusion Criteria: Peritoneal carcinomatosis Moderate or severe ascites requiring medical intervention Prior hepatectomy, ablation or chemoembolization of liver lesion Prior pelvic radiotherapy Clinical or radiological evidence of brain metastasis/leptomeningeal involvement Symptomatic asthma or COPD or any lung condition requiring treatment with steroids 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 No Regorafenib prior to or during the Study Period 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 1st day of study treatment o 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 o All infections must be resolved and the patient 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 procedure 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

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: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AlloStim® treatment<br>The treatment schedule includes: (1) the priming step with two ID AlloStim® injections (Days 0 and 3), an additional two ID injections followed by IV infusion of AlloStim® (Days 7 and 10); (2) the vaccination step with cryoablation of a single metastatic lesion followed by injection of AlloStim® into the ablated tumor and IV infusion of AlloStim® on protocol day 14, followed by IV infusion of AlloStim® on Day 17 (3) the activation step with an IV study drug infusion on Day 21 and (4) the booster step with IV booster infusions of AlloStim® on days 49 and 77. Additional booster infusions can be administered monthly at the discretion of the Investigator. | Biological: AlloStim®<br>* AlloStim® is derived from the blood of normal blood donors and is intentionally mismatched to the recipient. CD4+ T-cells are separated from the blood and differentiated and expanded for 9-days in culture to make an intermediary called T-Stim. AlloStim is made by incubating T-Stim cells for 4h with antibody coated microbeads. The cells with the beads still attached are suspended in infusion media and loaded into syringes. The syringes are shipped refrigerated to the point-of-care.<br>Procedure: cryoablation<br>* percutaneous ablation of a single metastatic tumor lesion usually in liver. The procedure is conducted under CT or ultrasound image-guidance.<br>|
| Other: Physician's Choice (PC)<br>All subjects will be assigned Physician's Choice (PC) therapy. PC can consist of best supportive care (BSC) or any US-FDA-approved cancer drug (e.g. Cetuximab) administrated as a monotherapy at the manufacturer's recommended dose. The treatment schedule shall be prospectively determined and administered as tolerated. | Procedure: cryoablation<br>* percutaneous ablation of a single metastatic tumor lesion usually in liver. The procedure is conducted under CT or ultrasound image-guidance.<br>Other: Physician's Choice (PC)<br>* Physician's Choice therapy can consist of best supportive care (BSC) or any US-FDA approved cancer drug (e.g. Cetuximab) administrated as a monotherapy at the manufacturer's recommended dose. The treatment schedule shall be prospectively determined and administered as tolerated<br>* Other names: monotherapy (e.g.Cetuximab);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | To assess whether cryoablation combined with AlloStim treatment (arm 1) provides an overall survival (OS) advantage when compared to treatment with cryoablation combined with physician's choice (arm 2). | from randomization within 30 days of accrual to death for any cause followed for up to 2 years from date of randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety | Safety will be evaluated by physical exam, changes in laboratory values and patient reported symptoms | 168 days from randomization | 
| Health-Related Quality of Life (HRQoL) | To assess change in HRQoL between treatment arms | 168 days from randomization | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cancer Vaccine, AlloStim®, Immunovative, Immunotherapy, Allogeneic Cell Therapy, Cryoablation