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Phase I Trial of Bi-shRNAfurin and GMCSF Augmented Autologous Tumor Cell Vaccine for Advanced Cancer

Phase 1
12 Years
Open (Enrolling)
Solid Tumors

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Trial Information

Phase I Trial of Bi-shRNAfurin and GMCSF Augmented Autologous Tumor Cell Vaccine for Advanced Cancer

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.

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

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

- Large tumors > 8 cm

- Pelvic osseous tumors ANY SIZE

- Bilateral pulmonary metastasis

- >2 unilateral pulmonary metastasis

4. 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.

5. 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.

6. Recovered from all clinically relevant toxicities related to prior therapies.

7. 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.

8. Age ≥12 years.

9. ECOG performance status (PS) 0-1.Pediatric patients with Lansky or Karnofsky
Performance Status Scale ≥ of 50%.

10. Estimated >4 month survival probability.

11. 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

12. 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.

13. 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.

13. Patients with uncontrolled autoimmune diseases.

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

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

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.

Outcome Time Frame:

Participants will be followed for life

Safety Issue:



United States: Food and Drug Administration

Study ID:

CL-PTL 101



Start Date:

December 2009

Completion Date:

December 2014

Related Keywords:

  • Solid Tumors
  • non-small cell lung cancer
  • melanoma
  • ovarian



Mary Crowley Cancer Research Centers Dallas, Texas  75201