Atezolizumab Trial in Endometrial Cancer - AtTEnd

• Sponsor: Mario Negri Institute for Pharmacological Research (Other)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT03603184
• Collaborator: Hoffmann-La Roche (Industry)
• Enrollment: 550
• Locations: 97
• Arms: 2
• Anticipated Duration (Months): 62
• Patients Per Site: 5.7
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Endometrial Cancer	Drug: Atezolizumab; Drug: Placebos; Drug: Paclitaxel; Drug: Carboplatin	Phase 3

Study Design

• Study Type: Interventional
• Anticipated Enrollment: 550 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: Oct 2, 2018
• Anticipated Primary Completion Date: Jul 1, 2022
• Anticipated Study Completion Date: Dec 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Experimental arm paclitaxel 175 mg/m2 + carboplatin AUC 5 or 6 will be administered every 21 days for 6-8 cycles or PD. Atezolizumab will be administered as I.V. infusion at a fixed dose of 1200 mg, every 21 days until objective radiological disease progression as assessed by the investigator if they do not meet any other discontinuation criteria (patient refusal, toxicity). Patients who are clinically stable at initial RECIST v 1.1 - defined progression - should continue on treatment until the next imaging assessment that should be ≥4 weeks and no longer than 8 weeks later.	Drug: Atezolizumab; Atezolizumab will be administered as I.V. infusion at a fixed dose of 1200 mg, every 21 days until objective radiological disease progression as assessed by the investigator if they do not meet any other discontinuation criteria (patient refusal, toxicity).; Other Names: Tecentriq ; Drug: Paclitaxel; Paclitaxel 175 mg/m2 will be administered every 21 days for 6-8 cycles or until progression of disease.; Drug: Carboplatin; Carboplatin AUC 5 or AUC 6 will be administered every 21 days for 6-8 cycles or until progression of disease.
Placebo Comparator: Control arm paclitaxel 175 mg/m2 + carboplatin AUC 5 or AUC 6 will be administered every 21 days for 6-8 cycles or PD. Placebo will be administered as I.V. infusion every 21 days until objective radiological disease progression as assessed by the investigator if they do not meet any other discontinuation criteria (patient refusal, toxicity). Patients who are clinically stable at initial RECIST v 1.1 - defined progression - should continue on treatment until the next imaging assessment that should be ≥4 weeks and no longer than 8 weeks later.	Drug: Placebos; Placebo will be administered as I.V. infusion every 21 days until objective radiological disease progression as assessed by the investigator if they do not meet any other discontinuation criteria (patient refusal, toxicity).; Drug: Paclitaxel; Paclitaxel 175 mg/m2 will be administered every 21 days for 6-8 cycles or until progression of disease.; Drug: Carboplatin; Carboplatin AUC 5 or AUC 6 will be administered every 21 days for 6-8 cycles or until progression of disease.

Outcome Measures

Primary Outcome Measures

1. OS [Up to two years after the last patient enrolled]

   OS is defined as the time from randomization until the date of death from any cause.

2. PFS [Up to two years after the last patient enrolled]

   PFS is defined as the time from randomization to the date of first progression or death from any cause, whichever comes first. Progression will be established as the radiological disease progression according to RECIST 1.1 or death from any cause, whichever occurs first.

Secondary Outcome Measures

1. Objective response rate [Up to two years after the last patient enrolled]

   Objective Response Rate (ORR), defined as the percentage of patients with an objective response as determined by RECIST 1.1

2. Duration of response [Up to two years after the last patient enrolled]

   Duration of response, defined as the time from the date of first documentation of response (complete response (CR) or partial response (PR), whichever occurs first) to the date of documented PD or death

3. Safety: Maximum toxicity grade [Up to 30 days after the end of treatment]

   Maximum toxicity grade experienced by each patient, for each toxicity, according to NCI-CTCAE v. 4.03

4. Safety: Number of patients experiencing grade 3-4 toxicity for each toxicity [Up to 30 days after the end of treatment]

   Number of patients experiencing grade 3-4 toxicity for each toxicity according to NCI-CTCAE v. 4.03

5. Safety: Type, frequency and nature of SAEs [Up to 30 days after the end of treatment]

   Type, frequency and nature of SAEs, according to NCI-CTCAE v. 4.03

6. Safety: Number of patients with at least a SAE [Up to 30 days after the end of treatment]

   Number of patients with at least a SAE according to NCI-CTCAE v. 4.03

7. Safety: Number of patients with at least a SADR [Up to two years after the last patient enrolled]

   Number of patients with at least a SADR, according to NCI-CTCAE v. 4.03

8. Safety: Number of patients with at least a SUSAR [Up to two years after the last patient enrolled]

   Number of patients with at least a SUSAR, according to NCI-CTCAE v. 4.03

9. Quality of life: EORTC QLQ-C30 questionnaire [Up to two years after the last patient enrolled]

   Mean changes from the baseline scores in quality of life by cycle and between treatment arms.

