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Preoperative Immunotherapy in Patients With Squamous Cell Carcinoma of the Head and Neck

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 : January 19, 2021
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 Biological: Tocilizumab Biological: Tiragolumab Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 55 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Study of Preoperative Immunotherapy in Patients With 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 Monotherapy
Participants will receive 840mg of atezolizumab over 15 days prior to definitive surgery.
Biological: Atezolizumab
Given intravenously (IV)
Other Name: Tecentriq

Experimental: Atezolizumab (Adjuvant)
Participants will receive 840mg of atezolizumab over 15 days prior to definitive surgery. The first 9 participants in Arm A (atezolizumab monotherapy) will also receive adjuvant atezolizumab 16 weeks after standard of care surgery and radiation, or chemoradiation therapy, at a fixed dose of 1200 mg IV every 3 weeks for an additional 12 cycles.
Biological: Atezolizumab
Given intravenously (IV)
Other Name: Tecentriq

Experimental: Atezolizumab + Tiragolumab
Participants will receive 840 mg of atezolizumab IV and 600 mg of Tiragolumab during the 15-day neoadjuvant period prior to definitive surgery.
Biological: Atezolizumab
Given intravenously (IV)
Other Name: Tecentriq

Biological: Tiragolumab
Given IV
Other Name: anti-TIGIT

Experimental: Atezolizumab + Tocilizumab
Participants will receive 840 mg of atezolizumab IV and 6 mg/kg of Tocilizumab during the 15-day neoadjuvant period prior to definitive surgery.
Biological: Atezolizumab
Given intravenously (IV)
Other Name: Tecentriq

Biological: Tocilizumab
Given IV
Other Name: Actemra




Primary Outcome Measures :
  1. Proportion of subjects with a >= 40% increase in the cluster of differentiation 3 (CD3) counts [ Time Frame: Up to 2 years ]
    Intratumoral CD3+ T-cells will be identified by immunohistochemistry in pre- and post-treatment tumor specimens. The analysis population for the primary outcome will be all patients who received at least 2 weeks of neoadjuvant therapy with pre- and post-treatment tumor specimens that are evaluable for CD3+ T-cells. 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 ]
    Patients who undergo surgery will be evaluable for R0 resection rate. R0 resection rate will be described by point estimate and 95% CI using the Pearson-Clopper method.


Secondary Outcome Measures :
  1. Changes in immune parameters using mass cytometry (CyTOF), histology and gene expression [ Time Frame: 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.

  2. Changes in peripheral immune responses using CyTOF [ Time Frame: 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.

  3. Number of participants with treatment-related adverse events [ Time Frame: Up to 30 days post-treatment ]
    Treatment-related adverse events will be classified according to Common Terminology Criteria for Adverse Events version 5. Evaluation of Safety Analyses will be performed for all patients having received at least one dose of treatment on study.



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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:

  1. Patients must have clinically suspected SCCHN that is amenable to surgical resection with therapeutic intent
  2. Be willing and able to provide written informed consent/assent for the trial
  3. Be >=18 years of age on day of signing informed consent.
  4. Agree to research analysis of an existing pre-treatment biopsy available that was obtained within 90 days prior to the day of consent or agree to a new biopsy for research (or clinical diagnosis) within the screening window. Needle biopsies must be at least 20 Gauge in diameter
  5. Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) performance scale
  6. Demonstrate adequate organ function as defined below. All screening labs should be performed within 14 days of treatment initiation

    • Absolute neutrophil count (ANC) >=1,500 /microliter (mcL)
    • Platelets >=100,000 / mcL
    • Hemoglobin >= 9 g/dL
    • Lymphocyte count >= 500/mcL
    • White blood count >=3,000/mcL or <=14,000/mcL
    • Serum creatinine =< 1.5 x upper limit of normal (ULN) OR ≥50 mL/min creatinine clearance by Cockcroft-Gault formula for participants in whom, in the Investigator's judgment, serum creatinine levels do not adequately reflect renal function. * 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

      * Excluding Gilbert's syndrome. Participants with Gilbert's syndrome will be eligible for the study. The diagnosis of Gilbert's syndrome is suspected in people who have persistent, slightly elevated levels of unconjugated bilirubin (<= 3.0 x ULN) without any other apparent cause. A diagnosis of Gilbert's syndrome will be based on the exclusion of other diseases on the basis of the following criteria: i. Unconjugated hyperbilirubinemia noted on several occasions ii. No evidence of hemolysis (normal hemoglobin, normal haptoglobin levels, reticulocyte count), and lactate dehydrogenase iii. Normal liver function tests iv. Absence of other diseases associated with unconjugated hyperbilirubinemia

    • Aspartate aminotransferase (AST) [serum glutamic-oxaloacetic transaminase (SGOT)] and alanine aminotransferase (ALT) [serum glutamate pyruvate transaminase (SGPT)] =< 3 x ULN
    • Albumin >= 2.5 mg/dL
    • 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
    • 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
  7. Female subject of childbearing potential should have a negative urine or serum pregnancy within 7 days 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
  8. Female subjects of childbearing potential must be willing to use an adequate method of contraception for the course of the study through 5 months after the last dose of study medication.
  9. Male subjects must agree to use an adequate method of contraception and refrain from donating sperm, 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:

  1. 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
  2. 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. Participants who have received acute and/or low-dose systemic immunosuppressive medications (e.g., a one-time dose of dexamethasone for nausea or chronic use of <=10 mg/day of prednisone or dose-equivalent corticosteroid) may be enrolled in the study after discussion with and approval by the Sponsor. The use of inhaled corticosteroids and mineralocorticoids (e.g., fludrocortisone) is allowed
  3. Has a known history of active Bacillus tuberculosis (TB).
  4. Has an acute primary infection or reactivation of Epstein-Barr virus (EBV).
  5. Known allergy or hypersensitivity to any of the study drugs or their excipients.
  6. 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
  7. 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
  8. 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 prostate cancer that is in remission under androgen deprivation-therapy for > 2 years or under watchful waiting with Prostate-specific antigen (PSA) doubling time > 6 months. Additional malignancies may be permitted after consultation with the Principal Investigator. Other exceptions may apply and require discussion between the Investigator and the Sponsor
  9. 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
  10. Has known history of, or any evidence of active, non-infectious pneumonitis requiring corticosteroids
  11. 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
  12. Patient has asthma requiring systemic corticosteroids at the time of screening. Inhaled corticosteroids for the treatment of asthma are permitted
  13. 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
  14. Has known medical, psychiatric or substance abuse disorders/conditions that in the opinion of the principal investigator would interfere with cooperation or interfere with safe completion of the trial.
  15. 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
  16. Has received prior therapy with an anti-CTLA4, anti-PD-1, anti-PD-L1, or anti-PD-L2 agent
  17. 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 IU/mL and eligible liver function will be allowed
  18. 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
  19. 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. Note for Arm C (atezolizumab + tocilizumab): Because IL-6 inhibition may interfere with the normal immune response to new antigen, patients should be brought up to date on all recommended vaccinations, except for live vaccines, prior to initiation of therapy with tocilizumab to maximize vaccine response.
  20. Known human immunodeficiency virus positive (HIV+) patients may be included but must have:

    1. A stable regimen of highly active anti-retroviral therapy (HAART)
    2. No requirement for concurrent antibiotics or antifungal agents for the prevention of opportunistic infections
    3. 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
  21. Major surgery (including joint surgery, excluding needle biopsies) within 8 weeks prior to screening or planned major surgery within 6 months following treatment allocation.
  22. Previous or Concomitant Medications

    1. Previous treatment with any cell-depleting therapies, including investigational agents or approved therapies, some examples include: CAMPATH, anti-CD4, anti-CD5, anti-CD3, anti-Cluster of Differentiation 19 (CD19) and anti-CD20.
    2. Treatment with intravenous gamma globulin, plasmapheresis or Prosorba column within 6 months of baseline.
    3. Previous treatment with tocilizumab (an exception to this criterion may be granted for upon application to the sponsor on a case-by-case basis).
    4. Any previous treatment with alkylating agents such as chlorambucil, or with total lymphoid irradiation.
    5. History of severe allergic or anaphylactic reactions to human, humanized or murine monoclonal antibodies.
  23. Evidence of serious uncontrolled concomitant cardiovascular, nervous system, pulmonary (including obstructive pulmonary disease), renal, hepatic, endocrine (include uncontrolled diabetes mellitus) or gastrointestinal disease (including complicated diverticulitis, ulcerative colitis, or Crohn's disease.)
  24. Any major episode of infection requiring hospitalization or treatment with IV antibiotics within 4 weeks of screening or oral antibiotics within 2 weeks prior to screening.

    a. Participants who receive prophylactic antibiotics for biopsy are eligible for the study.

  25. Patients with reproductive potential not willing to use an effective method of contraception.
  26. Patients with lack of peripheral venous access.

    Additional Exclusion Criteria for Arm B (Atezolizumab + Tiragolumab)

  27. Patients with a history of anaphylactic reactions to human, chimeric, or mouse monoclonal antibodies or to any components of tiragolumab.

    Additional Exclusion Criteria for Arm C (Atezolizumab + Tocilizumab)

  28. Known active infection of bacterial, viral, fungal, mycobacterial or other infections, including, but not limited to, TB (i.e., has signs and symptoms of TB) and atypical mycobacterial disease, hepatitis B and C, and herpes zoster, but excluding fungal infections of nail beds.
  29. Pre-existing central nervous system (CNS) demyelinating or seizure disorders.
  30. History of diverticulitis, chronic ulcerative lower gastrointestinal (GI) disease (e.g., crohn disease, ulcerative colitis), or other symptomatic lower GI conditions that might predispose a patient to GI perforation.
  31. Current liver disease unrelated to the underlying cancer diagnosis, as determined by the investigator.
  32. History of, or currently active, primary or secondary immunodeficiency.

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: Andy Chon (415) 476-2351 andrew.chon@ucsf.edu

Locations
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United States, California
University of San Francisco, California Recruiting
San Francisco, California, United States, 94143
Contact: Andy Chon    415-476-2351    andrew.chon@ucsf.edu   
Contact    877-827-3222    cancertrials@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) )
ML40180 ( Other Identifier: Genentech )
First Posted: October 17, 2018    Key Record Dates
Last Update Posted: January 19, 2021
Last Verified: January 2021
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
Squamous Cell Carcinoma of Head and Neck
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Squamous Cell
Head and Neck Neoplasms
Neoplasms by Site
Atezolizumab
Antineoplastic Agents