Carcinoma, Non-Small-Cell Lung Clinical Trial
Official title:
Randomized Phase I/II Study of Ablative Radiotherapy +/- MEDI 4736 (Durvalumab) for Medically Inoperable Early-Stage Non-Small Cell Lung Cancer
Verified date | December 2023 |
Source | Jonsson Comprehensive Cancer Center |
Contact | n/a |
Is FDA regulated | No |
Health authority | |
Study type | Interventional |
This study uses durvalumab (MEDI 4736), an experimental type of drug made by Astra Zeneca Pharmaceuticals, (limited partnership) LP, which in early studies has shown to possibly reduce the growth of certain types of lung cancer. The Investigators will enroll up to 105 subjects into the study. After an initial safety sample of 15 individuals receiving durvalumab (MEDI 4736) and Stereotactic Ablative Body Radiotherapy (SABR), if it is shown to be safe to administer this combination of therapies, the next enrolled subjects will be randomized in a 1:1 fashion (each subject with a "50-50 chance" like the flip of a coin) to receive either SABR and durvalumab (MEDI 4736), or SABR alone. Once treatment is completed, all subjects will return to the University of California at Los Angeles (UCLA) for regular follow-up visits to check on their health and outcomes. At visits both prior to and after treatment special blood samples will be drawn to be studied by UCLA scientists to look into the basic science aspects of how durvalumab (MEDI 4736) and radiation work in the body. It is hoped that we will learn more about the basic safety and science of durvalumab (MEDI 4736) combined with Stereotactic Ablative Body Radiotherapy (SABR) vs. SABR alone, while extending the life and quality of life of these subjects.
Status | Active, not recruiting |
Enrollment | 18 |
Est. completion date | June 1, 2025 |
Est. primary completion date | June 1, 2024 |
Accepts healthy volunteers | No |
Gender | All |
Age group | 18 Years and older |
Eligibility | Inclusion Criteria: For inclusion in the study subjects must fulfill all of the following criteria: 1. Written informed consent obtained from the patient/legal representative prior to performing any protocol-related procedures, including screening evaluation. 2. Newly diagnosed, untreated, biopsy proven non-small cell lung cancer. 3. Medically inoperable or patient refusal to surgery as defined by any single of the following criteria: a. Determined unfit for surgery by thoracic surgeon or radiation oncologist as documented in the medical record b. Pulmonary function test (PFTS) showing Forced Expiratory Volume in the first second (FEV1) = 1.2 L or diffusing Lung Capacity (DLC) <60%, c. Poor exercise tolerance or failed pre-operative cardiac work-up, d. Patient refusal to undergo definitive surgery as documented in clinical note by a surgeon, pulmonologist, medical oncologist, or radiation oncologist. 4. Clinically stage I disease by American Joint Committee on Cancer (AJCC) 7th edition. (N0, M0, T stages T1-T2a) or patients with stage T2bN0M0 (clinical stage IIA) disease 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. 5. Age > 18 years at time of study entry. 6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 - 1. 7. Adequate normal organ and marrow function as defined below: - Haemoglobin = 9.0 g/dL. - Absolute neutrophil count (ANC) = 1.5 x 109/L (> 1500 per mm3). - Platelet count = 100 x 109/L (>100,000 per mm3). - 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 glutamic pyruvic transaminase (SGPT) = 2.5 x institutional upper limit of normal unless liver metastases are present, in which case it must be = 5x ULN. - Serum creatinine creatinine clearance (CL) >40 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine collection for determination of creatinine clearance: Males: Creatinine CL (mL/min) = Weight (kg) x (140 - Age) . 72 x serum creatinine (mg/dL) Females: Creatinine CL (mL/min) = Weight (kg) x (140 - Age) x 0.85 72 x serum creatinine (mg/dL) 8. 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. 9. 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. Exclusion Criteria: 1. ECOG Performance status >1. 2. Patients with metastatic or node positive NSCLC. 3. Patients with prior radiation therapy to the same bronchopulmonary segment. 4. 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. a. However, 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. 5. Patients with history of idiopathic pulmonary fibrosis, idiopathic pneumonitis, drug induced pneumonitis, or evidence of active pneumonitis on screening chest CT scan. 6. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site). 7. Participation in another clinical study with an investigational product during the last 6 months. 8. Any previous treatment with a Programmed Death-1 (PD1) or Programmed Death-Ligand 1(PD-L1) inhibitor, including durvalumab, and therapeutic anticancer vaccine. 9. History of another primary malignancy except for: 1. 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. 2. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease. 3. Adequately treated carcinoma in situ without evidence of disease e.g., cervical cancer in situ. 10. Mean QT interval corrected for heart rate (QTc) =470 ms calculated from 3 electrocardiograms (ECGs) using Frediricia's Correction. 11. 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. 12. Any unresolved = Grade 2 pulmonary toxicity from previous anti-cancer therapy. 13. Any prior Grade =3 immune-related adverse event (irAE) while receiving any previous immunotherapy agent, or any unresolved irAE >Grade 1. 14. History of primary immunodeficiency. 15. History of allogeneic organ transplant. 16. History of hypersensitivity to durvalumab or any excipient. 17. 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. 18. Known history of previous clinical diagnosis of tuberculosis. 19. History of leptomeningeal carcinomatosis. 20. Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving durvalumab. 21. 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. 22. Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results. 23. Subjects with uncontrolled seizures. - |
Country | Name | City | State |
---|---|---|---|
Australia | Peter MacCallum Cancer Centre | Melbourne E. | Victoria |
United States | University of Colorado | Denver | Colorado |
United States | Jonsson Comprehensieve Cancer Center | Los Angeles | California |
United States | New York Weill Cornell Cancer Center at Cornell University | New York | New York |
Lead Sponsor | Collaborator |
---|---|
Jonsson Comprehensive Cancer Center | AstraZeneca |
United States, Australia,
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Other | germline mutations as indicators | Germline mutations as determined by DNA sequencing will be studied to see if these mutations can predict a patients' response to treatment and treatment-related toxicities. | 2 years | |
Other | nonsynonymous mutational load and intratumoral heterogeneity as indicators | Tumor genetics (nonsynomonous mutational load and intratumoral heterogeneity) will be evaluated as possible indicators for clinical outcome (progression-free survival, overall survival, and toxicity) in patients receiving radiation therapy alone and patients treated with radiation therapy with durvalumab (MEDI 4736) . | 2 years | |
Other | Changes to circulating lymphocytes as indicators | changes to circulating lymphocytes including cluster of differentiation 8 (CD-8), Tumor (T)-regulatory cells, and myeloid suppressor cells before, during and after radiation therapy alone or in combination with durvalumab (MEDI 4736) and correlations with progression free-survival, overall survival and toxicity | 2 years | |
Primary | Phase I: The number and severity of study participants' treatment-related adverse events as assessed by CTCAE v4.0. | the safety and tolerability associated with radiation therapy and durvalumab (MEDI 4736) | 4 months | |
Primary | Phase II: Median Progression-Free Survival | Progression Free Survival for patients treated with radiation therapy with and without durvalumab (MEDI 4736) will be determined by both the 2-year progression free survival rate (percentage) and the median progression free survival (in years). | 2 year | |
Secondary | Overall survival | the efficacy of radiation therapy and durvalumab in terms of overall survival | 2 year | |
Secondary | Primary Tumor Control | the efficacy of radiation therapy and durvalumab in terms of primary tumor control | 2 year | |
Secondary | Intralobar recurrence rates | the efficacy of radiation therapy and durvalumab in terms of intralobar recurrence rates | 2 year | |
Secondary | mediastinal recurrences | the efficacy of radiation therapy and durvalumab in terms of mediastinal recurrences | 2 year | |
Secondary | hilar and mediastinal recurrences | the efficacy of radiation therapy and durvalumab in terms of hilar and mediastinal recurrences | 2 year | |
Secondary | rate of distant recurrences | the efficacy of radiation therapy and durvalumab (MEDI 4736) in terms of the rate of distant recurrences | 2 years | |
Secondary | rates of grade 3 or higher non-hematological toxicities | rates of grade 3 or higher non-hematological toxicities with the combination of radiation therapy and durvalumab MEDI 4736) | 2 years |
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