Trial of Adjuvant FANG™ Vaccine for High Risk Stage III/IV Ovarian Cancer (FANG Ovarian)

This study is currently recruiting participants. (see Contacts and Locations)
Verified May 2014 by Gradalis, Inc.
Sponsor:
Information provided by (Responsible Party):
Gradalis, Inc.
ClinicalTrials.gov Identifier:
NCT01309230
First received: February 25, 2011
Last updated: May 12, 2014
Last verified: May 2014
  Purpose

This is a 2:1 randomized Phase II open-label trial of FANG™ autologous tumor cell vaccine. Tumor will be harvested at the time of surgical debulking (standard of medical care).

Part 1 Patients achieving clinical complete Response (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 of greater than 10 to 20 U/mL versus 0 ≤ 10 U/mL then randomized 2:1 (Note: patients with Stage IIIc ovarian cancer will be additionally evaluated as a subset using descriptive statistics only). Group A, FANG™ (n=40) will receive 1.0 x 10^7 cells / intradermal injection of gene transfected autologous tumor cells once a month for up to 12 doses as long as sufficient material is available. Group B (n=20) will be followed as per standard of care without maintenance therapy. A minimum harvest aliquot to produce 4 monthly injections will be required for entry into the study. These patients will be managed in an outpatient setting. 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) tissue harvest, ≤24 hours of Cycle 1 chemotherapy, ≤ 24 hours Cycle 3 chemotherapy, baseline (screening); prior to FANG™ injection at Months 2, 4, 6 and EOT. CA-125 will be monitored at baseline, every month for the first year, every 3 months ± 2 weeks for the second and third year. At recurrence, patients in Group B will be stratified into cisplatin-sensitive and -resistant groups and treated with second line chemotherapy. The response rate and duration of response to second-line therapy in patients with or without prior FANG™ will be compared.

Part 2 Six patients will have had FANG™ prepared and stored from ovarian tumor cells obtained at the time of primary surgical debulking. Patients meeting eligibility criteria will receive 6 cycles of adjuvant chemotherapy. Although paclitaxel 175 mg/m2 over 3 hours followed by carboplatin AUC 5-7.5 IV over 1 hour Day 1 every 3 weeks for 6 cycles is preferred for consistency, pending individual patient requirements, alternative regimens are those classified as Level 1 Category of Evidence per NCCN Guidelines Version 3.2012. FANG vaccine will be administered 24 (± 2 hours) hours after completion of the second cycle of chemotherapy post debulking and continue every 3 weeks through completion of chemotherapy and then every 4 weeks thereafter. Patients will not receive maintenance therapy other than that specified by protocol. Patients will be allowed to continue FANG™ for up to 12 cycles or as long as vaccine is available; conversely, patients who exhaust FANG™ supply may continue completion of 6 cycles of chemotherapy alone. Hematologic function, liver enzymes, renal function and electrolytes will be monitored weekly during chemotherapy. Immune function analysis including ELISPOT analysis of cytotoxic T cell function to autologous tumor antigens will be monitored at tissue harvest (≤ 24 hours) and ≤ 24 hours prior to chemotherapy Cycles 1, 2, 3, 6, (Cycles 8, 10, and 12 if applicable) and EOT; thereafter, at 6 months intervals. Although no CA- 125 restriction, the following data will be collected: pre-operative CA-125, CA-125 immediately prior to the second cycle of chemotherapy post debulking, and CA-125 prior to every second (2nd) chemotherapy cycle. CA-125 will be collected starting 2 months post final chemotherapy every 2 months for the first year then quarterly thereafter.


Condition Intervention Phase
Ovarian Cancer
Biological: FANG™
Drug: Standard of care observational follow-up
Biological: FANG™ and adjuvant chemotherapy
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Randomized Phase II Trial of Adjuvant Bi-shRNAfurin and GMCSF Augmented Autologous Tumor Cell Vaccine (FANG™) for High Risk Stage III/IV Ovarian Cancer

Resource links provided by NLM:


Further study details as provided by Gradalis, Inc.:

Primary Outcome Measures:
  • To determine and compare time to recurrence (TTR) [ Time Frame: Participants will be followed for life. ] [ Designated as safety issue: No ]

    Part 1 Primary Objective(s):

    • To determine and compare time to recurrence (TTR) following the administration of bi-shRNAfurin and GMCSF autologous tumor cell (FANGTM) vaccine in high risk patients with Stage III/IV ovarian cancer NED following tumor debulking surgery and chemotherapy to standard of care post treatment observation.
    • To assess time to recurrence (TTR) in following the administration of bishRNAfurin and GMCSF autologous tumor cell (FANG™) vaccine in Group A and those being followed as per standard of care in Group B in the patient subset of Stage IIIc ovarian cancer NED following tumor debulking surgery and chemotherapy (descriptive statistics only).


Secondary Outcome Measures:
  • Immune Function [ Time Frame: Blood will be collected at baseline, Months 2, 3, 4, and EOT ] [ Designated as safety issue: Yes ]

    Part 1 Secondary Objectives:

    • To identify and determine the effect of FANGTM autologous tumor cell vaccine on immune surrogate markers.
    • To assess the predictive potential of initial tumor infiltrating lymphocyte (TIL) and tumor associated macrophage (TAM) phenotypes.
    • To enlarge the safety database of FANGTM autologous tumor cell vaccine in patients with minimal disease.

    Part 2 Primary Objective:

    • To determine the ELISPOT response rate and time to achieving ELISPOT response (≥10 spots and >2x baseline) during concurrent chemotherapy and FANG™ vaccine following debulking surgery in patients with ovarian cancer.



