Testing the Addition of an Antibody to Standard Chemoradiation followed by the Antibody for One Year to Standard Chemoradiation followed by One Year of the Antibody in Patients with Unresectable Stage III Non-Small Cell Lung Cancer
- STEP 1 INCLUSION ELIGIBILITY CRITERIA - CONCURRENT THERAPY
- Patient must have one of the following: * Newly diagnosed stage IIIA/B/C non-small cell lung cancer (NSCLC) (per the American Joint Committee on Cancer [AJCC] 8th edition) that is unresectable and is histologically and/or cytologically confirmed * Nodal recurrence after surgery for early stage NSCLC
- Patient must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- Body weight > 30 kg of patients
- Patient should have a life expectancy greater than 12 weeks
- Patient must have a baseline electrocardiography (ECG) obtained within 6 weeks of registration
- Patient must have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1. Baseline imaging assessments and measurements used to evaluate all measurable or non-measurable sites of disease must be done within 4 weeks prior to registration
- Absolute neutrophil count (ANC) >= 1500 cells/uL (obtained =< 7 days prior to registration)
- White blood cells (WBC) counts >= 2500/uL (obtained =< 7 days prior to registration)
- Platelet count >= 100,000/uL (obtained =< 7 days prior to registration)
- Hemoglobin >= 9.0 g/dL (obtained =< 7 days prior to registration)
- Total bilirubin =< 1.5 x upper limit of normal (ULN) with the following exception: patients with known Gilbert disease who have serum bilirubin level < 3 x ULN may be enrolled (obtained =< 7 days prior to registration)
- Aspartate aminotransferase (AST) and alanine transaminase (ALT) =< 3.0 x ULN (obtained =< 7 days prior to registration)
- Serum creatinine =< 1.5 x ULN or creatinine clearance >= 50 mL/min on the basis of the Cockcroft-Gault glomerular filtration rate estimation (obtained =< 7 days prior to registration)
- International normalized ratio (INR) and activated partial thromboplastin time (aPTT) =< 1.5 x ULN (obtained =< 7 days prior to registration)
- Patient must have pulmonary function tests (PFTs) with both forced expiratory volume in 1 second (FEV1) and diffusion capacity of the lung for carbon monoxide (DLCO) >= 40% of predicted, obtained within 5 months of registration
- Patient should be expected to have lung volume (V)20 of =< 35%
- Patients with nodal recurrence after surgery for early-stage NSCLC are eligible if the following criteria are met: * No prior chemotherapy or radiation was ever administered for this lung cancer * Prior curative-intent surgery was at least 90 days prior to the nodal recurrence * No prior radiation was administered to the region of study cancer that would cause overlap of treatment fields
- Patients who are human immunodeficiency virus (HIV) positive may participate in the study IF they meet all of the following eligibility requirements: * They must be stable on their anti-retroviral regimen, and they must be healthy from an HIV perspective * They must have a CD4 count of greater than 250 cells/mcL * They must not be receiving prophylactic therapy for an opportunistic infection
- Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial. Patients must not have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to registration
- Women must not be pregnant or breast-feeding due to the potential harm to an unborn fetus and possible risk for adverse events in nursing infants with the treatment regimens being used. Patients must also not expect to conceive or father children from the time of registration, while on study treatment, and until 90 days after the last dose of study treatment
- All females of childbearing potential must have a negative blood test or urine study, with a minimum sensitivity 50 mlU/L or equivalent units of human chorionic gonadotropin (HCG), within 7 days prior to registration to rule out pregnancy. A female of childbearing potential is any woman, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy; or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e. has had menses at any time in the preceding 24 consecutive months)
- Women of childbearing potential (WOCBP) and males who are sexually active with WOCBP must use accepted and highly effective method(s) of contraception during sexual intercourse for at least one week prior to the start of treatment, during protocol treatment, and continue for 90 days after the last dose of protocol treatment * Highly effective methods of contraception include Etonogestrel-releasing implants (Implanon or Norplant), Intravaginal: Ethinylestradiol/etonogestrel-releasing intravaginal devices: e.g., NuvaRing, injection: Medroxyprogesterone injection: e.g., Depo-Provera, combined pill: Normal and low dose combined oral contraceptive pill, patch: Norelgestromin/ethinylestradiol-releasing transdermal system: e.g., Ortho Evra, Minipillc: Progesterone based oral contraceptive pill using desogestrel: Cerazette is currently the only highly effective progesterone based pill * Methods that are considered inadequate include male or female condom with or without spermicide; female cap, diaphragm, or sponge with or without spermicide; non-copper containing intrauterine device; progestogen-only oral hormonal contraceptive pills where inhibition of ovulation is not the primary mode of action [excluding Cerazette/desogestrel which is considered highly effective]; and triphasic combined oral contraceptive pills)
- STEP 2 INCLUSION ELIGIBILITY CRITERIA - CONSOLIDATION
- Patients with any > grade 2 non-hematologic or > grade 3 hematologic toxicities must recover to grade 2 (or less) within 45 days after the end of concurrent chemo/radiation, with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria
- STEP 1 EXCLUSION ELIGIBILITY CRITERIA - CONCURRENT THERAPY
- Patient must not have any active, known or suspected autoimmune disease and neuromuscular paraneoplastic syndromes including, but not limited to myasthenia gravis, Lambert-Eaton myasthenic syndrome, limbic encephalitis, myositis, Guillain-Barré, systemic lupus erythematosus, and systemic sclerosis. Patients with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia), not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are eligible
- Patient must not have a history of active hepatitis B (chronic or acute) or hepatitis C infection. 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 hepatitis C virus ribonucleic acid (HCV RNA)
- Patient must not have a known active tuberculosis infection
- Patient must not have any severe infections within 4 weeks prior to registration including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia
- Patient must not have signs or symptoms of severe infection (sepsis) within 2 weeks prior registration
- Patient must not have been treated with systemic immunostimulatory agents (including but not limited to interferon-a [IFN-a], interleukin [IL]-2) within 6 weeks or five half-lives of the drug (whichever is shorter) prior to registration; or treated with an investigational agent within 4 weeks prior to registration (or within five half-lives of the investigational agent, whichever is longer)
- Patient must not have a history of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
- Patient must not have been treated with systemic immunosuppressive medications (equivalent to > 10 mg prednisone per day) or other immunosuppressive medications within 7 days of registration. Inhaled or topical steroids and adrenal replacement steroid doses equivalent to > 10 mg prednisone per day are permitted in the absence of active autoimmune disease
- Patient must not have had a prior allogeneic bone marrow transplantation or prior solid organ transplantation
- Patient must not have a history of idiopathic pulmonary fibrosis, pneumonitis (including drug induced), organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia, etc.), or evidence of active pneumonitis on screening chest computed tomography (CT) scan within 4 weeks of registration
- Patient must not have had any prior systemic treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell costimulation or immune checkpoint pathways
- Patient with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better. For example, patients must not have the following: * Unstable angina and/or congestive heart failure requiring hospitalization within 180 days prior to registration * Uncontrolled cardiac arrhythmia within 180 days prior to registration
- Patient must not have an 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 adverse events (AEs) or compromise the ability of the patient to give written informed consent
- Patient must not have received a live, attenuated vaccine within 4 weeks prior to registration
- Patient must not have unintentional weight loss > 10% within 30 days prior to registration
- Patient must not have had past radiation to the current intended treatment site
- Patient must not donate blood while on study treatment
- STEP 2 EXCLUSION ELIGIBILITY CRITERIA - CONSOLIDATION
- Patients must not receive any non-protocol anti-cancer therapy after the end of chemo/radiation or during consolidation
- Patients with suspected cases of >= grade 2 pneumonitis (non-infectious) are not eligible for consolidative MEDI4736 (durvalumab) and will proceed onto follow-up instead
- Patients must not have disease progression on the first post-treatment (for concurrent chemo/radiation) chest CT scan, which must be obtained within 14 days after the last dose of radiation therapy. If so, the patient is not eligible for consolidative MEDI4736 (durvalumab) and will proceed onto follow-up instead
Palm Beach Gardens
West Palm Beach
Elk Grove Village
West Des Moines
Grosse Pointe Woods
Saint Louis Park
Thief River Falls
I. To evaluate whether there is an improvement in overall survival with concomitant chemotherapy/radiation therapy/MEDI4736 (durvalumab) followed by one year (12 cycles) of MEDI4736 (durvalumab) as compared to concomitant chemotherapy/radiation followed by one year (12 cycles) of MEDI4736 (durvalumab).
I. To evaluate the difference in response using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria to assess whether or not MEDI4736 (durvalumab) added to concomitant chemo/radiation results in an improvement in response rates.
II. To evaluate any difference in progression free survival (PFS) with concomitant chemotherapy/radiation therapy/MEDI4736 (durvalumab) followed by one year (12 cycles) of MEDI4736 (durvalumab) as compared to concomitant chemotherapy/radiotherapy followed by one year of MEDI4736 (durvalumab).
III. To evaluate whether the incidence of recurrence and recurrence pattern is affected by giving MEDI4736 (durvalumab) during chemo/radiation.
IV. To evaluate any difference in toxicity when MEDI4736 (durvalumab) is added to concomitant chemo/radiation using the Common Terminology Criteria for Adverse Events (CTCAE).
STEP 1 (CONCURRENT THERAPY): Patients are randomized to 1 of 2 arms.
ARM A: Patients receive durvalumab intravenously (IV) over 60 minutes on days 1 and 15 of cycle 1 and day 1 of cycle 2. Patients also receive 1 of 3 treatment regimens per investigator choice: 1) etoposide IV over 60 minutes on days 1-5 and cisplatin IV over 60 minutes on days 1 and 8 every 28 days for 2 cycles; 2) pemetrexed disodium IV over 60 minutes and cisplatin IV over 60-120 minutes on day 1 every 21 days for 2 cycles; or 3) paclitaxel IV over 60 minutes and carboplatin IV over 30 minutes on day 1 every 7 days for 6 cycles. Treatment continues in the absence of disease progression or unacceptable toxicity. Beginning on day 1 of chemotherapy, patients receive radiation therapy 5 days a week for 6 weeks.
ARM B: Patients receive 1 of 3 investigator's choice treatment regimens and radiation therapy as in Arm A.
STEP 2 (CONSOLIDATION THERAPY): Within 14 days after the last dose of radiation (from Step 1), all patients then receive durvalumab IV over 60 minutes on day 1. Treatment repeats every 28 days for 12 cycles in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 3 months if less than 2 years from study entry, every 6 months if 2-5 years from study entry, and then yearly for years 5-10 from study entry.
Trial Phase Phase III
Trial Type Treatment
ECOG-ACRIN Cancer Research Group
Nathan Adam Pennell
- Primary ID EA5181
- Secondary IDs NCI-2019-06124
- Clinicaltrials.gov ID NCT04092283