Clinical Trials /

Chemoradiation With or Without Atezolizumab in Treating Patients With Limited Stage Small Cell Lung Cancer

NCT03811002

Description:

This phase II/III trial studies how well chemotherapy and radiation therapy (chemoradiation) with or without atezolizumab works in treating patients with limited stage small cell lung cancer. Drugs used in chemotherapy, such as etoposide, cisplatin, and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Immunotherapy with monoclonal antibodies, such as atezolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving chemoradiation with or without atezolizumab may work better in treating patients with limited stage small cell lung cancer.

Related Conditions:
  • Small Cell Lung Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2/Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Chemoradiation With or Without Atezolizumab in Treating Patients With Limited Stage Small Cell Lung Cancer
  • Official Title: Limited Stage Small Cell Lung Cancer (LS-SCLC): A Phase II/III Randomized Study of Chemoradiation Versus Chemoradiation Plus Atezolizumab

Clinical Trial IDs

  • ORG STUDY ID: NCI-2019-00178
  • SECONDARY ID: NCI-2019-00178
  • SECONDARY ID: NRG-LU005
  • SECONDARY ID: NRG-LU005
  • SECONDARY ID: U10CA180868
  • NCT ID: NCT03811002

Conditions

  • Limited Stage Lung Small Cell Carcinoma
  • Stage I Lung Cancer AJCC v8
  • Stage IA1 Lung Cancer AJCC v8
  • Stage IA2 Lung Cancer AJCC v8
  • Stage IA3 Lung Cancer AJCC v8
  • Stage IB Lung Cancer AJCC v8
  • Stage II Lung Cancer AJCC v8
  • Stage IIA Lung Cancer AJCC v8
  • Stage IIB Lung Cancer AJCC v8
  • Stage III Lung Cancer AJCC v8
  • Stage IIIA Lung Cancer AJCC v8
  • Stage IIIB Lung Cancer AJCC v8
  • Stage IIIC Lung Cancer AJCC v8

Interventions

DrugSynonymsArms
AtezolizumabMPDL 3280A, MPDL 328OA, MPDL-3280A, MPDL3280A, MPDL328OA, RG7446, RO5541267, TecentriqArm II (etoposide, cisplatin, carboplatin, radiation therapy)
CarboplatinBlastocarb, Carboplat, Carboplatin Hexal, Carboplatino, Carboplatinum, Carbosin, Carbosol, Carbotec, CBDCA, Displata, Ercar, JM-8, Nealorin, Novoplatinum, Paraplatin, Paraplatin AQ, Paraplatine, Platinwas, RibocarboArm I (etoposide, cisplatin, carboplatin, radiation therapy)
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 I (etoposide, cisplatin, carboplatin, radiation therapy)
EtoposideDemethyl Epipodophyllotoxin Ethylidine Glucoside, EPEG, Lastet, Toposar, Vepesid, VP 16, VP 16-213, VP-16, VP-16-213, VP16Arm I (etoposide, cisplatin, carboplatin, radiation therapy)

Purpose

This phase II/III trial studies how well chemotherapy and radiation therapy (chemoradiation) with or without atezolizumab works in treating patients with limited stage small cell lung cancer. Drugs used in chemotherapy, such as etoposide, cisplatin, and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Immunotherapy with monoclonal antibodies, such as atezolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving chemoradiation with or without atezolizumab may work better in treating patients with limited stage small cell lung cancer.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To compare progression free survival (PFS) for patients with limited stage small cell lung
      cancer (LS-SCLC) treated with chemoradiation +/- atezolizumab. (Phase II) II. To compare
      overall survival (OS) for patients with LS-SCLC treated with chemoradiation +/- atezolizumab.
      (Phase III)

      SECONDARY OBJECTIVES:

      I. To compare progression free survival (PFS) for patients with limited stage small cell lung
      cancer (LS-SCLC) treated with chemoradiation +/- atezolizumab. (Phase III) II. To determine
      overall response rate (ORR), rates of local control, and distant metastases free survival
      with chemoradiation +/- atezolizumab.