10. Quality of life: QLQ-EN24 questionnaire [Up to two years after the last patient enrolled]

    Mean changes from the baseline score in quality of life by cycle and between treatment arms.

11. Quality of life: GP5 item [Up to two years after the last patient enrolled]

    Proportion of patients reporting each response option at each assessment timepoint by treatment arm for item GP5 from the FACT G instrument.

12. Compliance: Number of administered cycles [Up to two year after the last patient enrolled]

    Number of administered cycles

13. Compliance: Reasons for discontinuation and treatment modification [Up to two year after the last patient enrolled]

    Number of patients for each reasons

14. Compliance: Dose intensity [Up to two year after the last patient enrolled]

    Entire dose administered during treatment

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Royal Adelaide hospital	Adelaide		Australia
2	Border Medical Oncology Research Unit	Albury		Australia
3	Pindara Private Hospital	Benowa		Australia
4	Box Hill Hospital	Box Hill		Australia
5	Frankston Hospital	Frankston		Australia
6	Gosford Hospital	Gosford		Australia
7	Royal Brisbane and Women's Hospital	Herston		Australia
8	Royal Hobart Hospital	Hobart		Australia
9	Liverpool Hospital	Liverpool		Australia
10	Icon Cancer Centre	Queensland		Australia
11	Northern Cancer Institute	Saint Leonards		Australia
12	Darling Downs Hospital and Health Service - Toowoomba Hospital	Toowoomba		Australia
13	Calvary Mater Newcastle	Waratah		Australia
14	Wollongong Hospital	Wollongong		Australia
15	Medizinische Universitaet Graz - Universitätsklinik für Frauenheilkunde und Geburtshilfe	Graz		Austria
16	Medical University of Innsbruck	Innsbruck		Austria
17	Charité Universitätsmedizin Berlin	Berlin		Germany
18	Kliniken Essen Mitte	Essen		Germany
19	UniversitätsKlinikum Heidelberg	Mannheim		Germany
20	Klinikum der Ludwig-Maximilians-Universität München (LMU)	Muenchen		Germany
21	AO SS Antonio e Biagio e Cesare Arrigo	Alessandria		Italy
22	Policlinico S. Orsola Malpighi	Bologna		Italy
23	Azienda Sanitaria dell'Alto Adige	Bolzano		Italy
24	ASST degli Spedali Civili di Brescia	Brescia		Italy
25	Fondazione Poliambulanza	Brescia		Italy
26	AOU Cagliari, Policlinico Universitario	Cagliari		Italy
27	Ospedale Sant Anna di Como	Como		Italy
28	AOU Careggi	Firenze		Italy
29	Ente ospedaliero Ospedali Galliera	Genova		Italy
30	ASST di Lecco	Lecco		Italy
31	Ospedale San Luca	Lucca		Italy
32	Istituto Europeo di Oncologia	Milan		Italy
33	Ospedale San Gerardo	Monza		Italy
34	Istituto Oncologico Veneto (IOV)	Padova		Italy
35	AOU di Parma	Parma		Italy
36	AOU Pisana	Pisa		Italy
37	AO Arcispedale Santa Maria Nuova	Reggio Emilia		Italy
38	Ausl Romagna	Rimini		Italy
39	Policlinico Umberto I, Università di Roma "La Sapienza"	Roma		Italy
40	Ospedale di Sondrio ASST Valtellina e Alto Lario	Sondrio		Italy
41	Ospedale SS Trinità	Sora		Italy
42	AO Ordine Mauriziano	Torino		Italy
43	AOU Città della Salute e della Scienza di Torino - Ospedale Sant'Anna	Torino		Italy
44	P.O Sant'Andrea Vercelli	Vercelli		Italy
45	Hirosaki University Hospital	Aomori		Japan
46	National Cancer Center Hospital East	Chiba		Japan
47	Shikoku Cancer Center	Ehime		Japan
48	Kurume University Hospital	Fukuoka		Japan
49	Hokkaido University Hospital	Hokkaido		Japan
50	Tohoku University Hospital	Miyagi		Japan
51	Niigata University Medical＆Dental Hospital	Niigata		Japan
52	Osaka University Hospital	Osaka		Japan
53	Shizuoka Cancer Center	Shizuoka		Japan
54	Keio University Hospital	Tokyo		Japan
55	Keimyung University Dongsan Medical Center	Daegu		Korea, Republic of
56	Ilsan Cha Medical Center	Gyeonggi-do		Korea, Republic of
57	Seoul National University Bundang Hospital	Gyeonggi-do		Korea, Republic of
58	Gachon University Gil Medical Center	Namdong-gu Incheon		Korea, Republic of
59	Asan Medical Center	Seoul		Korea, Republic of
60	Gangnam Severance Hospital	Seoul		Korea, Republic of
61	Konkuk University Medical Center	Seoul		Korea, Republic of
62	Samsung Medical Center	Seoul		Korea, Republic of
63	Seoul St. Mary's Hospital	Seoul		Korea, Republic of
64	Severance Hospital	Seoul		Korea, Republic of
65	Auckland city Hospital	Auckland		New Zealand
66	Hospital De Sant Pau I La Santa Creu	Barcelona		Spain
67	Hospital Universitario Vall d´Hebron Institute of Oncology (VHIO)	Barcelona		Spain
68	Institut Català d'Oncologia (ICO) Girona	Girona		Spain
69	Institut Català d'Oncologia (ICO), L'Hospitalet- Hospital Duran I Reynals	Hospitalet de Llobregat		Spain
70	Hospital 12 de Octubre	Madrid		Spain
71	Hospital Universitario La Paz	Madrid		Spain
72	MD Anderson Cancer Center	Madrid		Spain
73	Hospital Universitario Central de Asturias	Oviedo		Spain
74	Hospital Clínico Universitario Santiago de Compostela	Santiago De Compostela		Spain
75	Hospital Universitario Miguel Servet Zaragoza	Zaragoza		Spain
76	Kantonsspital	Baden		Switzerland
77	Universitätsspital	Basel		Switzerland
78	Inselspital	Bern		Switzerland
79	Kantonsspital	Luzern		Switzerland
80	Frauenfeld	Thurgau		Switzerland
81	IOSI	Ticino		Switzerland
82	Chang Gung Memorial Hospital-Kaohsiung	Kaohsiung City		Taiwan
83	Kaohsiung Veterans General Hospital	Kaohsiung		Taiwan
84	Mackay Memorial Hospital	Taipei City		Taiwan
85	National Taiwan University Hospital	Taipei		Taiwan
86	Taipei Veterans General Hospital	Taipei		Taiwan
87	Chang Gung Memorial Hospital-Linkou	Taoyuan City		Taiwan
88	Royal Derby Hospital	Derby		United Kingdom
89	Royal Devon & Exeter Hospital	Exeter		United Kingdom
90	Beatson West of Scotland Cancer Centre, Gartnavel General Hospital	Glasgow		United Kingdom
91	Velindre Cancer Centre	Glasgow		United Kingdom
92	Imperial College Healthcare NHS Trust	London		United Kingdom
93	Royal Marsden Hospital	London		United Kingdom
94	St Bartholomew's Hospital	London		United Kingdom
95	The Christie NHS Foundation Trust	Manchester		United Kingdom
96	NUHT - Nottingham University Hospital NHS Trust	Nottingham		United Kingdom
97	Derriford Hospital	Plymouth		United Kingdom

Sponsors and Collaborators

• Mario Negri Institute for Pharmacological Research
• Hoffmann-La Roche

Investigators

• Principal Investigator: Nicoletta Colombo, MD, Istituto Europeo di Oncologia (IEO) - Milan

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Mario Negri Institute for Pharmacological Research
• ClinicalTrials.gov Identifier: NCT03603184
• Other Study ID Numbers: IRFMN-EN-7556
• First Posted: Jul 27, 2018
• Last Update Posted: Feb 1, 2022
• Last Verified: Jan 1, 2022

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Mario Negri Institute for Pharmacological Research: endometrial cancer; neoplasm; immunotherapy
• Additional relevant MeSH terms: Endometrial Neoplasms; Paclitaxel; Carboplatin; Atezolizumab

Study Results

No Results Posted as of Feb 1, 2022