A Study to Investigate Atezolizumab Subcutaneous in Patients With Previously Treated Locally Advanced or Metastatic Non-Small Cell Lung Cancer

Study Overview
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Brief Summary
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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.

Official Title
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A Randomized, Multicenter, Phase Ib/III Study to Investigate the Pharmacokinetics, Efficacy, and Safety of Atezolizumab Subcutaneous Compared With Atezolizumab Intravenous in Patients With Previously Treated Locally Advanced or Metastatic Non-Small Cell Lung Cancer

Conditions
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Non-Small Cell Lung Cancer

Intervention / Treatment
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* Drug: Atezolizumab
* Drug: rHuPH20


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 Exclusion Criteria: 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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Intervention study model can be sequential or in parallel.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Atezolizumab (Part 2)<br>Atezolizumab | Drug: Atezolizumab<br>* Atezolizumab will be administered as per the schedule specified in arm or cohort.<br>* Other names: Tecentriq;|
| Experimental: Cohort 1: Atezolizumab+rHuPH20 (Part 1)<br>Atezolizumab+recombinant human hyaluronidase (rHuPH20), followed by Atezolizumab | Drug: Atezolizumab<br>* Atezolizumab will be administered as per the schedule specified in arm or cohort.<br>* Other names: Tecentriq;Drug: rHuPH20<br>* rHuPH20 will be administered as per the scheduled specified in the cohort for Part 1.<br>* Other names: ENHANZE;|
| Experimental: Cohort 2: Atezolizumab+rHuPH20 (Part 1)<br>Atezolizumab+rHuPH20, followed by Atezolizumab | Drug: Atezolizumab<br>* Atezolizumab will be administered as per the schedule specified in arm or cohort.<br>* Other names: Tecentriq;Drug: rHuPH20<br>* rHuPH20 will be administered as per the scheduled specified in the cohort for Part 1.<br>* Other names: ENHANZE;|
| Experimental: Cohort 3: Atezolizumab+rHuPH20(Part 1)<br>Atezolizumab+rHuPH20, followed by Atezolizumab | Drug: Atezolizumab<br>* Atezolizumab will be administered as per the schedule specified in arm or cohort.<br>* Other names: Tecentriq;Drug: rHuPH20<br>* rHuPH20 will be administered as per the scheduled specified in the cohort for Part 1.<br>* Other names: ENHANZE;|
| Experimental: Atezolizumab + rHuPH20 (Part 2)<br>Atezolizumab + rHuPH20 | Drug: Atezolizumab<br>* Atezolizumab will be administered as per the schedule specified in arm or cohort.<br>* Other names: Tecentriq;Drug: rHuPH20<br>* rHuPH20 will be administered as per the scheduled specified in the cohort for Part 1.<br>* Other names: ENHANZE;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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: 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) | 
| 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) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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: 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: 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 1: Serum Atezolizumab Concentration at Specified Timepoint During SC Administration | Cycle length =21 days for cohorts 1 and 3 and 14 days for cohort 2. Day=D; Cycle=C. | 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 | 
| Part 1: Percentage of Participants With Adverse Events (AEs) | 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). | Baseline up to data cutoff date for primary analysis, April 26, 2022 (up to approximately 17 months) | 
| Part 2: Percentage of Participants With AEs | 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). | 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) | 
| Part 2: Model Predicted Ctrough of Atezolizumab at Cycle 1 |  | Cycle 1 (Cycle length=21 days) | 
| Part 2: Model Predicted Ctrough at Steady State (Cthrough,ss) of Atezolizumab | 1 cycle=21 days Abbreviations used-Cycle=C; Day =D; Atezolizumab=atezo. | 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) | 
| Part 2: Model Predicted AUC at Steady State (AUCss) of Atezolizumab | 1 cycle=21 days Abbreviations used-Cycle=C; Day =D; Atezolizumab=atezo | 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) | 
| Part 2: Objective Response Rate (ORR) | 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. | From treatment initiation until disease progression or loss of clinical benefit (Up to approximately 72 months). | 
| Part 2: Progression-Free Survival (PFS) | 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). | From study start to the first occurrence of disease progression or death from any cause, whichever occurs first (Up to approximately 72 months). | 
| Part 2: Overall Survival (OS) | OS defined as the time from study entry to death from any cause. | From study start to death from any cause (Up to approximately 72 months) | 
| Part 2: Duration of Response (DOR) | 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. | From first occurrence of documented objective response to disease progression or death from any cause, whichever occurs first (up to approximately 72 months) | 
| 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 | 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. | From Day 1 of Cycles 1-6 and then every other cycle up to treatment discontinuation visit (Up to approximately 72 months) | 
| Part 2: Overall Satisfaction With Treatment Over Time, Assessed by the Modified Satisfaction With Therapy (SWT) Scale of the Cancer Therapy Satisfaction Questionnaire (CTSQ) | 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. | Day 1 Cycle 3 or at treatment discontinuation visit (Up to approximately 72 months) | 
| Part 2: Overall Patient-reported AE's Burden Over Time, Assessed by the Treatment-related Symptom Burden Item From the EORTC IL57 | 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. | Day 1 of Cycles 1-6 and then every other cycle up to treatment discontinuation visit (Up to approximately 72 months) | 
| 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: 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 | 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. | 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) | 
| Part 2: Convenience, Ease of Administration, and Overall Satisfaction With Atezolizumab SC Assessed Using HCP Subcutaneous Perspective Questionnaire | 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. | After HCP has completed administering at least 3 doses of atezolizumab SC across all participants in Part 2 (Up to approximately 72 months) |