Ovarian Cancer
Conditions
Keywords
Stage III, Stage IV, epithelial ovarian cancer, ovarian cancer, Adjuvant bi-shRNAfurin and GMCSF, immunotherapy, Vigil, FANG, Autologous Tumor Cell Vaccine
Brief summary
This was a clinical trial for women with ovarian cancer scheduled to have an operation to remove the cancerous tissue. The cancer cells removed during the planned surgery were used to attempt to make the investigational product, named Vigil. Vigil is considered an immunotherapy. In this study, participants who met the requirements to be in the study and if Vigil was successfully made from the participants cancer cells, participants underwent treatment with their standard chemotherapy regimen. At the end of the standard chemotherapy regimen and if there was no evidence of remaining cancer, participants were randomly assigned to receive the Vigil or would be assigned to the standard of care group, which in this study meant no further treatment was given to the participant. The purpose of this study was to compare the difference between the participants who received Vigil versus the usual care after completion of standard chemotherapy and to determine if Vigil delayed or prevented ovarian cancer from coming back.
Detailed description
This was a Phase II open-label study of Vigil™ autologous tumor cell vaccine trial administered to women with Stage III/IV epithelial ovarian cancer. Tumor was harvested at the time of surgical debulking (standard of medical care). Participants who achieved clinical complete response (CR) following primary surgical debulking and front-line doublet chemotherapy were randomized 2:1 to either treatment with Vigil (Group A) or standard of care without maintenance therapy (Group B). After randomization, participants were stratified into cohorts by baseline CA-125 (greater than 10 to less than 20 units/mL versus less than or equal to 10 units/mL). For data analysis, participants could further be stratified by surgical stage (Stage IV or suboptimal debulking (\> 1cm residual), Stage III disease versus Stage III disease with optimal debulking (\< 1cm residual). Participants enrolled in Group A (Vigil) received 1.0 x 10e7 cells / intradermal injection of gene transfected autologous tumor cells, Vigil™, once a month for up to 12 doses as long as sufficient material was available or until trial endpoints were met. Enough harvested tissue to provide a minimum of 4 monthly injections was required for entry into the study. Participants enrolled in Group B (Standard of Care, SOC) were observed and assessed until trial endpoints were met. Protocol Amendment 8, June 19, 2014 removed randomization such that all patients screening for enrollment into the main portion of the trial (including those who previously had tumor tissue harvested) would be assigned to Group A (Vigil). Both groups of participants were seen once a month in an outpatient setting. Hematologic function, liver enzymes, renal function and electrolytes were monitored monthly. Immune function analysis including ELISPOT analysis of cytotoxic T cell function to autologous tumor antigens were monitored at (≤ 24 hours before the third cycle chemotherapy (post debulking), baseline (screening); prior to Vigil injection at Months 2, 3, 6 and EOT. CA-125 was monitored at baseline, every month for the first year, every 3 months +/- 2 weeks for the second and third year. Participants assigned to group A were allowed to continue treatment with Vigil 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) developed related to study treatment, the vaccine dose was reduced by 50% and continued on a monthly basis. Efficacy assessments included time to disease recurrence, immune surrogate markers, and quality of life questionnaire (FACT-O, Version 4). Safety assessments included physical examination, performance status, and vital signs. Adverse events were recorded using CTCAE version 3.
Interventions
BIOLOGICALVigil™
Vigil is composed of autologous tumor cells harvested from the patient at the time of initial de-bulking surgery which are then transfected extracorporeally, with a plasmid encoding for the gene for GM-CSF, an immune-stimulatory cytokine, and a bifunctional, short hairpin RNA which specifically knocks down the expression of furin, the critical convertase responsible for production of the two TGβ isoforms.
Sponsors
Gradalis, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Participants were randomized 2 (Group A (Vigil)):1 (Group B (Standard of Care)). Randomization was only applicable to participants enrolled prior to approval of Protocol Amendment 8, dated June 19, 2014. All participants enrolled after approval of Protocol Amendment 8 were assigned to Group A (Vigil).
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Tissue Inclusion Criteria Patients were eligible for tissue procurement for the Vigil™ vaccine manufacturing process if they met all of the following criteria: 1. Presumptive Stage III/IV papillary serous or endometrioid ovarian cancer. 2. Per Amendment #8, treatment naïve, high risk ovarian cancer was no longer be stratified, but the following information was 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. Tissue
Exclusion criteria
Patients who met any of the following criteria were not eligible for tissue procurement for the Vigil manufacturing: 1. Medical condition requiring any form of chronic systemic immunosuppressive therapy (steroid or other) except physiologic replacement doses of hydrocortisone or equivalent (no more than 30 mg hydrocortisone or 10 mg prednisone equivalent daily) for \< 30 days duration. 2. Known history of other malignancy unless having undergone curative intent therapy without evidence of that disease for ≥ 3 years except cutaneous squamous cell and basal cell skin cancer, superficial bladder cancer, in situ cervical cancer or other in situ cancers were allowed if definitively resected. 3. Brain metastases unless treated with curative intent (gamma knife or surgical resection) and without evidence of progression for ≥ 2 months. 4. Any documented history of autoimmune disease with exception of Type 1 diabetes on stable insulin regimen, hypothyroidism on stable dose of replacement thyroid medication, vitiligo, or asthma not requiring systemic steroids. 5. Known HIV or chronic Hepatitis B or C infection. 6. Known history of allergies or sensitivities to gentamicin. 7. History of or current evidence of any condition (including medical, psychiatric or substance abuse disorder), therapy, or laboratory abnormality that might confound the results of the study, interfere with the patient's participation for the full duration of the study, or was not in the best interest of the patient to participate, in the opinion of the treating Investigator. Study Enrollment Inclusion Criteria Patients were registered for inclusion in this study if they met all of the following 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 have completed at least 5 but no more than 6 cycles platinum/taxane adjuvant or interval debulking and chemotherapy (or chemotherapy as per recommendations of NCCN guidelines, category 1 (IP chemotherapy included)). (Patients who completed surgery/chemotherapy with a CA-125 \>20 U/mL pre-registration had the option of being followed up to 2 months if serial CA-125 values continued 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 have been 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. Study Enrollment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Recurrence (TTR) | Treatment start to the date of first recurrence or date of death if the participant died before recurrence. Radiographic assessment at baseline, </= 1 week prior to Cycle 4, at Standard of Care intervals, and when CA-125>35 U/mL, approximately 3 years. | Time to recurrence is the time to progression by Radiological Tumor Assessment by local investigators using the Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1. Disease recurrence was defined as the appearance of any measurable or evaluable lesion or as asymptomatic CA-125 levels \>35 U/mL at two consecutive measurements, at least one month apart. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Positive for T-cell and Immune Activation Markers | Blood was collected at tissue procurement, prior to the 1st and 3rd cycles of chemotherapy post debulking, at screening, months 2, 4, 6, end of treatment, and quarterly until recurrence, up to 3 years. | Gamma interferon (γ-IFN) secretion measured by ELISpot assay was used as a marker for T-cell and immune activation to cancer specific neoantigens. Any participant that had greater than or equal to 10 spots were considered positive. |
| Predictive Potential of Tumor Infiltrating Lymphocyte (TIL) and Tumor Associated Macrophage (TAM) Phenotypes | From tissue procurement until recurrence. | Predictive potential for TIL and TAM was expected to be measured from tissue collected at baseline and at recurrence. |
| Vigil Related Adverse Events (AEs) | From first dose of Vigil until 30 days following last dose of Vigil, up to 13 months. | AEs were reported using Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. |
Countries
United States
Participant flow
Pre-assignment details
Thirty-nine (39) subjects had product manufactured and consented to randomize on CL-PTL-105.
Participants by arm
| Arm | Count |
|---|---|
| Group A (Vigil™) Vigil immunotherapy was administered at a concentration of at 1 x 10e7 cells/injection via intradermal injection for a minimum of 4 doses and a maximum of 12 doses starting ≥3 weeks following completion of chemotherapy (no longer than 2.5 months post chemotherapy). Participants were treated monthly for up to 12 months as long as sufficient Vigil was available and the participant was clinically stable. | 28 |
| Group B (Observational - Standard of Care) Participants received standard of care without maintenance therapy. | 11 |
| Total | 39 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Observation arm closed | 0 | 2 |
| Overall Study | Withdrawal by Subject | 0 | 2 |
Baseline characteristics
| Characteristic | Group A (Vigil™) | Group B (Observational - Standard of Care) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 10 Participants | 4 Participants | 14 Participants |
| Age, Categorical Between 18 and 65 years | 18 Participants | 7 Participants | 25 Participants |
| CA-125 Level CA-125 > 10 U/ML but ≤ 20 U/mL | 10 Participants | 8 Participants | 18 Participants |
| CA-125 Level CA-125 > 20 U/mL | 1 Participants | 0 Participants | 1 Participants |
| CA-125 Level CA-125 ≤ to 10 U/mL | 17 Participants | 3 Participants | 20 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 27 Participants | 11 Participants | 38 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 27 Participants | 11 Participants | 38 Participants |
| Region of Enrollment United States | 28 participants | 11 participants | 39 participants |
| Sex: Female, Male Female | 28 Participants | 11 Participants | 39 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 20 / 28 | 7 / 11 |
| other Total, other adverse events | 28 / 28 | 9 / 11 |
| serious Total, serious adverse events | 3 / 28 | 0 / 11 |
Outcome results
Primary
Time to Recurrence (TTR)
Time to recurrence is the time to progression by Radiological Tumor Assessment by local investigators using the Response Evaluation Criteria in Solid Tumors (RECIST), Version 1.1. Disease recurrence was defined as the appearance of any measurable or evaluable lesion or as asymptomatic CA-125 levels \>35 U/mL at two consecutive measurements, at least one month apart.
Time frame: Treatment start to the date of first recurrence or date of death if the participant died before recurrence. Radiographic assessment at baseline, </= 1 week prior to Cycle 4, at Standard of Care intervals, and when CA-125>35 U/mL, approximately 3 years.
Population: Participants who achieved complete clinical response (cCR) at the time of study entry were included in the analysis. After randomization, two participants from Group A were deemed unevaluable as they did not achieve cCR.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Group A (Vigil™) | Time to Recurrence (TTR) | 18.2 months |
| Group B (Observational - Standard of Care) | Time to Recurrence (TTR) | 12.4 months |
Secondary
Number of Participants Positive for T-cell and Immune Activation Markers
Gamma interferon (γ-IFN) secretion measured by ELISpot assay was used as a marker for T-cell and immune activation to cancer specific neoantigens. Any participant that had greater than or equal to 10 spots were considered positive.
Time frame: Blood was collected at tissue procurement, prior to the 1st and 3rd cycles of chemotherapy post debulking, at screening, months 2, 4, 6, end of treatment, and quarterly until recurrence, up to 3 years.
Population: Only participants that were deemed evaluable were included in the analysis. Any participants that were determined to not be in complete response (cCR) after study entry were excluded from analysis.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Group A (Vigil™) | Number of Participants Positive for T-cell and Immune Activation Markers | 26 Participants |
| Group B (Observational - Standard of Care) | Number of Participants Positive for T-cell and Immune Activation Markers | 0 Participants |
Secondary
Predictive Potential of Tumor Infiltrating Lymphocyte (TIL) and Tumor Associated Macrophage (TAM) Phenotypes
Predictive potential for TIL and TAM was expected to be measured from tissue collected at baseline and at recurrence.
Time frame: From tissue procurement until recurrence.
Population: Biopsies were not collected at recurrence, therefore the outcome could not be analyzed. Data were not analyzed.
Secondary
Vigil Related Adverse Events (AEs)
AEs were reported using Common Terminology Criteria for Adverse Events (CTCAE) version 3.0.
Time frame: From first dose of Vigil until 30 days following last dose of Vigil, up to 13 months.
Population: Participants were counted at most once per preferred term and at most once per system organ class.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Group A (Vigil™) | Vigil Related Adverse Events (AEs) | Grade 3 or higher | 0 adverse events |
| Group A (Vigil™) | Vigil Related Adverse Events (AEs) | Grade 2 | 1 adverse events |
| Group A (Vigil™) | Vigil Related Adverse Events (AEs) | Grade 1 | 24 adverse events |
| Group B (Observational - Standard of Care) | Vigil Related Adverse Events (AEs) | Grade 3 or higher | 0 adverse events |
| Group B (Observational - Standard of Care) | Vigil Related Adverse Events (AEs) | Grade 2 | 3 adverse events |
| Group B (Observational - Standard of Care) | Vigil Related Adverse Events (AEs) | Grade 1 | 28 adverse events |