| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with high risk uterine LMS, FIGO stage I (confined to corpus +/-cervix). |
|
| E.1.1.1 | Medical condition in easily understood language |
| High risk uterine leiomyosarcoma |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10046799 |
| E.1.2 | Term | Uterine leiomyosarcoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To determine whether overall survival of patients with uterus-limited high-grade leiomyosarcoma is superior among patients assigned to treatment with adjuvant gemcitabine plus docetaxel followed by doxorubicin compared to patients assigned to observation. |
|
| E.2.2 | Secondary objectives of the trial |
1. To determine whether treatment with adjuvant gemcitabine plus docetaxel followed by doxorubicin improves recurrence-free survival of patients with uterus-limited high-grade leiomyosarcoma compared to observation.
2. To explore the impact of potential predictors of recurrence or death such as patient age, and institution reported tumor size, cervix involvement (yes or no), and mitotic rate. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
- Patients with high risk uterine LMS, FIGO stage I (confined to corpus +/- cervix). Patients with known uterine serosa involvement are not eligible.
Patients should have had, at least, a complete hysterectomy (including removal of the cervix). Bilateral salpingo-oophorectomy is not required.
- Institutional pathology review calls the uterine leiomyosarcoma “highgrade.”
- Additionally, if the pathology report indicates a mitotic rate, the mitotic rate should be greater than or equal to 5 mitoses/10 high power field.
All patients must be no longer than 12 weeks (3 months) from surgical resection of cancer at the time of enrollment on study. If a patient requires a second operation to complete her surgery, i.e. trachelectomy to remove the cervix and/or BSO, the 12 weeks may be counted from the time of the second operation.
- All patients must have no evidence of persistent or metastatic disease as documented by a post-resection CT of the chest/abdomen/pelvis or by CT chest + MRI abdomen/pelvis. The post-resection imaging studies should be performed within 4 weeks of registration on study.
- Patients must have adequate:
1- Bone marrow function: Absolute neutrophil count (ANC) greater than or equal to 1,500/mcl (ANC 1.5 x 109/liter (L).
Platelets greater than or equal to100,000/mcl (Platelets 100 x 109/L).
Hemoglobin greater than 8.0 g/dl (= 80 g/L; or 4.9 mmol/L).
2- Renal function: creatinine less than or equal to 1.5 x institutional upper
limit normal (ULN.)
3- Hepatic function: Bilirubin within normal range. SGOT (AST), SGPT (ALT), and alkaline phosphatase less than or equal to 2.5 x ULN.
Patients with a history of Gilbert’s syndrome may be eligible provided total bilirubin is less than or equal to 1.5 x ULN and the AST, ALT, Alkaline phosphatase meet the criteria detailed.
4- Neurologic function: Neuropathy (sensory and motor) less than or equal to CTCAE grade 1.
- Patients with GOG performance status of 0 or 1; ECOG performance status of 0 or,1; or KPS >= 80%.
-Patients who have met the pre-entry requirements specified in Section 7.0.
GOG-0277-7-
- Patients must have signed an approved informed consent.
- Patients participating through U.S. sites must sign an approved and authorization permitting release of personal health information.
- Patients must be a minimum of 18 years of age.
- Patients should be free of active infection requiring antibiotics (with the exception of an uncomplicated UTI). |
|
| E.4 | Principal exclusion criteria |
- Patients who have had prior therapy with docetaxel or gemcitabine or doxorubicin at any time in their history.
- Patients with a history of other invasive malignancies, with the exception of non-melanoma skin cancer, are ineligible if there is any evidence of other malignancy being present within the last five years. Patients are also ineligible if their previous cancer treatment contraindicates this protocol therapy.
- Patients with a history of severe hypersensitivity reaction to Taxotere® (docetaxel) or other drugs formulated with polysorbate 80.
- Patients with GOG performance status of 2, 3 or 4; or ECOG performance status of 2, 3 or 4.
- Patients who are breast-feeding.
- Patients with a known history of congestive heart failure or cardiac ejection fraction < 50% (or less than institutional normal limits). ECHO or MUGA is not required prior to enrollment. For patients assigned to the chemotherapy arm, an
ECHO or MUGA should be done within 6 months of starting treatment.
- Patients with a history of prior whole pelvic radiation.
- Concurrent treatment with hormone replacement therapy is permitted at the discretion of the treating physician. Patients who have been taking hormonal/hormone blocking agents for breast cancer or breast cancer prevention or other indication are eligible. Use of anti-hormonal agents (tamoxifen, medroxyprogesterone, aromatase inhibitors) is permitted at the discretion of the
treating physician. Documentation of concurrent medications is required.
- Patients with recurrent uterine LMS.
- Patients who are known to be HIV (human immunodeficiency virus) positive are not eligible due to the high risk for infectious complications of the myelsuppressive therapy used in the experimental arm of this study.
GOG-0277-8-
- Patients with gross residual or metastatic tumor findings following complete surgical treatment for uterine LMS. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The intention-to-treat principle will be applied in the primary
analysis comparing the distribution of time to death with censoring between assigned treatment arms. The logrank test will be used to test the null hypothesis of independence between survival and randomized treatment.
Kaplan-Meier estimates will be used to graph survival distribution curves for each treatment arm. The death hazard ratio (experimental to control) will be estimated using a Cox Proportional Hazards model and a 95% Wald confidence
interval will be reported. |
|
| E.5.2 | Secondary end point(s) |
| Recurrence free survival. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
The intention-to-treat principle will be applied in the secondary analysis comparing the distribution of time to recurrence or death with censoring between assigned treatment arms.
The recurrence or death hazard ratio (experimental to control) will be estimated using Cox’s proportional hazards model and a 95% Wald confidence interval will be reported. The logrank test will be used to test the null hypothesis of independence between recurrence-free survival and randomized treatment. It is
expected that this analysis will have 85% power to detect a 37.5% relative decrease in the hazard of recurrence or death (133 events) at the time that overall survival data will be mature. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | No |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
|
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 29 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Austria |
| Belgium |
| Denmark |
| France |
| Germany |
| Greece |
| Italy |
| Netherlands |
| Norway |
| Poland |
| Serbia |
| Slovakia |
| Spain |
| Sweden |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
1. Thirty days after all patients have stopped protocol treatment
2. The trial is mature for the analysis of the primary endpoint as defined in the protocol
3. The database has been fully cleaned and frozen for this analysis |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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