Randomized Phase II Adjuvant Chemotherapy ± FANG™ in Colorectal Carcinoma With Liver Metastases
Condition: Colon Cancer
MeSH terms: Carcinoma; Neoplasm Metastasis; Colonic Neoplasms; Colorectal Neoplasms
Intervention: Vigil™ Vaccine; Placebo
Intervention description: Patients will receive 1 x 10^7 cells (Group A) or placebo (Group B) via intradermal injection for a minimum of 5 doses and a maximum of 12 doses starting post-surgery Week 4-8 (C1W1D1) and continuing C1W3D1, C2W3D1, then every 28 days. Starting C1W4D1, all patients will receive modified FOLFOX6 (oxaliplatin 85 mg/m2 D1, l-leucovorin 200 mg/m2 D1, fluorouracil 400 mg/m2 IV bolus (or short infusion) D1, fluorouracil 2400 mg/m2 46 hours continuous infusion every 14 days x 6 cycles (1 cycle = 4 weeks).; Patients will receive 1 x 10^7 cells (Group A) or placebo (Group B) via intradermal injection for a minimum of 5 doses and a maximum of 12 doses starting post-surgery Week 4-8 (C1W1D1) and continuing C1W3D1, C2W3D1, then every 28 days. Starting C1W4D1, all patients will receive modified FOLFOX6 (oxaliplatin 85 mg/m2 D1, l-leucovorin 200 mg/m2 D1, fluorouracil 400 mg/m2 IV bolus (or short infusion) D1, fluorouracil 2400 mg/m2 46 hours continuous infusion every 14 days x 6 cycles (1 cycle = 4 weeks).
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Participant)
Enrollment: 3.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: colorectal carcinoma; colon cancer; liver metastases

Summary:

      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.
    

Eligibility criteria:

        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.