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

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

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.

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.

Inclusion Criteria:

1. Adult males and female subjects aged 18-80 years at screening visit

2. Pathologically confirmed diagnosis of colorectal adenocarcinoma

3. Presenting with metastatic disease:

   • Primary can be intact or previously resected
   • Metastatic lesion(s) in liver must be non-resectable
   • Extrahepatic disease acceptable

4. At least one liver lesion able to be visualized by ultrasound and determined to be safely assessable for percutaneous cryoablation

5. 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

6. ECOG performance score: 0-1

7. 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)

8. 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

9. EKG without clinically relevant abnormalities

10. Female subjects: Not pregnant or lactating

11. Patients with child bearing potential must agree to use adequate contraception

12. Study specific informed consent in the native language of the subject.

Exclusion Criteria:

1. Bowel obstruction or high risk for obstruction

2. Moderate or severe ascites requiring medical intervention

3. Clinical evidence or radiological evidence of brain metastasis or leptomeningeal involvement

4. Symptomatic asthma or COPD

5. Pulmonary lymphangitis or symptomatic pleural effusion (grade ≥ 2) that results in pulmonary dysfunction requiring active treatment or oxygen saturation <92% on room air

6. Bevacizumab (Avastin®) treatment within 6 weeks of scheduled cryoablation procedure

7. Regorafenib prior to the Study Period

8. Taking anticoagulant medication for concomitant medical condition (unless can be safely discontinued for invasive cryoablation, biopsy and intratumoral injection procedures)

9. Prior allogeneic bone marrow/stem cell or solid organ transplant

10. 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

11. Prior diagnosis of an active autoimmune disease (e.g., rheumatoid arthritis, multiple sclerosis, autoimmune thyroid disease, uveitis). Well controlled Type I diabetes allowed

12. Prior experimental therapy

13. History of blood transfusion reactions

14. Known allergy to bovine products

15. 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

16. Cardiac disease of symptomatic nature

17. History of HIV positivity or AIDS

18. 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

19. History of severe hypersensitivity to monoclonal antibody drugs or any contraindication to any of the study drugs

20. Psychiatric or addictive disorders or other condition that, in the opinion of the investigator, would preclude study participation.

21. Subjects that lack ability to provide consent for themselves