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Testing the Addition of Radiation Therapy to the Usual Immune Therapy Treatment (Atezolizumab) for Extensive Stage Small Cell Lung Cancer, The RAPTOR Trial

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ClinicalTrials.gov Identifier: NCT04402788
Recruitment Status : Recruiting
First Posted : May 27, 2020
Last Update Posted : May 7, 2021
Sponsor:
Collaborator:
NRG Oncology
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Tracking Information
First Submitted Date  ICMJE May 22, 2020
First Posted Date  ICMJE May 27, 2020
Last Update Posted Date May 7, 2021
Actual Study Start Date  ICMJE August 17, 2020
Estimated Primary Completion Date April 30, 2027   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 22, 2020)
  • Progression-free survival (PFS) (Phase II) [ Time Frame: From randomization to any documented progression or death due to any cause, whichever occurs first, assessed up to 6 years ]
    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. 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.
  • Overall survival (OS) (Phase III) [ Time Frame: From randomization to the date of death due to any cause, assessed up to 6 years ]
    Will compare arm I to arm 2 based on OS 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.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 22, 2020)
  • Incidence of adverse events [ Time Frame: Up to 6 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 National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE, version [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.
  • PFS (Phase III) [ Time Frame: Up to 6 years ]
    Assessed per Response Evaluation Criteria in Solid Tumors (RECIST). Will compare the distributions of PFS between treatment arms using a one-sided stratified log-rank test in all randomized eligible patients at 0.025 level. 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. The associated 95% CI will be calculated using Greenwood's formula and based on a log-log transformation applied on the survival function. If one stratum has less than 10 events, the stratification factor which contains the level with the smallest number of patients will be removed from the stratified analyses.
  • PFS in patients with 1-3 distinct visible tumors and > 3 distinct visible tumors [ Time Frame: Up to 6 years ]
    Will be similarly summarized and compared between experimental and control. The interaction between the treatment groups and tumor number groups will also be explored in Cox regression model.
  • OS in patients with 1-3 distinct visible tumors and > 3 distinct visible tumors [ Time Frame: Up to 6 years ]
    Will be similarly summarized and compared between experimental and control. The interaction between the treatment groups and tumor number groups will also be explored in Cox regression model.
  • PFS in patients receiving consolidation radiotherapy to all visible disease and patients who do not receive consolidation radiotherapy to all visible disease [ Time Frame: Up to 6 years ]
  • OS in patients receiving consolidation radiotherapy to all visible disease and patients who do not receive consolidation radiotherapy to all visible disease [ Time Frame: Up to 6 years ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: May 22, 2020)
Tumor burden [ Time Frame: Up to 6 years ]
Tumor burden determined by central radiographic assessment, using both tumor number and tumor volume will be associated with PFS and OS benefit. The PFS and OS will be similarly summarized and compared between experimental and control in the following subgroups: 1) high or low tumor burden, using >= 4, 5, or 6 metastases as a cutoff; 2) high or low tumor burden, using the median of centrally reviewed radiographic tumor volume as a cutoff.
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Testing the Addition of Radiation Therapy to the Usual Immune Therapy Treatment (Atezolizumab) for Extensive Stage Small Cell Lung Cancer, The RAPTOR Trial
Official Title  ICMJE Randomized Phase II/III Trial of Consolidation Radiation + Immunotherapy for ES-SCLC: RAPTOR Trial
Brief Summary This phase II/III trial compares the effect of adding radiation therapy to the usual maintenance therapy with atezolizumab versus atezolizumab alone in patients who have already received atezolizumab plus chemotherapy for the treatment of small cell lung cancer that has spread outside of the lung or to other parts of the body (extensive stage). 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. Radiation therapy uses high energy x-rays to kill tumor cells and shrink tumors. Giving radiation therapy in addition to atezolizumab may extend the time without extensive small cell lung cancer growing or spreading compared to atezolizumab alone.
Detailed Description

PRIMARY OBJECTIVES:

I. To compare investigator-assessed progression free survival (PFS) between atezolizumab plus radiotherapy and atezolizumab alone. (Phase II) II. To compare overall survival (OS) between atezolizumab plus radiotherapy and atezolizumab alone. (Phase III)

SECONDARY OBJECTIVES:

I. To assess the toxicity between the atezolizumab plus radiotherapy arm and the atezolizumab arm.

II. To assess the impact of adding radiotherapy on PFS and OS in patients with 1-3 visible tumors and > 3 visible tumors.

III. To assess the impact of adding radiotherapy on PFS and OS in patients receiving consolidation radiotherapy to all visible disease ("complete consolidation") and patients who do not receive consolidation radiation to all visible disease ("incomplete consolidation").

EXPLORATORY OBJECTIVE:

I. To assess the association between pre-treatment tumor burden (determined by central radiographic assessment, using both tumor number and tumor volume), and PFS and OS benefit.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive atezolizumab intravenously (IV) over 60 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive atezolizumab IV over 60 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo radiation therapy once daily (QD) on days 1-5 during weeks 1-5 only.

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

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Extensive Stage Lung Small Cell Carcinoma
Intervention  ICMJE
  • Drug: Atezolizumab
    Given IV
    Other Names:
    • MPDL 3280A
    • MPDL 328OA
    • MPDL-3280A
    • MPDL3280A
    • MPDL328OA
    • RG7446
    • RO5541267
    • Tecentriq
  • Radiation: Radiation Therapy
    Undergo radiation therapy
    Other Names:
    • Cancer Radiotherapy
    • ENERGY_TYPE
    • Irradiate
    • Irradiated
    • Irradiation
    • Radiation
    • Radiation Therapy, NOS
    • Radiotherapeutics
    • Radiotherapy
    • RT
    • Therapy, Radiation
Study Arms  ICMJE
  • Active Comparator: Arm I (atezolizumab)
    Patients receive atezolizumab IV over 60 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
    Intervention: Drug: Atezolizumab
  • Experimental: Arm II (atezolizumab, radiation therapy)
    Patients receive atezolizumab IV over 60 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients undergo radiation therapy QD on days 1-5 during weeks 1-5 only.
    Interventions:
    • Drug: Atezolizumab
    • Radiation: Radiation Therapy
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: May 6, 2021)
138
Original Estimated Enrollment  ICMJE
 (submitted: May 22, 2020)
324
Estimated Study Completion Date  ICMJE April 30, 2027
Estimated Primary Completion Date April 30, 2027   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Pathologically proven diagnosis of extensive stage small cell lung cancer
  • Partial response (PR) or stable disease (SD) after 4-6 cycles of etoposide/platinum (E/P) doublet plus atezolizumab by re-staging scans (positron emission tomography [PET]/computed tomography [CT] scan, diagnostic CT scan, magnetic resonance imaging [MRI] optional per treating physician); atezolizumab should continue through randomization. Patients must be randomized within 9 weeks of last dose of etoposide/platinum or 6 weeks from completion of prophylactic cranial irradiation (PCI)
  • At the time of enrollment, patients must have had measurable disease (per Response Evaluation Criteria in Solid Tumors [RECIST]) and 3 or fewer observable liver metastases and no evidence of progressive disease (per RECIST) at time of enrollment
  • 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
  • Appropriate stage for study entry based on the following diagnostic workup:

    • History/physical examination within 14 days prior to registration;
    • Imaging within 42 days prior to registration to include:

      • MRI brain with contrast or CT brain with contrast
      • CT chest, abdomen and pelvis or whole body PET/CT scan after the fourth cycle of chemotherapy
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 at the time of registration
  • Absolute neutrophil count (ANC) >= 1,000/cells/mm^3 (within 14 days prior to registration)
  • Platelets >= 75,000 cells/mm^3 (within 14 days prior to registration)
  • Hemoglobin >= 8 g/dL (within 14 days prior to registration)
  • Total bilirubin =< 1.5 x upper limit of normal (ULN) (within 14 days prior to registration)
  • Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x ULN (AST and/or ALT =< 5 ULN for patients with liver involvement) (within 14 days prior to registration)
  • Alkaline phosphatase =< 2.5 x ULN (=< 5 ULN for patients with documented liver involvement or bone metastases) (within 14 days prior to registration)
  • Serum creatinine =< 2.0 x ULN (within 14 days prior to registration)
  • Adequate renal function within 30 days prior to registration defined as follows: glomerular filtration rate (GFR) >= 40 mL/min/1.73 m^2
  • Upfront radiation therapy of symptomatic metastatic site (excluded brain metastases) is permissible if causing patient pain or impending fracture
  • Patients with bone metastases are eligible. However, to assess response after radiation for bone metastases, must order at least diagnostic CT scan to measure response
  • For women of childbearing potential, a negative serum or urine pregnancy test within 14 days prior to registration.

    • Note: Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause. The following age-specific requirements apply:

      • Women < 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy)
      • Women >= 50 years of age would be considered post-menopausal if they have been amenorrheic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses > 1 year ago, had chemotherapy-induced menopause with last menses > 1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy)
  • Patients positive for human immunodeficiency virus (HIV) on effective anti-retroviral therapy with undetectable viral load within 6 months and a stable regimen of highly active anti-retroviral (HAART) HIV-positive patients must have no requirement for concurrent antibiotics or antifungal agents for the prevention of opportunistic infections
  • The patient or a legally authorized representative must provide study-specific informed consent prior to study entry

Exclusion Criteria:

  • Metastatic disease invading the liver (> 3 metastases), heart or > 10 metastatic sites detectable after induction systemic therapy. Each visible bone metastasis on radiographic scan count as one site. For site of bony metastases, must order diagnostic CT scan for assessment of response

    • Intracranial, visible brain metastases on radiographic imaging before induction system therapy is excluded
  • Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for 5 years prior to randomization. Cancers with a negligible risk of metastasis or death (e.g., expected 5-year OS > 90%) treated with expected curative outcome are eligible (such as adequately treated carcinoma in situ of the cervix or oral cavity; localized prostate cancer treated surgically with curative intent, or ductal carcinoma in situ treated surgically with curative intent)
  • Prior radiotherapy except in the thorax, where there may be some overlap in the mediastinum and spine, as long as overlap fields meet dose constraints
  • History of autoimmune disease, including, but not limited to: systemic lupus erythematosus; rheumatoid arthritis; inflammatory bowel disease (e.g. Crohn's, ulcerative colitis); vascular thrombosis associated with antiphospholipid syndrome; Wegener's granulomatosis; Sjogren's syndrome; Guillain-Barre syndrome; multiple sclerosis; vasculitis; or glomerulonephritis. Note: the follow are eligible:

    • Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid replacement hormone are eligible
    • Patients with controlled type 1 diabetes mellitus on a stable insulin regimen are eligible
    • Patients with eczema, psoriasis, lichen simplex chronicus of vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis would be excluded) are permitted provided that they meet the following conditions:

      • Patients with psoriasis must not have ocular manifestations within the past year
      • Rash must cover less than 10% of body surface area (BSA)
      • Disease is well controlled on topical steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%, fluocinolone 0.01%, desonide 0.05%, alclometasone dipropionate 0.05%)
      • No acute exacerbations of underlying condition within the last 12 months (not requiring psoralen plus ultraviolet A radiation [PUVA], methotrexate, retinoids, biologic agents, oral calcineurin inhibitors or oral steroids)
  • Severe, active co-morbidity defined as follows:

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

      • 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 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;
    • History of recent myocardial infarction within 6 months prior to registration.
    • Clinically significant interstitial lung disease
  • Pregnancy: Administration of atezolizumab may have an adverse effect on pregnancy and poses a risk to the human fetus, including embryo-lethality. Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study treatment, and for 5 months (150 days) after the last dose of study agent. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately
  • Women who are breastfeeding and unwilling to discontinue
  • History of allogeneic organ transplant
  • Patients who have had immunotherapy-induced pneumonitis
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04402788
Other Study ID Numbers  ICMJE NCI-2020-03472
NCI-2020-03472 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
NRG-LU007 ( Other Identifier: NRG Oncology )
NRG-LU007 ( Other Identifier: CTEP )
U10CA180868 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
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
Responsible Party National Cancer Institute (NCI)
Study Sponsor  ICMJE National Cancer Institute (NCI)
Collaborators  ICMJE NRG Oncology
Investigators  ICMJE
Principal Investigator: Quynh-Nhu Nguyen NRG Oncology
PRS Account National Cancer Institute (NCI)
Verification Date March 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP