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

• ClinicalTrials.gov Identifier: NCT02609984
• Recruitment Status: Terminated
• First Posted: November 20, 2015
• Results First Posted: May 14, 2020
• Last Update Posted: July 7, 2020
• Sponsor: Immune Design
• Collaborator: Genentech, Inc.
• Information provided by (Responsible Party): Immune Design

Tracking Information

• First Submitted Date: November 14, 2015
• First Posted Date: November 20, 2015
• Results First Submitted Date: April 30, 2020
• Results First Posted Date: May 14, 2020
• Last Update Posted Date: July 7, 2020
• Actual Study Start Date: April 29, 2015
• Actual Primary Completion Date: February 6, 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 30, 2020)

• Progression-Free Survival (PFS) Per Modified Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) [ Time Frame: Up to approximately 36.1 months ]
  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.
• Overall Survival (OS) [ Time Frame: Up to approximately 36.1 months ]
  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.

Original Primary Outcome Measures (submitted: November 19, 2015)

Progression Free Survival [ Time Frame: Up to 2 years after first study injection ]

Progression-free survival (PFS) with CMB305 (sequentially administered LV305 and G305) in combination with atezolizumab or with atezolizumab alone

Current Secondary Outcome Measures (submitted: April 30, 2020)

• Number of Participants Experiencing a Dose-Limiting Toxicity (DLT) [ Time Frame: Up to approximately 42 days ]
  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
• Number of Participants Who Experienced At Least One Adverse Event (AE) [ Time Frame: Up to approximately 36.1 months ]
  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.
• Number of Participants Who Discontinued Study Treatment Due to an Adverse Event (AE) [ Time Frame: Up to approximately 24 months ]
  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.
• Progression-Free Survival (PFS) Rate at Month 3 Per Modified Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) [ Time Frame: Month 3 ]
  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.
• Progression-Free Survival (PFS) Rate at Month 6 Per Modified Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) [ Time Frame: Month 6 ]
  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.
• Time to Next Treatment (TTNT) [ Time Frame: Up to approximately 36.1 months ]
  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.
• Distant Metastasis Free Survival (DMFS) [ Time Frame: Up to approximately 36.1 months ]
  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.
• Number of Participants Positive for Anti-New York Esophageal Squamous Cell Carcinoma-1 (NY-ESO-1) Antibody at Baseline [ Time Frame: Baseline (Day 1) ]
  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.
• Number of Participants Positive for Anti-New York Esophageal Squamous Cell Carcinoma-1 (NY-ESO-1) Antibody After Induction With Treatment [ Time Frame: Up to approximately 24 months ]
  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.
• Number of Participants Positive for Anti-New York Esophageal Squamous Cell Carcinoma-1 (NY-ESO-1) T Cells at Baseline [ Time Frame: Baseline (Day 1) ]
  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.
• Number of Participants Positive for Anti-New York Esophageal Squamous Cell Carcinoma-1 (NY-ESO-1) T Cells After Induction With Treatment [ Time Frame: Up to approximately 24 months ]
  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.

Original Secondary Outcome Measures (submitted: November 19, 2015)

• Safety as Evaluated by Adverse Events, Laboratory Findings and Patient Discontinuations [ Time Frame: Up to 2 years after first study injection ]
  Safety of CMB305 in combination with atezolizumab or atezolizumab alone will be assessed by the following measures. Adverse events and serious adverse events,(according to CTCAE v4.03); laboratory findings and patient discontinuations at all timepoints will be evaluated. Study deaths and adverse events (serious and non-serious) that lead to discontinuation will be evaluated.
• Progression Free Survival Rates [ Time Frame: Up to six months after first study injection ]
  Progression-free survival rates at 3 and 6 months after start of study treatment
• Best Overall Response Rate [ Time Frame: Up to 2 years after first study injection ]
  Best overall response rate (ORR; by Response Evaluation Criteria in Solid Tumors [RECIST] v1.1 modified to use immune-related Response Criteria [irRC]) and response duration up to 24 months after starting treatment
• Overall Survival [ Time Frame: Up to 2 years after first study injection ]
  Overall survival (OS) after CMB305 in combination with atezolizumab or with atezolizumab alone

Current Other Pre-specified Outcome Measures (submitted: April 30, 2020)

Overall Response Rate (ORR) Per Modified Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) [ Time Frame: Up to approximately 36.1 months ]

ORR was determined in all participants and was defined as the percentage of participants who had a confirmed Complete Response (CR: Disappearance of all lesions in 2 consecutive observations ≥4 weeks apart) or a Partial Response (PR: ≥30% decrease in tumor burden compared with baseline in 2 observations ≥4 weeks apart) per RECIST 1.1 modified to use irRC confirmation and unidimensional tumor measurements as assessed by BICR. Participants with missing data were considered non-responders. The percentage of participants who experienced a CR or PR is presented.

• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

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

Brief Summary

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: 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.
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

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

Intervention

• Biological: CMB305
  A combination of LV305 administered intradermally (ID) and G305 administered intramuscularly (IM)
• Biological: atezolizumab
  IV Infusion
  Other Name: TECENTRIQ®

Study Arms

• Experimental: CMB305 (sequentially administered LV305 and G305)+Atezolizumab
  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.
  Interventions:

  • Biological: CMB305
  • Biological: atezolizumab
• Active Comparator: Atezolizumab
  Participants received 1200 mg/day atezolizumab by IV infusion Q3W for up to approximately 2 years.
  Intervention: Biological: atezolizumab

• Publications *: Chawla SP, Van Tine BA, Pollack SM, Ganjoo KN, Elias AD, Riedel RF, Attia S, Choy E, Okuno SH, Agulnik M, von Mehren M, Livingston MB, Keedy VL, Verschraegen CF, Philip T, Bohac GC, Yurasov S, Yakovich A, Lu H, Chen M, Maki RG. Phase II Randomized Study of CMB305 and Atezolizumab Compared With Atezolizumab Alone in Soft-Tissue Sarcomas Expressing NY-ESO-1. J Clin Oncol. 2022 Apr 20;40(12):1291-1300. doi: 10.1200/JCO.20.03452. Epub 2021 Jul 14.

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: April 30, 2020): 89
• Original Estimated Enrollment (submitted: November 19, 2015): 80
• Actual Study Completion Date: February 6, 2019
• Actual Primary Completion Date: February 6, 2019 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02609984
• Other Study ID Numbers: IMDZ-C232; V943A-002 ( Other Identifier: Merck ); IMDZ-C232 ( Other Identifier: Immune Design )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Immune Design
• Original Responsible Party: Same as current
• Current Study Sponsor: Immune Design
• Original Study Sponsor: Same as current
• Collaborators: Genentech, Inc.
• Investigators: Not Provided
• PRS Account: Immune Design
• Verification Date: June 2020