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Hormone Receptor Positive endometrIal Carcinoma Treated by Dual mTORC1/mTORC2 Inhibitor and Anastrozole (VICTORIA) (VICTORIA)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT02730923
Recruitment Status : Active, not recruiting
First Posted : April 7, 2016
Last Update Posted : February 4, 2021
Information provided by (Responsible Party):
Centre Leon Berard

Brief Summary:

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).

Condition or disease Intervention/treatment Phase
Endometrial Carcinoma Metastatic Carcinoma Hormone Receptor Positive Tumor Drug: AZD2014 Drug: Anastrozole Phase 1 Phase 2

Detailed Description:


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.


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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 72 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Multicentric, Randomized, Non Comparative, Open-label Phase I/II Evaluating AZD2014 (Dual Mammalian Target of Rapamycin Complex 1/2 (mTORC1/mTORC2) Inhibitor) in Combination With Anastrozole Versus Anastrozole Alone in the Treatment of Metastatic Hormone Receptor-positive Endometrial Adenocarcinoma
Actual Study Start Date : April 2016
Actual Primary Completion Date : November 2019
Estimated Study Completion Date : October 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Hormones
Drug Information available for: Anastrozole

Arm Intervention/treatment
Experimental: Arm A: AZD2014 plus anastrozole Drug: AZD2014

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.

Drug: Anastrozole

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.

Other Name: Arimidex

Active Comparator: Arm B: anastrozole alone Drug: Anastrozole

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.

Other Name: Arimidex

Primary Outcome Measures :
  1. 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 [ Time Frame: during the first 8 weeks of follow up ]

    Severe toxicities defined as

    • Any grade ≥ 4 treatment related toxicity
    • Any grade≥ 3 treatment related toxicity lasting more than 7 days

  2. The 8-week non progression rate using RECIST v1.1 to assess tumor response to treatment [ Time Frame: 8 weeks after start of treatment ]

Secondary Outcome Measures :
  1. 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) ]
  2. 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 ]
  3. Overall survival (OS) defined as the duration of time from start of treatment to time of death. [ Time Frame: 3 years ]
  4. 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 ]
  5. Duration of objective response as per RECIST v1.1 [ Time Frame: Up to 3 years ]
  6. 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. ]
  7. 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 ]
  8. 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 ]
  9. The expression of components of rRNA methylation complex analysed by real time quantitative PCR (RTqPCR) [ Time Frame: Baseline and 8 weeks after treatment ]
  10. The levels of circulating anti-fibrillarin (anti-FBL) autoantibody on serum samples by Elisa assays [ Time Frame: Baseline and 8 weeks after treatment ]
  11. Levels of expression of fibrillarin assessed by immunohistochemistry (IHC) [ Time Frame: Baseline and 8 weeks after treatment ]
  12. Levels of expression of nucleolin assessed by IHC [ Time Frame: Baseline and 8 weeks after treatment ]
  13. Levels of expression of protein B23 assessed by IHC [ Time Frame: Baseline and 8 weeks after treatment ]
  14. Levels of expression of upstream binding factor (UBF) assessed by IHC [ Time Frame: Baseline and 8 weeks after treatment ]
  15. Levels of expression of phosphorylated UBF assessed by IHC [ Time Frame: Baseline and 8 weeks after treatment ]

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Postmenopausal female patient at the time of consent
  • Histologically-confirmed diagnosis of advanced or recurrent endometrial carcinoma, not amenable to curative treatments. Carcinosarcoma are not eligible.
  • Documented estrogen receptor and/or progesterone receptor positive endometrial cancer. Hormone receptor positivity is defined according to routine practice at each participating site.
  • Availability of a pre-treatment tumor sample (archival formalin-fixed paraffin-embedded (FFPE) block or fresh biopsy if feasible) and presence of at least one biopsiable tumor lesion for on-treatment biopsy
  • Documented disease progression after no more than one prior first-line chemotherapy regimen and/or more than 2 lines endocrine therapy in the metastatic setting
  • Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) 0 or 1 and minimum life expectancy of 8 weeks
  • At least one measurable lesion according to response evaluation criteria in solid tumor (RECIST 1.1)
  • Adequate bone marrow, renal and liver function as shown by:

    • Absolute neutrophil count > 1.5 x 109/L, Platelets > 100 x 109/L, Hemoglobin (Hb) >9 g/dL
    • Serum bilirubin ≤ 1.5 upper limit of normal (ULN), alanine aminotransferase and aspartate aminotransferase ≤ 2.5 ULN (≤ 5 ULN in patients with liver metastases)
    • Creatinine clearance > 50 mL/min (using Cockcroft formula, or MDRD formula for patients over 65 years Appendix 3 - Creatinine Clearance)
  • Fasting serum cholesterol ≤ 300 mg/dL (7.75 mmol/L) AND fasting triglycerides ≤ 2.5 ULN (lipid-lowering drugs allowed),
  • Fasting plasma glucose ≤7 mmol/L (126 mg/dL)
  • Recovered from prior significant treatment-related toxicity i.e. no persistent treatment-related toxicity > Grade 1 as per Common Terminology Criteria for Adverse Events (CTCAE) v4.3, except grade 2 alopecia, grade 2 anemia but with Hb >9 g/dL.
  • Minimal wash-out period before the start of the study drugs for the following treatments:

    • Any anti-cancer treatment approved or investigational medicinal product :> 21 days
    • Any chemotherapy, radiation therapy, androgens : > 21 days (not including palliative radiotherapy at focal sites).
    • Any monoclonal antibody therapy: > 4 weeks
    • Major surgery: > 4 weeks
    • Minor surgery (excluding tumour biopsies) >14 days.
    • Any haemopoietic growth factors (e.g., filgrastim [granulocyte colony-stimulating factor (G-CSF)], sargramostim [granulocyte-macrophage colony-stimulating factor (GM-CSF)]): > 14 days
    • Vaccinated with live, attenuated vaccines : > 4 weeks.
    • Sensitive or narrow therapeutic range substrates of the drug metabolising organic anion-transporting polypeptide 1B1 (OATP1B1), organic anion-transporting polypeptide 1B3 (OATP1B3), MATE1 and MATE2K : see the appropriate wash-out period (a minimum of 5 x reported elimination half-life) in Appendix 5 - Restricted CYP and transporter related co-medications)
  • Potent or moderate inhibitors or inducers of CYP3A4/5, Pgp (MDR1) and BCRP - Restricted CYP and transporter related co-medications
  • Patient willing to follow sunlight-protection measures. Patients should be advised of the need for sunlight protection measures during administration of AZD2014, and should be advised to adopt such measures for a period of 3 months after receiving their final dose of AZD2014.
  • Patient able and willing to provide informed consent with ability to understand and willingness for follow-up visits.
  • Covered by a medical insurance

Exclusion Criteria:

  • Patient pre-treated by a non-steroidal aromatase inhibitor
  • Active uncontrolled or symptomatic central nervous system metastases or spinal cord compression
  • Clinically relevant abnormal levels of potassium or sodium.
  • Use of any forbidden concomitant treatment during the treatment period:

    • Any anti-cancer treatment (approved or investigational) not mentioned in the protocol
    • Chronic treatment with corticosteroids or other immunosuppressive agents. Stable low dose of corticosteroids are allowed (unless contra-indicated) provided that they were initiated before the last disease progression or were started at least 4 weeks prior to study treatment. Topical or inhaled corticosteroids are allowed.
    • Potent or moderate inhibitors or inducers of CYP3A4/5, Pgp (MDR1) and BCRP (see Appendix 5 - Restricted CYP and transporter related co-medications)
    • Sensitive or narrow therapeutic range substrates of the drug transporters OATP1B1, OATP1B3, MATE1 and MATE2K outside the wash out period and restrictions presented in Appendix 5 - Restricted CYP and transporter related co-medications)
  • Patient with known hypersensitivity to anastrozole or to any of the excipients (Lactose monohydrate, Povidone, Sodium starch glycollate, Magnesium stearate, Hypromellose, Macrogol 300, Titanium dioxide)
  • History of hypersensitivity to active or inactive excipients of AZD2014 or drugs with a similar chemical structure or class to AZD2014
  • History of other malignancies except for basal cell or squamous cell skin cancer, in situ cervical cancer, unless they have been disease-free for at least five years
  • Patient who has any severe and/or uncontrolled medical conditions such as:

    • Recent history of specific cardiovascular events, or laboratory parameters that may affect cardiac parameters including : unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction ≤6 months prior to start of study drug, serious uncontrolled cardiac arrhythmia, or any other clinically significant cardiac disease; Symptomatic congestive heart failure of New York heart Association Class III or IV
    • Mean resting corrected QT interval (QTc), calculated using Fridericia's formula, > 470 msec obtained from 3 electrocardiograms (ECGs), family or personal history of long or short QT syndrome, Brugada syndrome or known history of QTc prolongation or Torsade de Pointes within 12 months of the patient entering in the study
    • Abnormal cardiac function at baseline :left ventricular ejection fraction (LVEF) <50%
    • Any evidence of interstitial lung disease and uncompensated respiratory conditions.
    • Active (acute or chronic) or uncontrolled severe infection, liver disease such as cirrhosis, decompensated liver disease, and active or chronic hepatitis (i.e. quantifiable hepatitis B virus (HBV-DNA) and/or positive HbsAg, quantifiable hepatitis C virus (HCV-RNA)),
    • Active, bleeding diathesis
    • Current refractory nausea and vomiting, chronic gastro-intestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of AZD2014.
    • Rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption
    • Type 1 and uncontrolled Type 2 diabetes
    • Pre-existing renal disease including glomerulonephritis, nephritic syndrome, Fanconi Syndrome or renal tubular acidosis.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02730923

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ICO - Paul Papin
Angers, France
Institut Sainte Catherine
Avignon, France, 84918
Hôpital Jean Minjoz
Besançon, France, 25030
Institut Bergonié
Bordeaux, France, 33076
Centre Francois Baclesse
Caen, France
GHM Institut Daniel Hollard
Grenoble, France, 38028
Centre Oscar Lambret
Lille, France
Centre Léon Bérard
Lyon, France
Institut régional du Cancer Montpellier (ICM)
Montpellier, France, 34298
Hcl - Chls
Pierre-benite, France
ICO - René Gauducheau
Saint-Herblain, France
Institut Gustave Roussy
Villejuif, France, 94805
Sponsors and Collaborators
Centre Leon Berard
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Principal Investigator: Pierre-Etienne HEUDEL, MD Centre Leon Berard
Additional Information:
Setiawan VW, Yang HP, Pike MC, McCann SE, Yu H, Xiang YB, Wolk A, Wentzensen N, Weiss NS, Webb PM, van den Brandt PA, van de Vijver K, Thompson PJ; Australian National Endometrial Cancer Study Group, Strom BL, Spurdle AB, Soslow RA, Shu XO, Schairer C, Sacerdote C, Rohan TE, Robien K, Risch HA, Ricceri F, Rebbeck TR, Rastogi R, Prescott J, Polidoro S, Park Y, Olson SH, Moysich KB, Miller AB, McCullough ML, Matsuno RK, Magliocco AM, Lurie G, Lu L, Lissowska J, Liang X, Lacey JV Jr, Kolonel LN, Henderson BE, Hankinson SE, Håkansson N, Goodman MT, Gaudet MM, Garcia-Closas M, Friedenreich CM, Freudenheim JL, Doherty J, De Vivo I, Courneya KS, Cook LS, Chen C, Cerhan JR, Cai H, Brinton LA, Bernstein L, Anderson KE, Anton-Culver H, Schouten LJ, Horn-Ross PL. Type I and II endometrial cancers: have they different risk factors? J Clin Oncol. 2013 Jul 10;31(20):2607-18. doi: 10.1200/JCO.2012.48.2596. Epub 2013 Jun 3. Review.

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Responsible Party: Centre Leon Berard Identifier: NCT02730923    
Other Study ID Numbers: VICTORIA (ET150036)
First Posted: April 7, 2016    Key Record Dates
Last Update Posted: February 4, 2021
Last Verified: February 2021
Keywords provided by Centre Leon Berard:
Clinical Trials, Randomized
Clinical Trial, Phase I
Clinical Trial, Phase II
Multicenter Trials
Aromatase Inhibitors
mTOR kinase inhibitor
Additional relevant MeSH terms:
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Endometrial Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Uterine Neoplasms
Genital Neoplasms, Female
Urogenital Neoplasms
Neoplasms by Site
Uterine Diseases
Antineoplastic Agents, Hormonal
Antineoplastic Agents
Aromatase Inhibitors
Steroid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Estrogen Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs