Trial of Adjuvant FANG™ Vaccine for High Risk Stage III/IV Ovarian Cancer
| Status: | Active, not recruiting |
|---|---|
| Conditions: | Ovarian Cancer, Cancer |
| Therapuetic Areas: | Oncology |
| Healthy: | No |
| Age Range: | 18 - Any |
| Updated: | 3/22/2019 |
| Start Date: | February 2011 |
| End Date: | December 2020 |
Open Label Phase II Trial of Adjuvant Bi-shRNAfurin and GMCSF Augmented Autologous Tumor Cell Vaccine (FANG™) for High Risk Stage III/IV Ovarian Cancer
This is a Phase II open-label trial of maintenance Vigil™ autologous tumor cell vaccine.
Tumor will be harvested at the time of surgical debulking (standard of medical care).
Subsequently, patients achieving clinical CR following primary surgical debulking and doublet
chemotherapy will be stratified for i) surgical stage (Stage IV or suboptimal debulking (>1
cm residual) Stage III disease versus Stage III patients with optimal debulking (<1 cm
residual)) and ii) post-op chemotherapy, pre-vaccine CA-125 >10 ≤ 20 U/mL versus 0≤10 U/ml.
(Note: patients with Stage IIIc ovarian cancer will be additionally evaluated as a subset
using descriptive statistics only). Patients will receive 1.0 x 10^7 cells / intradermal
injection of gene transfected autologous tumor cells, Vigil™ once a month for up to 12 doses
as long as sufficient material is available. Enough harvested tissue to provide a minimum of
4 monthly injections will be required for entry into the study. Hematologic function, liver
enzymes, renal function and electrolytes will be monitored monthly. Immune function analysis
including ELISPOT analysis of cytotoxic T cell function to autologous tumor antigens will be
monitored at (≤24 hours before) tissue harvest, ≤24 hours before the first cycle of
chemotherapy (post debulking), ≤24 hours before the third cycle of chemotherapy (post
debulking), baseline (screening), prior to Vigil™ injection Months 2, 4, 6 and at EOT. The
dates of the last dose of chemotherapy and the administration of Vigil™ vaccine #1 will be
recorded. Treatment will be continued until disease recurrence or exhaustion of the patient's
vaccine supply. If ≥ Grade 2 toxicity by NCI Common Toxicity Criteria (excluding Grade 2
fever ≤ 24 hours and Grade 2 and 3 injection site reactions) develops related to study
treatment the vaccine dose will be reduced by 50% and continued on a monthly basis. If a
single patient develops ≥ Grade 3 toxicity (other than injection site reaction) related to
study treatment the trial will be placed on hold for reevaluation of design in discussion
with FDA. During this hold, no new subjects will initiate dosing, but subjects already being
dosed may continue dosing as scheduled if deemed clinically appropriate by the PI.
Tumor will be harvested at the time of surgical debulking (standard of medical care).
Subsequently, patients achieving clinical CR following primary surgical debulking and doublet
chemotherapy will be stratified for i) surgical stage (Stage IV or suboptimal debulking (>1
cm residual) Stage III disease versus Stage III patients with optimal debulking (<1 cm
residual)) and ii) post-op chemotherapy, pre-vaccine CA-125 >10 ≤ 20 U/mL versus 0≤10 U/ml.
(Note: patients with Stage IIIc ovarian cancer will be additionally evaluated as a subset
using descriptive statistics only). Patients will receive 1.0 x 10^7 cells / intradermal
injection of gene transfected autologous tumor cells, Vigil™ once a month for up to 12 doses
as long as sufficient material is available. Enough harvested tissue to provide a minimum of
4 monthly injections will be required for entry into the study. Hematologic function, liver
enzymes, renal function and electrolytes will be monitored monthly. Immune function analysis
including ELISPOT analysis of cytotoxic T cell function to autologous tumor antigens will be
monitored at (≤24 hours before) tissue harvest, ≤24 hours before the first cycle of
chemotherapy (post debulking), ≤24 hours before the third cycle of chemotherapy (post
debulking), baseline (screening), prior to Vigil™ injection Months 2, 4, 6 and at EOT. The
dates of the last dose of chemotherapy and the administration of Vigil™ vaccine #1 will be
recorded. Treatment will be continued until disease recurrence or exhaustion of the patient's
vaccine supply. If ≥ Grade 2 toxicity by NCI Common Toxicity Criteria (excluding Grade 2
fever ≤ 24 hours and Grade 2 and 3 injection site reactions) develops related to study
treatment the vaccine dose will be reduced by 50% and continued on a monthly basis. If a
single patient develops ≥ Grade 3 toxicity (other than injection site reaction) related to
study treatment the trial will be placed on hold for reevaluation of design in discussion
with FDA. During this hold, no new subjects will initiate dosing, but subjects already being
dosed may continue dosing as scheduled if deemed clinically appropriate by the PI.
Despite a gradual improvement in their overall survival over the past decade, approximately
75% of women with Stage IIIC ovarian cancer who achieve a complete clinical response will
relapse as will 50% of those achieving pathologic complete response at a median time of 18-24
months. Phase III studies of both maintenance and consolidation therapeutic interventions
have not translated into an overall survival advantage. Preliminary studies of immunotherapy
in patients with ovarian cancer suggest target accessibility (potential immunogenicity) to
immune mediated approaches. In an effort to overcome limitations of immunostimulatory cancer
vaccines, we designed a novel autologous whole cell vaccine, Vigil™, incorporating the
rhGMCSF transgene and the bifunctional shRNA^furin (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 (i.e. antigen→immunogen), 3) enhance effector
potency, and 4) subvert endogenous cancer-induced immune resistance. A Phase I assessment of
Vigil™ vaccine in 33 advanced solid tumor patients (1 of them being a pediatric patient 15
years of age) receiving ≥1 vaccination (at a dose of 1.0 x 10^7 or 2.5 x 10^7
cells/injection/month for a maximum of 12 vaccinations) demonstrated safety of the Vigil™
vaccine. Furthermore, proof of principle was established in the manufactured vaccines with
increased mean GMCSF expression post-transfection to 1135 pg/10^6 cells/ml and knockdown of
furin, TGFb1 and TGFb2 at 78%, 93%, and 95%, respectively). In addition, although a Phase I
study, the data suggested an overall survival benefit.
75% of women with Stage IIIC ovarian cancer who achieve a complete clinical response will
relapse as will 50% of those achieving pathologic complete response at a median time of 18-24
months. Phase III studies of both maintenance and consolidation therapeutic interventions
have not translated into an overall survival advantage. Preliminary studies of immunotherapy
in patients with ovarian cancer suggest target accessibility (potential immunogenicity) to
immune mediated approaches. In an effort to overcome limitations of immunostimulatory cancer
vaccines, we designed a novel autologous whole cell vaccine, Vigil™, incorporating the
rhGMCSF transgene and the bifunctional shRNA^furin (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 (i.e. antigen→immunogen), 3) enhance effector
potency, and 4) subvert endogenous cancer-induced immune resistance. A Phase I assessment of
Vigil™ vaccine in 33 advanced solid tumor patients (1 of them being a pediatric patient 15
years of age) receiving ≥1 vaccination (at a dose of 1.0 x 10^7 or 2.5 x 10^7
cells/injection/month for a maximum of 12 vaccinations) demonstrated safety of the Vigil™
vaccine. Furthermore, proof of principle was established in the manufactured vaccines with
increased mean GMCSF expression post-transfection to 1135 pg/10^6 cells/ml and knockdown of
furin, TGFb1 and TGFb2 at 78%, 93%, and 95%, respectively). In addition, although a Phase I
study, the data suggested an overall survival benefit.
Tissue Procurement Inclusion Criteria:
1. Presumptive Stage III/IV papillary serous or endometrioid ovarian cancer.
2. Per Amendment #8, treatment naïve, high risk ovarian cancer will no longer be
stratified, but the following information will be collected:
1. Stage IV or suboptimal (>1 cm residual) Stage III disease versus Stage III
patients with optimal (≤1 cm residual) disease,
2. CA-125 ≤10 U/ml versus CA-125 greater than 10 but less than or equal to 20 U/ml
3. IP chemotherapy versus IV chemotherapy
3. Availability of "golf-ball" size 10-30 grams tissue at time of primary surgical
debulking.
4. ECOG performance status (PS) 0-2 prior to tumor debulking laparotomy.
5. Ability to understand and the willingness to sign a written informed consent document
for tissue harvest.
INCLUSION CRITERIA:
1. Histologically confirmed Stage III/IV papillary serous or endometrioid ovarian cancer.
2. Clinically defined CR (no cancer related symptoms, normal physical examination and CT
scan abdomen/pelvis and CXR, and CA-125 ≤20 U/ml) following completion of primary
surgical debulking. Patients enrolled must complete at least 5 but no more than 6
cycles platinum/taxane adjuvant or interval debulking + chemotherapy (or chemotherapy
as per recommendations of NCCN guidelines, category 1 (IP chemotherapy included)).
(Patients who complete surgery/chemotherapy with a CA-125 >20 U/mL pre-registration
have the option of being followed up to 2 months if serial CA-125 values continue to
decrease at a rate of CA-125 decrease of 50% per month.)
3. Successful manufacturing of 4 vials of Vigil™ vaccine.
4. Recovered from all clinically relevant toxicities related to prior protocol specific
therapies (including neuropathy to ≤Grade 2).
5. ECOG performance status (PS) 0-1.
6. Normal organ and marrow function as defined below:
Absolute granulocyte count ≥ 1,500/mm3 Absolute lymphocyte count ≥ 200/mm3 Platelets ≥
75,000/mm3 Total bilirubin ≤ 2 mg/dL AST(SGOT)/ALT(SGPT) ≤ 2x institutional upper
limit of normal Creatinine < 1.5 mg/dL
7. Patients must be off all "statin" drugs for ≥ 2 weeks prior to initiation of therapy.
8. Ability to understand and the willingness to sign a written informed protocol specific
consent document.
EXCLUSION CRITERIA:
1. Surgery involving general anesthesia, radiotherapy, or immunotherapy within 4 weeks
prior to randomization. Chemotherapy within 3 weeks prior to Vigil™ vaccine
administration. Steroid therapy within 1 week prior to vaccine administration.
2. Patient must not have received any other investigational agents within 4 weeks vaccine
administration.
3. Patients with history of brain metastases.
4. Patients with compromised pulmonary disease.
5. Short term (<30 days) concurrent systemic steroids ≤ 0. 25 mg/kg prednisone per day
(maximum 7.5 mg/day) and bronchodilators (inhaled steroids) are permitted; other
steroid regimens and/or immunosuppressives are excluded.
6. Prior splenectomy.
7. Prior malignancy (excluding nonmelanoma carcinomas of the skin and carcinoma in-situ
cervix) 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 with known HIV.
11. Patients with chronic Hepatitis B and C infection.
12. Patients with uncontrolled autoimmune diseases.
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