Trial of Bi-shRNA-furin and Granulocyte Macrophage Colony Stimulating Factor (GMCSF) Augmented Autologous Tumor Cell Vaccine for Advanced Cancer (FANG)

This study is currently recruiting participants. (see Contacts and Locations)
Verified December 2013 by Gradalis, Inc.
Sponsor:
Information provided by (Responsible Party):
Gradalis, Inc.
ClinicalTrials.gov Identifier:
NCT01061840
First received: February 2, 2010
Last updated: December 2, 2013
Last verified: December 2013
  Purpose

Autologous FANG vaccine expresses rhGMCSF and bi-shRNAfurin from the FANG plasmid. The GMCSF protein is a potent stimulator of the immune system, recruiting immune effectors to the site of intradermal injection and promoting antigen presentation. The furin bifunctional shRNA blocks furin protein production at the post transcriptional and translational levels. This decrease in furin in turn decreases the conversion of the proforms TGFβ1 and TGFβ2 proteins. Also, reduced furin protein levels have a negative feedback inhibition on TGFβ1 and TGFβ2 gene expression, decreasing the levels of their mRNAs. The resulting decrease in TGFβ1 and TGFβ2 proteins reduces the local immunosuppression they cause and promotes tumor surface antigen and MHC protein display.


Condition Intervention Phase
Ewing's Sarcoma
Ovarian Cancer
Biological: FANG
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I Trial of Bi-shRNAfurin and GMCSF Augmented Autologous Tumor Cell Vaccine for Advanced Cancer

Resource links provided by NLM:


Further study details as provided by Gradalis, Inc.:

Primary Outcome Measures:
  • To determine safety following the administration of bi-shRNAfurin and GMCSF autologous tumor cell (FANG) vaccine in advanced solid tumor patients who have no acceptable form of standard therapy with curative intent. [ Time Frame: Participants will be followed for life ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • To determine time to progression. To Evaluate the effect of vaccine on immune stimulation. To evaluate whether lower cell doses would activate ELISPOT responses and to compare durability of dose elicited responses. [ Time Frame: Participants will be followed for life. ] [ Designated as safety issue: No ]

Estimated Enrollment: 60
Study Start Date: December 2009
Estimated Study Completion Date: December 2016
Estimated Primary Completion Date: December 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1 x 10 ^7 cells/injection
FANG
Biological: FANG
Patients will be treated once a month as long as sufficient material is available for up to 12 doses
Other Names:
  • bi-shRNAfurin and GMCSF Augmented Autologous Tumor
  • Cell Vaccine
Experimental: 2.5 x 10 ^7 cells/injection
FANG
Biological: FANG
Patients will be treated once a month as long as sufficient material is available for up to 12 doses
Other Names:
  • bi-shRNAfurin and GMCSF Augmented Autologous Tumor
  • Cell Vaccine
Experimental: 1 x 10^6 or 4 x 10^6 cells/injection
FANG
Biological: FANG
Patients will be treated once a month as long as sufficient material is available for up to 12 doses
Other Names:
  • bi-shRNAfurin and GMCSF Augmented Autologous Tumor
  • Cell Vaccine

Detailed Description:

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, we have designed a novel autologous vaccine to address inability to fully identify cancer associated antigens, antigen recognition by the immune system (i.e. antigen to immunogen), effector potency, and cancer-induced resistance. We have completed clinical investigations using two different gene vaccine approaches to induce enhancement of tumor antigen recognition which have demonstrated therapeutic efficacy. Specifically, both the use of a GMCSF gene transduced vaccine (GVAX®) and a TGFβ2 antisense gene vaccine (Lucanix®), in separate trials, have demonstrated similar beneficial effects without any evidence of significant toxicity in advanced cancer patients. The GMCSF transgene directly stimulates increased expression of tumor antigen(s) and enhances dendritic cell migration to the vaccination site. TGFβ2 blockade following intracellular TGFβ2 antisense gene expression reduces production of immune inhibiting activity at the vaccine site. This appears to be one of the primary mechanisms of inhibition of immune responsiveness in glioblastoma and lung cancer. In a subsequent Phase I trial we combined both active principles in one autologous vaccine, TAG. TAG vaccine has an excellent safety profile in the first nineteen patients treated (enrollment open to any solid tumor) with one documented CR (melanoma). However, TGFβ1 is the dominant TGFβ family inhibitory effector in the majority of other solid tumors. We describe a unique method of inhibiting both TGFβ1 and TGFβ2 through RNA interference with Furin. We will harvest autologous cancer cells from patients with advanced refractory cancer. We have constructed a bi-shRNAfurin / GMCSF (FANG) expression vector plasmid and have successfully demonstrated preclinical activity of the vector function following transfection by electroporation and irradiation of ex vivo autologous tumor cells.

  Eligibility

Ages Eligible for Study:   12 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Histologically confirmed advanced or metastatic non-curable solid tumor (if limited to a single lesion may not be a candidate for curative surgery or radiation therapy). Successful vaccine manufacture has resulted from tissue/fluid obtained from the following major organ systems: digestive, endocrine, reproductive, respiratory, and urinary.
  2. For the purpose of the Pediatric study patients with histologic diagnosis of ESFT including: Ewing sarcoma or primitive neuroectodermal tumor (malignant neuroepithelioma) of the bone or soft tissues, Askin's tumor of the chest and with central nervous system tumors are eligible.
  3. Patients with recurrent or refractory ESFT Patients with de novo poor prognosis/ high risk ESFT: (Eligible for vaccine manufacturing at diagnosis but ONLY ELIGIBLE FOR IMMUNOTHERAPY IF DEMONSTRATES PERSISTENT/RECURRENT/ REFRACTORY DISEASE)

    • Large tumors > 8 cm
    • Pelvic osseous tumors ANY SIZE
    • Bilateral pulmonary metastasis
    • >2 unilateral pulmonary metastasis
  4. Patients with well differentiated thyroid cancer are eligible for protocol as follows:

    1. Surgically unresectable locally recurrent disease and/or metastatic disease following RAI ablation (if locally recurrent and ultrasound (US) positive, baseline FDG-PET or MRI will be obtained).
    2. Patients with microscopic and/or gross extra thyroidal disease extension without RAI uptake but with a) FDG-PET positive disease or b) suppressed thyroglobulin >1 ng/mL or c) stimulated thyroglobulin >10 ng/L.
    3. Patients with tracheal/esophageal involvement especially if pathology shows 1) high mitotic activity or 2) necrosis.

    Note: in Categories a and b, patients can be followed using US locally in addition to standard diagnostic followup menu but, if US only is positive, a FDG-PET or MRI will be obtained. If negative, a rising thyroglobulin titer is required in which case response will be monitored by continued US and suppressed and/or stimulated thyroglobulin. Thyroglobulin titer cannot be used if anti-thyroglobulin antibodies are present).

  5. Completed all acceptable therapies with curative intent that are the current standard of care for their respective diseases. If no conventional therapy available, patient may participate after review by sponsor.
  6. Clinically (medically) indicated procedure (i.e. biopsy of lesions of recurrent disease, palliative management via resection, thoracentesis, etc.) to collect viable tumor in sufficient quantity ("golf ball size" estimated weight ~30 grams, pleural and/or ascites fluid estimated volume ≥ 500mL) for vaccine processing.
  7. Recovered from all clinically relevant toxicities related to prior therapies.
  8. Patients will be allowed to participate following single prior CNS treatment with stereotactic radiotherapy +/- whole brain irradiation and stable without steroid requirement for ≥2 months or following ≥2 prior CNS treatments with stereotactic radiotherapy +/- whole brain irradiation and stable without steroid requirement for ≥4 months.
  9. Age ≥12 years.
  10. ECOG performance status (PS) 0-1.Pediatric patients with Lansky or Karnofsky Performance Status Scale ≥ of 50%.
  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. Pediatric patients must sign an assent with a parent or legal guardian sign a written informed consent.
  14. Negative pregnancy test.

Exclusion Criteria:

  1. Surgery involving general anesthesia, chemotherapy, radiotherapy, steroid therapy, or immunotherapy within 4 weeks prior to entering the study. Collection of lumenal tissue must be avoided.
  2. Patient must not have received any other investigational agents within 30 days prior to study entry.
  3. Patients with known active or symptomatic brain metastases.
  4. Patients with compromised pulmonary disease.
  5. 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. Patients requiring steroids following previous CNS radiation for metastatic disease are excluded (see inclusion criteria 5).
  6. Prior splenectomy.
  7. Prior malignancy (excluding nonmelanoma carcinomas of the skin) unless in remission for ≥ 2 years.
  8. Kaposi's Sarcoma.
  9. 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.
  10. Patients who are pregnant or nursing.
  11. Patients with known HIV.
  12. Patients with chronic Hepatitis B and C infection. For patients with hepatocellular carcinoma (HCC), the presence of chronic HBV and HCV is NOT an exclusion. Patients must have a viral titer (via nucleic acid test)< 50IU/ml x 2 at a minimum of 2 weeks apart.
  13. Patients with uncontrolled autoimmune diseases.
  14. Patients must be off all "statin" drugs for ≥2 weeks prior to initiation of therapy.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01061840

Locations
United States, Texas
Mary Crowley Cancer Research Centers Recruiting
Dallas, Texas, United States, 75230
Contact: Referral Office    972-566-3000    referral@marycrowley.org   
Principal Investigator: Minal Barve, MD         
Sponsors and Collaborators
Gradalis, Inc.
Investigators
Principal Investigator: Minal Barve, MD Mary Crowley Cancer Research Centers
  More Information

Publications:
Responsible Party: Gradalis, Inc.
ClinicalTrials.gov Identifier: NCT01061840     History of Changes
Other Study ID Numbers: CL-PTL 101
Study First Received: February 2, 2010
Last Updated: December 2, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by Gradalis, Inc.:
Ewing's Sarcoma
Ovarian Cancer

Additional relevant MeSH terms:
Ovarian Neoplasms
Sarcoma, Ewing's
Sarcoma
Endocrine Gland Neoplasms
Neoplasms by Site
Neoplasms
Ovarian Diseases
Adnexal Diseases
Genital Diseases, Female
Genital Neoplasms, Female
Urogenital Neoplasms
Endocrine System Diseases
Gonadal Disorders
Osteosarcoma
Neoplasms, Bone Tissue
Neoplasms, Connective Tissue
Neoplasms, Connective and Soft Tissue
Neoplasms by Histologic Type

ClinicalTrials.gov processed this record on July 22, 2014