A Phase III Randomized Trial of Gemcitabine plus Docetaxel followed by Doxorubicin v. observation for uterus-limited, High Grade Uterine Leiomyosarcoma

• Register: EUCTR
• Last refreshed on: 27 July 2020
• Main ID: EUCTR2012-002852-17-FR
• Date of registration: 28/02/2014
• Prospective Registration: Yes
• Primary sponsor: EORTC
• Public title: A Phase III Randomized Trial of Gemcitabine plus Docetaxel followed by Doxorubicin v. observation for uterus-limited, High Grade Uterine Leiomyosarcoma
• Scientific title: A PHASE III RANDOMIZED TRIAL OF GEMCITABINE (NSC# 613327) PLUS DOCETAXEL (NSC# 628503) FOLLOWED BY DOXORUBICIN (NSC# 123127) V. OBSERVATION FOR UTERUS-LIMITED, HIGH GRADE UTERINE LEIOMYOSARCOMA
• Date of first enrolment: 17/03/2014
• Target sample size: 216
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2012-002852-17
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes; Randomised: yes; Open: yes; Single blind: no; Double blind: no; Parallel group: no; Cross over: no; Other: no; If controlled, specify comparator, Other Medicinial Product: no; Placebo: no; Other: yes; Other specify the comparator: Observation; Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Austria, Belgium, Denmark, France, Germany, Greece, Italy, Netherlands, Norway, Poland, Serbia, Slovakia, Spain, Sweden, United Kingdom, United States

Contacts

• Name: Regulatory Affairs Unit
• Affiliation: EORTC

• Name: Regulatory Affairs Unit
• Affiliation: EORTC

Key inclusion & exclusion criteria

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).
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 200
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 16

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.


Age minimum:
Age maximum:
Gender:
Female: yes
Male: no

Health Condition(s) or Problem(s) studied

Patients with high risk uterine LMS, FIGO stage I (confined to corpus +/-cervix).
MedDRA version: 20.0 Level: PT Classification code 10046799 Term: Uterine leiomyosarcoma System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Therapeutic area: Diseases [C] - Cancer [C04]

Intervention(s)

Trade Name: Gemzar (Gemcitabine 200 mg)
Pharmaceutical Form: Powder for solution for infusion
INN or Proposed INN: GEMCITABINE
CAS Number: 122111-03-9
Other descriptive name: GEMCITABINE HYDROCHLORIDE
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 200-

Trade Name: Gemzar (Gemcitabine 1000 mg)
Pharmaceutical Form: Powder for solution for infusion
INN or Proposed INN: GEMCITABINE
CAS Number: 122111-03-9
Other descriptive name: GEMCITABINE HYDROCHLORIDE
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 1000-

Trade Name: Taxotere® (Docetaxel)
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: Docetaxel
CAS Number: 114977-28-5
Other descriptive name: DOCETAXEL
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 40-

Trade Name: Doxorubicin (Adriamycin)
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: DOXORUBICIN HYDROCHLORIDE
CAS Number: 25316-40-9
Concentration unit: mg milligram(s)
Concentration type: range
Concentration number: 10-150

Primary Outcome(s)

Secondary Objective: 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.

Main Objective: 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.

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.

Primary end point(s): Overall survival

Secondary Outcome(s)

Secondary end point(s): Recurrence free survival.

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.

Secondary ID(s)

GOG-0277

NCT01533207

2012-002852-17-GB

EORTC-55116-62114

Source(s) of Monetary Support

EORTC

Ethics review

Status: Approved
Approval date: 29/01/2014
Contact: