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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

NCT04402788

Description:

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.

Related Conditions:
  • Small Cell Lung Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2/Phase 3

Trial Eligibility

Document

Title

  • Brief Title: 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: Randomized Phase II/III Trial of Consolidation Radiation + Immunotherapy for ES-SCLC: RAPTOR Trial

Clinical Trial IDs

  • ORG STUDY ID: NCI-2020-03472
  • SECONDARY ID: NCI-2020-03472
  • SECONDARY ID: NRG-LU007
  • SECONDARY ID: NRG-LU007
  • SECONDARY ID: U10CA180868
  • NCT ID: NCT04402788

Conditions

  • Extensive Stage Lung Small Cell Carcinoma

Interventions

DrugSynonymsArms
AtezolizumabMPDL 3280A, MPDL 328OA, MPDL-3280A, MPDL3280A, MPDL328OA, RG7446, RO5541267, TecentriqArm I (atezolizumab)

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
Arm I (atezolizumab)Active ComparatorPatients receive atezolizumab IV over 60 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
  • Atezolizumab
Arm II (atezolizumab, radiation therapy)ExperimentalPatients 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.
  • Atezolizumab

Eligibility Criteria

        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)

          -  Adequate renal function =< 2.0 x ULN

               -  Adequate renal function within 30 days prior to registration defined as follows:
                  glomerular filtration rate (GFR) >= 40 mL/min/1.73 m^2

          -  Upfront central nervous system (CNS) radiotherapy for treatment of brain metastases is
             permitted provided there is no evidence of CNS progression at the time of
             randomization and patients are clinically stable on a dose of steroids < 10 mg
             prednisone a day or equivalent. Upfront radiation therapy of symptomatic metastatic
             site 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)

          -  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

          -  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);

               -  Patients positive for human immunodeficiency virus (HIV) are allowed on study,
                  but HIV-positive patients must have:

                    -  A stable regimen of highly active anti-retroviral therapy (HAART)

                    -  No requirement for concurrent antibiotics or antifungal agents for the
                       prevention of opportunistic infections

                    -  A CD4 count above 250 cells/mcL and an undetectable HIV viral load on
                       standard PCR-based tests

               -  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
      
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:From randomization to any documented progression or death due to any cause, whichever occurs first, assessed up to 6 years
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Incidence of adverse events
Time Frame:Up to 6 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 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.
Measure:PFS (Phase III)
Time Frame:Up to 6 years
Safety Issue:
Description: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.
Measure:PFS in patients with 1-3 distinct visible tumors and > 3 distinct visible tumors
Time Frame:Up to 6 years
Safety Issue:
Description: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.
Measure:OS in patients with 1-3 distinct visible tumors and > 3 distinct visible tumors
Time Frame:Up to 6 years
Safety Issue:
Description: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.
Measure: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
Safety Issue:
Description:
Measure: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
Safety Issue:
Description:

Details

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

Last Updated

September 3, 2020