Clinical trial NCT03624244: Evaluation of Clinical Impact of Interruption VS Maintenance of AI in Patients with Locally Advanced/ Metastatic Low Grade Endometrial Stromal Sarcoma (LGESS)
Official title: Randomized Comparative Prospective Multicentre Phase II Trial Evaluating Clinical Impact of Interruption VS Maintenance of AI in Patients with Locally Advanced/ Metastatic LGESS
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Low Grade Endometrial Stromal Sarcoma
Keywords: Low Grade Endometrial Stromal Sarcoma
Aromatase inhibitors
Lead sponsor: Centre Leon Berard
Sponsor class: OTHER
First posted: 2018-08-10
Enrollment: 40
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Phase II comparative multicentre prospective randomised (1:1 ratio) open-label study
Primary purpose: TREATMENT

Brief summary: The primary objective is to compare the progression-free survival (PFS) between aromatase inhibitors interruption and aromatase inhibitors maintenance strategies in patients with a locally advanced or metastatic Low Grade Endometrial Stromal Sarcoma (LGESS).

Detailed description: Uterine sarcomas are rare tumors with an incidence of 1.7/100 000 women per year, including 20% of endometrial stromal sarcomas (ESS). Patients with low grade ESS (LGESS) have a good prognosis with a 5-year overall survival rates ranging from 66 to 98%, depending on the stage of the disease.

Majority of LGESS report estrogen receptor (ER) and/or progesterone receptor positive and a chromosomal translocation with JAZF1-SUZ12.

Based on the current European Society of Medical Oncology (ESMO)guidelines, the standard treatment for patients with early/non metastatic ESS is total hysterectomy plus or less bilateral salpingo-oophorectomy. The use of hormonal therapy (HT) for advanced or metastatic disease is recommended based on retrospective data from small series providing evidence that HT have an anti-tumor activity on LGESS. HT includes aromatase inhibitors (AI), progestins and gonadotrophin-releasing hormone.

Very few data are available in this rare disease, but retrospective analyses show that AI may provide response rates of 46 to 67% in metastatic LGESS patients (7% complete response, 60% partial response), with a mean duration of response of 24 months.

Even if AI are effective and well tolerated, chronical mild to moderate (grade 1-2) side-effects (arthritis, hot-flashes, osteoporosis, hypercholesterolemia, cardiac events) have a negative impact on patient's well-being because of the treatment long term duration and need to be balanced in such long term survival.

To date, the question of the optimal duration of HT in LGESS is still pending. The investigator propose an open-label, randomized, multicenter phase II study aiming at determining the feasibility of interruption of AI in patients with locally advanced or metastatic LGESS after long term stabilization or response to AI. The study will use a sequential bayesian design allowing for continuous monitoring of the main efficacy outcome, thus leading to a smaller more informative trial, and specifically tied to decision making. This design is particularly suited to characterize efficacy signals in the context of a very rare pathology. Moreover JAZF1-JJAZ1 fusion gene is not identified in all LGESS.

Ancillary studies will provide precious data aiming at:

* Identifying predictive factors of prolonged response to HT or late resistance (Next Generation Sequencing and Comparative Genome Hybridization).
* Evaluating sociobehavioral (only for French sites) of patients by following questionnaire: Zimbardo Time Perspective Inventory (ZTPI) , Functional, Communicative and Critical Health Literacy/ 14-item Health Literacy Scale (FCCHL/HLS14), VICAN, Fear of Cancer Recurrence (FCR) and Patient-Generated Index (PGI).

Eligibility criteria: Inclusion Criteria:

* Age≥18 years;
* Histological confirmation of low grade ESS;
* Locally advanced or metastatic disease at diagnosis or patient experiencing a tumor effraction during hysterectomy;
* Treatment with aromatase inhibitors (Anastrozole or Exemestane or Letrozole ) initiated either: for at least 24 months (in patients with no residual disease or non-measurable disease at the last AI initiation) OR for at least 36 months (in patients with measurable disease at the last AI initiation);
* Disease must be controlled at the time of the randomisation (objective response or stable disease) by the aromatase inhibitor initiated either for at least 24 or 36 months
* Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ≤ 2
* Covered by a medical insurance;
* Signed informed consent prior to any study-specific procedure.

Exclusion Criteria:

* Pregnant or breastfeeding woman;
* Patient concurrently using other approved or investigational antineoplastic agents;
* Major concurrent disease affecting cardiovascular system, liver, kidneys, hematopoietic system or else considered as clinically important by the investigator and that could be incompatible with patient's participation in this trial or would likely interfere with study procedures or results;
* Prior history of malignancies other than study disease (except for basal cell or squamous cell carcinoma of the skin or carcinoma in situ of the cervix) unless the patient has been free of the disease for at least 3 years;
* Patients using prohibited concomitant and/or concurrent medications
* Contra-indication according to SmPCs.
* Patient requiring tutorship or curatorship.

Primary outcomes:
measure: Progression free survival
timeFrame: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 60 months
Secondary outcomes:
measure: Overall survival
timeFrame: From date of randomization to death due to any cause, assessed up to 60 months
measure: Time to first subsequent chemotherapy/treatment or death
timeFrame: From date of randomization to the earliest date of chemotherapy/treatment start date following study treatment discontinuation, or death due to any cause, whichever came first, assessed up to 60 months
measure: Objective response rate after reintroduction of AI in the experimental arm
timeFrame: From the date of AI reintroduction in the experimental arm to the date of subsequent progression or date of death due to any cause, whichever came first, assessed up to 60 months
measure: Progression free survival after reintroduction of AI in the experimental arm
timeFrame: From the date of AI reintroduction in the experimental arm to the date of subsequent progression or date of death due to any cause, whichever came first, assessed up to 60 months
measure: Duration of response to AI after reintroduction
timeFrame: From the date of first objective response following the reintroduction of AI to the date of the first subsequent documented radiological progression or death due to any cause, whichever came first, assessed up to 60 months
measure: Incidence of Treatment-Emergent Adverse Events
timeFrame: From date of randomization to follow-up visit Month 36 or death due to any cause, whichever came first, assessed up to 60 months
measure: Quality of Life using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30)
timeFrame: Every 6 months until the 36th month for each patient
Other outcomes:
Locations:
city: Besançon
country: France
facility: CHU Besançon
city: Bordeaux
country: France
facility: Insitut Bergonié
city: Caen
country: France
facility: Centre François Baclesse
city: Clermont-Ferrand
country: France
facility: Centre Jean Perrin
city: Lille
country: France
facility: Centre Oscar Lambret
city: Limoges
country: France
facility: CHU Dupuytren
city: Lyon
country: France
facility: Centre Léon Bérard
city: Marseille
country: France
facility: Hopital La Timone
city: Marseille
country: France
facility: Hopital La Timone
city: Marseille
country: France
facility: Institut Paoli Calmette
city: Montpellier
country: France
facility: Institut de Cancérologie de Montpellier
city: Nice
country: France
facility: Centre Antoine Lacassagne
city: Paris
country: France
facility: Hopital Pitié Salpétrière
city: Paris
country: France
facility: AP-HP Hopîtal Cochin
city: Paris
country: France
facility: Insitut Curie
city: Reims
country: France
facility: Institut Godinot
city: Rouen
country: France
facility: Centre Henri Becquerel
city: Saint-Herblain
country: France
facility: ICO Centre René Gauducheau
city: Saint-Priest-en-Jarez
country: France
facility: CHUSE
city: Saint-Étienne
country: France
facility: Hopital Privé de la Loire
city: Tours
country: France
facility: CHU Tours
city: Villejuif
country: France
facility: Institut Gustave Roussy
Study officials:
affiliation: Centre Leon Berard
name: Isabelle RAY-COQUARD, MD PhD
role: PRINCIPAL_INVESTIGATOR
References: