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A Study Evaluating the Efficacy of the Combination of Hypofractionated Stereotactic Radiation Therapy With the Anti-PDL1 Immune Checkpoint Inhibitor Durvalumab in NSCLC Patients With 1 to 4 Brain Metastases

NCT03955198

Description:

This study is a phase II, multicenter, randomized and comparative study designed to evaluate whether the combination of hypofractionated stereotactic radiation therapy with the anti-PD-L1 Durvalumab in patients with brain metastases from NSCLC (Non-Small-Cell Lung Carcinoma) improves brain tumor control compared to hypofractionated stereotactic radiation therapy alone. Patients will be assigned in one of the two following arms: - Arm A (control arm): radiotherapy alone - Arm B (Experimental arm): combined treatment radiotherapy with anti-PD-L1 durvalumab Total duration of treatment will be 12 months (at maximum in the experimental arm). Patients will be followed for a maximum of 2 years following the date of randomization.

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

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Multicentric Phase II, Open-label Study Evaluating the Efficacy of the Combination of Hypofractionated Stereotactic Radiation Therapy With the Anti-PDL1 Immune Checkpoint Inhibitor Durvalumab in NSCLC Patients With 1 to 4 Brain Metastases
  • Official Title: A Multicentric Phase II, Open-label Study Evaluating the Efficacy of the Combination of Hypofractionated Stereotactic Radiation Therapy With the Anti-PDL1 Immune Checkpoint Inhibitor Durvalumab in NSCLC Patients With 1 to 4 Brain Metastases

Clinical Trial IDs

  • ORG STUDY ID: 18POUM06
  • NCT ID: NCT03955198

Conditions

  • Brain Metastases
  • NSCLC

Purpose

This study is a phase II, multicenter, randomized and comparative study designed to evaluate whether the combination of hypofractionated stereotactic radiation therapy with the anti-PD-L1 Durvalumab in patients with brain metastases from NSCLC (Non-Small-Cell Lung Carcinoma) improves brain tumor control compared to hypofractionated stereotactic radiation therapy alone. Patients will be assigned in one of the two following arms: - Arm A (control arm): radiotherapy alone - Arm B (Experimental arm): combined treatment radiotherapy with anti-PD-L1 durvalumab Total duration of treatment will be 12 months (at maximum in the experimental arm). Patients will be followed for a maximum of 2 years following the date of randomization.

Trial Arms

NameTypeDescriptionInterventions
Arm A (control arm): radiotherapy aloneOther
    Arm B (Experimental arm): radiotherapy + durvalumabExperimental

      Eligibility Criteria

              Inclusion Criteria:
      
                1. Histologically or cytologically confirmed non-small cell lung cancer (NSCLC)
      
                2. Stage IV metastatic disease with intra-cranial progressive disease documented by MRI
                   evidence
      
                3. Patient with 1 to 4 brain metastases (< 3.5 cm on T1 post-gadolinium sequence)
                   accessible to hFSRT
      
                4. Patient with no evidence of extra-cranial progressive disease on 18-FDG PET-CT
      
                5. Patient with wild type EGFR and ALK
      
                6. Age ≥ 18 years at time of study entry
      
                7. ECOG performance status < 2 i.e. 0 or 1
      
                8. Body weight >30kg
      
                9. Life expectancy of at least 3 months
      
               10. Previously treated patients even with immunotherapy are accepted
      
               11. Adequate Hematology laboratory data within 6 weeks prior to start of treatment:
                   Absolute neutrophils> 1.5 x 109/L, Platelets ≥ 100 x 109/L, Hemoglobin ≥ 9 g/dL
      
               12. Adequate Biochemistry laboratory data within 6 weeks prior to start of treatment:
                   Total bilirubin ≤ 1.5 x ULN (except patient with confirmed Gilbert's syndrome or liver
                   metastasis: Total bilirubin ≤ 3 X ULN), Transaminases ≤ 2.5 x ULN, Alkalin
                   phosphatases ≤ 5 x ULN, Creatinine clearance > 40 mL/min (Cockcroft)
      
               13. Patients who have received prior anti-PD-1, anti PD-L1 or anti CTLA-4 are accepted, if
                   the following conditions are completed:
      
                     -  All AEs while receiving prior immunotherapy must have completely resolved or
                        resolved to baseline prior to screening for this study
      
                     -  Must not have experienced a ≥Grade 3 immune related AE or an immune related
                        neurologic or ocular AE of any grade while receiving prior immunotherapy. NOTE:
                        Patients with endocrine AE of ≤Grade 2 are permitted to enroll if they are stably
                        maintained on appropriate replacement therapy and are asymptomatic
      
                     -  Must not have required the use of additional immunosuppression other than
                        corticosteroids for the management of an AE, not have experienced recurrence of
                        an AE if re-challenged, and not currently require maintenance doses of > 10 mg
                        prednisone or equivalent per day.
      
               14. Women should be post-menopaused or willing to accept the use an effective
                   contraceptive regimen during the treatment period and at least 3 months after the end
                   of the study treatment. All non-menopaused women should have a negative pregnancy test
                   within 72 hours prior to registration. Men should accept to use an effective
                   contraception during treatment period and at least 3 months after the end of the study
                   treatment
      
               15. Patient is willing and able to comply with the protocol for the duration of the study
                   including undergoing treatment and scheduled visits and examinations including follow
                   up
      
               16. Signed written informed consent
      
              Exclusion Criteria:
      
                1. Central nervous system complications for whom urgent neurosurgical intervention is
                   indicated (e.g., resection, shunt placement)
      
                2. Brain metastases in the brainstem
      
                3. Known leptomeningeal metastases
      
                4. All other cancer histology other than NSCLC
      
                5. Prior history of brain radiotherapy
      
                6. Patient with associated extra-cranial progressive disease documented by 18-FDG PET-CT
      
                7. Patient unable to have MRI for any reason (e.g., due to pacemaker, ferromagnetic
                   implants, claustrophobia, extreme obesity)
      
                8. Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the
                   exception of alopecia, vitiligo, and the laboratory values defined in the inclusion
                   criteria
      
                     1. Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after
                        consultation with the Study Physician
      
                     2. Patients with irreversible toxicity not reasonably expected to be exacerbated by
                        treatment with durvalumab may be included only after consultation with the Study
                        Physician
      
                9. Participation in another therapeutic trial within the 30 days prior to entering this
                   study (participation in a survival follow-up period of a clinical study is not an
                   exclusion criterion)
      
               10. Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment.
                   Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone
                   replacement therapy) is acceptable.
      
               11. Current or prior use of immunosuppressive medication within 14 days before the first
                   fraction of RT (exception: systemic corticosteroids at physiologic doses not exceeding
                   10 mg/day of prednisone or equivalent are allowed as well as steroids as premedication
                   for hypersensitivity reactions (eg, CT scan premedication) - Topical, inhaled, nasal
                   and ophthalmic steroids are not prohibited)
      
               12. Active suspected or prior documented autoimmune disease (including inflammatory bowel
                   disease, celiac disease, diverticulitis with the exception of diverticulosis, systemic
                   lupus erythematosus, sarcoidosis syndrome, or Wegener syndrome [granulomatosis with
                   polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc]).
                   Note: participants with vitiligo or alopecia, residual hypothyroidism due to
                   autoimmune condition only requiring hormone replacement, patients with celiac disease
                   controlled by diet alone, psoriasis not requiring systemic treatment, or conditions
                   not expected to recur in the absence of an external trigger, are permitted to enroll
      
               13. Known primary immunodeficiency or active HIV (positive HIV 1/2 antibodies)
      
               14. Known active or chronic viral hepatitis or history of any type of hepatitis within the
                   last 6 months indicated by positive test for hepatitis B surface antigen (HBV sAG) or
                   hepatitis C virus ribonucleic acid (HCV antibody)
      
               15. History of active tuberculosis (clinical evaluation that includes clinical history,
                   physical examination and radiographic findings, and TB testing in line with local
                   practice)
      
               16. 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 AEs or compromise the ability of the patient to give written
                   informed consent
      
               17. History of another primary malignancy except for:
      
                     1. Malignancy treated with curative intent and with no known active disease ≥5 years
                        before the first dose of IP and of low potential risk for recurrence
      
                     2. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence
                        of disease
      
                     3. Adequately treated carcinoma in situ without evidence of disease
      
               18. History of severe allergic reactions to any unknown allergens or any components of the
                   study drug
      
               19. Major surgical procedure (as defined by the Investigator) within 28 days prior to the
                   first dose of IP. Note: Local surgery of isolated lesions for palliative intent is
                   acceptable.
      
               20. History of allogenic organ transplantation
      
               21. Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note:
                   Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to
                   30 days after the last dose of IP
      
               22. Female patients who are pregnant or breastfeeding or male or female patients of
                   reproductive potential who are not willing to employ effective birth control from
                   screening to 90 days after the last dose of durvalumab
            
      Maximum Eligible Age:N/A
      Minimum Eligible Age:18 Years
      Eligible Gender:All
      Healthy Volunteers:No

      Primary Outcome Measures

      Measure:Time to intra-cranial progression according to Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria
      Time Frame:24 months for each patient
      Safety Issue:
      Description:

      Secondary Outcome Measures

      Measure:Progression-free survival
      Time Frame:24 months for each patient
      Safety Issue:
      Description:
      Measure:Safety will be assessed by the toxicity grading of the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE v 5.0)
      Time Frame:24 months for each patient
      Safety Issue:
      Description:
      Measure:Quality of life will be evaluated using European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - Core 30 (EORTC QLQ-C30)
      Time Frame:24 months for each patient
      Safety Issue:
      Description:
      Measure:Quality of life will be evaluated using European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - Brain Cancer Module
      Time Frame:24 months for each patient
      Safety Issue:
      Description:

      Details

      Phase:Phase 2
      Primary Purpose:Interventional
      Overall Status:Not yet recruiting
      Lead Sponsor:Institut Claudius Regaud

      Trial Keywords

      • Brain Metastases
      • NSCLC
      • Anti-PD-L1
      • Durvalumab
      • Radiation therapy
      • Hypo-fractionated stereotactic irradiation

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