Ovarian Granulosa Cell Tumor, Ovarian Gynandroblastoma, Ovarian Sertoli-Leydig Cell Tumor, Ovarian Sex Cord-Stromal Tumor, Ovarian Sex Cord-Stromal Tumor, Not Otherwise Specified, Ovarian Sex Cord Tumor With Annular Tubules, Ovarian Steroid Cell Tumor
Conditions
Brief summary
This randomized phase II trial studies paclitaxel and carboplatin to see how well they work compared with bleomycin sulfate, etoposide phosphate, and cisplatin in treating patients with sex cord-ovarian stromal tumors that have spread to other places in the body and usually cannot be cured or controlled with treatment (advanced) or has returned (recurrent). Drugs used in chemotherapy work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving more than one drug (combination chemotherapy) may kill more tumor cells. It is not yet known which chemotherapy regimen is more effective in treating sex cord-ovarian stromal tumors.
Detailed description
PRIMARY OBJECTIVES: I. To assess the activity of paclitaxel and carboplatin with respect to progression free survival (using bleomycin, etoposide, and cisplatin \[BEP\] as a reference) for newly diagnosed advanced or recurrent chemonaive ovarian sex cord-stromal tumors. SECONDARY OBJECTIVES: I. To estimate the toxicity of paclitaxel and carboplatin, and bleomycin, etoposide, and cisplatin in this patient population. II. To estimate overall survival for paclitaxel and carboplatin relative to that of BEP. III. To evaluate response rate in the subset of patients with measurable disease. TERTIARY OBJECTIVES: I. To collect fixed and/or frozen tumor tissue for future translational research studies. II. To explore the utility of inhibin A and inhibin B as prognostic and predictive biomarkers for ovarian sex cord-stromal tumors and to examine changes in these markers with treatment. OUTLINE: Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive paclitaxel intravenously (IV) over 3 hours and carboplatin IV over 1 hour on day 1. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity. ARM II: Patients receive bleomycin sulfate IV on day 1 and etoposide phosphate\* IV over 1 hour and cisplatin IV over 30 minutes on days 1-5. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. NOTE: \*Patients who have received prior radiotherapy receive etoposide phosphate on days 1-4. After completion of study therapy, patients are followed up every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter.
Interventions
BIOLOGICALBleomycin Sulfate
Given IV
DRUGCarboplatin
Given IV
DRUGCisplatin
Given IV
DRUGEtoposide Phosphate
Given IV
OTHERLaboratory Biomarker Analysis
Correlative studies
DRUGPaclitaxel
Given IV
Sponsors
National Cancer Institute (NCI)
GOG Foundation
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients with histologically confirmed ovarian stromal tumor \[granulosa cell tumor, ganulosa cell-theca cell tumor, Sertoli-Leydig cell tumor (androblastoma), steroid (lipid) cell tumor, gynandroblastoma, unclassified sex cord-stromal tumor, sex cord tumor with annular tubules\] * Patients must have newly diagnosed, stage IIA - IV disease and must be entered within eight weeks from surgery; they may have either measurable residual disease by Response Evaluation Criteria In Solid Tumors (RECIST) criteria, or they may have no measurable residual disease; OR, they must have biopsy-proven recurrent disease of any stage and have never received cytotoxic chemotherapy * Patients must have a Gynecologic Oncology Group (GOG) performance grade of 0, 1, or 2 * Patients of childbearing potential must have a negative serum pregnancy test and must agree to practice an effective means of birth control * Patients in the measureable disease cohort must have at least one target lesion to be used to assess response on this protocol as defined by RECIST 1.1; tumors within a previously irradiated field will be designated as non-target lesions unless progression is documented or a biopsy is obtained to confirm persistence at least 90 days following completion of radiation therapy * Absolute neutrophil count (ANC) greater than or equal to 1,500/mcl, equivalent to Common Terminology Criteria for Adverse Events (CTCAE) grade 1 * Platelet greater than or equal to 100,000/mcl * Creatinine no greater than the institutional upper limits of normal * Bilirubin less than or equal to 1.5 x upper limit of normal (ULN) (CTCAE grade 1) * Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase \[AST\]) less than or equal to 3.0 x ULN (CTCAE grade 1) * Alkaline phosphatase less than or equal to 2.5 x ULN (CTCAE grade 1) * Neuropathy (sensory and motor) less than or equal to CTCAE grade 1 * No signs of clinically significant hearing loss * Patients must have signed an approved informed consent and authorization permitting release of personal health information * Patients must have pulmonary function sufficient to receive bleomycin, with normal lung expansion, absence of crackles on auscultation, and normal carbon monoxide diffusion (DLCO), defined as greater than 80% predicted * Patients with a history of hypersensitivity reactions to prior chemotherapy administered for previous cancer diagnoses are eligible to participate in the study, unless the hypersensitivity reaction consisted of anaphylaxis not amenable to desensitization * Recovery from effects of recent surgery, radiotherapy, or chemotherapy * Patients must be entered within 8 weeks after surgery performed for either 1) initial diagnosis, staging, and/or cytoreduction, or 2) (if done) management of recurrent disease in a chemonaive patient * 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
Exclusion criteria
* Patients who have received any prior cytotoxic chemotherapy or biologics for sex cord-stromal tumors (SCSTs) * Patients with apparent stage I disease who have not undergone a staging procedure * Patients with a history of other invasive malignancies, with the exception of non-melanoma skin cancer, are excluded if there is any evidence of other malignancy being present within the last five years * Woman who are pregnant or breastfeeding * Patients with medical history or conditions not otherwise previously specified which in the opinion of the investigator should exclude participation in this study; the investigator can consult the study chair or study co-chairs for uncertainty in this regard
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free Survival (PFS) | From start of treatment to time of progression or death, whichever occurs first. Median follow-up time was 48 months. | The relationship of randomized treatment to progression free survival. The RECIST 1.1 criteria are used for disease progression. This is the criteria: progression is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Tumor Response Rate | Median followup time was 48 months. | Proportion of evaluable patients with complete or partial tumor response by RECIST 1.1 criteria. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. (ORR = CR + PR). |
| Overall Survival (OS) | From start of treatment to time of death or the date of last contact, assessed up to 10 years. Median follow-up time was 48 months. | The relationship of treatment to overall survival will be assessed. The number of death events in the treatment arm is reported. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change in Inhibin A and Inhibin B Levels | Baseline to up to 2 years | Pre-treatment levels of inhibin A and inhibin B will be examined in relation to OS and PFS in Cox proportional hazards models. Changes from baseline in inhibin levels will be compared between treatment groups using mixed effects models accounting for the longitudinal nature of the data. The repeated measures of inhibin will also be explored versus overall survival and PFS using time-dependent covariates in Cox proportional hazards models. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm I (Paclitaxel, Carboplatin) Patients receive paclitaxel IV over 3 hours and carboplatin IV over 1 hour on day 1. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity.
Carboplatin: Given IV
Laboratory Biomarker Analysis: Correlative studies
Paclitaxel: Given IV | 31 |
| Arm II (Bleomycin Sulfate, Etoposide Phosphate, Cisplatin) Patients receive bleomycin sulfate IV on day 1 and etoposide IV over 1 hour and cisplatin IV over 30 minutes on days 1-5. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.
Bleomycin Sulfate: Given IV
Cisplatin: Given IV
Etoposide Phosphate: Given IV
Laboratory Biomarker Analysis: Correlative studies | 32 |
| Total | 63 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 2 |
| Overall Study | Death | 1 | 0 |
| Overall Study | Disease Progression | 5 | 0 |
| Overall Study | Patient Refused | 0 | 3 |
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Arm I (Paclitaxel, Carboplatin) | Arm II (Bleomycin Sulfate, Etoposide Phosphate, Cisplatin) | Total |
|---|---|---|---|
| Age, Continuous | 50.71 years STANDARD_DEVIATION 12.51 | 44.05 years STANDARD_DEVIATION 13.86 | 47.33 years STANDARD_DEVIATION 13.53 |
| Age, Customized 20 - 29 years | 2 Participants | 7 Participants | 9 Participants |
| Age, Customized 30 - 39 years | 2 Participants | 5 Participants | 7 Participants |
| Age, Customized 40 - 49 years | 13 Participants | 6 Participants | 19 Participants |
| Age, Customized 50 - 59 years | 6 Participants | 10 Participants | 16 Participants |
| Age, Customized >= 60 years | 8 Participants | 4 Participants | 12 Participants |
| Cell Type Granulosa Cell Tumor | 28 Participants | 27 Participants | 55 Participants |
| Cell Type Lipid Cell Tumor | 1 Participants | 0 Participants | 1 Participants |
| Cell Type Sertoli-leydig Cell Tumor | 0 Participants | 3 Participants | 3 Participants |
| Cell Type Sex Cord Stromal Tumor, Unclassified | 2 Participants | 2 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants | 8 Participants | 11 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 27 Participants | 23 Participants | 50 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 2 Participants |
| Measurable Disease Measurable Disease | 11 Participants | 12 Participants | 23 Participants |
| Measurable Disease No Measurable Disease | 20 Participants | 20 Participants | 40 Participants |
| Performance Status 0 | 21 Participants | 28 Participants | 49 Participants |
| Performance Status 1 | 9 Participants | 4 Participants | 13 Participants |
| Performance Status 2 | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants | 5 Participants | 11 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 | 1 Participants | 2 Participants |
| Race (NIH/OMB) White | 23 Participants | 25 Participants | 48 Participants |
| Sex: Female, Male Female | 31 Participants | 32 Participants | 63 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 | 5 / 31 | 8 / 32 |
| other Total, other adverse events | 31 / 31 | 29 / 32 |
| serious Total, serious adverse events | 6 / 31 | 11 / 32 |
Outcome results
Primary
Progression-free Survival (PFS)
The relationship of randomized treatment to progression free survival. The RECIST 1.1 criteria are used for disease progression. This is the criteria: progression is defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progressions).
Time frame: From start of treatment to time of progression or death, whichever occurs first. Median follow-up time was 48 months.
Population: Intent to Treat
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Arm I (Paclitaxel, Carboplatin) | Progression-free Survival (PFS) | 27.7 months |
| Arm II (Bleomycin Sulfate, Etoposide Phosphate, Cisplatin) | Progression-free Survival (PFS) | 19.7 months |
Secondary
Overall Survival (OS)
The relationship of treatment to overall survival will be assessed. The number of death events in the treatment arm is reported.
Time frame: From start of treatment to time of death or the date of last contact, assessed up to 10 years. Median follow-up time was 48 months.
Population: Intent to Treat
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm I (Paclitaxel, Carboplatin) | Overall Survival (OS) | 5 Participants |
| Arm II (Bleomycin Sulfate, Etoposide Phosphate, Cisplatin) | Overall Survival (OS) | 8 Participants |
Secondary
Tumor Response Rate
Proportion of evaluable patients with complete or partial tumor response by RECIST 1.1 criteria. Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. Partial Response (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. (ORR = CR + PR).
Time frame: Median followup time was 48 months.
Population: Patients with at least one target lesion by RECIST 1.1 criteria and and at least one CT tumor assessment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm I (Paclitaxel, Carboplatin) | Tumor Response Rate | 0.43 proportion of participants |
| Arm II (Bleomycin Sulfate, Etoposide Phosphate, Cisplatin) | Tumor Response Rate | 0.54 proportion of participants |
Other Pre-specified
Change in Inhibin A and Inhibin B Levels
Pre-treatment levels of inhibin A and inhibin B will be examined in relation to OS and PFS in Cox proportional hazards models. Changes from baseline in inhibin levels will be compared between treatment groups using mixed effects models accounting for the longitudinal nature of the data. The repeated measures of inhibin will also be explored versus overall survival and PFS using time-dependent covariates in Cox proportional hazards models.
Time frame: Baseline to up to 2 years