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Trial registered on ANZCTR


Registration number
ACTRN12619000900112
Ethics application status
Approved
Date submitted
23/05/2019
Date registered
27/06/2019
Date last updated
22/02/2023
Date data sharing statement initially provided
27/06/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Atezolizumab Trial in Endometrial cancer.
Scientific title
Phase III Double-Blind Randomized Placebo Controlled Trial of Atezolizumab in Combination with Paclitaxel and Carboplatin in Women with Advanced/Recurrent Endometrial Cancer.
Secondary ID [1] 297111 0
IRFMN-EN-7556
Secondary ID [2] 298265 0
CTC 0246
Secondary ID [3] 298266 0
ANZGOG 1807/2019
Universal Trial Number (UTN)
Trial acronym
AtTEnd
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Endometrial Cancer 312878 0
Condition category
Condition code
Cancer 311370 311370 0 0
Womb (Uterine or endometrial cancer)

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Two out of three participants will randomly receive paclitaxel 175mg/m2 and carboplatin AUC 5 or AUC 6 plus atezolizumab 1200mg administered intravenously every 3 weeks for 6-8 cycles, or until treatment no longer seems to be controlling your cancer.
One out of three participants will randomly receive paclitaxel 175mg/m2 and carboplatin AUC 5 or AUC 6 plus placebo, a substance that has no active medicine in it. Treatment will be administered intravenously every 3 weeks for 6-8 cycles or until treatment no longer seems to be controlling your cancer.
Carboplatin can be administered at the dose of AUC 6 or AUC 5 according to the standard clinical practice at each site.
Intervention code [1] 314512 0
Treatment: Drugs
Comparator / control treatment
The control treatment is paclitaxel and carboplatin plus placebo (histidine
acetate, sucrose and polysorbate 20).
Control group
Placebo

Outcomes
Primary outcome [1] 320099 0
Overall Survival.
Timepoint [1] 320099 0
Time from randomization until the date of death from any cause.
Primary outcome [2] 320100 0
Progression-free Survival assessed using RECIST 1.1 progression criteria.
Timepoint [2] 320100 0
Time from randomization to the first date at which progression criteria are met by RECIST v 1.1 or death from any cause, whichever occurs first. For patients who continue treatment after the first radiological detection of progression, progression should be confirmed at the next assessment 4-8 weeks later according to irRECIST.
Secondary outcome [1] 370531 0
Objective response defined as either complete response (CR) or partial response (PR) as determined by the investigator using RECIST v1.1.
Timepoint [1] 370531 0
Duration of the trial.
Secondary outcome [2] 370532 0
Duration of response
Timepoint [2] 370532 0
Time from the date of first documentation of response (complete response (CR) or partial response (PR), whichever occurs first) to the date of documented progressive disease (PD) or death.
Secondary outcome [3] 370533 0
Second Progression Free Survival (PFS2).
Timepoint [3] 370533 0
Time from randomization to the earliest of the progression event subsequent to that used for the primary variable Progression Free Survival (PFS), or date of death. The date of second progression will be recorded by the investigator and defined according to local standard clinical practice.
Secondary outcome [4] 370534 0
Safety and tolerability assessed for adverse events using MedDRA terms (version 20.0) and graded according to CTCAE version 4.03 (review of medical records).

This will also be assessed using number of deaths, and laboratory data (review of serum assays), vital signs and electrocardiograms, (review of medical records), outside normal ranges.
Timepoint [4] 370534 0
Duration of the trial.
Secondary outcome [5] 370535 0
Composite outcome of health related Quality of Life and Patient Function assessed using EORTC QLQ-C30 and QLQ-EN24 and FACT-G questionnaires.
Timepoint [5] 370535 0
EORTC QLQ-C30 and QLQ-EN24 questionnaires will be completed at cycle 1, 3 and 6 during chemotherapy, then after the end of chemotherapy, at cycle 4 and thereafter every 12 weeks during the maintenance phase until treatment discontinuation.

FACT-G questionnaires will be completed at cycles 3 and 6 during chemotherapy, then after the end of chemotherapy, at cycle 4 and thereafter every 12 weeks during the maintenance phase until treatment discontinuation.

The planned maximum follow up period is 24 months from the completion of the enrollment phase.

Secondary outcome [6] 370536 0
Health economic data (patient utilities) will be assessed using the EQ-5D-5L.
Timepoint [6] 370536 0
EQ-5D-5L questionnaires will be completed at cycle 1, 3 and 6 during chemotherapy, then after the end of chemotherapy, at cycle 4 and thereafter every 12 weeks during the maintenance phase until treatment discontinuation.

The planned maximum follow up period is 24 months from the completion of the enrollment phase.
Secondary outcome [7] 414166 0
To evaluate the pharmacokinetics (PK) of atezolizumab.
The blood samples for PK/ADA analyses will be transferred to identified laboratories for further processing (ICON, 8282 Halsey Road, Whitesboro, NY, USA, 13492; PPD Laboratories, 2244 Dabney Road, Richmond, VA 23230)."
Timepoint [7] 414166 0
Blood samples for PK will be collected from all patients pre-infusion at cycle 1, 2, 4, 8, 16 and at the time of atezolizumab/placebo discontinuation (in most of cases the last blood samples will be collected at the end of treatment visit). The end of treatment visit should be performed up to 30 days after the last study treatment administration. (EOT - disease progression or patient refusal, toxicity, patient withdrawal) An additional PK sample must be collected at 30 (± 10) minutes after atezolizumab/placebo infusion at Cycle 1.
Secondary outcome [8] 414167 0
To determine the prevalence at baseline and the incidence during the study of anti-drug antibodies (ADAs) via blood sample collection.
Timepoint [8] 414167 0
Blood samples ADA and ctDNA will be collected from all patients pre-infusion at cycle 1, 2, 4, 8, 16 and at the time of atezolizumab/placebo discontinuation (in most of cases the last blood samples will be collected at the end of treatment visit). The end of treatment visit should be performed up to 30 days after the last study treatment administration. (EOT - disease progression or patient refusal, toxicity, patient withdrawal)