      III. To characterize immune mediated and non-immune mediated toxicity from chemoradiotherapy
      plus atezolizumab.

      IV. To compare quality of life, as measured by the Functional Assessment of Cancer
      Therapy-Trial Outcome Index (FACT-TOI), for patients undergoing chemoradiation +/-
      atezolizumab.

      V. To evaluate the quality-adjusted survival, using scores from the 5-level EuroQol
      5-dimensional questionnaire (EQ-5D-5L), of atezolizumab plus chemoradiotherapy with
      chemoradiotherapy for patients with LS-SCLC.

      VI. To characterize fatigue, as measured by the Patient-Reported Outcomes Measurement
      Information System (PROMIS), following chemoradiation +/- atezolizumab.

      VII. To determine whether blood based tumor mutational burden (bTMB) and tissue-based tumor
      mutational burden (tTMB) predict for clinical outcomes.

      EXPLORATORY OBJECTIVES:

      I. To collect biospecimens at baseline and multiple timepoints throughout treatment and
      follow up, to allow for future analyses.

      II. To characterize patient-reported symptomatic toxicities measured by the Patient-Reported
      Outcomes - Common Terminology Criteria for Adverse Evens (PRO-CTCAE).

      OUTLINE: Patients are randomized to 1 of 2 arms.

      ARM I: Patients receive etoposide intravenously (IV) on days 1-3 and cisplatin IV or
      carboplatin IV on day 1. Cycles repeat every 21 days for 3 cycles in the absence of disease
      progression or unacceptable toxicity. Patients also undergo three-dimensional conformal
      radiation therapy (3D-CRT) or intensity-modulated radiation therapy (IMRT) twice daily (BID)
      for approximately 3 weeks or once daily (QD) for approximately 6-7 weeks in the absence of
      disease progression or unacceptable toxicity.

      ARM II: Patients receive treatment as in Arm I. Patients also receive atezolizumab IV over
      30-60 minutes on day 1 or 2 of each chemotherapy cycle. Cycles repeat every 3 weeks for 17
      cycles (1 year) in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up every 3 months for 2 years,
      then every 6 months for 3 years.
    

Trial Arms

NameTypeDescriptionInterventions
Arm I (etoposide, cisplatin, carboplatin, radiation therapy)ExperimentalPatients receive etoposide IV on days 1-3 and cisplatin IV or carboplatin IV on day 1. Cycles repeat every 21 days for 3 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo 3D-CRT or IMRT BID for approximately 3 weeks or QD for approximately 6-7 weeks in the absence of disease progression or unacceptable toxicity.
  • Carboplatin
  • Cisplatin
  • Etoposide
Arm II (etoposide, cisplatin, carboplatin, radiation therapy)Active ComparatorPatients receive treatment as in Arm I. Patients also receive atezolizumab IV over 30-60 minutes on day 1 or 2 of each chemotherapy cycle. Cycles repeat every 3 weeks for 17 cycles (1 year) in the absence of disease progression or unacceptable toxicity.
  • Atezolizumab
  • Carboplatin
  • Cisplatin
  • Etoposide

Eligibility Criteria

        Inclusion Criteria:

          -  Pathologically (histologically or cytologically) proven diagnosis of limited stage
             small cell lung cancer (Stage Tx, T1-T4, N1-3, M0, American Joint Committee on Cancer
             [AJCC] staging, 8th edition [Ed.]), within 60 days prior to registration

          -  Patients must have received one cycle of platinum/etoposide chemotherapy prior to
             study registration, with study registration required within 21 days from day 1 of
             first cycle of chemotherapy and protocol treatment designed to begin 21 days after
             initiation of cycle 1. If patient has not recovered from cycle 1 chemotherapy
             toxicities, then an additional 14 days is permitted

          -  Patients must have had measurable disease (per Response Evaluation Criteria in Solid
             Tumors [RECIST], version 1.1) prior to the required cycle of platinum/etoposide
             chemotherapy

          -  Minimal staging requirements include:

               -  History/physical examination within 30 days prior to registration

               -  Positron emission tomography (PET)/computed tomography (CT) scan for staging
                  within 45 days prior to registration

               -  CT chest/abdomen with IV contrast (unless contraindicated based on kidney
                  function) within 30 days prior to registration - this can be obtained as part of
                  PET/CT if CT imaging is of diagnostic quality

               -  Magnetic resonance imaging (MRI) scan of the brain with contrast (preferred) or
                  CT scan of the brain with contrast (allowable if there is a contraindication with
                  MRI with contrast) within 30 days prior to registration

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 within 30 days
             prior to registration

          -  Absolute neutrophil count (ANC)/granulocytes >= 1, 500/cells/mm^3 (pre-cycle 1)

          -  Platelet count >= 100,000 cells/mm^3 (pre-cycle 1)

          -  Hemoglobin >= 9 g/dL (pre-cycle 1)

          -  Total bilirubin =< 1.5 x upper limit of normal (ULN) (pre-cycle 1)

          -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and
             alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.0 x
             ULN (pre-cycle 1)

          -  Serum creatinine =< 1.5 x ULN OR calculated creatinine clearance >= 60 ml/min (for
             carboplatin: creatinine clearance [CrCl] >= 50 by Cockcroft-Gault) (pre-cycle 1)

          -  Patients presenting with a pleural effusion will be eligible if thoracentesis is
             cytologically negative and non-bloody or if pleural fluid is too small a volume to
             effectively sample by thoracentesis and does not show increased metabolic activity on
             CT/PET imaging

          -  Negative serum pregnancy test within 14 days of registration for pre-menopausal women
             of childbearing potential

          -  The patient or a legally authorized representative must provide study-specific
             informed consent prior to study entry

        Exclusion Criteria:

          -  Definitive clinical or radiologic evidence of metastatic disease

          -  Definitive surgical resection of small cell lung cancer

          -  Prior invasive malignancy (except non-melanomatous skin cancer, localized prostate
             cancer, or any early stage cancer treated with curative intent resection) unless
             disease free for a minimum of 2 years (carcinoma in situ of the breast, oral cavity,
             or cervix are all permissible)

          -  More than 1 cycle of prior platinum-based chemotherapy for SCLC prior to enrollment;
             note that prior chemotherapy for a different cancer is allowable

          -  Prior radiotherapy to the lungs or mediastinum that would result in clinically
             significant overlap of radiation therapy fields; prior tangent fields for breast
             cancer with minimal overlap with target volumes are allowed per approval of study
             principal investigators (PIs)

          -  Patients with cytologically positive pleural or pericardial fluid are not eligible

          -  An active, known or suspected autoimmune disease. Patients are permitted to enroll if
             they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to
             autoimmune condition only requiring hormone replacement, psoriasis not requiring
             systemic treatment, or conditions not expected to recur in the absence of an external
             trigger

          -  Active or prior documented inflammatory bowel disease (e.g., Crohn's disease,
             ulcerative colitis)

          -  History of allogeneic organ transplant

          -  History of primary immunodeficiency

          -  Severe, active co-morbidity defined as follows:

               -  Known clinically significant liver disease, including active viral, alcoholic, or
                  other hepatitis, cirrhosis, fatty liver, and inherited liver disease

               -  Any other diseases, metabolic dysfunction, physical examination finding, or
                  clinical laboratory finding giving reasonable suspicion of a disease or condition
                  that contraindicates the use of an investigational drug or that may affect the
                  interpretation of the results or render the patient at high risk from treatment
                  complications

               -  Active tuberculosis

               -  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, a positive anti-HBc (antibody to hepatitis B core
                  antigen), and a negative viral deoxyribonucleic acid (DNA) test (only obtained if
                  HBsAg is found positive) are eligible. Patients positive for hepatitis C virus
                  (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative
                  for HCV ribonucleic acid (RNA)

               -  Known immunosuppressive disease, for example history of bone marrow transplant or
                  chronic lymphocytic leukemia (CLL)

               -  CD4 count < 200 cells/microliter. Note that patients who are human
                  immunodeficiency virus (HIV) positive are eligible, provided they are under
                  treatment with highly active antiretroviral therapy (HAART) and have a CD4 count
                  >= 200 cells/microliter within 30 days prior to registration. Note also that HIV
                  testing is not required for eligibility for this protocol

               -  Chronic obstructive pulmonary disease (COPD) requiring chronic oral steroid
                  therapy of > 10 mg prednisone daily or equivalent at the time of registration.
                  Inhaled corticosteroids are not exclusionary

               -  Unstable angina and/or congestive heart failure requiring hospitalization within
                  the last 3 months

               -  Transmural myocardial infarction within the last 3 months

               -  Clinically significant interstitial lung disease

          -  A condition requiring systemic treatment with either corticosteroids (> 10 mg daily
             prednisone equivalents) or other immunosuppressive medications within 14 days of study
             drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg
             daily prednisone equivalents are permitted in the absence of active autoimmune disease

          -  Pregnancy or women of childbearing potential and men who are sexually active and not
             willing/able to use medically acceptable forms of contraception for the duration of
             study treatment and for 150 days after the last dose of study drug (Arm 2); this
             exclusion is necessary because the treatment involved in this study may be
             significantly teratogenic
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression-free survival (PFS) (Phase II)
Time Frame:Time from randomization to any documented progression or death due to any cause, whichever occurs first, assessed up to 5 years
Safety Issue:
Description:Progressive disease (PD) will be determined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Will compare the distributions of PFS between treatment arms using a one-sided stratified log-rank test in all randomized eligible patients. The rates at various timepoints (e.g., every 6 months after randomization) and medians of PFS for each arm will be estimated using the Kaplan-Meier method (1958). The associated 95% confidence interval (CI) will be calculated using Greenwood's formula and based on a log-log transformation applied on the survival function. Results from an unstratified analysis will also be provided.

Secondary Outcome Measures

Measure:PFS (phase III)
Time Frame:Time from randomization to any documented progression or death due to any cause, whichever occurs first, assessed up to 5 years
Safety Issue:
Description:The primary hypotheses for the phase II and III portions will be evaluated by comparing arm 1 to arm 2 based on PFS (phase II) and OS (phase III) using a stratified log-rank test. Hazard ratios will be estimated using a stratified Cox regression model. Event rates over time will be estimated within each treatment group using the Kaplan-Meier method.
Measure:Incidence of adverse events
Time Frame:Up to 5 years
Safety Issue:
Description:For each patient, the maximum severity reported for both immune mediated and non-immune mediated adverse events will be used in the summaries. Adverse events will be summarized regardless of relationship to protocol treatment as assessed by the investigator. All adverse events, adverse events leading to withdrawal, interruption or modification of protocol treatment, Grade >= 3 adverse events, and serious adverse events will be summarized. Deaths and cause of death will be summarized. The rate of treatment-related adverse events using NCI Common Terminology Criteria for Adverse Events (CTCAE, v.5.0) will be reported with the frequency and severity (e.g., type, grade, and attribution) by arm, the analysis will be performed at the time of both phase II and phase III (if applicable) primary endpoint analyses. All adverse events will be classified as either immune or non-immune mediated.
Measure:Objective response rate (ORR)
Time Frame:Up to 5 years
Safety Issue:
Description:Will be defined as the proportion of all randomized subjects whose best overall response (BOR) is either a complete response (CR) or partial response (PR) per RECIST 1.1 criteria. ORR will be compared using a two-sided 5% level Cochran-Mantel Haenszel (CMH) test stratified by the same stratification factors used for randomization. An associated odds ratio and 95% CI will be calculated. The ORR and its corresponding 95% exact CI will also be calculated by Clopper-Pearson for each treatment arm. The difference in ORR between the two treatment arms along with the two-sided 95% CI will be estimated using the following CMH method of weighting, adjusting for the stratification factors.
Measure:Local control
Time Frame:Up to 5 years
Safety Issue:
Description:Will be defined as freedom from local progression, in which a failure is defined as intrathoracic tumor progression by RECIST 1.1 criteria. Local control will be analyzed as competing risks data based on cause-specific hazards approaches, where deaths without local failure will be considered as a competing event and analyzed as "censoring" of local failure. The rates at various timepoints (e.g., every 6 months after randomization) and medians of PFS for each arm will be estimated using the Kaplan-Meier method (1958). The associated 95% CI will be calculated using Greenwood's formula and based on a log-log transformation applied on the survival function. Results from an unstratified analysis will also be provided.
Measure:Distant metastases-free survival (DMFS)
Time Frame:Time between the date of randomization and the first date of documented distant metastases or death due to any cause, whichever occurs first, assessed up to 5 years
Safety Issue:
Description:Will compare the distributions of DMFS between treatment arms using a one-sided stratified log-rank test in all randomized eligible patients. The rates at various timepoints (e.g., every 6 months after randomization) and medians of DMFS for each arm will be estimated using the Kaplan-Meier method (1958). The associated 95% CI will be calculated using Greenwood's formula and based on a log-log transformation applied on the survival function. Results from an unstratified analysis will also be provided.
Measure:Quality of life (QoL)
Time Frame:Up to 15 months after the end of the 4th cycle of chemotherapy
Safety Issue:
Description:Will be measured by the Functional Assessment of Cancer Therapy-Trial Outcome Index (FACT-TOI). Fisher's exact test will be used to compare the proportions of patients experiencing clinically meaningful deterioration (CMD) between the two arms. FACT-TOI deterioration rates and associated 95% confidence interval will be calculated for each treatment group, based on all randomized subjects. Clopper-Pearson method will be used for calculating 95% CI. The deterioration rates of each arm will also be compared using the CMH test, stratified by histology. FACT-TOI at baseline and at each subsequent assessment, as well as their change from baseline will be summarized using descriptive statistics by treatment group as randomized. The scores at baseline and subsequent time points, as well the changes from baseline at each time point for each treatment group will be compared using the two-sample t-test.
Measure:Quality-adjusted survival
Time Frame:Up to 2 years
Safety Issue:
Description:Assessed using score from the 5-level EuroQol 5-dimensional questionnaire (EQ-5D-5L). Defined as the weighted sum of different time episodes added up to a total quality-adjusted life-year. Subjects' overall health state on a visual analog scale (VAS) at each assessment time point will be summarized using descriptive statistics by treatment group, as randomized. Proportion of subjects reporting problems for the five EQ-5D-5L dimensions at each assessment time point will be summarized by level of problem and by treatment group, as randomized. Percentages will be based on number subjects assessed at assessment time point. Subjects' overall health state on a visual analog scale (EQ-VAS) at each assessment time point will be summarized using descriptive statistics by treatment group, as randomized. Proportion of subjects reporting problems for the five EQ-5D dimensions at each assessment time point will be summarized by level of problem and by treatment group, as randomized.
Measure:Level of fatigue
Time Frame:Up to 2 years
Safety Issue:
Description:Will be measured by the Patient-Reported Outcomes Measurement Information System (PROMIS). Baseline and PROMIS at each subsequent assessment, as well as their change from baseline will be summarized using descriptive statistics by treatment group as randomized. The change from baseline to subsequent timepoints may be compared between treatment arms using a t-test, or Wilcoxon test if the data is non-normal.
Measure:Blood based tumor mutational burden (bTMB) and tissue-based tumor mutational burden (tTMB)
Time Frame:Up to 5 years
Safety Issue:
Description:Correlation with clinical outcomes will be done by summarizing the statistical power to detect interaction effects (ratio of hazard ratios) of 0.33 when the marker positive prevalence is 20%, at 2-sided significance level of 0.05.

Details

Phase:Phase 2/Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

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