Study to Compare the Safety and Efficacy of CMB305 With Atezolizumab to Atezolizumab Alone in Participants With Sarcoma (IMDZ-C232/V943A-002)

Study Overview
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Brief Summary
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This is an open-label Phase 2 randomized study that will examine the use of the study agents, CMB305 (sequentially administered LV305 which is a dendritic cell-targeting viral vector expressing the New York Esophageal Squamous Cell Carcinoma 1 gene [NY-ESO-1] and G305 which is a NY-ESO-1 recombinant protein plus glucopyranosyl lipid adjuvant-stable emulsion [GLA-SE]) in combination with atezolizumab or atezolizumab alone, in participants with locally advanced, relapsed or metastatic sarcoma (synovial or myxoid/round cell liposarcoma) expressing the NY-ESO-1 protein. There is no formal primary hypothesis for this study.

Detailed Description
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This study is designed to investigate and examine the time to progression and overall survival for CMB305 in combination with atezolizumab or atezolizumab alone in the treatment of participants with sarcoma expressing NY-ESO-1 protein.

Official Title
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A Randomized, Open-Label, Phase 2 Trial of CMB305 (Sequentially Administered LV305 and G305) and Atezolizumab in Patients With Locally Advanced, Relapsed, or Metastatic Sarcoma Expressing NY-ESO-1

Conditions
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Sarcoma, Myxoid/Round Cell Liposarcoma, Synovial Sarcoma, Metastatic Sarcoma, Recurrent Adult Soft Tissue Sarcoma, Locally Advanced Sarcoma, Liposarcoma

Intervention / Treatment
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* Biological: CMB305
* Biological: atezolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Locally advanced, relapsed, or metastatic sarcoma with measurable tumor burden following therapy, as defined by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1); the total of all lesions must be ≤12 cm (for synovial sarcoma) or ≤15 cm (for myxoid/round cell liposarcoma [MRCL]) Tumor histology consistent with synovial sarcoma or MRCL Tumor specimen positive for NY-ESO-1 expression by immunohistochemistry (IHC) Inadequate response, relapse, and/or unacceptable toxicity with ≥1 prior systemic, surgical, or radiation cancer therapies Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 Exclusion Criteria: Investigational therapy within 4 weeks prior to CMB305 dosing Prior administration of other NY-ESO-1-targeting immunotherapeutics Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), anti-programmed cell death receptor 1 (PD-1), and anti-programmed cell death ligand (PD-L1) therapeutic antibodies, or any other antibody or drug targeting T-cell costimulation Treatment with systemic immunostimulatory agents (including but not limited to interleukin-2) within 4 weeks or five half-lives of the drug, whichever is shorter, prior to first dose Significant immunosuppression Other cancer therapies, including chemotherapy, radiation, biologics or kinase inhibitors within 3 weeks prior to the first scheduled dosing 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, Guillain-Barré syndrome, multiple sclerosis, vasculitis, or glomerulonephritis History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia), risk of pulmonary toxicity, or evidence of active pneumonitis on screening chest computed tomography (CT) scan. History of radiation pneumonitis in the radiation field (fibrosis) is permitted History of other cancer within 3 years Evidence of active tuberculosis or recent (<1 week prior to first scheduled dosing) clinically significant infection requiring systemic therapy Evidence of active hepatitis B (HepB), hepatitis C (HepC), or Human Immunodeficiency Virus (HIV) infection Known active or untreated central nervous system (CNS) metastases Pregnant, planning to become pregnant within 6 months of treatment, or nursing Known allergy(ies) to any component of CMB305, atezolizumab, or severe allergic reactions to monoclonal antibodies, fusion proteins, or Chinese hamster ovary (CHO) cell products

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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CMB305 (sequentially administered LV305 and G305)+Atezolizumab<br>Participants received CMB305 treatment in combination with 1200 mg/day atezolizumab administered by intravenous (IV) infusion every 3 weeks (Q3W) for up to approximately 2 years. CMB305 treatment consisted of 2 doses of LV305 administered intradermally (ID) on Days 0 and 14 followed every 2 weeks with alternating doses of G305 administered intramuscularly (IM) and LV305. LV305 was administered at a dose of 1×10^10 vector genomes and G305 at a dose of 5 mcg glucopyranosyl lipid A stable emulsion mixed with 250 mcg of NY ESO-1 protein. | Biological: CMB305<br>* A combination of LV305 administered intradermally (ID) and G305 administered intramuscularly (IM)<br>Biological: atezolizumab<br>* IV Infusion<br>* Other names: TECENTRIQ®;|
| Active Comparator: Atezolizumab<br>Participants received 1200 mg/day atezolizumab by IV infusion Q3W for up to approximately 2 years. | Biological: atezolizumab<br>* IV Infusion<br>* Other names: TECENTRIQ®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) Per Modified Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | PFS was defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurred first, per RECIST 1.1 modified to use immune-related response criteria (irRC) confirmation and unidimensional tumor measurements as assessed by Blinded Independent Central Review (BICR). PD was defined as ≥20% increase in tumor burden compared with nadir (at any single time point) in 2 consecutive observations ≥4 weeks apart. If there was no disease progression or death, participants were censored at the date of their last disease assessment. The PFS was analyzed using the product-limit (Kaplan-Meier) method for censored data. | Up to approximately 36.1 months | 
| Overall Survival (OS) | OS was determined for all participants and was defined as the time from randomization to death due to any cause. Participants were censored at the date of their last follow-up. The OS was analyzed using the product-limit (Kaplan-Meier) method for censored data. | Up to approximately 36.1 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Experiencing a Dose-Limiting Toxicity (DLT) | DLTs will be evaluated during the safety run-in period. Any treatment emergent Grade 3 or higher adverse event (AE) that occurs in the first 42 days after initiation of study treatment, that is deemed possibly, probably or definitely related to the combination of CMB305 and atezolizumab will be considered a DLT with the following exceptions: Alopecia or vomiting (unless not controlled by optimal anti-emetics) Hepatic enzyme elevations associated with the baseline Grade 2 abnormalities Grade 3 laboratory AEs that are asymptomatic and return to baseline or to Grade 1 within 3 days, unless identified specifically as DLT by the investigator or the Data Monitoring Committee (DMC) Grade 3 fatigue Grade 3 systemic reactions (such as fever, headache, influenza like symptoms, myalgia, malaise, or nausea) that return to baseline or Grade 1 within 3 days of study inoculation | Up to approximately 42 days | 
| Number of Participants Who Experienced At Least One Adverse Event (AE) | An AE was defined as any untoward medical occurrence in a participant administered a study treatment and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the study treatment or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that was temporally associated with the use of study treatment, was also an AE. The number of participants who experienced at least one AE is presented. | Up to approximately 36.1 months | 
| Number of Participants Who Discontinued Study Treatment Due to an Adverse Event (AE) | An AE was defined as any untoward medical occurrence in a participant administered a study treatment and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the study treatment or protocol-specified procedure. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre-existing condition that was temporally associated with the use of study treatment, was also an AE. The number of participants who discontinued study treatment due to an AE is presented. | Up to approximately 24 months | 
| Progression-Free Survival (PFS) Rate at Month 3 Per Modified Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | PFS was defined as the time from randomization to the first documented PD or death due to any cause, whichever occurred first, per RECIST 1.1 modified to use irRC confirmation and unidimensional tumor measurements as assessed by BICR. PD was defined as ≥20% increase in tumor burden compared with nadir (at any single time point) in 2 consecutive observations ≥4 weeks apart. If there was no disease progression or death, participants were censored at the date of their last disease assessment. The PFS was analyzed using the product-limit (Kaplan-Meier) method for censored data. Participants were evaluated every 6 weeks with radiographic imaging to assess their response to treatment. The PFS rate was calculated as the percentage of participants with PFS at Month 3. | Month 3 | 
| Progression-Free Survival (PFS) Rate at Month 6 Per Modified Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | PFS was defined as the time from randomization to the first documented PD or death due to any cause, whichever occurred first, per RECIST 1.1 modified to use irRC confirmation and unidimensional tumor measurements as assessed by BICR. PD was defined as ≥20% increase in tumor burden compared with nadir (at any single time point) in 2 consecutive observations ≥4 weeks apart. If there was no disease progression or death, participants were censored at the date of their last disease assessment. The PFS was analyzed using the product-limit (Kaplan-Meier) method for censored data. Participants were evaluated every 6 weeks with radiographic imaging to assess their response to treatment. The PFS rate was calculated as the percentage of participants with PFS at Month 6. | Month 6 | 
| Time to Next Treatment (TTNT) | TTNT was the time from date of randomization to the start date of subsequent treatment. Participants were treated for up to approximately 2 years and then followed until next treatment or death. Participants who did not receive subsequent treatment were censored at the date of last contact or death. The TTNT was analyzed using the product-limit (Kaplan-Meier) method for censored data. | Up to approximately 36.1 months | 
| Distant Metastasis Free Survival (DMFS) | DMFS was the time between the date of randomization and the date of first distant metastasis or date of death (whatever the cause), whichever occurs first. Participants without metastasis and death were censored at the date of last contact or death. The DMFS was analyzed using the product-limit (Kaplan-Meier) method for censored data. | Up to approximately 36.1 months | 
| Number of Participants Positive for Anti-New York Esophageal Squamous Cell Carcinoma-1 (NY-ESO-1) Antibody at Baseline | The number of participants with anti-NY-ESO-1 antibodies at baseline was measured using an enzyme-linked immunosorbent assay (ELISA) with recombinant NY-ESO1 protein. A titer of >1:100 was considered positive. The number of participants that were anti-NY-ESO-1 antibody positive at baseline is presented. | Baseline (Day 1) | 
| Number of Participants Positive for Anti-New York Esophageal Squamous Cell Carcinoma-1 (NY-ESO-1) Antibody After Induction With Treatment | The number of participants with anti-NY-ESO-1 antibodies induced after treatment was measured using an enzyme-linked immunosorbent assay (ELISA) with recombinant NY-ESO1protein. A titer of >1:100 was considered positive. The induction of anti-NY-ESO-1 antibody response was deﬁned as a ≥4-fold increase in the titer or the presence of a newly positive response after the ﬁrst dose of treatment. The number of participants that were anti-NY-ESO-1 antibody positive after induction with treatment is presented. | Up to approximately 24 months | 
| Number of Participants Positive for Anti-New York Esophageal Squamous Cell Carcinoma-1 (NY-ESO-1) T Cells at Baseline | Anti-NY-ESO-1 CD4 and CD8 positive T-cell responses were measured by interferon gamma detecting enzyme-linked ImmunoSpot (ELISPOT) using isolated CD4 and CD8 positive T cells from peripheral blood mononuclear cells (PBMCs) expanded in vitro with a NY-ESO-1 peptide pool (20-mer peptides, 10-mer overlap) and considered positive if there were >50 spot-forming units/50,000 cells observed for NY-ESO-1 peptides and a ≥2-fold increase in spot-forming units compared with a negative control. The number of participants that were anti-NY-ESO-1 T cell positive at baseline is presented. | Baseline (Day 1) | 
| Number of Participants Positive for Anti-New York Esophageal Squamous Cell Carcinoma-1 (NY-ESO-1) T Cells After Induction With Treatment | Anti-NY-ESO-1 CD4 and CD8 positive T-cell responses were measured by interferon gamma detecting enzyme-linked ImmunoSpot (ELISPOT) using isolated CD4 and CD8 positive T cells expanded with a NY-ESO-1 peptide (20-mer peptides, 10-mer overlap) and considered positive if there were >50 spot-forming units (SPU)/50,000 cells observed for NY-ESO-1 peptides and a ≥2-fold increase in SPU compared with a negative control. The induction of an anti-NYESO-1 CD4 or CD8 positive T-cell response was deﬁned as de novo positive or ≥2-fold rise in the number of SPU after the ﬁrst dose. A fluorescence-activated cell sorting (FACS)-based intracellular cytokine staining assay for interferon gamma or tumor necrosis factor alpha after stimulation with NY-ESO-1 peptide was also used and staining ≥2-fold above the baseline value was considered positive for T-cell responses. The number of participants that were anti-NY-ESO-1 T cell positive after induction with treatment is presented. | Up to approximately 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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immunotherapy, CMB305, LV305, GLA-SE, atezolizumab, NY-ESO-1