Testing the Addition of a New Immunotherapy Drug, Atezolizumab (MPDL3280A), to the Usual Chemoradiation (CRT) Therapy Treatment for Limited Stage Small Cell Lung Cancer (LS-SCLC)
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| ClinicalTrials.gov Identifier: NCT03811002 |
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Recruitment Status :
Recruiting
First Posted : January 22, 2019
Last Update Posted : March 15, 2023
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Sponsor:
National Cancer Institute (NCI)
Collaborator:
NRG Oncology
Information provided by (Responsible Party):
National Cancer Institute (NCI)
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Brief Summary:
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.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Limited Stage Lung Small Cell Carcinoma Stage I Lung Cancer AJCC v8 Stage II Lung Cancer AJCC v8 Stage III Lung Cancer AJCC v8 | Radiation: 3-Dimensional Conformal Radiation Therapy Drug: Atezolizumab Procedure: Biospecimen Collection Drug: Carboplatin Drug: Cisplatin Drug: Etoposide Radiation: Intensity-Modulated Radiation Therapy Other: Quality-of-Life Assessment Other: Questionnaire Administration | Phase 2 Phase 3 |
Show detailed description
| Study Type : | Interventional (Clinical Trial) |
| Estimated Enrollment : | 545 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| Official Title: | Limited Stage Small Cell Lung Cancer (LS-SCLC): A Phase III Randomized Study of Chemoradiation Versus Chemoradiation Plus Atezolizumab |
| Actual Study Start Date : | May 28, 2019 |
| Estimated Primary Completion Date : | December 28, 2026 |
| Estimated Study Completion Date : | December 28, 2026 |
Resource links provided by the National Library of Medicine
MedlinePlus Genetics related topics:
Lung cancer
MedlinePlus related topics:
Lung Cancer
Drug Information available for:
Atezolizumab
| Arm | Intervention/treatment |
|---|---|
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Experimental: Arm I (etoposide, cisplatin, carboplatin, radiation therapy)
Patients 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. Patients undergo blood specimen collection throughout the trial.
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Radiation: 3-Dimensional Conformal Radiation Therapy
Undergo 3D-CRT
Other Names:
Procedure: Biospecimen Collection Correlative studies
Other Names:
Drug: Carboplatin Given IV
Other Names:
Drug: Cisplatin Given IV
Other Names:
Drug: Etoposide Given IV
Other Names:
Radiation: Intensity-Modulated Radiation Therapy Undergo IMRT
Other Names:
Other: Quality-of-Life Assessment Ancillary studies
Other Name: Quality of Life Assessment Other: Questionnaire Administration Ancillary studies |
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Active Comparator: Arm II (etoposide, cisplatin, carboplatin, radiation therapy)
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. Patients undergo blood specimen collection throughout the trial.
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Radiation: 3-Dimensional Conformal Radiation Therapy
Undergo 3D-CRT
Other Names:
Drug: Atezolizumab Given IV
Other Names:
Procedure: Biospecimen Collection Correlative studies
Other Names:
Drug: Carboplatin Given IV
Other Names:
Drug: Cisplatin Given IV
Other Names:
Drug: Etoposide Given IV
Other Names:
Radiation: Intensity-Modulated Radiation Therapy Undergo IMRT
Other Names:
Other: Quality-of-Life Assessment Ancillary studies
Other Name: Quality of Life Assessment Other: Questionnaire Administration Ancillary studies |
Primary Outcome Measures :
- Overall survival (OS) [ Time Frame: From randomization to date of death due to any cause, assessed up to 5 years ]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.
Secondary Outcome Measures :
- Progression free survival (PFS) [ Time Frame: Time from randomization to any documented progression or death due to any cause, whichever occurs first, assessed up to 5 years ]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.
- Incidence of adverse events [ Time Frame: Up to 5 years ]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 the primary endpoint analyses. All adverse events will be classified as either immune or non-immune mediated.
- Objective response rate (ORR) [ Time Frame: Up to 5 years ]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.
- Time to progression [ Time Frame: Up to 5 years ]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.
- 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 ]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.
- Quality of life (QoL) [ Time Frame: Up to 15 months after the end of the 4th cycle of chemotherapy ]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.
- Quality-adjusted survival [ Time Frame: Up to 2 years ]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.
- Level of fatigue [ Time Frame: Up to 2 years ]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.
- Blood based tumor mutational burden (bTMB) and tissue-based tumor mutational burden (tTMB) [ Time Frame: Up to 5 years ]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.
Other Outcome Measures:
- Patient-reported symptomatic toxicities [ Time Frame: Up to 15 months after completion of chemoradiation therapy ]Will be measured by Patient Reported Outcomes - Common Terminology Criteria for Adverse Events (PRO-CTCAE). For each symptom and each domain (i.e., frequency, severity, and interference), counts and frequencies will be summarized for the worst score experienced by the patient by treatment arm.
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| Ages Eligible for Study: | 18 Years and older (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Criteria
Inclusion Criteria:
- Pathologically (histologically or cytologically) proven diagnosis of limited stage small cell lung cancer (Stage Tx, T1-T4, N0-3, 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 pre-registration (prior to study entry). Study registration must be within 21 days from day 1 of the pre-registration cycle of chemotherapy.
- Patients must have had measurable disease (per Response Evaluation Criteria in Solid Tumors [RECIST], version 1.1) prior to the required pre-registration cycle of platinum/etoposide chemotherapy
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Minimal staging requirements include:
- History/physical examination within 30 days prior to registration
- Positron emission tomography (PET)/computed tomography (CT) scan for staging within 60 days prior to registration
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CT chest and CT abdomen with IV contrast (unless contraindicated based on kidney function) within 60 days prior to registration; magnetic resonance imaging (MRI) abdomen with IV contrast allowed in place of CT abdomen
- Note: If contrast allergy exists, premedication per institutional guidelines should be performed prior to obtaining CT with contrast. The only exception to this is a documented life-threatening allergy
- 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
- Age >= 18
- Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 within 30 days prior to registration
- Absolute neutrophil count (ANC) >= 1,500/cells/mm^3 (prior to pre-registration cycle)
- Platelet count >= 100,000 cells/mm^3 (prior to pre-registration cycle)
- Hemoglobin >= 9 g/dL (prior to pre-registration cycle)
- Total bilirubin =< 1.5 x upper limit of normal (ULN) (prior to pre-registration cycle)
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.0 x ULN (prior to pre-registration cycle)
- Adequate renal function within 30 days prior to registration defined as follows: Creatinine clearance >= 30 mL/min by the Cockcroft-Gault (C-G) equation
- 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
- Hepatitis B/C testing prior to enrollment for patients that have not been tested before. Note: This is required even if the patient has never shown or had symptoms of hepatitis
- Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
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
- Any prior atezolizumab or other immunotherapy agent
- 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
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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
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Active hepatitis B (chronic or acute) or hepatitis C infection. Note that if hepatitis status is unknown, hepatitis B/C testing is required
- 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). (The HCV RNA test must be performed for patients who have a positive HCV antibody test.)
- Known immunosuppressive disease, for example history of bone marrow transplant or chronic lymphocytic leukemia (CLL)
- 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.
Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03811002
Locations
Show 546 study locations
Sponsors and Collaborators
National Cancer Institute (NCI)
NRG Oncology
Investigators
| Principal Investigator: | Kristin A Higgins | NRG Oncology |
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
| Responsible Party: | National Cancer Institute (NCI) |
| ClinicalTrials.gov Identifier: | NCT03811002 |
| Other Study ID Numbers: |
NCI-2019-00178 NCI-2019-00178 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ) NRG-LU005 ( Other Identifier: NRG Oncology ) NRG-LU005 ( Other Identifier: CTEP ) U10CA180868 ( U.S. NIH Grant/Contract ) |
| First Posted: | January 22, 2019 Key Record Dates |
| Last Update Posted: | March 15, 2023 |
| Last Verified: | December 2022 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | Yes |
| Plan Description: | NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page |
| URL: | https://grants.nih.gov/policy/sharing.htm |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
Additional relevant MeSH terms:
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Lung Neoplasms Small Cell Lung Carcinoma Carcinoma, Small Cell Respiratory Tract Neoplasms Thoracic Neoplasms Neoplasms by Site Neoplasms Lung Diseases Respiratory Tract Diseases Carcinoma, Bronchogenic Bronchial Neoplasms Carcinoma Neoplasms, Glandular and Epithelial Neoplasms by Histologic Type Cisplatin |
Carboplatin Etoposide Etoposide phosphate Atezolizumab Podophyllotoxin Antibodies, Monoclonal Antineoplastic Agents Antineoplastic Agents, Phytogenic Topoisomerase II Inhibitors Topoisomerase Inhibitors Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Immunologic Factors Physiological Effects of Drugs Keratolytic Agents |