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

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.

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.

Eligibility Criteria:
Inclusion Criteria:

1. Adult males and female subjects aged 18 years or older at screening visit
2. Pathological diagnosis of colorectal adenocarcinoma
3. 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
4. KRAS/BRAF mutant disease or KRAS wild type w/previous anti-EGFR treatment
5. At least one liver lesion able to be visualized by ultrasound and determined to be safely assessable for percutaneous cryoablation
6. 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
7. ECOG performance score: 0-1
8. 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)
9. 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
10. EKG without clinically relevant abnormalities
11. Female subjects: Not pregnant or lactating
12. Subjects with child bearing potential must agree to use adequate contraception
13. Study specific informed consent in the native language of the subject

Exclusion Criteria:

1. Peritoneal carcinomatosis
2. Moderate or severe ascites requiring medical intervention
3. Prior hepatectomy, ablation or chemoembolization of liver lesion
4. Prior pelvic radiotherapy
5. Clinical or radiological evidence of brain metastasis/leptomeningeal involvement
6. Symptomatic asthma or COPD or any lung condition requiring treatment with steroids
7. Pulmonary lymphangitis or symptomatic pleural effusion (grade ≥ 2) that results in pulmonary dysfunction requiring active treatment or oxygen saturation \<92% on room air
8. Bevacizumab (Avastin®) treatment within 6 weeks of scheduled cryoablation
9. No Regorafenib prior to or during the Study Period
10. Anticoagulant medication for concomitant medical condition (unless can be safely discontinued for invasive cryoablation, biopsy and intratumoral injection procedures)
11. Prior allogeneic bone marrow/stem cell or solid organ transplant
12. 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
13. Prior diagnosis of an active autoimmune disease (e.g., rheumatoid arthritis, multiple sclerosis, autoimmune thyroid disease, uveitis). Well controlled Type I diabetes allowed.
14. Prior experimental therapy
15. History of blood transfusion reactions
16. Known allergy to bovine products
17. 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
18. Cardiac disease of symptomatic nature
19. History of HIV positivity or AIDS
20. 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
21. History of severe hypersensitivity to monoclonal antibody drugs or any contraindication to any of the study drugs
22. Psychiatric or addictive disorders or other condition that, in the opinion of the investigator, would preclude study participation