Eligibility
Key inclusion criteria
1. Newly diagnosed, histologically-confirmed with residual disease after surgery either measurable or evaluable, or inoperable stage III-IV endometrial carcinoma/carcinosarcoma, after diagnostic biopsy, and naïve to first line systemic anti-cancer treatment. Recurrent endometrial cancer patients if not yet treated with a chemotherapy line for recurrent disease. Hormonal treatment (including but not limited to progestins, tamoxifen, luteinizing hormone-releasing hormone agonists, aromatase inhibitors) without chemotherapy is allowed.
2. Eastern Cooperative Oncology Group (ECOG) performance status 0-2.
3. Aged 18 years or older.
4. In recurrent patients, only one prior line of systemic platinum-based regimen is permitted if the platinum-free interval equal to or greater than 6 months. Such prior line is the up-front/adjuvant treatment which can be concurrent chemoradiation or concurrent chemoradiation followed by chemotherapy or only chemotherapy.
5. Patients with history of primary breast cancer may be eligible provided they completed their definitive anticancer treatment more than 3 years ago and they remain breast cancer disease free prior to start of study treatment.
6. Previous pelvic and outside pelvis radiation is allowed, except for whole abdominal radiotherapy, if completed more than 6 weeks ago.
7. Signed informed consent and ability to comply with treatment and follow-up.
8. Representative Formalin-Fixed Paraffin-Embedded tumor sample or, only if unfeasible, at least 20 unstained slides from initial surgery or from diagnostic biopsy, in case surgery was not performed, available and sent to central laboratory for Micro Satellite (MS) determination prior to randomization.
9. Patients must have normal organ and bone marrow function :
a. Haemoglobin equal to or greater than 10.0 g/dL.
b. Absolute neutrophil count (ANC) equal to or greater than 1.5 x 109/L.
c. Platelet count equal to or greater than 100 x 109/L.
d. Total bilirubin less than or equal to 1.5 x institutional upper limit of normal (ULN).
e. Aspartate aminotransferase /Serum Glutamic Oxaloacetic Transaminase (ASAT/SGOT)) and Alanine aminotransferase /Serum Glutamic Pyruvate Transaminase (ALAT/SGPT)) less than or equal to 2.5 x ULN, unless liver metastases are present in which case they must be less than or equal to 5 x ULN.
f. Serum creatinine less than or equal to 1.5 x institutional ULN
Minimum age
18 Years
Maximum age
No limit
Sex
Females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Other malignancy within the last 5 years except: adequately treated non-melanoma skin cancer, curatively treated in situ cancer of the cervix, ductal carcinoma in situ (DCIS) of the breast. Patients with a history of localized malignancy diagnosed over 5 years ago may be eligible provided they completed their adjuvant systemic therapy prior to randomization and that the patient remains free of recurrent or metastatic disease
2. Patients with uterine leiomyosarcoma
3. Major surgery within 4 weeks of starting study treatment or patients who have not completely recovered from the effects of any major surgery
4. Previous allogeneic bone marrow transplant or previous solid organ transplantation
5. Administration of other simultaneous chemotherapy drugs, any other anticancer therapy or anti-neoplastic hormonal therapy, or simultaneous radiotherapy during the trial treatment period (hormonal replacement therapy is permitted).
6. Prior treatment with CD137 agonists or immune checkpoint blockade therapies,
anti-PD1, or anti-PDL1 therapeutic antibodies or anti-CTLA4
7. Treatment with systemic immunostimulatory agents (including but not limited to interferon-alpha (IFN-a) and interleukin-2 (IL-2) within 4 weeks or five half-lives of the drug (whichever is shorter) prior to Cycle 1, Day 1
8. Treatment with systemic corticosteroids or other systemic immunosuppressive medications (including but not limited to prednisone, dexamethasone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor [TNF] agents) within 2 weeks prior to Cycle 1, Day 1, or anticipated requirement for systemic
immunosuppressive medications during the trial. However, please note that the use of inhaled corticosteroids for chronic obstructive pulmonary disease or for asthma is allowed, as well as the use of mineralocorticoids (e.g., fludrocortisones) and low-dose supplemental corticosteroids for adrenocortical insufficiency and for patients with orthostatic hypotension. The use of corticosteroids as premedication for paclitaxel-based regimen is allowed)
9. History of autoimmune disease, including but not limited to myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener’s granulomatosis, Sjögren’s syndrome, GuillainBarré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis [please note: patients with a history of autoimmune hypothyroidism on a stable dose of thyroid replacement hormone are eligible; patients with controlled Type 1 diabetes mellitus on a stable insulin regimen are eligible; history of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, Organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia) is permitted]
10. Immunocompromised patients, e.g. patients who are known to be serologically
positive for human immunodeficiency virus (HIV)
11. Patients with active hepatitis B (defined as having a positive hepatitis B surface antigen [HBsAg] test at screening) or hepatitis C
a. Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined as having a negative HBsAg test and a positive total hepatitis B core antibody [HBcAb]) are eligible only if hepatitis B virus (HBV) DNA is negative. The HBV DNA test will be performed only for patients who have a positive total HBcAb test
b. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA. The HCV RNA test will be performed only for patients who have a positive HCV antibody test
12. Evidence of active tuberculosis
13. Signs or symptoms of infection within 2 weeks prior to Cycle 1, Day 1
14. Administration of a live, attenuated vaccine within 4 weeks prior to Cycle 1, Day 1 or anticipation that such a live attenuated vaccine will be required during the study. Influenza vaccination should be given during influenza season only (example approximately October to March in the Northern Hemisphere). Patients must not receive live, attenuated influenza vaccine.
15. Clinically significant (e.g. active) cardiovascular disease, including:
a. Myocardial infarction or unstable angina within less than or equal to 6 months of randomization,
b. New York Heart Association (NYHA) greater than or equal to grade 2 congestive heart failure (CHF),
c. Poorly controlled cardiac arrhythmia despite medication (patients with rate controlled atrial fibrillation are eligible),
d. Peripheral vascular disease greater than or equal to grade 3 (e.g. symptomatic and interfering with activities of daily living [ADL] requiring repair or revision)
16. Resting ECG with QTc greater than 470 msec on 2 or more time points within a 24 hour period or family history of long QT syndrome
17. History or clinical suspicion of brain metastases or spinal cord compression. CT/MRI
of the brain is mandatory (within 4 weeks prior to randomization) in case of suspected brain metastases. Spinal MRI is mandatory (within 4 weeks prior to randomization) in any case of suspected central nervous system (CNS) involvement
18. History or evidence upon neurological examination of central nervous system (CNS)
disease, unless asymptomatic and adequately treated with standard medical therapy
19. Evidence of any other disease, metabolic dysfunction, physical examination finding
or laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or puts the patient at high risk for treatment related complications
20. Women of childbearing potential (less than 2 years after last menstruation) not willing to use highly-effective means of contraception
21. Pregnant or lactating women
22. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
23. Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary cells or to any component of the atezolizumab formulation
24. Known hypersensitivity reaction or allergy to drugs chemically related to carboplatin, paclitaxel, or their excipients that contraindicates the subject’s participation

