Randomized Phase II Adjuvant Chemotherapy ± FANG™ in Colorectal Carcinoma With Liver Metastases (FANG-CLM)

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.

Study Overview

• Status: Terminated
• Conditions: Colon Cancer
• Intervention / Treatment: Biological: Vigil™ Vaccine; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 3
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Texas
    • Dallas, Texas, United States, 75230
      • Mary Crowley Cancer Research Centers

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: SINGLE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Vigil™; 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; 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).; Other Names: formerly known as FANG™
PLACEBO_COMPARATOR: Placebo; 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; 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).
EXPERIMENTAL: Vigil™ Vaccine (6 patient run-in); 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; 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).; Other Names: formerly known as FANG™

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Enzyme-Linked ImmunoSorbent Spot (ELISPOT) (Part 1)	To determine if subjects will have a positive (defined as >10 ELISPOTS from baseline) immune response to Vigil. Blood was collected to compare ELISPOT results from baseline until 30 days after last dose.	Baseline, End of Treatment (30 days after last dose) up to 12 months
Number of Alive Subjects (Part 1)	For Part 1, this was to determine the overall survival rate in patients with CLM following resection +/= ablation with curative intent treated with adjuvant chemotherapy and Vigil™ by following these patients up to 24 months.	24 Months

Collaborators and Investigators

• Sponsor: Gradalis, Inc.

Publications and helpful links

General Publications

• Senzer N, Barve M, Kuhn J, Melnyk A, Beitsch P, Lazar M, Lifshitz S, Magee M, Oh J, Mill SW, Bedell C, Higgs C, Kumar P, Yu Y, Norvell F, Phalon C, Taquet N, Rao DD, Wang Z, Jay CM, Pappen BO, Wallraven G, Brunicardi FC, Shanahan DM, Maples PB, Nemunaitis J. Phase I trial of "bi-shRNAi(furin)/GMCSF DNA/autologous tumor cell" vaccine (FANG) in advanced cancer. Mol Ther. 2012 Mar;20(3):679-86. doi: 10.1038/mt.2011.269. Epub 2011 Dec 20.
• Nemunaitis J, Barve M, Orr D, Kuhn J, Magee M, Lamont J, Bedell C, Wallraven G, Pappen BO, Roth A, Horvath S, Nemunaitis D, Kumar P, Maples PB, Senzer N. Summary of bi-shRNA/GM-CSF augmented autologous tumor cell immunotherapy (FANG) in advanced cancer of the liver. Oncology. 2014;87(1):21-9. doi: 10.1159/000360993. Epub 2014 Jun 25.
• Ghisoli M, Barve M, Mennel R, Lenarsky C, Horvath S, Wallraven G, Pappen BO, Whiting S, Rao D, Senzer N, Nemunaitis J. Three-year Follow up of GMCSF/bi-shRNA(furin) DNA-transfected Autologous Tumor Immunotherapy (Vigil) in Metastatic Advanced Ewing's Sarcoma. Mol Ther. 2016 Aug;24(8):1478-83. doi: 10.1038/mt.2016.86. Epub 2016 Apr 25.
• Ghisoli M, Barve M, Schneider R, Mennel R, Lenarsky C, Wallraven G, Pappen BO, LaNoue J, Kumar P, Nemunaitis D, Roth A, Nemunaitis J, Whiting S, Senzer N, Fletcher FA, Nemunaitis J. Pilot Trial of FANG Immunotherapy in Ewing's Sarcoma. Mol Ther. 2015 Jun;23(6):1103-1109. doi: 10.1038/mt.2015.43. Epub 2015 Mar 19.
• Ghisoli M, Rutledge M, Stephens PJ, Mennel R, Barve M, Manley M, Oliai BR, Murphy KM, Manning L, Gutierrez B, Rangadass P, Walker A, Wang Z, Rao D, Adams N, Wallraven G, Senzer N, Nemunaitis J. Case Report: Immune-mediated Complete Response in a Patient With Recurrent Advanced Ewing Sarcoma (EWS) After Vigil Immunotherapy. J Pediatr Hematol Oncol. 2017 May;39(4):e183-e186. doi: 10.1097/MPH.0000000000000822.
• Oh J, Barve M, Matthews CM, Koon EC, Heffernan TP, Fine B, Grosen E, Bergman MK, Fleming EL, DeMars LR, West L, Spitz DL, Goodman H, Hancock KC, Wallraven G, Kumar P, Bognar E, Manning L, Pappen BO, Adams N, Senzer N, Nemunaitis J. Phase II study of Vigil(R) DNA engineered immunotherapy as maintenance in advanced stage ovarian cancer. Gynecol Oncol. 2016 Dec;143(3):504-510. doi: 10.1016/j.ygyno.2016.09.018. Epub 2016 Sep 24.
• Long-term followup of bi-shRNAfurin and GMCSF augmented autologous tumor cell immunotherapy treated colorectal cancer patients in phase I and IIa studies. Minal A. Barve, Anton M. Melnyk, Luisa Manning, Gladice Wallraven, Martin Birkhofer, and John J. Nemunaitis Journal of Clinical Oncology 2017 35:15_suppl, e15100-e15100
• Barve V, Adams N, Stanbery L, Manning L, Horvath S, Wallraven G, Bognar E, Barve M, Nemunaitis J. Case Report: Marked Survival Advantage of Two Colorectal Cancer Patients with Liver Metastases Treated with Vigil and FOLFOX-6. Vaccines (Basel). 2021 Oct 18;9(10):1201. doi: 10.3390/vaccines9101201.

Study record dates

Study Major Dates

• Study Start: March 1, 2012
• Primary Completion (ACTUAL): August 1, 2016
• Study Completion (ACTUAL): August 1, 2016

Study Registration Dates

• First Submitted: January 4, 2012
• First Submitted That Met QC Criteria: January 5, 2012
• First Posted (ESTIMATE): January 6, 2012

Study Record Updates

• Last Update Posted (ACTUAL): November 1, 2021
• Last Update Submitted That Met QC Criteria: October 21, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Keywords: colon cancer; liver metastases; colorectal carcinoma
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Neoplastic Processes; Carcinoma; Colorectal Neoplasms; Neoplasm Metastasis; Colonic Neoplasms
• Other Study ID Numbers: CL-PTL 107