Durvalumab and Radiation Therapy with or without Tremelimumab in Treating Patients with Stage III Non-Small Cell Lung Cancer That Can Be Removed by Surgery
This phase II trials studies the side effects and best dose of durvalumab and radiation therapy with or without tremelimumab in treating patients with stage III non-small cell lung cancer that can be removed by surgery. Immunotherapy with monoclonal antibodies, such as durvalumab and tremelimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. It is not yet known whether durvalumab and radiation therapy with or without tremelimumab will work better in treating patients with non-small cell lung cancer.
- Written informed consent and any locally‐required authorization (e.g., Health Insurance Portability and Accountability Act [HIPAA] in the United States of America [USA], European Union [EU] Data Privacy Directive in the EU) obtained from the subject prior to performing any protocol‐related procedures, including screening evaluations
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- Life expectancy of >= 6 months
- Body weight > 30kg
- 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 unless liver metastases are present, in which case it must be =< 5 x ULN
- Serum creatinine clearance (CL) > 40 mL/min by the Cockcroft‐Gault formula or by 24‐hour urine collection for determination of creatinine clearance
- Subjects with a histologically‐confirmed diagnosis of stage III non‐small cell lung cancer
- Subjects with non‐small cell lung cancer that has been deemed surgically resectable with lobectomy, by an attending thoracic surgeon
- Evidence of post‐menopausal status or negative urinary or serum pregnancy test for female pre‐menopausal subjects. 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)
- 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
- Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site)
- Participation in another clinical study with an investigational product during the last 4 weeks or the equivalent of 5 half‐lives of the first dose of study treatment, whichever is shorter
- 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
- Any previous treatment with a PD1 or PD‐L1 agent including durvalumab or an CTLA‐4 drug, including tremelimumab
- Any unresolved toxicity National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) grade >= 2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria
- Subjects with grade >= 2 neuropathy will be evaluated on a case‐by‐case basis after consultation with the study physician
- Subjects with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab may be included only after consultation with the study physician
- Any concurrent chemotherapy, investigational product (IP), biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non‐cancer‐related conditions (e.g., hormone replacement therapy) is acceptable
- Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks of the first dose of study drug
- Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of IP. Note: Local surgery of isolated lesions for palliative intent is acceptable
- History of allogenic organ transplantation
- Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc]). The following are exceptions to this criterion: subjects with vitiligo or alopecia, subjects with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement, any chronic skin condition that does not require systemic therapy, subjects without active disease in the last 5 years may be included but only after consultation with the study physician, subjects with celiac disease controlled by diet alone
- Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, 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
- 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 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
- History of active primary immunodeficiency
- Active infection including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings, and tuberculosis [TB] testing in line with local practice), hepatitis B (known positive hepatitis B virus [HBV] surface antigen [HBsAg] result), hepatitis C, or human immunodeficiency virus [positive HIV 1/2 antibodies]). Subjects with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody [anti‐HBc] and absence of HBsAg) are eligible. Subjects positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV ribonucleic acid (RNA)
- Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab or tremelimumab. 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., computed tomography [CT] scan premedication)
- Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note: Subjects, if enrolled, should not receive live vaccine whilst receiving IP and up to 30 days after the last dose of IP
- Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients
- Prior randomization or treatment in a previous durvalumab and/or tremelimumab clinical study regardless of treatment arm assignment
- Has history of (non‐infectious) pneumonitis that required steroids, evidence of interstitial lung disease or active, non‐infectious pneumonitis
- Prior history of thoracic irradiation for any indication
- Subjects who are only deemed suitable for surgical management of stage III NSCLC with pneumonectomy, as determined by an attending thoracic surgeon
- Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results
- Female patients who are pregnant or breastfeeding or male or female patients of reproductive potential who are not willing to employ or employing an effective method of birth control from screening to 180 days after the last dose of durvalumab + tremelimumab combination therapy or 100 days after the last dose of durvalumab monotherapy, whichever is the longer time period
- Uncontrolled psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the subject to give written consent
- If a patient withdraws from participation in the study, then his or her enrollment code cannot be reused. Withdrawn patients will not be replaced
Locations & Contacts
Trial Objectives and Outline
I. Evaluate the safety and tolerability of preoperative ‘immunoradiation’ with durvalumab (cohort 1) +/‐ durvalumab plus tremelimumab (cohort 2) concurrent with and after thoracic radiation (45Gy in 25 fractions), followed by surgery, in patients with resectable stage III non-small cell lung cancer (NSCLC).
II. Evaluate the feasibility of preoperative ‘immunoradiation’ with durvalumab (cohort 1) +/‐ durvalumab plus tremelimumab (cohort 2) concurrent with and after thoracic radiation, followed by surgery, in patients with resectable stage III NSCLC.
I. Examine pathologic responses in post‐treatment resection specimens, in patients with resectable stage III NSCLC treated with preoperative immunoradiation followed by surgery.
II. Examine radiologic responses in stage III resectable NSCLC treated with preoperative immunoradiation, using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and immune‐related (ir) RECIST criteria.
III. Evaluate recurrence‐free survival (RFS) in patients with stage III resectable NSCLC treated with preoperative immunoradiation followed by surgery, where RFS is defined as the time from commencement of therapy until the development of local or distant recurrent disease.
IV. Evaluate surgical morbidity and mortality in patients with stage III resectable NSCLC treated with preoperative immunoradiation followed by surgery, where morbidity is defined as the number treatment‐related adverse events (AEs), and mortality is the number of deaths, from the day of surgery until 30 days postoperatively or 100 days after the last dose of immunotherapy, whichever is longer.
V. Evaluate overall survival (OS) in patients with stage III resectable NSCLC treated with preoperative immunoradiation followed by surgery, where OS is defined as the time from commencement of therapy until death from any cause.
I. Examine changes in the genomic and neoantigen landscapes, T-cell receptor (TCR) repertoire, circulating tumor deoxyribonucleic acid (ctDNA) and immune reactivity pre and post immunoradiation both systemically and in the tumor microenvironment, in patients with stage III resectable NSCLC treated with preoperative immunoradiation followed by surgery.
OUTLINE: Patients are assigned to 1 of 2 cohorts.
COHORT I: Patients receive durvalumab intravenously (IV) over 60 minutes on day 1. Treatment repeats every 4 weeks for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Patients concurrently undergo radiation therapy once daily (QD) 5 days a week for 5 weeks. After 6-8 weeks, patients undergo a lobectomy.
COHORT II: Patients receive durvalumab IV over 60 minutes and tremelimumab IV over 60 minutes each on day 1. Treatment repeats every 4 weeks for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Patients concurrently undergo radiation therapy QD 5 days a week for 5 weeks. After 6-8 weeks, patients undergo a lobectomy.
After completion of study treatment, patients are followed up at 30 days, 100 days, and then every 12 weeks.
Trial Phase & Type
Johns Hopkins University / Sidney Kimmel Cancer Center
Secondary IDs NCI-2018-03088, IRB00127418, CRMS-66593
Clinicaltrials.gov ID NCT03237377