Fallopian Tube Cancer, Ovarian Cancer, Peritoneal Cavity Cancer
Conditions
Keywords
recurrent ovarian epithelial cancer, stage II ovarian epithelial cancer, stage III ovarian epithelial cancer, stage IV ovarian epithelial cancer, fallopian tube cancer, peritoneal cavity cancer
Brief summary
This was a Phase 1, non-randomized, open-label, multicenter study of the ALVAC(2)-NY-ESO-1(M)/TRICOM vaccine administered with the granulocyte macrophage-colony stimulating factor (GM-CSF) sargramostim in patients with NY-ESO-1- or LAGE-1-positive epithelial ovarian, fallopian tube, or primary peritoneal cavity cancers who had completed standard therapy for primary or recurrent disease and would have normally entered a period of observation. The primary study objective was to determine the safety and tolerability of study vaccination, with secondary objectives including the determination of clinical and immunological responses.
Detailed description
Patients received subcutaneous (SC) injections with 0.5 mL of ALVAC(2)-NY-ESO-1(M)/TRICOM on Day 1 and 100 μg of the GM-CSF sargramostim on Days 1 through 4 in continuous 28-day cycles for up to 6 cycles. No dose escalation of either vaccine component was permitted. Patients received study vaccinations until disease progression or unacceptable toxicity. Safety was evaluated by continuous monitoring of adverse events (AEs), concomitant medications, and vital signs, as well as through hematology and chemistry laboratory testing and physical examinations. Efficacy was determined through tumor response evaluations, cancer antigen (CA)-125 levels, and cellular and humoral immune responses (i.e., NY-ESO-1-specific T cells, antibodies to NY-ESO-1 and ALVAC, and delayed-type hypersensitivity \[DTH\] testing).
Interventions
BIOLOGICALALVAC(2)-NY-ESO-1(M)/TRICOM vaccine
The vaccine comprises the modified canary pox vector, ALVAC(2), inserted with the following genes: NYESO-1(M), TRICOM (LFA-3, ICAM-1, B7.1), vvE3L, vvK3L. The vaccine is administered at a dose of 0.5 mL SC.
BIOLOGICALSargramostim
The GM-CSF sargramostim is administered at a dose of 100 μg SC.
Sponsors
Roswell Park Cancer Institute
New York University Cancer Institute
Ludwig Institute for Cancer Research
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
All patients received the same study treatment.
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Histologically documented epithelial carcinoma arising in the ovary, fallopian tube or peritoneum, from stage II-IV at diagnosis, treated with initial surgery and chemotherapy with at least one platinum-based chemotherapy regimen. 2. Complete response to frontline therapy as evidenced by negative clinical examination, CA-125 tumor marker, and computed tomography (CT) scan. In addition, if second look surgery was performed (by laparoscopy or laparotomy), the result must have been either negative or microscopic positive. These patients would have normally entered a period of observation after standard management. 3. Patients with recurrent disease were eligible if they had completed surgery and/or chemotherapy for recurrent disease and would have normally entered a period of observation after completion of standard management. Eligible patients could have had asymptomatic residual measurable disease on physical examination and/or CT scan, and/or could have had an elevated CA-125 or could have been in complete clinical remission (defined as a serum CA-125 ≤ 35 IU/mL, CT scan without objective evidence of disease, and normal physical examination). 4. Tumor expression of 1) NY-ESO-1 by reverse transcription-polymerase chain reaction (RT-PCR) (preferably) or immunohistochemistry (IHC); or 2) LAGE-1 by RT-PCR. Patients whose primary surgery was performed outside the study site were pre-screened and required to release tissue sections or blocks to the study site in order to determine tumor expression of NY-ESO-1 by IHC. 5. Expected survival of at least 6 months. 6. Full recovery from surgery. 7. Karnofsky performance status of 70 or more. 8. Laboratory parameters for vital functions were required to be in the normal range. Laboratory abnormalities that were not clinically significant were generally permitted, except for the following laboratory parameters, which were required to be within the ranges specified: * neutrophil count: ≥ 1.5 × 10\^9/L * lymphocyte count: ≥ 0.5 × 10\^9/L * platelet count: ≥ 100 × 10\^9/L * serum creatinine: ≤ 2 mg/dL * serum bilirubin (total): ≤ 2 mg/dL * hemoglobin: ≥ 10 g/dL 9. Have been informed of other treatment options. 10. Age ≥ 18 years. 11. Able and willing to give valid written informed consent.
Exclusion criteria
1. Metastatic disease to the central nervous system for which other therapeutic options, including radiotherapy, may have been available. 2. Other serious illnesses (e.g., serious infections requiring antibiotics, bleeding disorders). 3. History of autoimmune disease (e.g., thyroiditis, lupus) except vitiligo. 4. Other malignancy within 3 years prior to entry into the study, except for treated non-melanoma skin cancer and cervical carcinoma in situ. 5. Known immunodeficiency or human immunodeficiency virus positivity. 6. Known allergy or history of life-threatening reaction to GM-CSF. 7. Known allergies to eggs, neomycin, and bovine products, determined by history. 8. History of severe allergic reactions to vaccines or unknown allergens. 9. Myocardial infarction, angina, congestive heart failure, cardiomyopathy, stroke or transient ischemic attack, chest pain or shortness of breath with activity, or other heart conditions being treated by a doctor. 10. Participation in any other clinical trial involving another investigational agent within 4 weeks prior to first dosing of study agent. 11. Mental impairment that could have compromised the ability to give informed consent and comply with the requirements of the study. 12. Lack of availability for immunological and clinical follow-up assessment. 13. Previous NY-ESO-1 vaccine therapy.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Treatment-emergent Adverse Events | Continuously for up to 26 weeks | Toxicity was graded in accordance with the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. Treatment-emergent adverse events (TEAEs) were reported based on clinical laboratory tests, physical examinations, and vital signs from pre-treatment through the study period. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Best Overall Tumor Response | Baseline and Weeks 12 and 24 | Tumor responses were evaluated using computed tomography and categorized according to the Response Evaluation Criteria in Solid Tumors (RECIST) (version 1.0) at baseline, at Week 12 (± 28 days), and at Week 24 (end of study). Per RECIST, target lesions are categorized as follows: Complete Response (CR): Disappearance of all target lesions \[no evidence of disease\]; Partial Response (PR): ≥ 30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD): ≥ 20% increase in the sum of the longest diameter of target lesions; Stable Disease (SD): small changes that do not meet above criteria. |
| Median Progression-free Survival (PFS) | Baseline and up to approximately 24 weeks | PFS was calculated from the date of the first dose of study drug to the date of documented progression or death, whichever occurred first. Patients without disease progression or death had their observation time censored at the date of the last valid disease assessment. PFS was summarized using Kaplan-Meier product-limit estimators. |
| Median Cancer Antigen 25 (CA-125) Values on Study | Baseline through Week 24 | Blood samples were collected for CA-125 testing as a component of disease evaluations at Baseline and Weeks 8, 12, 16, 20, and 24 (end of study) or every 2 to 3 months on study according to standard institutional practice. |
| Number of Patients With NY-ESO-1 and LAGE-1 Antigen Positivity | Baseline through Week 24 | Blood samples were collected for measurement of NY-ESO-1 and LAGE-1 antigen positivity at Baseline and Weeks 4, 8 ,12, 16, 20, and 24 (end of study). Antibody testing was performed by enzyme-linked immunosorbent assay (ELISA). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| ALVAC(2)-NY-ESO-1(M)/TRICOM + GM-CSF Patients received SC injections with ALVAC(2)-NY-ESO-1(M)/TRICOM (0.5 mL) on Day 1 and the GM-CSF sargramostim (100 μg) on Days 1 through 4 in continuous 28-day cycles for up to 6 cycles. | 13 |
| Total | 13 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Noncompliance | 1 |
| Overall Study | Progressive Disease | 3 |
Baseline characteristics
| Characteristic | ALVAC(2)-NY-ESO-1(M)/TRICOM + GM-CSF |
|---|---|
| Age, Continuous | 57.5 years STANDARD_DEVIATION 9.5 |
| Body Mass Index | 25.7 kg/m^2 STANDARD_DEVIATION 5.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 13 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 13 Participants |
| Region of Enrollment United States | 13 Participants |
| Sex: Female, Male Female | 13 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 13 |
| other Total, other adverse events | 12 / 13 |
| serious Total, serious adverse events | 0 / 13 |
Outcome results
Primary
Number of Patients With Treatment-emergent Adverse Events
Toxicity was graded in accordance with the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. Treatment-emergent adverse events (TEAEs) were reported based on clinical laboratory tests, physical examinations, and vital signs from pre-treatment through the study period.
