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

NCT02730923 | Unknown Phase 1 DMC

• 1 other identifier: VICTORIA (ET150036)
• Study Type: interventional
• Target: 72
• Locations: 1 country
• Sites: 12

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).

Conditions

Endometrial Carcinoma; Metastatic Carcinoma; Hormone Receptor Positive Tumor

Keywords

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

Outcome Measures

Primary Outcomes (2)

• 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

  during the first 8 weeks of follow up

• The 8-week non progression rate using RECIST v1.1 to assess tumor response to treatment

  8 weeks after start of treatment

Secondary Outcomes (15)

• Number of patients with AE graded using CTCAE V4

  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

  up to 3 years

• Overall survival (OS) defined as the duration of time from start of treatment to time of death.

  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)

  Up to 3 years

• Duration of objective response as per RECIST v1.1

  Up to 3 years

Study Arms (2)

Arm A: AZD2014 plus anastrozole

EXPERIMENTAL

Drug: AZD2014; Drug: Anastrozole

Arm B: anastrozole alone

ACTIVE COMPARATOR

Drug: Anastrozole

Interventions

AZD2014 DRUG

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.

Arm A: AZD2014 plus anastrozole

Anastrozole DRUG

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.

Also known as: Arimidex

Arm A: AZD2014 plus anastrozole; Arm B: anastrozole alone

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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:

You may not qualify if:

• 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
• Haemorrhagic or thrombotic stroke, including transient ischemic attack (TIA) or any other CNS bleeding.
• 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

Sponsors & Collaborators

• Centre Leon Berard: lead

Study Sites (12)

ICO - Paul Papin

Angers, France

Location

Institut Sainte Catherine

Avignon, 84918, France

Location

Hôpital Jean Minjoz

Besançon, 25030, France

Location

Institut Bergonié

Bordeaux, 33076, France

Location

Centre Francois Baclesse

Caen, France

Location

GHM Institut Daniel Hollard

Grenoble, 38028, France

Location

Centre Oscar Lambret

Lille, France

Location

Centre Léon Bérard

Lyon, France

Location

Institut régional du Cancer Montpellier (ICM)

Montpellier, 34298, France

Location

Hcl - Chls

Pierre-Bénite, France

Location

ICO - René Gauducheau

Saint-Herblain, France

Location

Institut Gustave Roussy

Villejuif, 94805, France

Location

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Related Links

• National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTC AE)

MeSH Terms

Conditions

Endometrial Neoplasms; Carcinoma

Interventions

vistusertib; Anastrozole

Condition Hierarchy (Ancestors)

Uterine Neoplasms; Genital Neoplasms, Female; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Uterine Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type

Intervention Hierarchy (Ancestors)

Nitriles; Organic Chemicals; Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Pierre-Etienne HEUDEL, MD

  Centre Leon Berard

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 18, 2016
• First Posted: April 7, 2016
• Study Start: April 1, 2016
• Primary Completion: November 1, 2019
• Study Completion: December 1, 2024
• Last Updated: February 13, 2024

Record last verified: 2023-09

Locations

FR (12)