Estimated Enrollment: 66
Study Start Date: February 2011
Estimated Study Completion Date: January 2016
Estimated Primary Completion Date: July 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Group A
intradermal autologous FANG™ (1.0 x 10^7 cells/injection; maximum of 12 vaccinations)
Biological: FANG™
intradermal autologous FANG™ (1.0 x 10^7 cells/injection; maximum of 12 vaccinations)
Active Comparator: Group B
standard of care observational follow-up
Drug: Standard of care observational follow-up
standard of care observational follow-up
Other Name: Standard of Care
Active Comparator: FANG™ and adjuvant chemotherapy
intradermal autologous FANG™ (1.0 x 10^7 cells/injection; maximum of 12 vaccinations) and adjuvant chemotherapy
Biological: FANG™ and adjuvant chemotherapy
intradermal autologous FANG™ (1.0 x 10^7 cells/injection; maximum of 12 vaccinations) and adjuvant chemotherapy

Detailed Description:

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, FANG™, 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 FANG™ 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 FANG™ vaccine. Furthermore, proof of principle was established in the manufactured vaccines with increased mean GMCSF expression post-transfection to 1135 pg/106 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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

INCLUSION CRITERIA:

  1. Histologically confirmed Stage III/IV papillary serous or endometrioid ovarian cancer.
  2. Treatment naïve, high risk ovarian cancer stratified as follows:

    PART 1

    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 to 20 U/ml
    3. IP chemotherapy versus IV chemotherapy

      PART 2

    4. Stage IV or suboptimal (>1 cm residual) Stage III disease versus Stage III patients with optimal (≤1 cm residual) disease
    5. Although no CA-125 restriction, the following data will be collected:

    i. 1. Pre-operative CA-125

    ii. 2. CA-125 immediately prior to the second cycle of chemotherapy post debulking, and prior to third cycle of chemotherapy post debulking

  3. Clinically defined CR (no cancer related symptoms, normal physical examination and CT scan abdomen/pelvis and chest x-ray, and CA-125 ≤ 20 U/mL) following completion of surgical debulking and completion of at least 5 but no more than 6 cycles platinum/taxane adjuvant or sandwiched 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-randomization have the option of being followed up to 2 months if serial CA-125 values continue to decrease at a rate of ≥ 50% per month.
  4. Availability of "golf-ball" size ~10-30 grams tissue at time of primary surgical debulking.
  5. Successful manufacturing of 4 vials of FANG™ vaccine.
  6. Recovered from all clinically relevant toxicities related to prior protocol specific therapy (including neuropathy ≤ Grade 2).
  7. ECOG performance status (PS) 0-2 prior to tumor debulking laparotomy.
  8. ECOG performance status (PS) 0-1 prior to FANG™ vaccine administration.
  9. Normal organ and marrow function as defined below:

    1. Absolute granulocyte count ≥ 1,500/mm^3
    2. Absolute lymphocyte count ≥ 200/mm^3
    3. Platelets ≥ 75,000/mm^3
    4. Total bilirubin ≤ 2 mg/dL
    5. AST(SGOT)/ALT(SGPT) ≤ 2x institutional upper limit of normal
    6. Creatinine <1.5 mg/dL
  10. Patients must be off all "statin" drugs for ≥ 2 weeks prior to initiation of therapy. Patients randomized to Group B may resume "statin" post registration.
  11. Ability to understand and the willingness to sign a written informed consent document for tissue harvesting.
  12. 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 FANG™ vaccine administration (Part 1 only). 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.
  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: NCT01309230

Locations
United States, Florida
Florida Cancer Specialists Recruiting
West Palm Beach, Florida, United States, 33401
Contact: Jenifer Bar-Nur, RN, BSN    561-472-1278    jbar-nur@flcancer.com   
Principal Investigator: Daniel L Spitz, MD, FACP         
United States, New Hampshire
Dartmouth-Hitchcock Medical Center/Norris Cotton Cancer Center Recruiting
Lebanon, New Hampshire, United States, 03756
Contact: Kathy Phipps, CCRP    603-653-3537    kathy.j.phipps@hitchcock.org   
Principal Investigator: Leslie R. DeMars, MD         
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         
Texas Oncology - Sammons Cancer Center Recruiting
Dallas, Texas, United States, 75246
Contact: Marnie Fisher, RN    214-370-1038    marnie.fisher@usoncology.com   
Principal Investigator: Erik Koon, MD         
Texas Oncology - Fort Worth Recruiting
Fort Worth, Texas, United States, 76104
Contact: Nori Sullivan, BSN, RN, CCRC    817-850-2010    nori.sullivan@usoncology.com   
Principal Investigator: Kenneth Hancock, MD         
United States, Washington
Cancer Care Northwest Recruiting
Spokane, Washington, United States, 99202
Contact: Rose Miller, RN, OCN    509-228-1687    Rose.Miller@ccnw.net   
Principal Investigator: Elizabeth Grosen, MD         
Sponsors and Collaborators
Gradalis, Inc.
  More Information

Publications:
Responsible Party: Gradalis, Inc.
ClinicalTrials.gov Identifier: NCT01309230     History of Changes
Other Study ID Numbers: CL-PTL 105
Study First Received: February 25, 2011
Last Updated: May 12, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Gradalis, Inc.:
Stage III
Stage IV
epithelial ovarian cancer
ovarian cancer
Adjuvant
immunotherapy

Additional relevant MeSH terms:
Ovarian Neoplasms
Endocrine Gland Neoplasms
Neoplasms by Site
Neoplasms
Ovarian Diseases
Adnexal Diseases
Genital Diseases, Female
Genital Neoplasms, Female
Urogenital Neoplasms
Endocrine System Diseases
Gonadal Disorders

ClinicalTrials.gov processed this record on July 20, 2014