Clinical Trials /

Phase II Study of Perioperative Immunotherapy in Patients With Advanced Non-Virally Associated Squamous Cell Carcinoma

NCT03708224

Description:

To determine the effect of neoadjuvant atezolizumab alone or in combination with emactuzumab, CPI-444, and other immune modulating agents on T-cell infiltration in advanced SCCHN. To determine the impact of neo-adjuvant immunotherapy on surgical outcomes.

Related Conditions:
  • Head and Neck Squamous Cell Carcinoma
  • Nasopharyngeal Squamous Cell Carcinoma
  • Oropharyngeal Squamous Cell Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Phase II Study of Perioperative Immunotherapy in Patients With Advanced Non-Virally Associated Squamous Cell Carcinoma
  • Official Title: A Phase II Study of Perioperative Immunotherapy in Patients With Advanced Non-Virally Associated Squamous Cell Carcinoma of the Head and Neck

Clinical Trial IDs

  • ORG STUDY ID: 177018
  • SECONDARY ID: 18-25114
  • NCT ID: NCT03708224

Conditions

  • Cancer
  • Carcinoma
  • Squamous Cell Carcinoma
  • Head and Neck Cancer

Interventions

DrugSynonymsArms
AtezolizumabAtezolizumab
EmactuzumabAtezolizumab and Emactuzumab

Purpose

To determine the effect of neoadjuvant atezolizumab alone or in combination with emactuzumab, CPI-444, and other immune modulating agents on T-cell infiltration in advanced SCCHN. To determine the impact of neo-adjuvant immunotherapy on surgical outcomes.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the effect of neoadjuvant atezolizumab alone or in combination with
      emactuzumab and other immune modulating agents on T-cell infiltration in advanced squamous
      cell carcinoma of the head and neck (SCCHN). (Translational) II. To determine the impact of
      neo-adjuvant immunotherapy on surgical outcomes. (Clinical)

      SECONDARY OBJECTIVES:

      I. To associate changes in CD3 infiltration with radiographic response in the surgical
      window. (Translational) II. To describe the changes in T-cell subtypes and other mediators of
      anti-tumor immune response induced by neoadjuvant atezolizumab alone or in combination with
      emactuzumab or other immune-modulating agents in advanced SCCHN patients. (Translational)
      III. To describe the impact of neoadjuvant, surgical, and adjuvant therapy on peripheral
      immune responses. (Translational) IV. To determine whether combined neo-adjuvant and adjuvant
      immune therapy improves 2-year relapse-free survival (RFS) in patients with SCCHN. (Clinical)
      V. To establish the safety/toxicity profile of each regimen in the perioperative and
      postoperative settings for patients with advanced SCCHN. (Clinical)

      EXPLORATORY OBJECTIVES:

      I. To establish immune-competent tumor xenograft models for future research. II. To
      characterize changes in the gut microbiome associated with each therapeutic combination.

      OUTLINE: Patients are assigned to 1 of 2 arms.

      ARM I: Patients receive atezolizumab intravenously (IV) over 30-60 minutes every 3 weeks for
      up to 2 courses prior to standard surgery and radiation. 16 weeks post-surgery, patients
      receive atezolizumab IV over 30-60 minutes every 3 weeks for up to 12 courses in the absence
      of disease progression or unacceptable toxicity.

      ARM II: Patients receive atezolizumab IV over 30-60 minutes and emactuzumab IV over 90
      minutes every 3 weeks for up to 2 courses prior to standard surgery and radiation. 16 weeks
      post-surgery, patients receive atezolizumab IV over 30-60 minutes every 3 weeks for up to 12
      courses in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up at 28 days and then
      periodically for up to 2 years.

      IV. To determine whether combined neo-adjuvant and adjuvant immune therapy improves 2-year
      relapse-free survival (RFS) in patients with SCCHN. (Clinical) V. To establish the
      safety/toxicity profile of each regimen in the perioperative and postoperative settings for
      patients with advanced SCCHN. (Clinical)

      EXPLORATORY OBJECTIVES:

      I. To establish immune-competent tumor xenograft models for future research. II. To
      characterize changes in the gut microbiome associated with each therapeutic combination.