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Central randomisation by computer.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Block design randomization procedure
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
Assuming a median OS in the control arm of 18 months (3), this study is designed to detect a HR of 0.70 that corresponds to a survival increase of 7.7 months. With two-sided 4.0% significance level (corrected for two tests to preserve an overall study alpha two-sided of 5%), taking into account one interim analysis, and with at least 83% power, 326 events are needed with a 1:2 randomization ratio. Assuming an accrual length of 24 months and a further follow-up period of 24 months, 496 patients are estimated to be enrolled.

Assuming a median PFS in the control arm of about 10 months (3) and a HR=0.70 (alpha two sided=1.0%; power=80%), 413 events (progression or death) are needed for PFS analysis. Such events will accrue at 24 months of follow-up. Taking into account a 10% of drop-outs, it will be necessary to enroll approximately 550 patients

Recruitment
Recruitment status
Active, not recruiting
Date of first participant enrolment
Anticipated
1/10/2019
Actual
9/09/2020
Date of last participant enrolment
Anticipated
31/07/2022
Actual
30/12/2021
Date of last data collection
Anticipated
31/07/2023
Actual
Sample size
Target
50
Accrual to date
Final
48
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,TAS,VIC
Recruitment hospital [1] 13768 0
Border Medical Oncology - Albury
Recruitment hospital [2] 13770 0
Liverpool Hospital - Liverpool
Recruitment hospital [3] 13771 0
Calvary Mater Newcastle - Waratah
Recruitment hospital [4] 13774 0
Box Hill Hospital - Box Hill
Recruitment hospital [5] 13777 0
Frankston Hospital - Frankston
Recruitment hospital [6] 13778 0
Toowoomba Hospital - Toowoomba
Recruitment hospital [7] 13779 0
Pindara Private Hospital - Benowa
Recruitment hospital [8] 13780 0
Royal Brisbane & Womens Hospital - Herston
Recruitment hospital [9] 13781 0
Icon Cancer Care South Brisbane - South Brisbane
Recruitment hospital [10] 13783 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [11] 13784 0
Royal Hobart Hospital - Hobart
Recruitment hospital [12] 23223 0
Gosford Hospital - Gosford
Recruitment hospital [13] 23224 0
Wollongong Hospital - Wollongong
Recruitment postcode(s) [1] 26518 0
2640 - Albury
Recruitment postcode(s) [2] 26520 0
2170 - Liverpool
Recruitment postcode(s) [3] 26521 0
2298 - Waratah
Recruitment postcode(s) [4] 26524 0
3128 - Box Hill
Recruitment postcode(s) [5] 26527 0
3199 - Frankston
Recruitment postcode(s) [6] 26528 0
4350 - Toowoomba
Recruitment postcode(s) [7] 26529 0
4217 - Benowa
Recruitment postcode(s) [8] 26530 0
4029 - Herston
Recruitment postcode(s) [9] 26531 0
4101 - South Brisbane
Recruitment postcode(s) [10] 26533 0
5000 - Adelaide
Recruitment postcode(s) [11] 26534 0
7000 - Hobart
Recruitment postcode(s) [12] 38591 0
2250 - Gosford
Recruitment postcode(s) [13] 38592 0
2500 - Wollongong
Recruitment outside Australia
Country [1] 21521 0
New Zealand
State/province [1] 21521 0
Auckland
Country [2] 21548 0
Italy
State/province [2] 21548 0
Country [3] 21549 0
Switzerland
State/province [3] 21549 0
Country [4] 21550 0
Germany
State/province [4] 21550 0
Country [5] 21551 0
Japan
State/province [5] 21551 0
Country [6] 21552 0
Austria
State/province [6] 21552 0
Country [7] 21553 0
Spain
State/province [7] 21553 0
Country [8] 21554 0
United Kingdom
State/province [8] 21554 0

