| Eligibility |
Inclusion Criteria:
1. Provision to sign and date the consent form
2. Stated willingness to comply with all study procedures and be available for the
duration of the study
3. Histologically or cytologically confirmed: stage II-IVB oral cavity, stage III-IVB
larynx, stage III-IVB hypopharynx, stage III-IVB sinonasal, or stage III-IVB HPV-
and/or p16-negative intermediate-high risk oropharynx head and neck cancer (AJCC 8th
edition)
4. Measurable disease defined as lesions that can be accurately measured in at least one
dimension (longest diameter to be recorded) as >10 mm by CT, PET/CT or MRI or >10 mm
on visual inspection by clinical exam
5. Patients who are deemed resectable by ENT surgeon without pre-existing medical
conditions that could inhibit surgery following neoadjuvant therapy, and do not refuse
surgery
6. Age = 18 years at time of study entry
7. ECOG performance status = 1
8. Body weight >30 kg
9. Adequate normal organ and marrow function as defined below:
- Hemoglobin =9.0 g/dL
- Absolute neutrophil count (ANC) =1.5 x 109/L (= 1500 per mm3) without granulocyte
colony-stimulating factor support.
- Lymphocyte count =0.5 × 109/L (500/µL)
- Platelet count =100 x 109/L (=100,000 per mm3) without transfusion
- Serum bilirubin =1.5 x institutional upper limit of normal (ULN). This will not
apply to patients with confirmed Gilbert's syndrome (persistent or recurrent
hyperbilirubinemia that is predominantly unconjugated in the absence of hemolysis
or hepatic pathology), who will be allowed only in consultation with their
physician.
- AST (SGOT)/ALT (SGPT)/ ALP =2.5 x institutional upper limit of normal
- Serum albumin = 25 g/L (2.5 g/dL)
- For patients not receiving therapeutic anticoagulation: INR or aPTT = 1.5 × ULN
- For patients receiving therapeutic anticoagulation: stable anticoagulant regimen
- Measured creatinine clearance (CL) >40 mL/min or Calculated creatinine CL>40
mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour
urine collection for determination of creatinine clearance:
Males:
Creatinine CL (mL/min) = Weight (kg) x (140 - Age) 72 x serum creatinine (mg/dL)
Females:
Creatinine CL (mL/min) = Weight (kg) x (140 - Age) x 0.85 72 x serum creatinine
(mg/dL)
10. Evidence of post-menopausal status or negative urinary or serum pregnancy test for
female pre-menopausal patients. See section 6.12 for additional details and
contraception requirements for patients on study. Women will be considered
post-menopausal if they have been amenorrheic for 12 months without an alternative
medical cause. The following age-specific requirements apply:
- Women <50 years of age would be considered post-menopausal if they have been
amenorrheic for 12 months or more following cessation of exogenous hormonal
treatments and if they have luteinizing hormone and follicle-stimulating hormone
levels in the post-menopausal range for the institution or underwent surgical
sterilization (bilateral oophorectomy or hysterectomy)
- Women =50 years of age would be considered post-menopausal if they have been
amenorrheic for 12 months or more following cessation of all exogenous hormonal
treatments, had radiation-induced menopause with last menses >1 year ago, had
chemotherapy-induced menopause with last menses >1 year ago, or underwent
surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or
hysterectomy)
11. Patient is willing and able to comply with the protocol for the duration of the study
including undergoing treatment and scheduled visits and examinations including follow
up
Exclusion Criteria:
1. Participation in another clinical study with an investigational product during the
last 3 months
2. Patients with active ILD / pneumonitis or with a history of ILD/ pneumonitis requiring
steroids
3. Concurrent enrollment in another clinical study, unless it is an observational
(non-interventional) clinical study or during the follow-up period of an
interventional study
4. Any previous treatment with a PD-1 or PD-L1 inhibitor, including durvalumab,
anti-PD-L2, anti-CD137, or anti-cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4)
antibody (including ipilimumab or any other antibody or drug specifically targeting
T-cell co-stimulation or checkpoint pathways)
5. Treatment with systemic immunostimulatory agents (including, but not limited to,
interferon and interleukin 2 [IL-2]) within 4 weeks or 5 half-lives of the drug
(whichever is longer) prior to initiation of study treatment
6. Receipt of the last dose of anticancer therapy (chemotherapy, immunotherapy, endocrine
therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal
antibodies, other investigational agent) 30 days prior to the first dose of study drug
for patients who have received prior TKIs [e.g., erlotinib, gefitinib and crizotinib]
and within 6 weeks for nitrosourea or mitomycin C. (If sufficient wash-out time has
not occurred due to the schedule or PK properties of an agent, a longer wash-out
period may be required.)
7. Patients with QTc interval > 470 msec during screening
8. Current or prior use of immunosuppressive medication within 14 days before the first
dose of atezolizumab, with the exceptions of intranasal and inhaled corticosteroids or
systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of
prednisone, or an equivalent corticosteroid. The following are exceptions to this
criterion:
- Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra
articular injection)
- Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of
prednisone or its equivalent
- Steroids as premedication for hypersensitivity reactions (e.g., CT scan
premedication)
9. Any concurrent chemotherapy, IP, biologic, or hormonal therapy that is not part of
standard NCCN indicated HNSCC adjuvant concurrent CRT.
Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone
replacement therapy) is acceptable.
10. History of allogenic organ or bone marrow transplantation
11. Major surgical procedure, other than for diagnosis, within 4 weeks prior to initiation
of study treatment, or anticipation of need for a major surgical procedure during the
study
12. Severe infection within 4 weeks prior to initiation of study treatment, including, but
not limited to, hospitalization for complications of infection, bacteremia, or severe
pneumonia
13. Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation
of study treatment. Patients receiving prophylactic antibiotics (e.g., to prevent a
urinary tract infection or chronic obstructive pulmonary disease exacerbation) are
eligible for the study.
14. Uncontrolled intercurrent illness, including but not limited to, ongoing or active
infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable
angina pectoris, uncontrolled cardiac arrhythmia, interstitial lung disease, serious
chronic gastrointestinal conditions associated with diarrhea, or psychiatric
illness/social situations that would limit compliance with study requirement,
substantially increase risk of incurring AEs or compromise the ability of the patient
to give written informed consent
15. Significant cardiovascular disease (such as New York Heart Association Class II or
greater cardiac disease, myocardial infarction, or cerebrovascular accident) within 3
months prior to initiation of study treatment, unstable arrhythmia, or unstable angina
16. History of another primary malignancy except for:
- Malignancy treated with curative intent and with no known active disease =3 years
before the first dose of IP and of low potential risk for recurrence
- Adequately treated non-melanoma skin cancer or lentigo maligna without evidence
of disease
- Adequately treated carcinoma in situ without evidence of disease
- Active or previously treated prostate cancer without distant metastasis
- Active or previously treated thyroid cancer without distant metastasis
- Active or previously treated DCIS or early stage breast cancer without distant
metastasis
17. History of leptomeningeal carcinomatosis
18. Uncontrolled tumor-related pain Patients requiring pain medication must be on a stable
regimen at study entry. Symptomatic lesions (e.g., bone metastases or metastases
causing nerve impingement) amenable to palliative radiotherapy should be treated prior
to enrollment. Patients should be recovered from the effects of radiation. There is no
required minimum recovery period.
Asymptomatic metastatic lesions that would likely cause functional deficits or
intractable pain with further growth (e.g., epidural metastasis that is not currently
associated with spinal cord compression) should be considered for loco-regional
therapy if appropriate prior to enrollment.
19. History of active primary immunodeficiency
20. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent
drainage procedures (once monthly or more frequently). Patients with indwelling
catheters (e.g., PleurX®) are allowed.
21. Uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5 mmol/L, calcium > 12
mg/dL or corrected serum calcium > ULN)
22. Active or history of autoimmune disease or immune deficiency, including, but not
limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus
erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid
antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome,
or multiple sclerosis (see Appendix 3 for a more comprehensive list of autoimmune
diseases and immune deficiencies), with the following exceptions:
- Patients with a history of autoimmune-related hypothyroidism (e.g., following
Hashimoto syndrome) who are stable on thyroid-replacement hormone are eligible
for the study
- Patients with vitiligo or alopecia
- Patients without active disease in the last 5 years may be included but only
after consultation with the Primary Investigator
- Patients with celiac disease controlled by diet alone
- Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen
are eligible for the study
- Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with
dermatologic manifestations only (e.g., patients with psoriatic arthritis are
excluded) or any chronic skin condition that does not require systemic therapy
are eligible for the study provided all of following conditions are met:
- Rash must cover < 10% of body surface area
- Disease is well controlled at baseline and requires only low-potency topical
corticosteroids
- No occurrence of acute exacerbations of the underlying condition requiring
psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic
agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids
within the previous 12 months
23. Active infection including tuberculosis (clinical evaluation that includes clinical
history, physical examination and radiographic findings, and TB testing in line with
local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result),
hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies). Patients
with a past or resolved HBV infection (defined as the presence of hepatitis B core
antibody [anti- HBc] and absence of HBsAg) are eligible. Patients positive for
hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative
for HCV RNA.
24. History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis
obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of
active pneumonitis on screening chest computed tomography (CT) scan. History of
radiation pneumonitis in the radiation field (fibrosis) is permitted.
25. Treatment with a live, attenuated vaccine within 120 days prior to initiation of study
treatment, or anticipation of need for such a vaccine during atezolizumab treatment or
within 150 days after the final dose of atezolizumab.
26. Female patients who are pregnant or breastfeeding or male or female patients of
reproductive potential who are not willing to employ highly effective birth control
from screening to about 1 80 days after the last dose of atezolizumab monotherapy.
Patient must have a negative serum or urine pregnancy test within 72 hours of study
entry.
27. Known allergy or hypersensitivity to any of the study drugs or any of the study drug
excipients
28. Patients with p16-positive oropharyngeal SCC. No verification of p16 status is needed
for laryngeal cancer or oral cavity cancer.
29. Patients with distant metastatic disease on initial screening imaging
30. Judgment by the investigator that the patient is unsuitable to participate in the
study and the patient is unlikely to comply with study procedures, restrictions and
requirements
31. History of severe allergic anaphylactic reactions to chimeric or humanized antibodies
or fusion proteins
32. Known hypersensitivity to Chinese hamster ovary cell products or to any component of
the atezolizumab formulation
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