Epithelial Ovarian Cancer, Fallopian Tube Cancer, Primary Peritoneal Cancer
Conditions
Keywords
recurrent epithelial ovarian cancer, recurrent fallopian tube cancer, recurrent primary peritoneal cavity cancer, ovarian serous cystadenocarcinoma, ovarian endometrioid adenocarcinoma, ovarian mucinous cystadenocarcinoma, ovarian undifferentiated adenocarcinoma, ovarian clear cell cystadenocarcinoma, ovarian mixed epithelial carcinoma, Brenner tumor
Brief summary
The purpose of this study is to compare the overall survival of patients treated with VTX-2337 + pegylated liposomal doxorubicin (PLD) versus those treated with PLD alone in women with recurrent or persistent, epithelial ovarian, fallopian tube or primary peritoneal cancer. VTX-2337, a small molecule agonist of Toll-like Receptor 8 (TLR8), activates multiple components of the innate immune system and is being developed as a novel therapeutic agent for use in oncology. Experimental data obtained in an animal model of ovarian cancer supports the combination of VTX-2337 with PLD. In this model, the combination of VTX-2337 and PLD resulted in a significant reduction in tumor growth compared to either agent alone and an increase in the number of T lymphocytes infiltrating the tumor. The combination of PLD and VTX-2337 has been tested in a small number of women with ovarian cancer in a Phase 1b study and appears to be generally well-tolerated.
Detailed description
OBJECTIVES Primary Objectives: * To compare the overall survival (OS) of patients treated with VTX-2337 + PLD versus those treated with PLD alone in women with recurrent or persistent, epithelial ovarian, fallopian tube or primary peritoneal cancer. * To compare the progression-free survival (PFS) between the two treatment groups using Immune-Related Response Evaluation Criteria in Solid Tumors (irRECIST). Secondary Objectives: * To compare the progression-free survival (PFS) between the two treatment groups using Response Evaluation Criteria In Solid Tumors (RECIST 1.1). * To compare the nature, frequency and severity of drug-related adverse events (AEs) between the two treatment groups. Exploratory Objectives: * To compare the best overall response rate (ORR) and duration of response (based on the probability of being in response function \[PBRF\]) between the two treatment groups using irRECIST and RECIST 1.1. * To compare the disease control rate (DCR) between the two treatment groups using irRECIST and RECIST 1.1. * To assess the impact of immune status and response on the clinical effects (OS, PFS, DCR, ORR, PBRF, AEs) of study treatment. * To assess the effect of TLR8 polymorphisms and BRCA1/BRCA2 mutations on the clinical effects (OS, PFS, DCR, ORR, PBRF, AEs) of study treatment. * To assess the effect of immune cell subsets, as measured by immunohistochemistry and micro RNA in primary tumor tissue (e.g. immune score), on the clinical effects (OS, PFS, DCR, ORR, PBRF, AEs) of study treatment. * To assess whether the presence of autoantibodies to tumor-derived proteins are predictive of the clinical effects (OS, PFS, DCR, ORR, PBRF, AEs) of study treatment. OUTLINE: This is Phase 2 multicenter clinical study to evaluate the efficacy and safety of the combination of VTX-2337 + PLD compared to PLD + Placebo. The dosing schedule will be the same for both treatment arms, and will be based on a 28-day cycle. The starting dose schedule is PLD on Day 1 plus VTX-2337 or placebo on Day 3, Day 10, and Day 17 for the first 4 cycles. Starting with cycle 5, the dose regimen will be PLD on Day 1 plus VTX-2337 or placebo on Day 3. Blood samples are collected periodically during cycle 1 for pharmacodynamics, pharmacogenomics, and other research studies. Patients will receive therapy until disease progression based on Immune-Related RECIST or until adverse effects prohibit further therapy. Following treatment completion, all patients will be followed with physical exams and histories every three months for the first two years, and then every six months for the next three years, and then
Interventions
Sponsors
Gynecologic Oncology Group
Celgene
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Patients must have recurrent or persistent epithelial ovarian, fallopian tube, or primary peritoneal carcinoma. 2. Patients with the following histologic cell types are eligible: serous adenocarcinoma, endometrioid adenocarcinoma, mucinous adenocarcinoma, undifferentiated carcinoma, clear cell adenocarcinoma, mixed epithelial adenocarcinoma, transitional cell carcinoma, malignant Brenner's tumor or adenocarcinoma not otherwise specified. 3. Patient must have measurable disease as defined by RECIST 1.1. 4. Patients must have received treatment with a platinum-based chemotherapeutic regimen for management of primary disease containing carboplatin, cisplatin or another organoplatinum compound. This initial treatment may have included intraperitoneal therapy, consolidation, non-cytotoxic agents or extended therapy administered after surgical or non-surgical assessment. Patients are allowed to receive, but are not required to receive, one additional cytotoxic regimen for management of recurrent or persistent disease. Patients are allowed to have received, but are not required to have received, biologic/targeted therapy (e.g., bevacizumab and/or PARP inhibitor) as part of their primary treatment regimen or for management of recurrent or persistent disease. 