Details
Description
Inclusion Criteria
Exclusion Criteria
Details
Title A Phase III, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Of Atezolizumab (Anti-Pd-L1 Antibody) As Adjuvant Therapy After Definitive Local Therapy In Patients With High-Risk Locally Advanced Squamous Cell Carcinoma Of The Head And Neck
IRB ROCH 1318
CC 18-309
Hospital Main Campus
Stage Advanced/Metastatic
Phase Phase 3
Disease Head and Neck, Squamous Cell Carcinoma of Head and Neck
Drug Atezolizumab
Description
Primary Objective- To evaluate the efficacy of atezolizumab compared with placebo
- To evaluate the efficacy of atezolizumab compared with placebo
- To evaluate clinical benefit in atezolizumab compared with placebo in terms of impact on HRQoL and physical functioning
Inclusion Criteria
- Signed Informed Consent Form
- Age ≥ 18 years at the time of signing the Informed Consent Form
- Ability to comply with the study protocol, in the investigator's judgment
- Histologically or cytologically confirmed SCCHN (HPV positive Stage III or HPV negative Stave IVA or IVB based on AJCC 8th Edition Cancer Staging Manual) involving the oral cavity, oropharynx, larynx, or hypopharynx
- HPV negative Stage IVA (T3/T4a + N2M0) regardless of tobacco use history
- HPV negative Stage IVB (T3/T4a + N3M0 or T4b + N2/N3M0) regardless of tobacco use history
- HPV-positive oropharyngeal carcinoma Stage III (clinical T1/T2 + N3M0) and ≥ 10 years of tobacco use history
- HPV-positive oropharyngeal carcinoma Stage III (clinical T3/T4 + N3M0 or pathologic T3/T4 + N2M0) regardless of tobacco use history
- HPV status as determined locally by p16 IHC, in situ hybridization, or by polymerase chain reaction-based assay
- Completed definitive local therapy (as defined below) and have scans (MRI or CT with contrast of head and neck region; CT with contrast of chest, abdomen, and pelvis) 10-12 weeks after completion of definitive local therapy confirming either CR, PR, or SD and within 4 weeks of randomization
- Primary surgery followed by either postoperative RT or concurrent CRT
- Induction chemotherapy followed by primary surgery alone (e.g., laryngectomy); or induction chemotherapy follow by primary surgery followed by RT or CRT; or induction chemotherapy followed by RT or CRT alone
- Concurrent CRT without primary or salvage surgery
- CRT followed by salvage neck dissection or salvage laryngectomy (only for patients with laryngeal cancer)
- Absence of metastatic disease as documented by radiographic scans
- Recovered from acute toxicities, except fatigue, xerostomia, dysgeusia, alopecia, associated with definitive treatment to Grade 1 or lower
- Patients with feeding tubes are eligible
- Availability of a representative pretreatment tumor specimen for exploratory biomarker research (see Section 4.5.6 for information on tumor specimens) The tissue sample must be submitted before or within 4 weeks after randomization; however, patients may be enrolled into the study before the pretreatment tumor tissue sample is submitted.
- ECOG PS of 0 or 1
- Life expectancy ≥ 12 weeks
- Adequate hematologic and end-organ function, defined by the following laboratory test results, obtained within 14 days prior to initiation of study treatment:
- ANC ≥ 1.5 x 109/L (1500/μL) without granulocyte colony-stimulating factor support
- Lymphocyte count ≥ 0.3 x 109/L (300/μL)
- Platelet count ≥ 100 x 109/L (100,000/μL) without transfusion
- Hemoglobin ≥ 90 g/L (9 g/dL), Patients may be transfused to meet this criterion.
- AST, ALT, and ALP ≤ 2.5 x ULN
- Serum bilirubin ≤ 1.5 x ULN with the following exception: Patients with known Gilbert disease: serum bilirubin level ≤ 3 x ULN
- Creatinine CL ≥ 20 mL/min (calculated by Cockcroft-Gault formula)
- Serum albumin ≥ 25 g/L (2.5 g/dL)
- For patients not receiving therapeutic anticoagulation: INR or aPTT ≤ 1.5 x ULN
- For patients receiving therapeutic anticoagulation: stable anticoagulant regimen
- Negative HIV test at screening
- Negative hepatitis B surface antigen (HBsAg) test at screening
- Negative total hepatitis B core antibody (HBcAb) test at screening, or positive total HBcAb test followed by a negative hepatitis B virus (HBV) DNA test at screening The HBV DNA test will be performed only for patients who have a positive total HBcAb test.
- Negative hepatitis C virus (HCV) antibody test at screening, or positive HCV antibody test followed by a negative HCV RNA test at screening The HCV RNA test will be performed only for patients who have a positive HCV antibody test.
- For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods with a failure rate of < 1% per year during the treatment period and for 5 months after the last dose of study treatment A woman is considered to be of childbearing potential if she is postmenarcheal, has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus). Examples of contraceptive methods with a failure rate of < 1% per year include bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices. The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.
Exclusion Criteria
- Patients who have received surgery alone as definitive local therapy
- HPV-negative patients who have a T1/T2 or N0/N1 tumor
- HPV-positive oropharyngeal carcinoma patients who have a clinical N0/N1/N2 or pathological N0/N1 nodal stage
- Patients, other than laryngeal cancer patients, who have persistent disease at the primary site and require salvage resection of primary tumor post CRT
- Squamous cell carcinoma of the nasopharynx
- Evidence of disease progression or metastatic disease during or following definitive local therapy documented in the 10- to 12-week post-definitive local therapy scans
- Uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5 mmol/L, calcium > 12 mg/dL or corrected serum calcium > ULN)
- 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, Sjogren syndrome, Guillain-Barre syndrome, or multiple sclerosis (see Appendix 7 for a more comprehensive list of autoimmune diseases and immune deficiencies), with the following exceptions:
- Patients with a history of autoimmune-related hypothyroidism who are on thyroid-replacement hormone are eligible for the study.
- 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) 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.
- 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 CT scan History of radiation pneumonitis in the radiation field (fibrosis) is permitted.
- Active tuberculosis
- 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
- 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
- History of malignancy other than SCCHN within 5 years prior to screening, with the exception of malignancies with a negligible risk of metastasis or death (e.g., 5-year OS rate > 90%), such as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer
- 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
- 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) may be eligible for the study.
- Prior allogeneic stem cell or solid organ transplantation
- Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the patient at high risk from treatment complications
- Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment, or anticipation of need for such a vaccine during atezolizumab treatment or within 5 months after the last dose of atezolizumab
- Current treatment with anti-viral therapy for HBV
- Prior neoadjuvant treatment or any systemic anti-cancer therapy without definitive local therapy (either surgery and/or radiation) for locally advanced head and neck cancer
- Treatment with investigational therapy within 28 days prior to initiation of study treatment
- Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including anti-CTLA-4, anti-PD-1, and anti-PD-L1 therapeutic antibodies
- 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
- Treatment with systemic immunosuppressive medication (including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-tumor necrosis factor-α [anti-TNF-α] agents) within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during study treatment, with the following exceptions:
- Patients who received acute, low-dose systemic immunosuppressant medication or a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of corticosteroids for a contrast allergy) may be eligible for the study after Medical Monitor approval has been obtained.
- Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma, or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible for the study.
- Patients who are receiving low-dose (equivalent to ≤ 10mg prednisone a day) corticosteroids for radiation induced mucositis, or mucosal edema are eligible for the study.
- History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins
- Known hypersensitivity to Chinese hamster ovary cell products or to any component of the atezolizumab formulation
- Pregnancy or breastfeeding, or intention of becoming pregnant during study treatment or within 5 months after the last dose of study treatment Women of childbearing potential must have a negative serum pregnancy test result within 14 days prior to initiation of study treatment.