Ovarian Cancer
Conditions
Keywords
Systemic Hedgehog, Hedgehog Pathway Inhibitor
Brief summary
The study was a Phase II, randomized, placebo-controlled, double-blind, multicenter clinical trial of vismodegib (GDC-0449) in patients with ovarian cancer in a second or third complete remission. Patients were randomized in a 1:1 ratio to either vismodegib or placebo. Randomization was stratified based on whether their cancer was in a second or third complete remission.
Interventions
Vismodegib 150 mg was provided in hard gelatin capsules.
Placebo to vismodegib consisted of the excipients for vismodegib without the active molecule in hard gelatin capsules matching the active drug product in color and size.
Sponsors
Genentech, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologic diagnosis of epithelial ovarian carcinoma, primary peritoneal carcinoma, or fallopian tube carcinoma * Must be in second or third complete remission, have received chemotherapy (platinum-based and/or non-platinum-based) for recurrent disease, and have achieved a complete remission after their most recent chemotherapy regimen. Complete remission is defined as no symptoms suggestive of persistent cancer, computed tomography (CT) scan of the chest/abdomen/pelvis without evidence of ovarian cancer within 4 weeks of randomization, and normal CA-125 (measured within 2 weeks of randomization) following completion of prior chemotherapy. The study investigator should confirm the status of disease remission by CT scan before patient enrollment. If patient has lymphadenopathy by CT scan and the investigator thinks that it is unlikely due to ovarian cancer, this patient is considered eligible. If indicated, a confirmatory biopsy should be performed. * Patients must have completed their most recent cytotoxic chemotherapy regimen (platinum-based or non-platinum based) no less than 3 weeks and no more than 14 weeks prior to randomization. * Archival tissue must be available and requested. * Negative pregnancy test on Day 1 (first day the patient receives vismodegib or placebo). * For women of childbearing potential: Use of two effective methods of contraception, including one barrier method.
Exclusion criteria
* Pregnancy or lactation. * Patients whose ovarian cancer is in first remission. * Patients must not have experienced more than two prior recurrences of disease. * Concurrent non-protocol-specified anti-tumor therapy, either approved or unapproved (eg, chemotherapy, hormonal therapy, other targeted therapy, radiation therapy, surgery, herbal therapy). Hormonal replacement therapies for treatment of postmenopausal symptoms do not exclude patients from this study. * Current, recent (within 4 weeks of Day 1), or planned participation in an experimental drug study while enrolled in this study. * History of other malignancies within 3 years of Day 1, except for tumors with a negligible risk for metastasis or death, such as adequately treated basal cell carcinoma (BCC) or squamous-cell carcinoma of the skin; ductal carcinoma in situ of the breast; or carcinoma in situ of the cervix. * Uncontrolled medical illnesses such as infection requiring intravenous (IV) antibiotics. * Life expectancy \< 12 weeks. * History of other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates use of an investigational drug or that might affect interpretation of the results of the study or render the patient at high risk from treatment complications.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) | From randomization date through the data cut-off date of May 15, 2010, up to 100 weeks | PFS was defined as the time between randomization and disease progression, as confirmed by radiography, or death for any reason. Since patients were in remission at the start of the study, they had no evidence of the presence of tumors. Disease progression was defined as radiographic evidence of a tumor. Tumor assessments by computed tomography (CT) of the chest, abdomen, and pelvis were performed at screening and every 8 weeks during the study. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) in Patients With Versus Without Hedgehog Antigen Tumor Expression | From randomization date through the data cut-off date of May 15, 2010, up to 100 weeks | Hedgehog antigen expression was measured with immunohistochemical methods in tumor tissue taken from each patient prior to enrollment in the study. The percentage of cells with (\> 0%) and without (0%) Hedgehog antigen expression was measured microscopically. PFS was defined as the time between randomization and disease progression, as confirmed by radiography, or death for any reason. Tumor assessments by computed tomography (CT) of the chest, abdomen, and pelvis were performed at screening and every 8 weeks during the study. |
| Overall Survival | From randomization date through the data cut-off date of May 15, 2010, up to 100 weeks | Overall survival was defined as the time from randomization until death by any cause. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Vismodegib 150 mg Patients received vismodegib 150 mg orally once daily until radiographically confirmed disease progression, intolerable toxicity, or withdrawal from the study. | 52 |
| Placebo to Vismodegib Patients received placebo to vismodegib orally once daily until radiographically confirmed disease progression, intolerable toxicity, or withdrawal from the study. | 52 |
| Total | 104 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 0 |
| Overall Study | Disease progression, radiographic | 33 | 37 |
| Overall Study | Patient decision to withdraw | 9 | 4 |
| Overall Study | Physician decision to withdraw patient | 1 | 0 |
| Overall Study | Reason for discontinuation not available | 1 | 1 |
Baseline characteristics
| Characteristic | Vismodegib 150 mg | Placebo to Vismodegib | Total |
|---|---|---|---|
| Age, Continuous | 57.3 years STANDARD_DEVIATION 10.2 | 58.6 years STANDARD_DEVIATION 8.9 | 57.9 years STANDARD_DEVIATION 9.6 |
| Sex: Female, Male Female | 52 Participants | 52 Participants | 104 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 | 51 / 52 | 44 / 52 |
| serious Total, serious adverse events | 6 / 52 | 3 / 52 |
Outcome results
Primary
Progression-free Survival (PFS)
PFS was defined as the time between randomization and disease progression, as confirmed by radiography, or death for any reason. Since patients were in remission at the start of the study, they had no evidence of the presence of tumors. Disease progression was defined as radiographic evidence of a tumor. Tumor assessments by computed tomography (CT) of the chest, abdomen, and pelvis were performed at screening and every 8 weeks during the study.
Time frame: From randomization date through the data cut-off date of May 15, 2010, up to 100 weeks
Population: Intent-to-treat patient population: All randomized patients.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Vismodegib 150 mg | Progression-free Survival (PFS) | 7.5 Months |
| Placebo to Vismodegib | Progression-free Survival (PFS) | 5.8 Months |
Secondary
Overall Survival
Overall survival was defined as the time from randomization until death by any cause.
Time frame: From randomization date through the data cut-off date of May 15, 2010, up to 100 weeks
Population: Intent-to-treat patient population: All randomized patients.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Vismodegib 150 mg | Overall Survival | NA Months |
| Placebo to Vismodegib | Overall Survival | NA Months |
Secondary
Progression-free Survival (PFS) in Patients With Versus Without Hedgehog Antigen Tumor Expression
Hedgehog antigen expression was measured with immunohistochemical methods in tumor tissue taken from each patient prior to enrollment in the study. The percentage of cells with (\> 0%) and without (0%) Hedgehog antigen expression was measured microscopically. PFS was defined as the time between randomization and disease progression, as confirmed by radiography, or death for any reason. Tumor assessments by computed tomography (CT) of the chest, abdomen, and pelvis were performed at screening and every 8 weeks during the study.
Time frame: From randomization date through the data cut-off date of May 15, 2010, up to 100 weeks
Population: Intent-to-treat patient population: All randomized patients. Tissue for evaluation was only available for 29 patients in the vismodegib group and 28 patients in the placebo group.
| Arm | Measure | Group | Value (MEDIAN) | Dispersion |
|---|---|---|---|---|
| Vismodegib 150 mg | Progression-free Survival (PFS) in Patients With Versus Without Hedgehog Antigen Tumor Expression | 0% of cells with hedgehog punctate stain | 7.00 Months | 95% Confidence Interval 3.48 |
| Vismodegib 150 mg | Progression-free Survival (PFS) in Patients With Versus Without Hedgehog Antigen Tumor Expression | > 0% of cells with Hedgehog punctate stain | 9.13 Months | — |
| Placebo to Vismodegib | Progression-free Survival (PFS) in Patients With Versus Without Hedgehog Antigen Tumor Expression | 0% of cells with hedgehog punctate stain | 5.32 Months | — |
| Placebo to Vismodegib | Progression-free Survival (PFS) in Patients With Versus Without Hedgehog Antigen Tumor Expression | > 0% of cells with Hedgehog punctate stain | 7.36 Months | — |