Clinical trial NCT03603184: Atezolizumab Trial in Endometrial Cancer - AtTEnd
Official title: Phase III Double-blind Randomized Placebo Controlled Trial of Atezolizumab in Combination With Paclitaxel and Carboplatin in Women With Advanced/Recurrent Endometrial Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Endometrial Cancer
Keywords: endometrial cancer
neoplasm
immunotherapy
Lead sponsor: Mario Negri Institute for Pharmacological Research
Sponsor class: OTHER
Collaborators: name: Hoffmann-La Roche
First posted: 2018-07-27
Enrollment: 549
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Atezolizumab is an engineered humanised monoclonal immunoglobulin G1 antibody that binds selectively to PD-L1 and prevents its interaction with PD-1 and B7-1.

In May 2016 atezolizumab was approved by the FDA for patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following any platinum-containing chemotherapy, or within 12 months of receiving chemotherapy before surgery (neoadjuvant) or after surgery (adjuvant); in October 2016 it was approved by the FDA for patients with metastatic non-small cell lung cancer (NSCLC) who have disease progression during or following platinum-containing chemotherapy, and have progressed on an appropriate FDA-approved targeted therapy if their tumor has EGFR or ALK gene abnormalities. Finally, in April 2017 atezolizumab was granted accelerated approval by FDA for the first-line treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin chemotherapy. Combinations of atezolizumab with chemotherapeutic agents and/or targeted therapies were studied in different solid tumors such as melanoma, NSCLC, renal cell carcinoma and colorectal carcinoma. From these studies the AE profile of atezolizumab combinations were consistent with that of the individual agents.

Finally, preliminary results of a Phase Ia study of Atezolizumab (NCT01375842) monotherapy in relapsed endometrial cancer were reported as abstract at ASCO 2017. Fifteen patients were evaluated for safety and efficacy with a minimum follow-up of 11.2 months. No G4-5 related AEs occurred. Regarding efficacy ORR was 13% \[2/15\] by RECIST. Atezolizumab seemed to have a favorable safety profile, with durable clinical benefit in some patients. Further studies with atezolizumab are warranted given its promising results in advanced endometrial cancer and the limited efficacy of current treatment options.


Eligibility criteria: Inclusion Criteria:

I-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 for recurrent disease.

I-2. Eastern Cooperative Oncology Group (ECOG) performance status 0-2 I-3. Age ≥ 18 years I-4. Only one prior line of systemic platinum-based regimen is permitted if the platinum-free interval ≥ 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.

I-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.

I-6. Previous pelvic and outside pelvis radiation is allowed if completed more than 6 weeks ago.

I-7. Signed informed consent and ability to comply with treatment and follow-up.

I-8. Representative FFPE 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.

I-9. Patients must have normal organ and bone marrow function :

1. Haemoglobin ≥ 10.0 g/dL.
2. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L.
3. Platelet count ≥ 100 x 109/L.
4. Total bilirubin ≤ 1.5 x institutional upper limit of normal (ULN).
5. Aspartate aminotransferase /Serum Glutamic Oxaloacetic Transaminase (ASAT/SGOT)) and Alanine aminotransferase /Serum Glutamic Pyruvate Transaminase (ALAT/SGPT)) ≤ 2.5 x ULN, unless liver metastases are present in which case they must be ≤ 5 x ULN.
6. Serum creatinine ≤ 1.5 x institutional ULN

Exclusion Criteria:

E-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.

E-2. Patients with uterine leiomyosarcoma . E-3. Major surgery within 4 weeks of starting study treatment or patients who have not completely recovered from the effects of any major surgery.

E-4. Previous allogeneic bone marrow transplant or previous solid organ transplantation.

E-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).

E-6. Prior treatment with CD137 agonists or immune checkpoint blockade therapies, anti-PD1, or anti-PDL1 therapeutic antibodies or anti-CTLA4 .

E-7. Treatment with systemic immunostimulatory agents (including but not limited to interferon-alpha (IFN-α) and interleukin-2 (IL-2) within 4 weeks or five half-lives of the drug (whichever is shorter) prior to Cycle 1, Day 1.

E-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).

E-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 anti-phospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis \[please note: patients with a history of autoimmune hypothyroidism on a stable dose of thyroid replacement hormone are eligible; patients with controlled Type 1 diabetes mellitus on a stable insulin regimen are eligible; history of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia) is permitted\].

E-10. Immunocompromised patients, e.g., patients who are known to be serologically positive for human immunodeficiency virus (HIV).

E-11. Patients with active hepatitis B (defined as having a positive hepatitis B surface antigen \[HBsAg\] test at screening) or hepatitis C .

1. 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.
2. 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.

E-12. Active tuberculosis (all patients will have tuberculin \[PPD\] skin test or Interferon-Gamma Releasing Assay \[IGRA\] done locally prior to inclusion to study) E-13. Signs or symptoms of infection within 2 weeks prior to Cycle 1, Day 1 E-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.

E-15. Clinically significant (e.g. active) cardiovascular disease, including:

1. Myocardial infarction or unstable angina within ≤ 6 months of randomization,
2. New York Heart Association (NYHA) ≥ grade 2 congestive heart failure (CHF),
3. Poorly controlled cardiac arrhythmia despite medication (patients with rate controlled atrial fibrillation are eligible),
4. Peripheral vascular disease grade ≥ 3 (e.g. symptomatic and interfering with activities of daily living \[ADL\] requiring repair or revision) E-16. Resting ECG with QTc \> 470 msec on 2 or more time points within a 24 hour period or family history of long QT syndrome.

E-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 .

E-18. History or evidence upon neurological examination of central nervous system (CNS) disease, unless asymptomatic and adequately treated with standard medical therapy.

E-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.

E-20. Women of childbearing potential (\<2 years after last menstruation) not willing to use highly-effective means of contraception.

E-21. Pregnant or lactating women. E-22. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins.

E-23. Known hypersensitivity or allergy to biopharmaceuticals produced in Chinese hamster ovary cells or to any component of the atezolizumab formulation.

E-24. Known hypersensitivity reaction or allergy to drugs chemically related to carboplatin, paclitaxel, or their excipients that contraindicates the subject's participation

Primary outcomes:
measure: PFS in the MSI
timeFrame: Up to 18 months after the last patient enrolled
measure: PFS
timeFrame: Up to 18 months after the last patient enrolled
measure: OS
timeFrame: Up to two years after the last patient enrolled
Secondary outcomes:
measure: Objective response rate
timeFrame: Up to three years after the last patient enrolled
measure: Duration of response
timeFrame: Up to two years after the last patient enrolled
measure: Safety: Maximum toxicity grade
timeFrame: Up to 30 days after the end of treatment
measure: Safety: Number of patients experiencing grade 3-4 toxicity for each toxicity
timeFrame: Up to 30 days after the end of treatment
measure: Safety: Type, frequency and nature of SAEs
timeFrame: Up to 30 days after the end of treatment
measure: Safety: Number of patients with at least a SAE
timeFrame: Up to 30 days after the end of treatment
measure: Safety: Number of patients with at least a SADR
timeFrame: Up to two years after the last patient enrolled
measure: Safety: Number of patients with at least a SUSAR
timeFrame: Up to two years after the last patient enrolled
measure: Quality of life: EORTC QLQ-C30 questionnaire
timeFrame: Up to two years after the last patient enrolled
measure: Quality of life: QLQ-EN24 questionnaire
timeFrame: Up to two years after the last patient enrolled
measure: Quality of life: GP5 item
timeFrame: Up to two years after the last patient enrolled
measure: Compliance: Number of administered cycles
timeFrame: Up to two year after the last patient enrolled
measure: Compliance: Reasons for discontinuation and treatment modification
timeFrame: Up to two year after the last patient enrolled
measure: Compliance: Dose intensity
timeFrame: Up to two year after the last patient enrolled
Other outcomes:
Locations:
city: Adelaide
country: Australia
facility: Royal Adelaide hospital
city: Albury
country: Australia
facility: Border Medical Oncology Research Unit
city: Auchenflower
country: Australia
facility: Icon Cancer Centre
city: Benowa
country: Australia
facility: Pindara Private Hospital
city: Box Hill
country: Australia
facility: Box Hill Hospital
city: Frankston
country: Australia
facility: Frankston Hospital
city: Gosford
country: Australia
facility: Gosford Hospital
city: Herston
country: Australia
facility: Royal Brisbane and Women's Hospital
city: Hobart
country: Australia
facility: Royal Hobart Hospital
city: Liverpool
country: Australia
facility: Liverpool Hospital
city: Saint Leonards
country: Australia
facility: Northern Cancer Institute
city: Toowoomba
country: Australia
facility: Darling Downs Hospital and Health Service - Toowoomba Hospital
city: Waratah
country: Australia
facility: Calvary Mater Newcastle
city: Wollongong
country: Australia
facility: Wollongong Hospital
city: Graz
country: Austria
facility: Medizinische Universitaet Graz - Universitätsklinik für Frauenheilkunde und Geburtshilfe
city: Innsbruck
country: Austria
facility: Medical University of Innsbruck
city: Berlin
country: Germany
facility: Charité Universitätsmedizin Berlin
city: Essen
country: Germany
facility: Kliniken Essen Mitte
city: Mannheim
country: Germany
facility: UniversitätsKlinikum Heidelberg
city: Muenchen
country: Germany
facility: Klinikum der Ludwig-Maximilians-Universität München (LMU)
city: Alessandria
country: Italy
facility: AO SS Antonio e Biagio e Cesare Arrigo
city: Bologna
country: Italy
facility: Policlinico S. Orsola Malpighi
city: Bolzano
country: Italy
facility: Azienda Sanitaria dell'Alto Adige
city: Brescia
country: Italy
facility: ASST degli Spedali Civili di Brescia
city: Brescia
country: Italy
facility: Fondazione Poliambulanza
city: Cagliari
country: Italy
facility: AOU Cagliari, Policlinico Universitario
city: Firenze
country: Italy
facility: AOU Careggi
city: Lecco
country: Italy
facility: ASST di Lecco
city: Lucca
country: Italy
facility: Ospedale San Luca
city: Milan
country: Italy
facility: Istituto Europeo di Oncologia
city: Monza
country: Italy
facility: Ospedale San Gerardo
city: Padova
country: Italy
facility: Istituto Oncologico Veneto (IOV)
city: Parma
country: Italy
facility: AOU di Parma
city: Pisa
country: Italy
facility: AOU Pisana
city: Reggio Emilia
country: Italy
facility: AO Arcispedale Santa Maria Nuova
city: Rimini
country: Italy
facility: Ausl Romagna
city: Roma
country: Italy