Time frame: Continuously for up to 26 weeks
Population: Patients who received at least 1 dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| ALVAC(2)-NY-ESO-1(M)/TRICOM + GM-CSF | Number of Patients With Treatment-emergent Adverse Events | Maximum Grade 2 TEAE | 6 Participants |
| ALVAC(2)-NY-ESO-1(M)/TRICOM + GM-CSF | Number of Patients With Treatment-emergent Adverse Events | Any TEAE | 12 Participants |
| ALVAC(2)-NY-ESO-1(M)/TRICOM + GM-CSF | Number of Patients With Treatment-emergent Adverse Events | Maximum Grade 1 TEAE | 6 Participants |
| ALVAC(2)-NY-ESO-1(M)/TRICOM + GM-CSF | Number of Patients With Treatment-emergent Adverse Events | Treatment-related TEAE | 12 Participants |
| ALVAC(2)-NY-ESO-1(M)/TRICOM + GM-CSF | Number of Patients With Treatment-emergent Adverse Events | SeriousTEAE | 0 Participants |
| ALVAC(2)-NY-ESO-1(M)/TRICOM + GM-CSF | Number of Patients With Treatment-emergent Adverse Events | Death | 0 Participants |
| ALVAC(2)-NY-ESO-1(M)/TRICOM + GM-CSF | Number of Patients With Treatment-emergent Adverse Events | TEAE Leading to Discontinuation | 0 Participants |
Secondary
Median Cancer Antigen 25 (CA-125) Values on Study
Blood samples were collected for CA-125 testing as a component of disease evaluations at Baseline and Weeks 8, 12, 16, 20, and 24 (end of study) or every 2 to 3 months on study according to standard institutional practice.
Time frame: Baseline through Week 24
Population: Patients with data available from at least 1 post-baseline response assessment. One patient discontinued the study prior to the Week 12 response assessment.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| ALVAC(2)-NY-ESO-1(M)/TRICOM + GM-CSF | Median Cancer Antigen 25 (CA-125) Values on Study | Baseline | 8.6 U/mL |
| ALVAC(2)-NY-ESO-1(M)/TRICOM + GM-CSF | Median Cancer Antigen 25 (CA-125) Values on Study | Week 8 | 9.7 U/mL |
| ALVAC(2)-NY-ESO-1(M)/TRICOM + GM-CSF | Median Cancer Antigen 25 (CA-125) Values on Study | Week 12 | 7.4 U/mL |
| ALVAC(2)-NY-ESO-1(M)/TRICOM + GM-CSF | Median Cancer Antigen 25 (CA-125) Values on Study | Week 16 | 9.4 U/mL |
| ALVAC(2)-NY-ESO-1(M)/TRICOM + GM-CSF | Median Cancer Antigen 25 (CA-125) Values on Study | Week 20 | 9.0 U/mL |
| ALVAC(2)-NY-ESO-1(M)/TRICOM + GM-CSF | Median Cancer Antigen 25 (CA-125) Values on Study | Week 24 | 8.0 U/mL |
Secondary
Median Progression-free Survival (PFS)
PFS was calculated from the date of the first dose of study drug to the date of documented progression or death, whichever occurred first. Patients without disease progression or death had their observation time censored at the date of the last valid disease assessment. PFS was summarized using Kaplan-Meier product-limit estimators.
Time frame: Baseline and up to approximately 24 weeks
Population: Patients with data available from at least 1 post-baseline response assessment. One patient discontinued the study prior to the Week 12 response assessment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| ALVAC(2)-NY-ESO-1(M)/TRICOM + GM-CSF | Median Progression-free Survival (PFS) | 167.5 days |
Secondary
Number of Patients With Best Overall Tumor Response
Tumor responses were evaluated using computed tomography and categorized according to the Response Evaluation Criteria in Solid Tumors (RECIST) (version 1.0) at baseline, at Week 12 (± 28 days), and at Week 24 (end of study). Per RECIST, target lesions are categorized as follows: Complete Response (CR): Disappearance of all target lesions \[no evidence of disease\]; Partial Response (PR): ≥ 30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD): ≥ 20% increase in the sum of the longest diameter of target lesions; Stable Disease (SD): small changes that do not meet above criteria.
Time frame: Baseline and Weeks 12 and 24
Population: Patients with data available from at least 1 post-baseline response assessment. One patient discontinued the study prior to the Week 12 response assessment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| ALVAC(2)-NY-ESO-1(M)/TRICOM + GM-CSF | Number of Patients With Best Overall Tumor Response | No evidence of disease | 10 Participants |
| ALVAC(2)-NY-ESO-1(M)/TRICOM + GM-CSF | Number of Patients With Best Overall Tumor Response | Progressive disease | 2 Participants |
Secondary
Number of Patients With NY-ESO-1 and LAGE-1 Antigen Positivity
Blood samples were collected for measurement of NY-ESO-1 and LAGE-1 antigen positivity at Baseline and Weeks 4, 8 ,12, 16, 20, and 24 (end of study). Antibody testing was performed by enzyme-linked immunosorbent assay (ELISA).
Time frame: Baseline through Week 24
Population: Patients with data available from at least 1 post-baseline response assessment. One patient discontinued the study prior to the Week 12 response assessment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| ALVAC(2)-NY-ESO-1(M)/TRICOM + GM-CSF | Number of Patients With NY-ESO-1 and LAGE-1 Antigen Positivity | LAGE-1: BL positive, Post-BL positive | 1 Participants |
| ALVAC(2)-NY-ESO-1(M)/TRICOM + GM-CSF | Number of Patients With NY-ESO-1 and LAGE-1 Antigen Positivity | NY-ESO-1: BL positive, Post-BL positive | 2 Participants |
| ALVAC(2)-NY-ESO-1(M)/TRICOM + GM-CSF | Number of Patients With NY-ESO-1 and LAGE-1 Antigen Positivity | NY-ESO-1: BL negative, Post-BL positive | 10 Participants |
| ALVAC(2)-NY-ESO-1(M)/TRICOM + GM-CSF | Number of Patients With NY-ESO-1 and LAGE-1 Antigen Positivity | LAGE-1: BL negative, Post-BL positive | 3 Participants |
| ALVAC(2)-NY-ESO-1(M)/TRICOM + GM-CSF | Number of Patients With NY-ESO-1 and LAGE-1 Antigen Positivity | LAGE-1: BL negative, Post-BL negative | 2 Participants |
| ALVAC(2)-NY-ESO-1(M)/TRICOM + GM-CSF | Number of Patients With NY-ESO-1 and LAGE-1 Antigen Positivity | LAGE-1: Not evaluable | 6 Participants |