PRIMARY OBJECTIVES:
I. To determine the effect of neoadjuvant atezolizumab alone or in combination with
tiragolumab, tocilizumab, or other immune modulating agent(s) on T-cell infiltration in
advanced 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 describe the changes in T-cell subtypes and other mediators of antitumor immune
response induced by neoadjuvant atezolizumab alone or in combination with tiragolumab,
tocilizumab, or other immune-modulating agent(s) in advanced SCCHN patients. (Translational).
II. To describe the impact of neoadjuvant, surgical, and adjuvant therapy on peripheral
immune responses. (Translational).
III. To establish the safety/toxicity profile of each regimen in the perioperative settings
for patients with advanced SCCHN. (Clinical).
EXPLORATORY OBJECTIVES:
I. To characterize changes in the gut microbiome associated with each therapeutic
combination.
II. To assess the correlation of disease status with C-Reactive Protein (CRP) and lactate
dehydrogenase (LDH) levels.
III. To assess the correlation of disease status with Interleukin 6 (IL-6) levels for
participants in Arm C (atezolizumab + tocilizumab).
IV. If leftover tissue and funding are available: To develop immune-competent tumor xenograft
models.
V. To determine whether neo-adjuvant immune therapy improves 2-year relapse-free survival
(RFS) in patients with SCCHN
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 A: Patients receive 2 infusions of atezolizumab intravenously (IV) over 30-60 minutes for
up to 15 days prior to definitive surgery and radiation.
Arm A (Adjuvant): Patients received 2 infusions of atezolizumab intravenously (IV) over 30-60
minutes for up to 15 days prior to definitive surgery and radiation. In addition to
neoadjuvant atezolizumab, the first 9 participants in Arm A (atezolizumab monotherapy)
received adjuvant atezolizumab beginning 16 weeks after surgery and radiation, or
chemoradiation therapy, every 3 weeks for up to 12 courses in the absence of disease
progression or unacceptable toxicity. Adjuvant atezolizumab will only be initiated if
radiation-associated adverse events have resolved to grade 2 or better.
Arm B: Patients receive atezolizumab IV over 30-60 minutes for up to 2 courses and
tiragolumab administered by IV infusion on Cycle 1 Day 1 of neoadjuvant treatment prior to
standard surgery.
Arm C: Patients receive atezolizumab IV over 30-60 minutes for up to 2 courses and
tocilizumab administered by IV infusion on Cycle 1 Day 1 of neoadjuvant treatment prior to
standard surgery. Tocilizumab will be administered (prior to atezolizumab administration) as
an intravenous infusion Atezolizumab will be administered 2 hours after the conclusion of the
tocilizumab infusion.
After completion of study treatment, patients are followed up at 30 days post surgery, 3
months, 6 months, 12 months, and at 24 months.
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.