facility: Policlinico Umberto I, Università di Roma "La Sapienza"
city: Sondrio
country: Italy
facility: Ospedale di Sondrio ASST Valtellina e Alto Lario
city: Sora
country: Italy
facility: Ospedale SS Trinità
city: Torino
country: Italy
facility: AO Ordine Mauriziano
city: Torino
country: Italy
facility: AOU Città della Salute e della Scienza di Torino - Ospedale Sant'Anna
city: Vercelli
country: Italy
facility: P.O Sant'Andrea Vercelli
city: Aomori
country: Japan
facility: Hirosaki University Hospital
city: Chiba
country: Japan
facility: National Cancer Center Hospital East
city: Ehime
country: Japan
facility: Shikoku Cancer Center
city: Fukuoka
country: Japan
facility: Kurume University Hospital
city: Hokkaido
country: Japan
facility: Hokkaido University Hospital
city: Miyagi
country: Japan
facility: Tohoku University Hospital
city: Niigata
country: Japan
facility: Niigata University Medical＆Dental Hospital
city: Osaka
country: Japan
facility: Osaka University Hospital
city: Shizuoka
country: Japan
facility: Shizuoka Cancer Center
city: Tokyo
country: Japan
facility: Keio University Hospital
city: Daegu
country: Korea, Republic of
facility: Keimyung University Dongsan Medical Center
city: Gyeonggi-do
country: Korea, Republic of
facility: Ilsan Cha Medical Center
city: Gyeonggi-do
country: Korea, Republic of
facility: Seoul National University Bundang Hospital
city: Incheon
country: Korea, Republic of
facility: Gachon University Gil Medical Center
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Seoul
country: Korea, Republic of
facility: Gangnam Severance Hospital
city: Seoul
country: Korea, Republic of
facility: Konkuk University Medical Center
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Seoul
country: Korea, Republic of
facility: Seoul St. Mary's Hospital
city: Seoul
country: Korea, Republic of
facility: Severance Hospital
city: Auckland
country: New Zealand
facility: Auckland city Hospital
city: Barcelona
country: Spain
facility: Hospital De Sant Pau I La Santa Creu
city: Barcelona
country: Spain
facility: Hospital Universitario Vall d´Hebron Institute of Oncology (VHIO)
city: Girona
country: Spain
facility: Institut Català d'Oncologia (ICO) Girona
city: Hospitalet de Llobregat
country: Spain
facility: Institut Català d'Oncologia (ICO), L'Hospitalet- Hospital Duran I Reynals
city: Madrid
country: Spain
facility: Hospital 12 de Octubre
city: Madrid
country: Spain
facility: Hospital Universitario La Paz
city: Madrid
country: Spain
facility: MD Anderson Cancer Center
city: Oviedo
country: Spain
facility: Hospital Universitario Central de Asturias
city: Santiago De Compostela
country: Spain
facility: Hospital Clínico Universitario Santiago de Compostela
city: Zaragoza
country: Spain
facility: Hospital Universitario Miguel Servet Zaragoza
city: Baden
country: Switzerland
facility: Kantonsspital
city: Basel
country: Switzerland
facility: Universitätsspital
city: Bellinzona
country: Switzerland
facility: IOSI
city: Bern
country: Switzerland
facility: Inselspital
city: Luzern
country: Switzerland
facility: Kantonsspital
city: Münsterlingen
country: Switzerland
facility: Frauenfeld
city: Winterthur
country: Switzerland
facility: Kantonsspital
city: Zürich
country: Switzerland
facility: Universitätsspital
city: Kaohsiung City
country: Taiwan
facility: Chang Gung Memorial Hospital-Kaohsiung
city: Taoyuan City
country: Taiwan
facility: Chang Gung Memorial Hospital-Linkou
city: Derby
country: United Kingdom
facility: Royal Derby Hospital
city: Exeter
country: United Kingdom
facility: Royal Devon & Exeter Hospital
city: Glasgow
country: United Kingdom
facility: Beatson West of Scotland Cancer Centre, Gartnavel General Hospital
city: Glasgow
country: United Kingdom
facility: Velindre Cancer Centre
city: London
country: United Kingdom
facility: Imperial College Healthcare NHS Trust
city: London
country: United Kingdom
facility: Royal Marsden Hospital
city: London
country: United Kingdom
facility: St Bartholomew's Hospital
city: Manchester
country: United Kingdom
facility: The Christie NHS Foundation Trust
city: Nottingham
country: United Kingdom
facility: NUHT - Nottingham University Hospital NHS Trust
city: Plymouth
country: United Kingdom
facility: Derriford Hospital
Study officials:
affiliation: Istituto Europeo di Oncologia (IEO) - Milan
name: Nicoletta Colombo, MD
role: PRINCIPAL_INVESTIGATOR
References: