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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03708224
Recruitment Status : Recruiting
First Posted : October 17, 2018
Last Update Posted : October 11, 2019
Sponsor:
Collaborator:
Genentech, Inc.
Information provided by (Responsible Party):
Alain Algazi, University of California, San Francisco

Brief Summary:
To determine the effect of neoadjuvant atezolizumab alone or in combination with other immune modulating agents on T-cell infiltration in advanced SCCHN. To determine the impact of neo-adjuvant immunotherapy on surgical outcomes.

Condition or disease Intervention/treatment Phase
Cancer Carcinoma Squamous Cell Carcinoma Head and Neck Cancer Biological: Atezolizumab Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine the effect of neoadjuvant atezolizumab alone or in combination with 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 cluster of differentiation 3 (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 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: This is a phase II, multi-arm, open-label trial of perioperative atezolizumab alone or in combination with other immune-modulating agents in advanced SCCHN. Based on the results of these initial cohorts, the trial will be amended to explore other novel atezolizumab-based combinations (such as atezolizumab in combination with another immuno-oncology (IO) agent, chemotherapeutics, or a molecularly targeted agent that could potentiate the activity of atezolizumab). Each of these new cohorts will be tested and enrolled to in sequential, non-randomized fashion.

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 another immune-modulating agent yet to be determined, 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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Study of Perioperative Immunotherapy in Patients With Advanced Non-Virally Associated Squamous Cell Carcinoma of the Head and Neck
Actual Study Start Date : March 27, 2019
Estimated Primary Completion Date : March 31, 2022
Estimated Study Completion Date : November 30, 2025

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Atezolizumab
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.
Biological: Atezolizumab
Given IV




Primary Outcome Measures :
  1. Proportion of subjects with a >= 40% increase in the CD3 counts [ Time Frame: Baseline up to 2 years ]
    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.

  2. R0 resection rate [ Time Frame: Up to 2 years ]
    R0 resection rate will be described by point estimate and 95% CI using the Pearson-Clopper method. Furthermore, an exact binomial test will be used to compare with the published R0 resection rate for this population of 77% as an exploratory analysis.


Secondary Outcome Measures :
  1. Changes in CD3 infiltration and clinical outcome [ Time Frame: Baseline up to 2 years ]
    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.

  2. Changes in immune parameters using mass cytometry (CyTOF), histology and gene expression [ Time Frame: Baseline up to 2 years ]
    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.

  3. Changes in peripheral immune responses using CyTOF [ Time Frame: Baseline up to 1 year post surgery ]
    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.

  4. Relapse free survival (RFS) [ Time Frame: At 2 years ]
    Point estimation and 95% CIs will be obtained for two-year RFS, and comparison with the historical control will be done by binomial test.

  5. Pathologic response [ Time Frame: Up to 2 years ]
    Point estimation and 95% CIs will be obtained for pathologic response; and comparison with the historical control will be done by binomial test.

  6. Incidence of adverse events graded according to Common Terminology Criteria for Adverse Events version 5 [ Time Frame: Up to 28 days post-treatment ]
    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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 /microliter (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 Bacillus tuberculosis (TB)
  • Hypersensitivity to atezolizumab, or any of its 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 cluster of differentiation 4 (CD4) count above 250 cells/mcL and an undetectable HIV viral load on standard polymerase chain reaction (PCR)-based tests

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03708224


Contacts
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Contact: Alain Algazi, MD 877-827-3222 cancertrials@ucsf.edu
Contact: Andy Chon 415-476-235 andrew.chon@ucsf.edu

Locations
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United States, California
University of San Francisco, California Recruiting
San Francisco, California, United States, 94115
Contact: Alain Algazi, MD    415-353-7552    alain.algazi@ucsf.edu   
Contact: Andy Chon    415-476-2351    andrew.chon@ucsf.edu   
Principal Investigator: Alain Algazi, MD         
Sponsors and Collaborators
Alain Algazi
Genentech, Inc.
Investigators
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Principal Investigator: Alain Algazi, MD University of California, San Francisco

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Responsible Party: Alain Algazi, Associate Professor, University of California, San Francisco
ClinicalTrials.gov Identifier: NCT03708224    
Other Study ID Numbers: 177018
NCI-2018-01992 ( Other Identifier: Clinical Trials Reporting Program (CTRP) )
First Posted: October 17, 2018    Key Record Dates
Last Update Posted: October 11, 2019
Last Verified: October 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Alain Algazi, University of California, San Francisco:
Cancer
Non-Virally Associated Squamous Cell Carcinoma
Head and Neck
Additional relevant MeSH terms:
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Carcinoma
Carcinoma, Squamous Cell
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Squamous Cell
Atezolizumab
Antibodies, Monoclonal
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs