A Study to Investigate Atezolizumab Subcutaneous in Patients With Previously Treated Locally Advanced or Metastatic Non-Small Cell Lung Cancer
- Registration Number
- NCT03735121
- Lead Sponsor
- Hoffmann-La Roche
- Brief Summary
This study will evaluate the pharmacokinetics, safety, and efficacy of atezolizumab subcutaneous (SC) compared with atezolizumab intravenous (IV) in participants with locally advanced or metastatic Non-Small Cell Lung Cancer (NSCLC) who have not been exposed to cancer immunotherapy (CIT) and for whom prior platinum-based therapy has failed. The study is comprised of two parts, as follows: A dose-finding part (Part 1, Phase Ib) will aim to identify the dose of atezolizumab SC to be tested in Part 2. A dose-confirmation part (Part 2, Phase III, randomized) will aim to confirm that the dose moved forward from Part 1 yields drug exposure that is comparable to that of atezolizumab IV.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 438
- Histologically or cytologically documented locally advanced or metastatic NSCLC
- Prior platinum-containing regimen or disease recurrence ≤ 6 months since prior platinum-based adjuvant/neoadjuvant regimen.
- Measurable disease as defined by RECIST v1.1
- Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
- Life expectancy ≥12 weeks
- Adequate hematologic and end-organ function
Additional Inclusion Criteria (Part 2 Only) • Availability of tissue and known epidermal growth factor receptor (EGFR) status
- Symptomatic, untreated, or actively progressing central nervous system (CNS) metastases
- Uncontrolled or symptomatic hypercalcemia
- Pregnancy or breastfeeding
- Active or history of autoimmune disease or immune deficiency
- History of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis
- Severe infection ≤ 4 weeks
- Treatment with therapeutic oral or IV antibiotics ≤ 2 weeks prior to study treatment
- Significant cardiovascular disease
- Prior allogeneic stem cell or solid organ transplantation
- Treatment with a live, attenuated vaccine ≤ 4 weeks
- Treatment with systemic immunostimulatory agents ≤ 4 weeks or 5 half-lives of the drug
- Treatment with systemic immunosuppressive medication ≤ 2 weeks
Additional Exclusion Criteria (Part 2 Only)
• Tested tumor programmed death-ligand-1 (PD-L1) expression status with an intention to treat the patient if positive
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Cohort 1: Atezolizumab+rHuPH20 (Part 1) rHuPH20 Atezolizumab+recombinant human hyaluronidase (rHuPH20), followed by Atezolizumab Atezolizumab + rHuPH20 (Part 2) rHuPH20 Atezolizumab + rHuPH20 Atezolizumab (Part 2) Atezolizumab Atezolizumab Cohort 3: Atezolizumab+rHuPH20(Part 1) rHuPH20 Atezolizumab+rHuPH20, followed by Atezolizumab Cohort 2: Atezolizumab+rHuPH20 (Part 1) rHuPH20 Atezolizumab+rHuPH20, followed by Atezolizumab Cohort 2: Atezolizumab+rHuPH20 (Part 1) Atezolizumab Atezolizumab+rHuPH20, followed by Atezolizumab Cohort 1: Atezolizumab+rHuPH20 (Part 1) Atezolizumab Atezolizumab+recombinant human hyaluronidase (rHuPH20), followed by Atezolizumab Cohort 3: Atezolizumab+rHuPH20(Part 1) Atezolizumab Atezolizumab+rHuPH20, followed by Atezolizumab Atezolizumab + rHuPH20 (Part 2) Atezolizumab Atezolizumab + rHuPH20
- Primary Outcome Measures
Name Time Method Part 1: Serum Trough Concentration (Ctrough) of Atezolizumab at Cycle 1 Pre-dose on Day 1 of Cycle 2 (Cycle length =21 days for cohorts 1 and 3 and 14 days for cohort 2) Part 2: Area Under the Concentration-Time Curve From Time Zero to 21 Days (AUC 0-21 d) at Cycle 1 From start of dosing up to Day 21 in Cycle 1 (Cycle length= 21 days) Part 2: Observed Serum Ctrough of Atezolizumab at Cycle 1 Predose on Day 1 of Cycle 2 (Cycle length =21 days for cohorts 1 and 3 and 14 days for cohort 2)
- Secondary Outcome Measures
Name Time Method Part 1: Maximum Observed Serum Concentration (Cmax) of Atezolizumab Predose and post dose on Day 1 of Cycle 1 and post dose on Days 3 and 8 of Cycle 1 (Cycle length = 21 days for cohorts 1 and 3 and 14 days for cohort 2) Part 1: Area Under the Concentration-time Curve (AUClast) of Atezolizumab Predose and up to 21 days post dose in Cycle 1 for cohorts 1 and 3 and from predose up to 14 days post last dose in Cycle 1 for cohort 2 (Cycle length= 21 days for cohorts 1 and 3 and 14 days for cohort 2) Part 2: Progression-Free Survival (PFS) From study start to the first occurrence of disease progression or death from any cause, whichever occurs first (Up to approximately 72 months). PFS is defined as the time from study start to the first occurrence of disease progression as determined by the investigator according to RECIST v1.1 or or death from any cause (whichever occurs first).
Part 2: Overall Survival (OS) From study start to death from any cause (Up to approximately 72 months) OS defined as the time from study entry to death from any cause.
Part 2: Duration of Response (DOR) From first occurrence of documented objective response to disease progression or death from any cause, whichever occurs first (up to approximately 72 months) DOR is defined as the time from first occurrence of a documented objective response to disease progression as determined by the investigator according to RECIST v1.1. or death from any cause, whichever occurs first. Objective response is defined as the percentage of participants having a CR or PR as determined by investigator assessment of radiographic disease per RECIST v1.1. CR is the disappearance of all target lesions and any pathological lymph nodes must have reduction in short axis to \< 10 mm. PR is defined as at least a 30% decrease in the SOD of target lesions, taking as reference the Baseline sum diameters in the absence of CR.
Part 1: Time to Maximum Serum Concentration (Tmax) of Atezolizumab Predose and post dose on Day 1 of Cycle 1 and post dose on Days 3 and 8 of Cycle 1 (Cycle length = 21 days for cohorts 1 and 3 and 14 days for cohort 2) Part 1: Serum Atezolizumab Concentration at Specified Timepoint During SC Administration Cohort 1: Pre&postdose:D1 &postdose: D3,8 of C1; Cohort 2: Pre&postdose: D1 of C1,3 & postdose: D3,8 of C1, Predose: D1 of C2; Cohort 3: Pre& postdose: D1 of C1,2 & postdose: D3,8 of C1, D2,4& 9 of C2& pre dose:D1 of C3 Cycle length =21 days for cohorts 1 and 3 and 14 days for cohort 2. Day=D; Cycle=C.
Part 2: Model Predicted Ctrough of Atezolizumab at Cycle 1 Cycle 1 (Cycle length=21 days) Part 1: Percentage of Participants With Adverse Events (AEs) Baseline up to data cutoff date for primary analysis, April 26, 2022 (up to approximately 17 months) An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events. AEs were reported based on the National Cancer Institute Common Terminology Criteria for AEs, version 5.0 (NCI-CTCAE, v5.0).
Part 2: Percentage of Participants With AEs From signing of informed consent form (ICF) until 30 days after last dose of study drug administration in Part 2 (Up to approximately 72 months) An AE is any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with the treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a pharmaceutical product, whether or not considered related to the pharmaceutical product. Preexisting conditions which worsen during a study are also considered as adverse events. AEs were reported based on the National Cancer Institute Common Terminology Criteria for AEs, version 5.0 (NCI-CTCAE, v5.0).
Part 2: Model Predicted Ctrough at Steady State (Cthrough,ss) of Atezolizumab Atezo SC: Pre&postdose C1D1, postdose C1 Days 2,4,8, Pre&postdose C2,D1 and Predose on D1 of C3,4,8,12 and 16 ; Atezo IV: Pre&postdose on C1D1, postdose C1 Days 2,4,8; Pre&postdose C2D1, Predose on D1 of C3,4,8,12, and 16 (up to approximately 16 months) 1 cycle=21 days Abbreviations used-Cycle=C; Day =D; Atezolizumab=atezo.
Part 2: Percentage of Participants With Ant-Drug Antibodies (ADAs) to Atezolizumab After SC or IV Administration From first dose of atezolizumab up to treatment discontinuation visit (Up to approximately 72 Months). Part 2: Convenience, Ease of Administration, and Overall Satisfaction With Atezolizumab SC Assessed Using HCP Subcutaneous Perspective Questionnaire After HCP has completed administering at least 3 doses of atezolizumab SC across all participants in Part 2 (Up to approximately 72 months) The HCP Subcutaneous Perspective Questionnaire consists of five items evaluating the convenience, ease of administration and overall satisfaction with atezolizumab SC, as well as reasons for HCP-reported satisfaction or dissatisfaction.
Part 2: Model Predicted AUC at Steady State (AUCss) of Atezolizumab Atezo SC: Pre&postdose C1D1, postdose C1 Days 2,4,8, Pre&postdose C2,D1 and Predose on D1 of C3,4,8,12 and 16 ; Atezo IV: Pre&postdose on C1D1, postdose C1 Days 2,4,8; Pre&postdose C2D1, Predose on D1 of C3,4,8,12, and 16 (up to approximately 16 months) 1 cycle=21 days Abbreviations used-Cycle=C; Day =D; Atezolizumab=atezo
Part 2: Functioning and Global Health Status Over Time, as Assessed by European Organization for Research and Treatment of Cancer (EORTC) Item Library (IL)57 From Day 1 of Cycles 1-6 and then every other cycle up to treatment discontinuation visit (Up to approximately 72 months) EORTC IL57 questionnaire has10 items and covers 3 scales: physical functioning (PF), role functioning (RF) \& global health status/quality of life (GHS/QoL) \& 1 item from EORTC Item Library. PF scale has 5 items evaluating the extent to which participants have trouble doing strenuous activities; taking long walks \& short walks; need to stay in bed or a chair; need help with eating, dressing, bathing/using toilet. RF scale has 2 items evaluating extent to which participants are limited in doing work \& pursuing leisure activities in previous week. GHS/QoL scale has 2 items evaluating participants' overall health \& QoL in previous week. Questions are answered on a 4-point Likert scale (where 1="Not at all" to 4="Very much") for physical and role functioning \& a 7-point scale (where 1="Very poor" to 7="Excellent") for GHS/QoL. For each scale, mean of the items are linearly transformed to obtain scores from 0-100, where 100 =best possible score. Higher score = better outcome.
Part 2: Overall Satisfaction With Treatment Over Time, Assessed by the Modified Satisfaction With Therapy (SWT) Scale of the Cancer Therapy Satisfaction Questionnaire (CTSQ) Day 1 Cycle 3 or at treatment discontinuation visit (Up to approximately 72 months) Modified SWT scale of the CTSQ consist of seven items that measures seven domains related to satisfaction with cancer therapy. These include worthwhile, difficulty, benefits, feelings about side effects, form of therapy, overall satisfaction, and if participants would choose the therapy taking everything into consideration. Each domain is rated on a 5-point scale, with 1 representing the worst response and 5 representing the best response, except in the case of one reverse-scored item. mean of the items are linearly transformed to obtain scores from 0-100, where 100 =best possible score Higher scores are associated with higher satisfaction.
Part 2: Percentage of Participants With ADAs to rHuPH20 After SC Administration Relative to the Prevalence of ADAs at Baseline From first dose of atezolizumab up to treatment discontinuation visit (Up to approximately 72 Months) Part 2: Convenience, Potential Time Savings, and Overall Satisfaction With Atezolizumab SC Compared With Atezolizumab IV as Assessed by the Health Care Professional (HCP) SC Versus IV Perspective Questionnaire After HCP has completed administering at least 3 doses of atezolizumab SC and IV across all participants in Part 2 (Up to approximately 72 months) The HCP Subcutaneous Versus IV Perspective Questionnaire consists of five items evaluating the number of atezolizumab SC and IV administrations done, convenience, potential time savings, and overall satisfaction with atezolizumab SC and atezolizumab IV, as well as reasons for HCP-reported satisfaction or dissatisfaction.
Part 2: Objective Response Rate (ORR) From treatment initiation until disease progression or loss of clinical benefit (Up to approximately 72 months). ORR is defined as the percentage of participants having a complete response (CR) or partial response (PR) as determined by investigator assessment of radiographic disease per Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1. CR is the disappearance of all target lesions and any pathological lymph nodes must have reduction in short axis to \< 10 millimeters (mm). PR is defined as at least a 30% decrease in the sum of diameters (SOD) of target lesions, taking as reference the Baseline sum diameters in the absence of CR.
Part 2: Overall Patient-reported AE's Burden Over Time, Assessed by the Treatment-related Symptom Burden Item From the EORTC IL57 Day 1 of Cycles 1-6 and then every other cycle up to treatment discontinuation visit (Up to approximately 72 months) The overall patient-reported AE burden was assessed using the a single item from the EORTC IL57 questionnaire i.e To what extent have you been troubled with side-effects from your treatment?. The questions is answered on a 4-point Likert scale where 1="Not at all" to 4="Very much". Higher scores indicates greater AE burden.
Trial Locations
- Locations (71)
Chulalongkorn Hospital
🇹🇭Bangkok, Thailand
Rajavithi Hospital
🇹🇭Bangkok, Thailand
Consultorio Dr. Miguel Angel Escudero
🇦🇷Salta, Argentina
INCA 1- Instituto Nacional de Câncer X
🇧🇷Rio de Janeiro, Brazil
Oncocentro Apys
🇨🇱Vina Del Mar, Chile
Faculty of Med. Siriraj Hosp.
🇹🇭Bangkok, Thailand
Prapokklao Hospital
🇹🇭Chanthaburi, Thailand
Mordovia State University
🇷🇺Saransk, Mordovija, Russian Federation
Multidisciplinary clinic Reaviz
🇷🇺Samara, Russian Federation
Groote Schuur Hospital ( Uni of Capetown )
🇿🇦Cape Town, South Africa
Fundación CENIT para la Investigación en Neurociencias
🇦🇷Buenos Aires, Argentina
Centro Oncologico Riojano Integral (CORI)
🇦🇷La Rioja, Argentina
Wilgers Oncology Centre
🇿🇦Pretoria, South Africa
Sandton Oncology Medical Group
🇿🇦Sandton, South Africa
Hospital Universitari Vall d'Hebron
🇪🇸Barcelona, Spain
Hospital Universitario La Paz
🇪🇸Madrid, Spain
Vajira Hospital
🇹🇭Bangkok, Thailand
Maharaj Nakorn Chiang Mai Hospital
🇹🇭ChiangMai, Thailand
James Lind Centro de Investigación Del Cáncer
🇨🇱Temuco, Chile
Jilin Cancer Hospital
🇨🇳Changchun, China
West China Hospital - Sichuan University
🇨🇳Chengdu City, China
Sir Run Run Shaw Hospital Zhejiang University
🇨🇳Hangzhou City, China
Jinan Central Hospital
🇨🇳Jinan City, China
Henan Cancer Hospital
🇨🇳Zhengzhou, China
Clinica CIMCA
🇨🇷San Jose, Costa Rica
ICIMED Instituto de Investigación en Ciencias Médicas
🇨🇷San Jose, Costa Rica
APHM
🇫🇷Marseille, France
Ico Rene Gauducheau
🇫🇷Saint Herblain, France
General Hospital "G.Papanikolaou"
🇬🇷Asvestochori, Greece
Sotiria Hospital
🇬🇷Athens, Greece
INTEGRA Cancer Institute
🇬🇹Ciudad de Guatemala, Guatemala
Hospital El Pilar
🇬🇹Ciudad de Guatemala, Guatemala
Grupo Angeles
🇬🇹Guatemala City, Guatemala
Oncomedica
🇬🇹Guatemala, Guatemala
Matrai Gyogyintezet
🇭🇺Matrahaza, Hungary
Református Pulmonológiai Centrum
🇭🇺Törökbálint, Hungary
Cuidados oncologicos
🇲🇽Querétaro, Queretaro, Mexico
Auckland City Hospital, Cancer and Blood Research
🇳🇿Auckland, New Zealand
Christchurch Clinical Studies Trust Ltd
🇳🇿Christchurch, New Zealand
Waikato Hospital - Cancer and Blood Research Trials Unit
🇳🇿Hamilton, New Zealand
Tauranga Hospital, Clinical Trials Unit
🇳🇿Tauranga, New Zealand
Centro Medico Monte Carmelo
🇵🇪Arequipa, Peru
Clínica San Gabriel
🇵🇪Lima, Peru
Oncosalud Sac
🇵🇪Lima, Peru
Clinica Internacional, Sede San Borja
🇵🇪Lima, Peru
Regionalny Szpital Specjalistyczny im. W. Bieganskiego
🇵🇱Grudzi?dz, Poland
Centrum Terapii Wspolczesnej
🇵🇱Lodz, Poland
Mazowieckie Centrum Leczenia Chorob Pluc i Gruzlicy
🇵🇱Otwock, Poland
Narodowy Instytut Onkologii im. M. Sklodowskiej-Curie
🇵🇱Warszawa, Poland
Prince of Songkla University
🇹🇭Hat Yai, Thailand
Udonthani Cancer Hospital, Udonthani
🇹🇭Muang,Udonthani, Thailand
Hacettepe Uni Medical Faculty Hospital
🇹🇷Ankara, Turkey
Ankara Bilkent City Hospital
🇹🇷Ankara, Turkey
Kartal Dr Lutfi Kirdar Sehir Hastanesi
🇹🇷Istanbul, Turkey
Medipol University Medical Faculty
🇹🇷Istanbul, Turkey
Ege Uni Medical Faculty Hospital
🇹🇷Izmir, Turkey
RCI Sumy Regional Clinical Oncological Dispensary
🇺🇦Sumy, Ukraine
Birmingham Heartlands Hospital
🇬🇧Birmingham, United Kingdom
Oncosite - Centro de Pesquisa Clinica Em Oncologia Ltda
🇧🇷Ijui, Rio Grande Do Sul, Brazil
Bradford Hill Centro de Investigaciones Clinicas
🇨🇱Recoleta, Chile
Asst Papa Giovanni XXIII
🇮🇹Bergamo, Lombardia, Italy
IRCCS Istituto Clinico Humanitas
🇮🇹Rozzano, Lombardia, Italy
Asan Medical Center
🇰🇷Seoul, Korea, Republic of
Samsung Medical Centre
🇰🇷Seoul, Korea, Republic of
Riga East Clinical University Hospital Latvian Oncology Centre
🇱🇻Riga, Latvia
Chelyabinsk Regional Clinical Oncology Dispensary
🇷🇺Chelyabinsk, Moskovskaja Oblast, Russian Federation
FSBI Russian Oncology Research Center n.a. Blokhin of MOH RF
🇷🇺Moscow, Moskovskaja Oblast, Russian Federation
MEDSI Clinical Hospital on Pyatnitsky Highway
🇷🇺Moscow, Moskovskaja Oblast, Russian Federation
Filial #1 Regional Oncology Dispensary of Nizhniy Novgorod
🇷🇺Nizhny Novgorod, Niznij Novgorod, Russian Federation
Murmansk Regional Clinical Hospital named after P.A. Bayandin
🇷🇺Murmansk, Russian Federation
Municipal Institution City Clinical Hospital #4 of Dnipro City Council
🇺🇦Dnipropetrovsk, Katerynoslav Governorate, Ukraine