PRIMARY OBJECTIVES:
I. To compare investigator-assessed progression free survival (PFS) between atezolizumab plus
radiotherapy and atezolizumab alone. (Phase II) II. To compare overall survival (OS) between
atezolizumab plus radiotherapy and atezolizumab alone. (Phase III)
SECONDARY OBJECTIVES:
I. To assess the toxicity between the atezolizumab plus radiotherapy arm and the atezolizumab
arm.
II. To assess the impact of adding radiotherapy on PFS and OS in patients with 1-3 visible
tumors and > 3 visible tumors.
III. To assess the impact of adding radiotherapy on PFS and OS in patients receiving
consolidation radiotherapy to all visible disease ("complete consolidation") and patients who
do not receive consolidation radiation to all visible disease ("incomplete consolidation").
EXPLORATORY OBJECTIVE:
I. To assess the association between pre-treatment tumor burden (determined by central
radiographic assessment, using both tumor number and tumor volume), and PFS and OS benefit.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM I: Patients receive atezolizumab intravenously (IV) over 60 minutes on day 1. Cycles
repeat every 21 days in the absence of disease progression or unacceptable toxicity.
ARM II: Patients receive atezolizumab IV over 60 minutes on day 1. Cycles repeat every 21
days in the absence of disease progression or unacceptable toxicity. Patients undergo
radiation therapy once daily (QD) on days 1-5 during weeks 1-5 only.
After completion of study treatment, patients are followed up every 3 months for 2 years,
every 6 months for 3 years, and then annually thereafter.
Inclusion Criteria:
- Pathologically proven diagnosis of extensive stage small cell lung cancer
- Partial response (PR) or stable disease (SD) after 4-6 cycles of etoposide/platinum
(E/P) doublet plus atezolizumab by re-staging scans (positron emission tomography
[PET]/computed tomography [CT] scan, diagnostic CT scan, magnetic resonance imaging
[MRI] optional per treating physician); atezolizumab should continue through
randomization. Patients must be randomized within 9 weeks of last dose of
etoposide/platinum or 6 weeks from completion of prophylactic cranial irradiation
(PCI)
- At the time of enrollment, patients must have had measurable disease (per Response
Evaluation Criteria in Solid Tumors [RECIST]) and 3 or fewer observable liver
metastases and no evidence of progressive disease (per RECIST) at time of enrollment
- Patients presenting with a pleural effusion will be eligible if thoracentesis is
cytologically negative and non-bloody or if pleural fluid is too small a volume to
effectively sample by thoracentesis and does not show increased metabolic activity on
CT/PET imaging
- Appropriate stage for study entry based on the following diagnostic workup:
- History/physical examination within 14 days prior to registration;
- Imaging within 42 days prior to registration to include:
- MRI brain with contrast or CT brain with contrast
- CT chest, abdomen and pelvis or whole body PET/CT scan any time after the
fourth cycle of chemotherapy and prior to registration
- Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 within 14 days
prior to registration
- Absolute neutrophil count (ANC) >= 1,000/cells/mm^3 (within 14 days prior to
registration)
- Platelets >= 75,000 cells/mm^3 (within 14 days prior to registration)
- Hemoglobin >= 8 g/dL (within 14 days prior to registration)
- Total bilirubin =< 1.5 x upper limit of normal (ULN) (within 14 days prior to
registration)
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and
alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x
ULN (AST and/or ALT =< 5 ULN for patients with liver involvement) (within 14 days
prior to registration)
- Alkaline phosphatase =< 2.5 x ULN (=< 5 ULN for patients with documented liver
involvement or bone metastases) (within 14 days prior to registration)
- Serum creatinine =< 2.0 x ULN (within 14 days prior to registration)
- Adequate renal function within 30 days prior to registration defined as follows:
glomerular filtration rate (GFR) >= 40 mL/min/1.73 m^2
- Upfront radiation therapy of symptomatic metastatic site (excluded brain metastases)
is permissible if causing patient pain or impending fracture
- Patients with bone metastases are eligible. However, to assess response after
radiation for bone metastases, must order at least diagnostic CT scan to measure
response
- For women of childbearing potential, a negative serum or urine pregnancy test within
14 days prior to registration.
