Randomized Phase II Adjuvant Chemotherapy ± FANG™ in Colorectal Carcinoma With Liver Metastases

Randomized Phase II Trial of Post-operative Adjuvant Chemotherapy ± FANG™ Autologous Tumor Cell Vaccine in Colorectal Carcinoma With Liver Metastases

Preliminary studies with a variety of vaccines suggest target accessibility (potential immunogenicity) in a variety of solid tumors to immune directed approaches. In an effort to overcome limitations of immunostimulatory cancer vaccines, Gradalis has designed a novel autologous vaccine to address inability to fully identify cancer associated antigens, antigen recognition by the immune system (i.e. antigen-->immunogen), effector potency, and cancer-induced resistance. In an effort to overcome limitations of immunostimulatory cancer vaccines, we designed a novel dual-modulatory autologous whole cell vaccine, Vigil™, incorporating the rhGMCSF transgene and the bifunctional shRNAfurin (to block proprotein conversion to active TGFb1 and b2) to 1) address the inability to fully identify cancer associated antigens, 2) effect antigen recognition by the immune system, 3) enhance effector potency, and 4) subvert endogenous cancer-induced immune resistance. We have also completed the Phase I assessment of Vigil™ vaccine in 30 advanced solid tumor patients (1.0 x 10^7 cells/injection/month for a maximum of 12 vaccinations) who have not experienced any significant adverse effects following 144 vaccinations, including 6 patients with colorectal carcinoma. Plasmid functionality, immune biomarker response, and preliminary evidence of anticancer activity have been observed. This is a two-part Phase II study of the Vigil™ autologous vaccine. Six patients will be enrolled into the Part 1 of the study to receive intradermal autologous Vigil™ cancer vaccine (1.0 x 10^7 cells/injection; maximum of 12 vaccinations). Part 2 of the study will be a randomized Phase II study of sandwich or adjuvant chemotherapy and intradermal autologous Vigil™ cancer vaccine (1.0 x 10^7 cells/injection; maximum of 12 vaccinations) versus sandwich or adjuvant chemotherapy and placebo in patients with colorectal carcinoma with either synchronous or metachronous liver metastases (CLM +/= pulmonary metastases) following resection +/= ablation with curative intent.Sandwich therapy indicates a combination of both pre-operative and postoperative chemotherapy as opposed to neo-adjuvant (all chemotherapy prior to surgery) or adjuvant (all chemotherapy following surgery) therapy. A minimum harvest aliquot to produce 4 monthly injections will be required for entry into the study. Patients in whom insufficient tissue (<4 doses) is collected or whose vaccine fails manufacturing release criteria will not receive vaccine.

Inclusion Criteria:

1. Histologically confirmed colorectal carcinoma with synchronous or metachronous liver metastases +/- pulmonary metastases.

2. Part 1 patients: May have multiple number of metastatic lesions as long as they can be rendered no evidence of disease (NED).

3. Part 2 patients: Maximum total number of metastatic lesions </= 6. (Patients with CLM with EHD other than lung will be evaluated on an individual basis by the sponsor).

   1. For patients with 1 but up to 3 total lesions, distribution must include both liver + pulmonary metastases.
   2. For patients with 4-6 total lesions, distribution may include liver +/- pulmonary metastases.

4. Candidate for surgical excision +/= ablation with curative intent based on pre-operative assessment incorporating a CT/PET scan.

5. Has been informed of all alternative ≥ first and/or second-line therapies that are the current standard of care. If no conventional frontline therapy indicated or acceptable by patient, patient may participate after review by sponsor.

6. Planned resected viable tumor in sufficient quantity ("golf ball size" estimated weight ~ 30 grams) for vaccine processing.

7. Recovered to ≤ Grade 1 (excluding alopecia) from all clinically relevant toxicities related to prior therapies.

8. Patients must be off all "statin" drugs for ≥ 2 weeks prior to initiation of therapy.

9. Age ≥18 years.

10. ECOG performance status (PS) 0-2.

11. Estimated >4 month survival probability.

12. Normal organ and marrow function as defined below:

    Absolute granulocyte count ≥1,500/mm3 Absolute lymphocyte count ≥ 500/mm3 Platelets ≥100,000/mm3 Total bilirubin </=2 mg/dL AST(SGOT)/ALT(SGPT) </=2x institutional upper limit of normal Creatinine <1.5 mg/dL

13. Ability to understand and the willingness to sign a written informed consent document.

14. Negative pregnancy test.

Exclusion Criteria:

1. Surgery involving general anesthesia, radiotherapy, steroid therapy, or immunotherapy within 4 weeks prior to entering the study. Collection of lumenal tissue must be avoided.
2. Prior therapeutic chemotherapy (excluding protocol defined sandwich chemotherapy). Prior approved sandwich / adjuvant therapy is permitted maximum of 3 cycles (1 cycle = 2 biweekly courses / 1 month) anterior therapy and at least 6 months between cessation of chemotherapy and the diagnosis of metastatic disease.
3. Prior surgical resection, ablation or radiation therapy for metastatic disease prior to or at the time of tissue procurement.
4. Portal, celiac or periaortic metastases.
5. Patient must not have received any other investigational agents within 30 days prior to study entry/ registration.
6. Patients with known active or symptomatic brain metastases.
7. Patients with compromised pulmonary disease.
8. Short term (<30 days) concurrent systemic steroids ≤ 0.125 mg/kg prednisone per day (maximum 10 mg/day) and bronchodilators (inhaled steroids) are permitted; other steroid regimens and/or immunosuppressives are excluded.
9. Prior splenectomy.
10. Prior malignancy (excluding nonmelanoma carcinomas of the skin) unless in remission for ≥ 2 years.
11. Kaposi's Sarcoma.
12. Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
13. Patients with known HIV.
14. Patients with chronic Hepatitis B and C infection.
15. Patients with uncontrolled autoimmune diseases.