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

Study Overview
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Brief Summary
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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.

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

Conditions
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Colon Cancer

Intervention / Treatment
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* Biological: Vigil™ Vaccine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed colorectal carcinoma with synchronous or metachronous liver metastases +/- pulmonary metastases. Part 1 patients: May have multiple number of metastatic lesions as long as they can be rendered no evidence of disease (NED). 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). For patients with 1 but up to 3 total lesions, distribution must include both liver + pulmonary metastases. For patients with 4-6 total lesions, distribution may include liver +/- pulmonary metastases. Candidate for surgical excision +/= ablation with curative intent based on pre-operative assessment incorporating a CT/PET scan. 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. Planned resected viable tumor in sufficient quantity (golf ball size estimated weight   30 grams) for vaccine processing. Recovered to ≤ Grade 1 (excluding alopecia) from all clinically relevant toxicities related to prior therapies. Patients must be off all statin drugs for ≥ 2 weeks prior to initiation of therapy. Age ≥18 years. ECOG performance status (PS) 0-2. Estimated >4 month survival probability. 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 Ability to understand and the willingness to sign a written informed consent document. Negative pregnancy test. Exclusion Criteria: Surgery involving general anesthesia, radiotherapy, steroid therapy, or immunotherapy within 4 weeks prior to entering the study. Collection of lumenal tissue must be avoided. 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. Prior surgical resection, ablation or radiation therapy for metastatic disease prior to or at the time of tissue procurement. Portal, celiac or periaortic metastases. Patient must not have received any other investigational agents within 30 days prior to study entry/ registration. Patients with known active or symptomatic brain metastases. Patients with compromised pulmonary disease. 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. Prior splenectomy. Prior malignancy (excluding nonmelanoma carcinomas of the skin) unless in remission for ≥ 2 years. Kaposi's Sarcoma. 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. Patients with known HIV. Patients with chronic Hepatitis B and C infection. Patients with uncontrolled autoimmune diseases.

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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Vigil™<br>Patients will receive 1 x 10^7 cells (Group A) via intradermal injection for a minimum of 4 doses and a maximum of 12 doses (vaccine) starting post-surgery Week 4-8 (C1W1D1) and continuing C1W3D1, C2W3D1, then every 28 days. | Biological: Vigil™ Vaccine<br>* 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).<br>* Other names: formerly known as FANG™;|
| Placebo Comparator: Placebo<br>Patients will receive placebo (Group B) via intradermal injection for a minimum of 4 doses and a maximum of 12 doses starting post-surgery Week 4-8 (C1W1D1) and continuing C1W3D1, C2W3D1, then every 28 days. | Drug: Placebo<br>* 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).<br>|
| Experimental: Vigil™ Vaccine (6 patient run-in)<br>Six patients will be enrolled into the Part 1 of the study to receive intradermal autologous Vigil™ cancer vaccine (1.0 x 10e7 cells/injection; maximum of 12 vaccinations). | Biological: Vigil™ Vaccine<br>* 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).<br>* Other names: formerly known as FANG™;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Immune Analysis in Tumor Biopsy and Blood (Part 1) | To evaluate and correlate Tumor Infiltrating Lymphocytes (TIL) in initial excised tumor and Enzyme-Linked ImmunoSorbent Spot (ELISPOT) responses to Vigil™ vaccine in blood of patients with CLM. | Up to 12 months | 
| Percent of Patients Who Progressed After Treatment (Part 2) | Response rate will also be evaluated in this study using the Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST) (unidimensional measurement) of the tumor lesions are used in the RECIST criteria.The response in patients with measurable disease will be reported using standard outcome measures for clinical trials: complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD). Any response to treatment (either PR or CR) requires two confirmatory staging at least 4 weeks apart. Patients will be evaluable for tumor response if measurable disease is present. | 24 months | 
| Percent of Patients Who Survived After Treatment (Part 2) | To determine and compare the overall survival rate in patients with CLM following resection +/- ablation with curative intent treated with sandwich or adjuvant chemotherapy and Vigil™ vaccine versus sandwich or adjuvant chemotherapy and placebo and compare with historical data. | 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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colorectal carcinoma, colon cancer, liver metastases