Avelumab and Stereotactic Body Radiation Therapy in Treating Patients with Non-responsive or Progressive Metastatic Non-small Cell Lung Cancer Previously Treated with Checkpoint Inhibitor
This pilot early phase I trial studies how well avelumab and stereotactic body radiation therapy (stereotactic ablative radiotherapy) work in treating patients with non-small cell lung cancer previously treated with a checkpoint inhibitor that has spread to other parts of the body and is non-responsive or growing, spreading, or getting worse. Immunotherapy with monoclonal antibodies, such as avelumab, may help the body’s immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Stereotactic body radiation therapy uses special equipment to position a patient and deliver radiation to tumors with high precision. This method can kill tumor cells with fewer doses over a shorter period and cause less damage to normal tissue. Giving avelumab and stereotactic body radiation therapy may kill more tumor cells and work better in treating patients with non-small cell lung cancer.
- Signed informed consent
- Ability to comply with the protocol
- Histologically proven metastatic non-small cell lung cancer
- At least two sites of measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1; one of which must be amenable to treatment with SAR and accessible for a mandatory pre-treatment biopsy and a post-treatment biopsy at physician discretion; if a pulmonary nodule is being considered for SAR it must range in size from 0.5-6 cm
- Have provided written consent for protocol directed biopsies
- Patients with treated supratentorial metastases are allowed if stable, the patient is off steroids or on a stable or decreasing dose of =< 10 mg daily prednisone (or equivalent) and no evidence of intracranial hemorrhage
- Archival tumor sample available; a minimum of 10 unstained slides; no fine needle aspiration (FNAs) allowed or tumor tissue from bone
- Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1
- Life expectancy >= 3 months
- Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (obtained within 14 days of the first study treatment)
- Platelet count >= 100 x 10^9/L (obtained within 14 days of the first study treatment)
- Hemoglobin >= 9 g/dL (may have been transfused) (obtained within 14 days of the first study treatment)
- Total bilirubin level =< 1.5 x the upper limit of normal (ULN) range (obtained within 14 days of the first study treatment)
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels =< 2.5 x ULN (obtained within 14 days of the first study treatment) or AST and ALT levels =< 5 x ULN (for subjects with documented metastatic disease to the liver)
- International normalized ratio (INR) and activated partial thromboplastin time (aPTT) =< 1.5 x ULN (obtained within 14 days of the first study treatment) (for patients on anticoagulation they must be receiving a stable dose for at least 1 week prior to randomization)
- Creatinine clearance >= 30 mL/min by Cockcroft-Gault formula (or local institutional standard method) (obtained within 14 days of the first study treatment)
- No history of severe hypersensitivity reactions to other monoclonal antibodies (mAbs)
- No other active malignancy
- No active autoimmune disease or a history of known or suspected autoimmune disease except as detailed in the exclusion criteria below
- No chemotherapy or radiotherapy within the past 28 days
- Any number of prior treatments is allowed; must have failed at least one treatment regimen for metastatic disease and must have failed platinum-based chemotherapy (including as treatment for localized disease), be deemed ineligible for platinum-based therapy by the treating medical oncologist, or refused platinum-based therapy
- Previously treated with a PD-1 inhibitor or PD-L1 inhibitor as either monotherapy or as part of a combination therapy with progression
- Highly effective contraception for both male and female subjects if the risk of conception exists; (Note: the effects of the trial drug on the developing human fetus are unknown; thus, women of childbearing potential and men able to father a child must agree to use 1 highly effective method of contraception, defined as methods with a failure rate of less than 1% per year; highly effective contraception is required at least 28 days prior, throughout and for at least one month after the last dose of avelumab treatment)
- Negative serum pregnancy test at screening for women of childbearing potential
- Patients whose tumors contain activating EGFR mutations or ALK rearrangement should be excluded from this study, unless disease has progressed on all available, approved therapies targeting the EGFR mutation or ALK rearrangement
- All subjects with brain metastases, except those meeting the following criteria: * Brain metastases that have been treated locally and are clinically stable for at least 2 weeks prior to enrollment * No ongoing neurological symptoms that are related to the brain localization of the disease (sequelae that are a consequence of the treatment of the brain metastases are acceptable) * Subjects must be either off steroids or on a stable or decreasing dose of =< 10 mg daily prednisone (or equivalent)
- Leptomeningeal disease
- Uncontrolled pleural or pericardial effusion or ascites that would require recurrent drainage
- Uncontrolled tumor related pain
- Uncontrolled hypercalcemia
- Pregnant and lactating women
- Uncontrolled concomitant disease
- Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure (>= New York Heart Association classification class II), or serious cardiac arrhythmia requiring medication
- Significant acute or chronic infections including, among others: * Known history of testing positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS) * Positive test for hepatitis B virus (HBV) surface antigen and / or confirmatory hepatitis C virus (HCV) ribonucleic acid (RNA) (if anti-HCV antibody tested positive)
- Oral or IV antibiotics within 2 weeks prior to enrollment
- Active tuberculosis
- Known severe hypersensitivity reactions to monoclonal antibodies (grade >= 3 National Cancer Institute [NCI]-Common Terminology Criteria for Adverse Events [CTCAE] version [v] 4.03), any history of anaphylaxis, or uncontrolled asthma (that is, 3 or more features of partially controlled asthma)
- Known hypersensitivity or allergy to any component of the avelumab formulation
- Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent: * Subjects with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible * Subjects requiring hormone replacement with corticosteroids are eligible if the steroids are administered only for the purpose of hormonal replacement and at doses =< 10 mg or 10 mg equivalent prednisone per day * Administration of steroids through a route known to result in a minimal systemic exposure (topical, intranasal, intro-ocular, or inhalation) are acceptable
- Patients with a prior allogeneic bone marrow transplantation or prior solid organ transplantation
- History of idiopathic pulmonary fibrosis (including pneumonitis), drug-induced pneumonitis, organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia), or evidence of active pneumonitis on screening chest computed tomography (CT) scan; a history of radiation pneumonitis in the radiation field (fibrosis) is permitted
- Treatment with systemic immunostimulatory agents (including but not limited to interferons or interleukin-2) within 4 weeks or five half-lives of the drug, whichever is shorter, prior to enrollment
- Persisting toxicity related to prior therapy of grade > 1 NCI-CTCAE v 4.03; however, alopecia and sensory neuropathy grade =< 2 is acceptable
- Known alcohol or drug abuse
- Any psychiatric condition that would prohibit the understanding or rendering of informed consent
- Current severe acute or chronic colitis, inflammatory bowel disease, pneumonitis, pulmonary fibrosis
- Other severe acute or chronic medical conditions including colitis, inflammatory bowel disease, pneumonitis, pulmonary fibrosis or psychiatric conditions including recent (within the past year) or active suicidal ideation or behavior; or laboratory abnormalities that may increase the risk associated with study participation or study treatment administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study
- Vaccination within 4 weeks of the first dose of avelumab and while on trial is prohibited except for administration of inactivated vaccines
- Current use of immunosuppressive medication, EXCEPT for the following: * Intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-articular injection) * Systemic corticosteroids at physiologic doses =< 10 mg/day of prednisone or equivalent * Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication)
Locations & Contacts
Contact: Megan Eileen Daly
Trial Objectives and Outline
I. To estimate objective overall response rate (ORR) of unirradiated lesions following stereotactic ablative radiotherapy (SAR) to a single metastatic lesion with concurrent avelumab in primary and secondary non-responders to a checkpoint inhibitor.
I. To determine the safety and toxicity profile of SAR with avelumab in checkpoint inhibitor progressors and non-responders.
II. To estimate progression-free survival following avelumab + SAR to a single metastatic lesion in primary and secondary non-responders to checkpoint inhibition.
I. To estimate ORR using the immune-related response criteria (iRECIST) of unirradiated lesions following SAR to a single metastatic lesion with concurrent avelumab in primary and secondary non-responders to a checkpoint inhibitor.
II. To explore the influence of SAR-associated tumor and critical organ dosimetry on clinical outcomes.
I. To bank blood and tissue specimens for use in future correlative studies.
Patients receive avelumab intravenously (IV) over 60 minutes on day 1. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity. Beginning on day 1 of course 1, patients also undergo SAR every 2 days for a total of 5 fractions.
After completion of study treatment, patients are followed up for 90 days.
Trial Phase & Type
No phase specified
University of California Davis Comprehensive Cancer Center
Megan Eileen Daly
Secondary IDs NCI-2017-01969
Clinicaltrials.gov ID NCT03158883