- Note: 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)
- Patients positive for human immunodeficiency virus (HIV) on effective anti-retroviral
therapy with undetectable viral load within 6 months and a stable regimen of highly
active anti-retroviral (HAART) HIV-positive patients must have no requirement for
concurrent antibiotics or antifungal agents for the prevention of opportunistic
infections
- The patient or a legally authorized representative must provide study-specific
informed consent prior to study entry
Exclusion Criteria:
- Metastatic disease invading the liver (> 3 metastases), heart or > 10 metastatic sites
detectable after induction systemic therapy. Each visible bone metastasis on
radiographic scan count as one site. For site of bony metastases, must order
diagnostic CT scan for assessment of response
- Intracranial, visible brain metastases on radiographic imaging before induction
system therapy is excluded
- Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free
for 5 years prior to randomization. Cancers with a negligible risk of metastasis or
death (e.g., expected 5-year OS > 90%) treated with expected curative outcome are
eligible (such as adequately treated carcinoma in situ of the cervix or oral cavity;
localized prostate cancer treated surgically with curative intent, or ductal carcinoma
in situ treated surgically with curative intent)
- Prior radiotherapy in the thorax that would result in overlapping radiation therapy
(RT) fields, unless the overlapping fields meet dose constraints for this trial
- History of autoimmune disease, including, but not limited to: systemic lupus
erythematosus; rheumatoid arthritis; inflammatory bowel disease (e.g. Crohn's,
ulcerative colitis); vascular thrombosis associated with antiphospholipid syndrome;
Wegener's granulomatosis; Sjogren's syndrome; Guillain-Barre syndrome; multiple
sclerosis; vasculitis; or glomerulonephritis. Note: the follow are eligible:
- Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid
replacement hormone are eligible
- Patients with controlled type 1 diabetes mellitus on a stable insulin regimen are
eligible
- Patients with eczema, psoriasis, lichen simplex chronicus of vitiligo with
dermatologic manifestations only (e.g., patients with psoriatic arthritis would
be excluded) are permitted provided that they meet the following conditions:
- Patients with psoriasis must not have ocular manifestations within the past
year
- Rash must cover less than 10% of body surface area (BSA)
- Disease is well controlled on topical steroids (e.g., hydrocortisone 2.5%,
hydrocortisone butyrate 0.1%, fluocinolone 0.01%, desonide 0.05%,
alclometasone dipropionate 0.05%)
- No acute exacerbations of underlying condition within the last 12 months
(not requiring psoralen plus ultraviolet A radiation [PUVA], methotrexate,
retinoids, biologic agents, oral calcineurin inhibitors or oral steroids)
- Severe, active co-morbidity defined as follows:
- Any other diseases, metabolic dysfunction, physical examination finding, or
clinical laboratory finding giving reasonable suspicion of a disease or condition
that contraindicates the use of an investigational drug or that may affect the
interpretation of the results or render the patient at high risk from treatment
complications;
- Active tuberculosis;
- Known clinically significant liver disease, including active viral, alcoholic, or
other hepatitis; cirrhosis; fatty liver; and inherited liver disease
- Patients with past or resolved hepatitis B infection (defined as having a
negative hepatitis B surface antigen [HBsAg] test and a positive anti-HBc
[antibody to hepatitis B core antigen] antibody test) are eligible
- Patients positive for hepatitis C virus (HCV) antibody are eligible only if
polymerase chain reaction (PCR) is negative for HCV ribonucleic acid (RNA).
(The HCV RNA test must be performed for patients who have a positive HCV
antibody test)
- Known immunosuppressive disease, for example history of bone marrow transplant or
chronic lymphocytic leukemia (CLL);
- Chronic obstructive pulmonary disease (COPD) requiring chronic oral steroid
therapy of > 10 mg prednisone daily or equivalent at the time of registration.
Inhaled corticosteroids are not exclusionary;
- Unstable angina and/or congestive heart failure requiring hospitalization within
the last 3 months;
- History of recent myocardial infarction within 6 months prior to registration.
- Clinically significant interstitial lung disease
- Pregnancy: Administration of atezolizumab may have an adverse effect on pregnancy and
poses a risk to the human fetus, including embryo-lethality. Women of child-bearing
potential and men must agree to use adequate contraception (hormonal or barrier method
of birth control; abstinence) prior to study entry, for the duration of study
treatment, and for 5 months (150 days) after the last dose of study agent. Should a
woman become pregnant or suspect she is pregnant while she or her partner is
participating in this study, she should inform her treating physician immediately
- Women who are breastfeeding and unwilling to discontinue
- History of allogeneic organ transplant
- Patients who have had immunotherapy-induced pneumonitis
