Clinical Trials /

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

NCT02730923

Description:

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).

Related Conditions:
  • Endometrial Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: VICTORIA (ET150036)
  • NCT ID: NCT02730923

Conditions

  • Endometrial Carcinoma
  • Metastatic Carcinoma
  • Hormone Receptor Positive Tumor

Interventions

DrugSynonymsArms
AZD2014Arm A: AZD2014 plus anastrozole
AnastrozoleArimidexArm A: AZD2014 plus anastrozole

Purpose

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).

Detailed Description

      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.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A: AZD2014 plus anastrozoleExperimental
  • AZD2014
  • Anastrozole
Arm B: anastrozole aloneActive Comparator
  • Anastrozole

Eligibility Criteria

        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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure: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
Safety Issue:
Description:Severe toxicities defined as Any grade ≥ 4 treatment related toxicity Any grade≥ 3 treatment related toxicity lasting more than 7 days

Secondary Outcome Measures

Measure: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)
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure:Overall survival (OS) defined as the duration of time from start of treatment to time of death.
Time Frame:3 years
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure:Duration of objective response as per RECIST v1.1
Time Frame:Up to 3 years
Safety Issue:
Description:
Measure: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.
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:
Measure:The expression of components of rRNA methylation complex analysed by real time quantitative PCR (RTqPCR)
Time Frame:Baseline and 8 weeks after treatment
Safety Issue:
Description:
Measure:The levels of circulating anti-fibrillarin (anti-FBL) autoantibody on serum samples by Elisa assays
Time Frame:Baseline and 8 weeks after treatment
Safety Issue:
Description:
Measure:Levels of expression of fibrillarin assessed by immunohistochemistry (IHC)
Time Frame:Baseline and 8 weeks after treatment
Safety Issue:
Description:
Measure:Levels of expression of nucleolin assessed by IHC
Time Frame:Baseline and 8 weeks after treatment
Safety Issue:
Description:
Measure:Levels of expression of protein B23 assessed by IHC
Time Frame:Baseline and 8 weeks after treatment
Safety Issue:
Description:
Measure:Levels of expression of upstream binding factor (UBF) assessed by IHC
Time Frame:Baseline and 8 weeks after treatment
Safety Issue:
Description:
Measure:Levels of expression of phosphorylated UBF assessed by IHC
Time Frame:Baseline and 8 weeks after treatment
Safety Issue:
Description:

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Centre Leon Berard

Trial Keywords

  • Clinical Trials, Randomized
  • Clinical Trial, Phase I
  • Clinical Trial, Phase II
  • Multicenter Trials
  • Aromatase Inhibitors
  • mTOR kinase inhibitor

Last Updated

February 22, 2018