      OUTLINE: Patients are assigned to 1 of 2 arms.

      ARM I: Patients receive atezolizumab intravenously (IV) over 30-60 minutes every 3 weeks for
      up to 2 courses prior to standard surgery and radiation. 16 weeks post-surgery, patients
      receive atezolizumab IV over 30-60 minutes every 3 weeks for up to 12 courses in the absence
      of disease progression or unacceptable toxicity.

      ARM II: Patients receive atezolizumab IV over 30-60 minutes and emactuzumab IV over 90
      minutes every 3 weeks for up to 2 courses prior to standard surgery and radiation. 16 weeks
      post-surgery, patients receive atezolizumab IV over 30-60 minutes every 3 weeks for up to 12
      courses in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up at 28 days and then
      periodically for up to 2 years.
    

Trial Arms

NameTypeDescriptionInterventions
AtezolizumabExperimentalARM I: Patients receive atezolizumab intravenously (IV) over 30-60 minutes every 3 weeks for up to 2 courses prior to standard surgery and radiation. 16 weeks post-surgery, patients receive atezolizumab IV over 30-60 minutes every 3 weeks for up to 12 courses in the absence of disease progression or unacceptable toxicity.
    Atezolizumab and EmactuzumabExperimentalARM II: Patients receive atezolizumab IV over 30-60 minutes and emactuzumab IV over 90 minutes every 3 weeks for up to 2 courses prior to standard surgery and radiation. 16 weeks post-surgery, patients receive atezolizumab IV over 30-60 minutes every 3 weeks for up to 12 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up at 28 days and then periodically for up to 2 years.

      Eligibility Criteria

              Inclusion Criteria:
      
                -  Patients must have histologically or cytologically confirmed stage III or stage IV
                   SCCHN that is amenable to surgical resection with curative intent. Primary tumors in
                   the oropharynx must test negative for human papillomavirus (HPV). Primary tumors in
                   the nasopharynx must test negative for Epstein-Barr virus (EBV). Tumors originating
                   outside of the oropharynx and nasopharynx will be presumed to be virus negative
      
                -  Patients must agree to undergo post-surgery adjuvant radiation therapy with or without
                   concurrent, weekly cisplatin at 40 mg/m2 (as clinically indicated)
      
                -  Be willing and able to provide written informed consent/assent for the trial
      
                -  Have measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST)
                   1.1
      
                -  Be willing to provide tissue from a newly obtained core or excisional biopsy of a
                   tumor lesion prior to the initiation of neoadjuvant treatment on protocol
      
                -  Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG)
                   performance scale
      
                -  Absolute neutrophil count (ANC) >=1,500 /mcL (performed within 14 days of treatment
                   initiation)
      
                -  Platelets >=100,000 / mcL (performed within 14 days of treatment initiation)
      
                -  Hemoglobin >= 9 g/dL (performed within 14 days of treatment initiation)
      
                -  Serum creatinine =< 1.5 x upper limit of normal (ULN) OR measured or calculated
                   creatinine clearance (glomerular filtration rate [GFR] can also be used in place of
                   creatinine or creatinine clearance [CrCl]) >= 30 mL/min for subject with creatinine
                   levels > 1.5 x institutional ULN (performed within 14 days of treatment initiation)
      
                   * Creatinine clearance should be calculated per institutional standard
      
                -  Serum total bilirubin =< 1.5 x ULN OR direct bilirubin =< ULN for subjects with total
                   bilirubin levels > 1.5 ULN (performed within 14 days of treatment initiation)
      
                -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and
                   alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x
                   ULN OR =< 5 x ULN for subjects with liver metastases (performed within 14 days of
                   treatment initiation)
      
                -  Albumin >= 2.5 mg/dL (performed within 14 days of treatment initiation)
      
                -  International normalized ratio (INR) or prothrombin time (PT) =< 1.5 x ULN unless
                   subject is receiving anticoagulant therapy as long as PT or partial thromboplastin
                   time (PTT) is within therapeutic range of intended use of anticoagulants (performed
                   within 14 days of treatment initiation)
      
                -  Activated partial thromboplastin rime (aPTT) =< 1.5 x ULN unless subject is receiving
                   anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use
                   of anticoagulants (performed within 14 days of treatment initiation)
      
                -  Female subject of childbearing potential should have a negative urine or serum
                   pregnancy within 72 hours prior to receiving the first dose of study medication. If
                   the urine test is positive or cannot be confirmed as negative, a serum pregnancy test
                   will be required
      
                -  Female subjects of childbearing potential must be willing to use an adequate method of
                   contraception - Contraception, for the course of the study through 5 months after the
                   last dose of study medication
      
                -  Male subjects must agree to use an adequate method of contraception. Contraception,
                   starting with the first dose of study therapy through 5 months after the last dose of
                   study therapy * Note: Abstinence is acceptable if this is the usual lifestyle and
                   preferred contraception for the subject
      
              Exclusion Criteria:
      
                -  Is currently participating and receiving study therapy or has participated in a study
                   of an investigational agent and received study therapy or used an investigational
                   device within 4 weeks of the first dose of treatment
      
                -  Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
                   other form of immunosuppressive therapy within 7 days prior to the first dose of trial
                   treatment
      
                -  Contraindication at study enrollment to adjuvant radiation therapy
      
                -  Has a known history of active TB (Bacillus tuberculosis)
      
                -  Hypersensitivity to atezolizumab, emactuzumab or any of their excipients
      
                -  Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study
                   day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from adverse events
                   due to agents administered more than 4 weeks earlier
      
                -  Has had prior targeted small molecule therapy, or radiation therapy within 2 weeks
                   prior to study day 1 or who has not recovered (i.e., =< grade 1 or at baseline) from
                   adverse events due to a previously administered agent or radiation therapy
      
                -  Has a known additional malignancy that is progressing or requires active treatment.
                   Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the
                   skin that has undergone potentially curative therapy, in situ cervical cancer,
                   low-grade thyroid cancer and indolent prostate cancer. Additional malignancies may be
                   permitted after consultation with the principal investigator Has active autoimmune
                   disease that has required systemic treatment in the past 2 years (i.e., with use of
                   disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement
                   therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy
                   for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic
                   treatment
      
                -  Has known history of, or any evidence of active, non-infectious pneumonitis requiring
                   corticosteroids
      
                -  Patient has known history of stage 2 or higher chronic obstructive pulmonary disease
                   (COPD). Stage 2 COPD is defined as forced expiratory volume in one second
                   (FEV1)/forced vital capacity (FVC) < 70%; 50% < FEV1 < 80% predicted, with dyspnea on
                   exertion
      
                -  Patient has asthma requiring systemic corticosteroids at the time of screening.
                   Inhaled corticosteroids for the treatment of asthma are permitted
      
                -  Has an active infection requiring systemic therapy
      
                -  Has a history or current evidence of any condition, therapy, or laboratory abnormality
                   that might confound the results of the trial, interfere with the subject's
                   participation for the full duration of the trial, or is not in the best interest of
                   the subject to participate, in the opinion of the treating investigator
      
                -  Has known psychiatric or substance abuse disorders that would interfere with
                   cooperation with the requirements of the trial
      
                -  Is pregnant or breastfeeding, or expecting to conceive or father children within the
                   projected duration of the trial, starting with the pre-screening or screening visit
                   through 120 days after the last dose of trial treatment
      
                -  Has received prior therapy with an anti-CTLA4, anti-PD-1, anti-PD-L1, or anti-PD-L2
                   agent
      
                -  Has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or
                   hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] quantitative has
                   been detected). HBsAg reactive on appropriate antiviral therapy with suppressed
                   hepatitis B virus (HBV) deoxyribonucleic acid (DNA) less than 100 and eligible liver
                   function will be allowed
      
                -  Current New York Heart Association (NYHA) class III or higher heart failure. Patients
                   with a prior history of heart failure that has resolved to class II or lower may
                   participate
      
                -  Patient has been treated with a live, attenuated vaccine within 4 weeks prior to
                   initiation of study treatment, or is anticipated to need such a vaccine during the
                   course of the study or within 5 months after the last dose of atezolizumab
      
                -  Known human immunodeficiency virus positive (HIV+) patients may be included but must
                   have:
      
                     -  A stable regimen of highly active anti-retroviral therapy (HAART)
      
                     -  No requirement for concurrent antibiotics or antifungal agents for the prevention
                        of opportunistic infections
      
                     -  A CD4 count above 250 cells/mcL and an undetectable HIV viral load on standard
                        polymerase chain reaction (PCR)-based tests
            
      Maximum Eligible Age:N/A
      Minimum Eligible Age:18 Years
      Eligible Gender:All
      Healthy Volunteers:No

      Primary Outcome Measures

      Measure:Proportion of subjects with a >= 40% increase in the CD3 counts
      Time Frame:Baseline up to 2 years
      Safety Issue:
      Description:Intratumoral CD3+ T-cells will be identified by immunohistochemistry in pre- and post-treatment tumor specimens. The proportion of patients with a >= 40% increase (from pre- to post-treatment) will be calculated. The exact 95% confidence intervals (CIs) using the Pearson-Clopper method and an exact binomial test will be used as an exploratory purpose. The change from pre-treatment to post-treatment CD3 count per mm^3 as a continuous measure will also be summarized.

      Secondary Outcome Measures

      Measure:Changes in CD3 infiltration and clinical outcome
      Time Frame:Baseline up to 2 years
      Safety Issue:
      Description:Correlation between fold change in CD3 infiltration and percent change in target lesions before and after neoadjuvant therapy will be assessed by Response Evaluation Criteria in Solid Tumors version 1.1. To associate changes (>= 40% increase pre-to-post-treatment) in CD3 infiltration with clinical outcome, Fisher-exact test will be used.
      Measure:Changes in immune parameters using mass cytometry (CyTOF), histology and gene expression
      Time Frame:Baseline up to 2 years
      Safety Issue:
      Description:The study will describe immune parameters at each time point by median and interquartile range (IQR) and compare the change between pre-treatment and surgical specimens by Wilcoxon singed rank test. Diversity of T-cell repertoires at each time point will be evaluated by clonality and compared by Wilcoxon singed ranked test. Moristas' distance will also be used to assess the change of T-cell repertoires.
      Measure:Changes in peripheral immune responses using CyTOF
      Time Frame:Baseline up to 1 year post surgery
      Safety Issue:
      Description:The study will describe immune parameters at each time point by median and IQR and compare the change between pre-treatment and surgical specimens by Wilcoxon singed rank test.
      Measure:Relapse free survival (RFS)
      Time Frame:At 2 years
      Safety Issue:
      Description:Point estimation and 95% CIs will be obtained for two-year RFS, and comparison with the historical control will be done by binomial test.
      Measure:Pathologic response
      Time Frame:Up to 2 years
      Safety Issue:
      Description:Point estimation and 95% CIs will be obtained for pathologic response; and comparison with the historical control will be done by binomial test.
      Measure:Incidence of adverse events graded according to Common Terminology Criteria for Adverse Events version 5
      Time Frame:Up to 28 days post-treatment
      Safety Issue:
      Description:The study will use descriptive statistics to report on the safety/toxicity and efficacy of treatment, including adverse events. The study will tabulate the safety/toxicity profile of each regimen.

      Details

      Phase:Phase 2
      Primary Purpose:Interventional
      Overall Status:Not yet recruiting
      Lead Sponsor:University of California, San Francisco

      Trial Keywords

      • Cancer
      • Non-Virally Associated Squamous Cell Carcinoma
      • Head and Neck

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