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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

NCT04092283

Description:

This phase III trial studies how well an antibody (durvalumab) with chemotherapy and radiation therapy (chemoradiation) works in treating patients with stage III non-small cell lung cancer that cannot be removed by surgery (unresectable). Immunotherapy with monoclonal antibodies, such as durvalumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. This study is being done to see if adding durvalumab to standard chemoradiation followed by additional durvalumab can extend patients life and/or prevent the tumor from coming back compared to the usual approach of chemoradiation alone followed by durvalumab.

Related Conditions:
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: 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
  • Official Title: Randomized Phase III Trial of MEDI4736 (Durvalumab) as Concurrent and Consolidative Therapy or Consolidative Therapy Alone for Unresectable Stage 3 NSCLC

Clinical Trial IDs

  • ORG STUDY ID: NCI-2019-06124
  • SECONDARY ID: NCI-2019-06124
  • SECONDARY ID: EA5181
  • SECONDARY ID: EA5181
  • SECONDARY ID: U10CA180820
  • NCT ID: NCT04092283

Conditions

  • Recurrent Lung Non-Small Cell Carcinoma
  • Stage III Lung Cancer AJCC v8
  • Stage IIIA Lung Cancer AJCC v8
  • Stage IIIB Lung Cancer AJCC v8
  • Stage IIIC Lung Cancer AJCC v8
  • Unresectable Lung Non-Small Cell Carcinoma

Interventions

DrugSynonymsArms
CarboplatinBlastocarb, Carboplat, Carboplatin Hexal, Carboplatino, Carboplatinum, Carbosin, Carbosol, Carbotec, CBDCA, Displata, Ercar, JM-8, Nealorin, Novoplatinum, Paraplatin, Paraplatin AQ, Paraplatine, Platinwas, RibocarboArm A (durvalumab, chemotherapy, durvalumab)
CisplatinAbiplatin, Blastolem, Briplatin, CDDP, Cis-diammine-dichloroplatinum, Cis-diamminedichloridoplatinum, Cis-diamminedichloro Platinum (II), Cis-diamminedichloroplatinum, Cis-dichloroammine Platinum (II), Cis-platinous Diamine Dichloride, Cis-platinum, Cis-platinum II, Cis-platinum II Diamine Dichloride, Cismaplat, Cisplatina, Cisplatinum, Cisplatyl, Citoplatino, Citosin, Cysplatyna, DDP, Lederplatin, Metaplatin, Neoplatin, Peyrone''s Chloride, Peyrone''s Salt, Placis, Plastistil, Platamine, Platiblastin, Platiblastin-S, Platinex, Platinol, Platinol- AQ, Platinol-AQ, Platinol-AQ VHA Plus, Platinoxan, Platinum, Platinum Diamminodichloride, Platiran, Platistin, PlatosinArm A (durvalumab, chemotherapy, durvalumab)
DurvalumabImfinzi, Immunoglobulin G1, Anti-(Human Protein B7-H1) (Human Monoclonal MEDI4736 Heavy Chain), Disulfide with Human Monoclonal MEDI4736 Kappa-chain, Dimer, MEDI-4736, MEDI4736Arm A (durvalumab, chemotherapy, durvalumab)
EtoposideDemethyl Epipodophyllotoxin Ethylidine Glucoside, EPEG, Lastet, Toposar, Vepesid, VP 16, VP 16-213, VP-16, VP-16-213, VP16Arm A (durvalumab, chemotherapy, durvalumab)
PaclitaxelAnzatax, Asotax, Bristaxol, Praxel, Taxol, Taxol KonzentratArm A (durvalumab, chemotherapy, durvalumab)
Pemetrexed DisodiumAlimta, Almita, LY231514, N-[4-[2-(2-Amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic Acid Disodium SaltArm A (durvalumab, chemotherapy, durvalumab)

Purpose

This phase III trial studies how well an antibody (durvalumab) with chemotherapy and radiation therapy (chemoradiation) works in treating patients with stage III non-small cell lung cancer that cannot be removed by surgery (unresectable). Immunotherapy with monoclonal antibodies, such as durvalumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. This study is being done to see if adding durvalumab to standard chemoradiation followed by additional durvalumab can extend patients life and/or prevent the tumor from coming back compared to the usual approach of chemoradiation alone followed by durvalumab.

Detailed Description

      PRIMARY OBJECTIVE:

      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).

      SECONDARY OBJECTIVES:

      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).

      OUTLINE:

      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 Arms

NameTypeDescriptionInterventions
Arm A (durvalumab, chemotherapy, durvalumab)ExperimentalSTEP 1 (CONCURRENT THERAPY): Patients receive durvalumab 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. 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.
  • Carboplatin
  • Cisplatin
  • Durvalumab
  • Etoposide
  • Paclitaxel
  • Pemetrexed Disodium
Arm B (chemotherapy, durvalumab)Active ComparatorSTEP 1 (CONCURRENT THERAPY): 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.
  • Carboplatin
  • Cisplatin
  • Durvalumab
  • Etoposide
  • Paclitaxel
  • Pemetrexed Disodium

Eligibility Criteria

        Inclusion Criteria:

          -  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

        Exclusion 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall survival (OS)
Time Frame:From randomization to death from any cause, assessed up to 10 years
Safety Issue:
Description:Will be estimated using the Kaplan-Meier method, and Cox proportional hazards models will be used to estimate the treatment hazard ratios. The primary comparison of OS will use a logrank test stratified on the randomization stratification factors with a one-sided type I error rate of 2.5%.

Secondary Outcome Measures

Measure:Progression-free survival (PFS)
Time Frame:From randomization to documented disease progression per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 or death from any cause, whichever occurs first, assessed up to 10 years
Safety Issue:
Description:Will be estimated using the Kaplan-Meier method, and Cox proportional hazards models will be used to estimate the treatment hazard ratios.
Measure:Best objective response
Time Frame:Up to 10 years
Safety Issue:
Description:Will be evaluated via RECIST1.1 criteria. will be compared using Fisher's exact tests with a one-sided type I error rate of 2.5%.
Measure:Incidence of adverse events
Time Frame:Up to 10 years
Safety Issue:
Description:Toxicity will be determined using the Common Terminology Criteria for Adverse Events (CTCAE) criteria. will be compared using Fisher's exact tests with a one-sided type I error rate of 2.5%
Measure:Local progression
Time Frame:Up to 10 years
Safety Issue:
Description:Will be defined as any progression confined to the ipsilateral lung or the N1-N3 nodal areas.

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

April 18, 2020