Funding & Sponsors
Funding source category [1] 301676 0
Other Collaborative groups
Name [1] 301676 0
MaNGO (Mario Negri Gynecologic Oncology group)
Country [1] 301676 0
Italy
Primary sponsor type
University
Name
The University of Sydney
Address
Camperdown NSW 2006
Country
Australia
Secondary sponsor category [1] 302760 0
None
Name [1] 302760 0
Address [1] 302760 0
Country [1] 302760 0
Other collaborator category [1] 280708 0
Other Collaborative groups
Name [1] 280708 0
MaNGO (Mario Negri Gynecologic Oncology group)
Address [1] 280708 0
Istituto di Ricerche Farmacologiche “Mario Negri”
Via La Masa 19, Milano
Italy
Europe
Country [1] 280708 0
Italy
Other collaborator category [2] 280709 0
Other Collaborative groups
Name [2] 280709 0
ANZGOG Australia New Zealand Gynaecological Oncology Group
Address [2] 280709 0
Level 6, Chris O’Brien Lifehouse
119-143 Missenden Road, CAMPERDOWN NSW 2050
Country [2] 280709 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 302395 0
Sydney Local Health District; Sydney Local Health District Ethics Review Committee (RPAH Zone)
Ethics committee address [1] 302395 0
Ethics committee country [1] 302395 0
Australia
Date submitted for ethics approval [1] 302395 0
18/03/2019
Approval date [1] 302395 0
10/04/2019
Ethics approval number [1] 302395 0
X19-0094

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 90090 0
Dr Yoland Antill
Address 90090 0
c/o Attend Trial
NHMRC Clinical Trials Centre
Locked Bag 77
Camperdown
NSW 1450
Country 90090 0
Australia
Phone 90090 0
+61 2 9562 5000
Fax 90090 0
Email 90090 0
attend@ctc.usyd.edu.au
Contact person for public queries
Name 90091 0
Katrina Dimante
Address 90091 0
c/o Attend Trial
NHMRC Clinical Trials Centre
Locked Bag 77
Camperdown
NSW 1450
Country 90091 0
Australia
Phone 90091 0
+61 2 9562 5000
Fax 90091 0
Email 90091 0
attend@ctc.usyd.edu.au
Contact person for scientific queries
Name 90092 0
Yoland Antill
Address 90092 0
c/o Attend Trial
NHMRC Clinical Trials Centre
Locked Bag 77
Camperdown
NSW 1450
Country 90092 0
Australia
Phone 90092 0
+61 2 9562 5000
Fax 90092 0
Email 90092 0
attend@ctc.usyd.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Please contact the CTC for publication and data sharing SOP


What supporting documents are/will be available?

No Supporting Document Provided


Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.