The investigators hypothesize that the dual inhibition of mTORC1/mTORC2 by AZD2014 combined with inhibition of aromatase enzyme by anastrozole will act synergistically and may be an interesting therapeutic option for endometrial cancer with a manageable toxicity profile. The investigators proposal is to conduct a multicenter, 2-step, randomized, Phase I/II trial to evaluate the safety and efficacy of a combination treatment associating anastrozole to AZD2014 in advanced endometrial cancer patients. The study is divided in 2 steps : * A safety run-in phase aiming to evaluate the safety of the proposed combination AZD2014 + anastrozole (Arm A) versus anastrozole alone (Arm B). No dose escalation is scheduled (doses are based on maximum tolerated dose (MTD) defined for AZD2014 and the summary of product characteristics (SPC) of anastrozole). However, dose de-escalation for AZD2014 will be applied in case of toxicity. * A two-stage randomized Phase II part aiming to evaluate the clinical benefit of the AZD2014 + anastrozole (Arm A) combination therapy versus anastrozole (Arm B).
TREATMENT PLAN : Following randomisation patients will receive Arm A : AZD2014 plus anastrozole or Arm B: anastrozole alone AZD2014 will be administered with an intermittent schedule i.e. 125 mg bis in die (BID) intermittent with 2 days on followed by 5 days off per week for a total weekly dose of 500 mg/week (250mg D1 and D2, 5 days off) Anastrozole will be administered at the standard dose defined in the SPC i.e. 1mg/d, per os, continuously. Both treatment will be administered until progressive disease (PD), unacceptable toxicity or willingness to stop. STATISTICS : A total of 72 patients will be randomized in the study. Safety run-in Phase on the first 9 patients randomized - As no dose escalation will be performed, the safety will be evaluated following the treatment and 8-week follow-up of the first 6 patients by the experimental association AZD2014+anastrozole (experimental arm). By similarity to a classic 3+3 design, based on binomial probabilities, there is a 90% probability of observing one or more patients with a toxicity event, if that event occurs in at least 32% of the target population. Assuming a 2:1 randomization ratio, a total of 9 patients (Arm A - Experimental: 6 patients, Arm B - Control: 3 patients) will be enrolled in this safety run-in phase and will be included in the evaluation of Phase II part. Phase II The sample size calculation was based on a Simon optimal two-stage design, with a minimum success (8-week non progression) rate considered of interest p1=60% and an uninteresting rate p0=40%. Assuming a type I error alpha of 0.05 and 80% power, 46 evaluable patients are needed in the experimental arm to reject the null hypothesis H0: p≤p0 versus the alternative hypothesis H1: p ≥ p1 in a unilateral situation (16 patients in Stage I and 30 additional patients in Stage II). With a 2:1 randomization and based on the assumption that 5% of the patients may be non-evaluable, a total of 72 patients will be included in the study : 48 patients in Arm A - experimental and 24 patients in Arm B - control). DATA ENTRY, DATA MANAGEMENT AND STUDY MONITORING All the data concerning the patients will be recorded in the electronic case report form (eCRF) throughout the study. serious adverse event (SAE) reporting will be also paper-based by e-mail and/or Fax. The sponsor will perform the study monitoring and will help the investigators to conduct the study in compliance with the clinical trial protocol, Good Clinical Practices (GCP) and local law requirements.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
72
Following inclusion, patients will be randomized (2:1) to receive Arm A : AZD2014 + anastrozole Arm B : anastrozole alone Mode of Action Selective and specific mTOR kinase inhibitor targeting both mTORC1 and mTORC2 complexes. Route of Administration Oral Dosage regimen 125mg BID with intermittent schedule (2 days of treatment followed by 5 days off (500mg/week)) Duration of treatment Until the patient experiences unacceptable toxicity, disease progression and/or treatment is discontinued per patient or investigator request.
Therapeutic Class Aromatase inhibitor Mode of Action Potent and highly selective non-steroidal aromatase inhibitor. Route of Administration Oral Dosage regimen 1 mg tablet once a day Duration of treatment Patients may continue treatment with anastrozole until the patient experiences unacceptable toxicity, disease progression and/or treatment is discontinued per patient or investigator request.
ICO - Paul Papin
Angers, France
Institut Sainte Catherine
Avignon, France
Hôpital Jean Minjoz
Besançon, France
Institut Bergonié
Bordeaux, France
Centre Francois Baclesse
Caen, France
GHM Institut Daniel Hollard
Grenoble, France
Centre Oscar Lambret
Lille, France
Centre Léon Bérard
Lyon, France
Institut régional du Cancer Montpellier (ICM)
Montpellier, France
Hcl - Chls
Pierre-Bénite, France
...and 2 more locations
Number of patients with severe toxicities occurring during the first 8 weeks of follow-up assessed using National Cancer Institute (NCI) common terminology criteria for adverse events (CTCAE) V4
Severe toxicities defined as * Any grade ≥ 4 treatment related toxicity * Any grade≥ 3 treatment related toxicity lasting more than 7 days
Time frame: during the first 8 weeks of follow up
The 8-week non progression rate using RECIST v1.1 to assess tumor response to treatment
Time frame: 8 weeks after start of treatment
Number of patients with AE graded using CTCAE V4
Time frame: For each participant, up to 30 days after the last dose of treatment (up to 3 years)
Progression-free survival (PFS) defined as the duration of time from start of treatment to time of progression or death, whichever occurs first
Time frame: up to 3 years
Overall survival (OS) defined as the duration of time from start of treatment to time of death.
Time frame: 3 years
Best response rate defined as (percentage of patients with complete response (CR), partial response (PR), stable disease (SD) or progressive disease (PD) according to RECIST V1.1)
Time frame: Up to 3 years
Duration of objective response as per RECIST v1.1
Time frame: Up to 3 years
Area under the curve (AUC) of AZD2014
Time frame: Week 1 Day 1: pre-dose, 2h and 6-8 hours later and Week 2 Day 1: pre-dose, 2h and 6-8 hours later.
Apparent clearance of AZD2014
Time frame: Week 1 Day 1: pre-dose, 2h and 6-8 hours later and Week 2 Day 1: pre-dose, 2h and 6-8 hours later
The accumulation of the 47S precursor ribosomal ribonucleic acid (rRNA), which reflects RNA polymerase I activity analysed by fluorescence in situ hybridization (FISH)
Time frame: Baseline and 8 weeks after treatment
The expression of components of rRNA methylation complex analysed by real time quantitative PCR (RTqPCR)
Time frame: Baseline and 8 weeks after treatment
The levels of circulating anti-fibrillarin (anti-FBL) autoantibody on serum samples by Elisa assays
Time frame: Baseline and 8 weeks after treatment
Levels of expression of fibrillarin assessed by immunohistochemistry (IHC)
Time frame: Baseline and 8 weeks after treatment
Levels of expression of nucleolin assessed by IHC
Time frame: Baseline and 8 weeks after treatment
Levels of expression of protein B23 assessed by IHC
Time frame: Baseline and 8 weeks after treatment
Levels of expression of upstream binding factor (UBF) assessed by IHC
Time frame: Baseline and 8 weeks after treatment
Levels of expression of phosphorylated UBF assessed by IHC
Time frame: Baseline and 8 weeks after treatment
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