5. Patients must have platinum-resistant disease, defined as having a platinum-free interval (PFI) of \< 12 months after first- or second-line platinum-based chemotherapy, or having disease progression while receiving second-line platinum-based chemotherapy. 6. Patients must have adequate bone marrow, renal, hepatic, and neurologic functions as defined by the following: * Bone marrow function: absolute neutrophil count (ANC) ≥ 1,500/mm3. This ANC cannot have been induced or supported by granulocyte colony stimulating factors. Platelets ≥ 100,000/mm3. Hemoglobin ≥ 9 g/dL. * Renal function: creatinine ≤ 1.5 x institutional upper limit normal (ULN). * Hepatic function: bilirubin \< 1.2 mg/dL, SGOT (AST) and SGPT (ALT) ≤ 3.0 x ULN and alkaline phosphatase ≤ 2.5 x ULN. 7. Patients must have recovered from effects of recent surgery, radiotherapy or chemotherapy: * Patients should be free of active infection requiring parenteral antibiotics. * Any hormonal therapy directed at the malignant tumor must be discontinued at least one week prior to registration. Continuation of hormone replacement therapy is permitted. * Any other prior therapy directed at the malignant tumor, including chemotherapy, biologic/targeted agents and immunologic agents, must be discontinued at least three weeks prior to registration. * Any prior radiation therapy must be completed at least four weeks prior to registration. 8. Patients must have a GOG performance status of 0 or 1. 9. Patients of childbearing potential must have a negative pregnancy test prior to the study entry and be practicing an effective form of contraception. If applicable, patients must discontinue breastfeeding prior to study entry. 10. Patients must meet the entry requirements and undergo the baseline procedures. 11. Patients must have signed an IRB-approved informed consent form and authorization permitting release of personal health information.
Exclusion criteria
1. Patients who have had treatment with VTX-2337, doxorubicin, PLD, or any other anthracycline. 2. Patients who have received an investigational agent \< 30 days prior to registration. 3. Patients who have received oral or parenteral corticosteroids \< 2 weeks prior to registration or who require ongoing systemic immunosuppressive therapy for any reason. 4. Patients with active autoimmune disease. Active refers to any condition currently requiring therapy. Examples of autoimmune disease include systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease and rheumatoid arthritis. 5. Patients with a history of other invasive malignancies, with the exception of non-melanoma skin cancer, are excluded if there is any evidence of the other malignancy being present within the last three years. 6. Patients who have received prior radiotherapy OTHER THAN for the treatment of ovarian, fallopian tube or primary peritoneal cancer within the last three years are excluded. 7. Patients who have received prior chemotherapy OTHER THAN for the treatment of ovarian, fallopian tube or primary peritoneal cancer within the last three years are excluded. 8. Patients with history or evidence upon physical examination of CNS disease, including primary brain tumor, seizures not controlled with standard medical therapy, any brain metastases, or history of cerebrovascular accident (CVA, stroke), transient ischemic attack (TIA) or subarachnoid hemorrhage within six months of the first date of treatment on this study. 9. Patients with clinically significant cardiovascular disease. 10. Patients who are pregnant or nursing. 11. Patients under the age of 18. 12. Patients with clinical symptoms or signs of gastrointestinal obstruction and/or who require parenteral hydration or nutrition.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | Survival is measured from date of enrollment and randomization on the study until death from any cause, or if alive at last contact, date of last contact. | Comparison of duration of survival between the 2 treatment groups |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) | Progression-free survival is measured from enrollment and randomization on the study until first indication of progression based on irRECIST criteria or death from any cause, or if progression-free at last contact, the date of last disease assessment. | Comparison of PFS between the 2 treatment groups |
| Frequency and Severity of Adverse Events (AEs) | Assessed during each cycle of therapy and within 30 days after the last cycle of therapy | An AE is any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug-related. An AE can be unfavorable and unintended sign, symptom, or disease which is temporally associated with the use of investigational product (IP), whether or not considered related to the IP. A serious AE = an AE occurring at any dose that: • Results in death • Is life- threatening • Requires or prolongs existing inpatient hospitalization • Results in persistent or significant disability/incapacity • Is a congenital anomaly/birth defect; • Constitutes an important medical event. The Investigator assessed the relationship of each AE to IP and graded the severity according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0: Grade (GR) 1 = Mild; asymptomatic or mild symptoms; GR 2 = Moderate (minimal, local or noninvasive intervention indicated); GR 3 = Severe or medically significant; GR 4 = Life-threatening; GR 5 = Death |
Countries
United States
Participant flow
Recruitment details
Enrollment was initiated on 2012-Aug-13 and terminated on 2014-Apr-11. During this time, 297 patients were enrolled.
Pre-assignment details
Prior to enrollment and treatment assignment, a completed eligibility checklist was electronically checked for completeness and compliance with eligibility criteria. Prior to treatment assignment, patients were stratified by prior platinum free interval (\<6 months or \>6-12 months) and performance status (0 or 1). Treatments were double-blinded.
Participants by arm
| Arm | Count |
|---|---|
| Pegylated Liposomal Doxorubicin (PLD) + Placebo Pegylated Liposomal Doxorubicin (PLD) 40 mg/m2 plus placebo | 149 |
| Pegylated Liposomal Doxorubicin (PLD)+VTX-2337 (VTX) Pegylated Liposomal Doxorubicin (PLD) 40 mg/m2 plus VTX-2337 3.0 mg/m2 | 148 |
| Total | 297 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Did not initiate treatment | 2 | 1 |
Baseline characteristics
| Characteristic | Pegylated Liposomal Doxorubicin (PLD)+VTX-2337 (VTX) | Pegylated Liposomal Doxorubicin (PLD) + Placebo | Total |
|---|---|---|---|
| Age, Continuous | 63.5 years | 61.6 years | 62.7 years |
| Age, Customized 40-49 years | 11 Participants | 22 Participants | 33 Participants |
| Age, Customized <40 years | 1 Participants | 4 Participants | 5 Participants |
| Age, Customized 50-59 years | 42 Participants | 39 Participants | 81 Participants |
| Age, Customized 60-69 years | 51 Participants | 50 Participants | 101 Participants |
| Age, Customized 70-79 years | 38 Participants | 31 Participants | 69 Participants |
| Age, Customized > 79 years | 5 Participants | 3 Participants | 8 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 0 = Fully active, no restrictions | 105 Participants | 104 Participants | 209 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 1=Restricted activity;ambulatory;can do light work | 43 Participants | 45 Participants | 88 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 4 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 145 Participants | 143 Participants | 288 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 2 Participants |
| Prior Chemotherapy Regimens 1 | 69 Participants | 81 Participants | 150 Participants |
| Prior Chemotherapy Regimens 2 | 74 Participants | 64 Participants | 138 Participants |
| Prior Chemotherapy Regimens 3 | 5 Participants | 4 Participants | 9 Participants |
| Prior Platinum-Free Interval as per Case Report Forms <= 6 months | 72 Participants | 79 Participants | 151 Participants |
| Prior Platinum-Free Interval as per Case Report Forms > 6 months | 76 Participants | 70 Participants | 146 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 3 Participants | 6 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants | 4 Participants | 10 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 | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 137 Participants | 141 Participants | 278 Participants |
| Sex: Female, Male Female | 148 Participants | 149 Participants | 297 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 | — / — | — / — |
| other Total, other adverse events | 147 / 147 | 147 / 147 |
| serious Total, serious adverse events | 30 / 147 | 36 / 147 |
Outcome results
Primary
Overall Survival
Comparison of duration of survival between the 2 treatment groups
Time frame: Survival is measured from date of enrollment and randomization on the study until death from any cause, or if alive at last contact, date of last contact.
Population: All enrolled patients
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pegylated Liposomal Doxorubicin (PLD) + Placebo | Overall Survival | 574 days |
| Pegylated Liposomal Doxorubicin (PLD)+VTX-2337 (VTX) | Overall Survival | 552 days |
Comparison: The null hypothesis is that the hazards of death are equal for both treatment groups. The primary assessment of this hypothesis was done with a stratified logrank test and the study was to be considered sufficiently mature to assess this hypothesis when at least 211 deaths had occurred among all individuals enrolled. Type I error was to be set to 0.08 for a one-sided test and the power for detecting a 30% reduction in the hazard (hazard ratio=0.70) due to VTX-2337 was 88.2%.p-value: 0.923Log Rank
Secondary
Frequency and Severity of Adverse Events (AEs)
An AE is any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug-related. An AE can be unfavorable and unintended sign, symptom, or disease which is temporally associated with the use of investigational product (IP), whether or not considered related to the IP. A serious AE = an AE occurring at any dose that: • Results in death • Is life- threatening • Requires or prolongs existing inpatient hospitalization • Results in persistent or significant disability/incapacity • Is a congenital anomaly/birth defect; • Constitutes an important medical event. The Investigator assessed the relationship of each AE to IP and graded the severity according to the National Cancer Institute Common Terminology Criteria for Adverse Events, Version 4.0: Grade (GR) 1 = Mild; asymptomatic or mild symptoms; GR 2 = Moderate (minimal, local or noninvasive intervention indicated); GR 3 = Severe or medically significant; GR 4 = Life-threatening; GR 5 = Death
Time frame: Assessed during each cycle of therapy and within 30 days after the last cycle of therapy
Population: All patients who initiated study treatment. There were 147 patients who initiated treatment on each arm.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pegylated Liposomal Doxorubicin (PLD) + Placebo | Frequency and Severity of Adverse Events (AEs) | Grade 3 | 83 participants |
| Pegylated Liposomal Doxorubicin (PLD) + Placebo | Frequency and Severity of Adverse Events (AEs) | Grade 4 | 10 participants |
| Pegylated Liposomal Doxorubicin (PLD) + Placebo | Frequency and Severity of Adverse Events (AEs) | Grade 2 | 40 participants |
| Pegylated Liposomal Doxorubicin (PLD) + Placebo | Frequency and Severity of Adverse Events (AEs) | Grade 5 | 6 participants |
| Pegylated Liposomal Doxorubicin (PLD) + Placebo | Frequency and Severity of Adverse Events (AEs) | Grade 1 | 8 participants |
| Pegylated Liposomal Doxorubicin (PLD)+VTX-2337 (VTX) | Frequency and Severity of Adverse Events (AEs) | Grade 5 | 7 participants |
| Pegylated Liposomal Doxorubicin (PLD)+VTX-2337 (VTX) | Frequency and Severity of Adverse Events (AEs) | Grade 1 | 3 participants |
| Pegylated Liposomal Doxorubicin (PLD)+VTX-2337 (VTX) | Frequency and Severity of Adverse Events (AEs) | Grade 2 | 44 participants |
| Pegylated Liposomal Doxorubicin (PLD)+VTX-2337 (VTX) | Frequency and Severity of Adverse Events (AEs) | Grade 4 | 3 participants |
| Pegylated Liposomal Doxorubicin (PLD)+VTX-2337 (VTX) | Frequency and Severity of Adverse Events (AEs) | Grade 3 | 90 participants |
Secondary
Progression-free Survival (PFS)
Comparison of PFS between the 2 treatment groups
Time frame: Progression-free survival is measured from enrollment and randomization on the study until first indication of progression based on irRECIST criteria or death from any cause, or if progression-free at last contact, the date of last disease assessment.
Population: All enrolled patients.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Pegylated Liposomal Doxorubicin (PLD) + Placebo | Progression-free Survival (PFS) | 159 days |
| Pegylated Liposomal Doxorubicin (PLD)+VTX-2337 (VTX) | Progression-free Survival (PFS) | 147 days |
Comparison: The null hypothesis is that the hazards of first progression or death are equal for both treatment groups. The primary assessment was to use a stratified logrank test and the study was to be considered sufficiently mature when survival is mature for analysis. Type I error was to be set to 0.02 for a one-sided test and the power for detecting a 31% reduction in the hazard (hazard ratio=0.69) due to VTX-2337 was expected to be approximately 83%.p-value: 0.943Log Rank