Stereotactic Body Radiation Therapy with or without Durvalumab in Treating Patients with Stage I-IIA Non-small Cell Lung Cancer That Cannot Be Removed by Surgery
This randomized phase I/II trials studies how will stereotactic body radiation therapy with or without durvalumab work in treating patients with stage I-IIA non-small cell lung cancer that cannot be removed by surgery. 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. Monoclonal antibodies, such as durvalumab, may interfere with the ability of tumor cells to grow and spread. It is not yet known whether stereotactic body radiation therapy with or without durvalumab may work better in treating patients with stage I-IIA non-small cell lung cancer.
Inclusion Criteria
- Written informed consent obtained from the patient/legal representative prior to performing any protocol-related procedures, including screening evaluation
- Newly diagnosed, untreated, biopsy proven non-small cell lung cancer
- Medically inoperable or patient refusal to surgery as defined by any single of the following criteria * Determined unfit for surgery by thoracic surgeon or radiation oncologist as documented in the medical record * Pulmonary function tests (PFTs) showing forced expiratory volume in 1 second (FEV1) =< 1.2 L or diffusion capacity of the lung (DLC) < 60% * Poor exercise tolerance or failed pre-operative cardiac work-up * Patient refusal to undergo definitive surgery as documented in clinical note by a surgeon, pulmonologist, medical oncologist, or radiation oncologist
- Clinically stage I disease by American Joint Committee on Cancer (AJCC) 7th edition (N0, M0, T stages T1-T2a) or patients with stage T2bN0M0 disease (clinical stage IIA), as determined by a computed tomography (CT) chest, abdomen, pelvis or a positron emission tomography (PET) CT =< 60 days of treatment start, who are medically unfit for standard of care chemotherapy as documented by a medical oncologist or radiation oncologist, or who refuse standard of care chemotherapy as documented by a medical oncologist or radiation oncologist
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 – 1
- Hemoglobin >= 9.0 g/dL
- Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (>= 1500 per mm^3)
- Platelet count >= 100 x 10^9/L (>= 100,000 per mm^3)
- Serum bilirubin =< 1.5 x institutional upper limit of normal (ULN); this will not apply to subjects 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
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal
- Serum creatinine clearance (CL) > 15 mL/min by the Cockcroft-Gault formula or by 24-hour urine collection for determination of creatinine clearance
- Female subjects must either be of non-reproductive potential (i.e., post-menopausal by history: >= 60 years old and no menses for 1 year without an alternative medical cause; OR history of hysterectomy, OR history of bilateral tubal ligation, OR history of bilateral oophorectomy) or must have a negative serum pregnancy test upon study entry
- Female subjects of child bearing potential and male subjects with partners of child bearing potential must agree to adequate contraceptive measures
- Subject 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
- Screening electrocardiogram (EKG) with corrected QT interval (QTc) < 470 ms
Exclusion Criteria
- ECOG performance status > 1
- Patients with metastatic or node positive non-small cell lung cancer (NSCLC)
- Patients with prior radiation therapy to the same bronchopulmonary segment
- History of automimmune disease including myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematous, rheumatoid arthritis, inflammatory bowel disease (e.g., Crohn’s disease, ulcerative colitis), vascular thrombosis associated with antiphospholipid syndrome, Wegner’s granulomatosis, Sjogren’s syndrome, Guillain-Barre syndrome, multiple sclerosis, or glomerulonephritis * Note: Patients with type 1 diabetes mellitus, vitiligo, alopecia, hypothyroidism requiring hormone replacement, Graves disease, or skin disorders not requiring systemic treatment are permitted to enroll
- Patients with history of idiopathic pulmonary fibrosis, idiopathic pneumonitis, drug induced pneumonitis, or evidence of active pneumonitis on screening chest CT (or PET CT) scan
- Involvement in the planning and/or conduct of the study in the present study
- Participation in another clinical study with an investigational product during the last 4 weeks
- Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab, and therapeutic anticancer vaccine
- History of another primary malignancy except for: * Malignancy treated with curative intent and with no known active disease * >= 5 years before the first dose of study drug 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 e.g., cervical cancer in situ
- Current or prior use of immunosuppressive medication within 28 days before the first dose of durvalumab, 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
- Any unresolved >= grade 2 pulmonary toxicity from previous anti-cancer therapy
- Any prior grade >= 3 immune-related adverse event (irAE) while receiving any previous immunotherapy agent, or any unresolved irAE > grade 1
- History of primary immunodeficiency
- History of allogeneic organ transplant
- History of hypersensitivity to durvalumab or any excipient
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active bleeding diatheses including any subject known to have evidence of acute or chronic hepatitis B, hepatitis C or human immunodeficiency virus (HIV), or psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the subject to give written informed consent
- Known active tuberculosis
- History of leptomeningeal carcinomatosis
- Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving durvalumab
- Female subjects who are pregnant, breast-feeding or male or female patients of reproductive potential who are not employing an effective method of birth control
- Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results
- Subjects with uncontrolled seizures
- Subjects who on screening EKG have a QTc >= 470 ms
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT03148327.
PRIMARY OBJECTIVES:
I. To determine the safety and tolerability profile with radiation therapy and durvalumab. (Phase I)
II. To determine the median progression-free survival (PFS) and 2 year PFS with radiation therapy and durvalumab combination versus radiation therapy alone combination versus radiation therapy alone. (Phase II)
SECONDARY OBJECTIVES:
I. To assess the efficacy of radiation therapy and durvalumab in terms of overall survival.
II. To assess the efficacy of radiation therapy and durvalumab in terms of primary tumor control.
III. To assess the efficacy of radiation therapy and durvalumab in terms of intralobar recurrence rates.
IV. To assess the efficacy of radiation therapy and durvalumab in terms of mediastinal recurrences.
V. To assess the efficacy of radiation therapy and durvalumab in terms of hilar and mediastinal recurrences.
VI. To assess the efficacy of radiation therapy and durvalumab in terms of the rate of distant recurrences.
VII. To assess rates of grade 3 or higher non-hematological toxicities with the combination of radiation therapy and durvalumab.
EXPLORATORY OBJECTIVES:
I. To assess if germline mutations predict rate of progression free-survival, overall survival and toxicity with radiation therapy alone or radiation therapy in combination with durvalumab.
II. To assess nonsynonmous mutational load and intratumoral heterogeneity as predictive markers for clinical outcome (progression-free survival, overall survival, and toxicity) in patients treated with radiation therapy alone versus radiation therapy and durvalumab, using next generation sequencing of baseline and relapsed tumors.
III. To assess changes to circulating lymphocytes including CD-8, T-regulatory cells, and myeloid suppressor cells before, during and after radiation therapy alone or in combination with durvalumab and correlations with progression free-survival, overall survival and toxicity.
OUTLINE: Patients are randomized to 1 of 2 regimens.
REGIMEN A: Patients receive durvalumab intravenously (IV) over 1 hours on day -5 and once every 4 weeks for up to 4 doses in the absence of disease progression or unacceptable toxicity. Patients also undergo stereotactic body radiation therapy starting on day 0 in 3, 4, or 10 fractions.
REGIMEN B: Patients undergo stereotactic body radiation therapy starting on day 0 in 3, 4, or 10 fractions.
After completion of study treatment, patients are followed for 2 years.
Trial PhasePhase I/II
Trial Typetreatment
Lead OrganizationUCLA / Jonsson Comprehensive Cancer Center
Principal InvestigatorAnn Raldow
- Primary ID17-000004
- Secondary IDsNCI-2017-00954
- ClinicalTrials.gov IDNCT03148327