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Induction of Immune-mediated aBscOpal Effect thrOugh STEreotactic Radiation Therapy in Metastatic Melanoma Patients Treated by PD-1 + CTLA-4 Inhibitors (BOOSTER MELANOMA)

NCT03354962

Description:

This study is a phase I/II, multicenter, open-label study starting with a phase I part followed by a Phase II part. The phase I part of the study aims at evaluating the safety and efficacy (in terms of abscopal effect at week 6) of the treatment combination schema of Stereotactic Body Radiation Therapy (SBRT) and PD-1 plus CTLA-4 inhibitors in patients with metastatic melanoma. Patients will be assigned in one of 3 cohorts depending the metastatic site. 18 patients will be enrolled in each cohort. Once the recommended optimal radiotherapy dose has been declared for the 3 cohorts, patients will be enrolled in the phase II part of the study in order to evaluate the activity (progression-free survival at 6 months) of SBRT given in combination with immune checkpoints inhibitors in patients with metastatic melanoma. 66 patients will be included in the phase II.

Related Conditions:
  • Melanoma
  • Mucosal Melanoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Induction of Immune-mediated aBscOpal Effect thrOugh STEreotactic Radiation Therapy in Metastatic Melanoma Patients Treated by PD-1 + CTLA-4 Inhibitors (BOOSTER MELANOMA)
  • Official Title: Induction of Immune-mediated aBscOpal Effect thrOugh STEreotactic Radiation Therapy in Metastatic Melanoma Patients Treated by PD-1 + CTLA-4 Inhibitors (BOOSTER MELANOMA)

Clinical Trial IDs

  • ORG STUDY ID: 17 CUTA 11
  • NCT ID: NCT03354962

Conditions

  • Melanoma

Purpose

This study is a phase I/II, multicenter, open-label study starting with a phase I part followed by a Phase II part. The phase I part of the study aims at evaluating the safety and efficacy (in terms of abscopal effect at week 6) of the treatment combination schema of Stereotactic Body Radiation Therapy (SBRT) and PD-1 plus CTLA-4 inhibitors in patients with metastatic melanoma. Patients will be assigned in one of 3 cohorts depending the metastatic site. 18 patients will be enrolled in each cohort. Once the recommended optimal radiotherapy dose has been declared for the 3 cohorts, patients will be enrolled in the phase II part of the study in order to evaluate the activity (progression-free survival at 6 months) of SBRT given in combination with immune checkpoints inhibitors in patients with metastatic melanoma. 66 patients will be included in the phase II.

Trial Arms

NameTypeDescriptionInterventions
ARM AActive Comparator
    ARM BExperimental

      Eligibility Criteria

              Inclusion Criteria:
      
                1. Patients with histologically-proven metastatic and/or unresectable melanoma (stage
                   IIIc-IV, M1a-c as per AJCC 8th Edition), including mucosal melanoma, without evidence
                   of active intra-cranial disease.
      
                2. Patients with tumor PD-L1 expression <1%.
      
                3. Patients are included regardless of BRAFV600 mutation status. BRAFV600 mutation status
                   must be documented.
      
                4. Patients with a metastatic lesion located on liver, lung, or bone and eligible for a
                   SBRT.
      
                5. Patients should present at least two lesions: one lesion to be irradiated and one
                   distant lesion that will serve as control. Lesion to be irradiated will be selected on
                   the basis of symptomatology, safety and/or location. Preferentially, both lesions
                   should be measurable per RECIST 1.1. If only the control lesion is measurable but not
                   the irradiated lesion, eligibility will be discussed with the sponsor.
      
                6. Age ≥18 years at the time of study entry.
      
                7. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1.
      
                8. Life expectancy of at least 3 months.
      
                9. Patients able to participate and willing to give informed consent prior to performance
                   of any study-related procedures and to comply with the study protocol.
      
               10. Screening laboratory values must meet the following criteria and should be obtained
                   prior to commencement of treatment:
      
                     -  White blood count (WBC) ≥ 2000/μL
      
                     -  Neutrophils ≥ 1500/μL
      
                     -  Platelets ≥ 100 x103/μL
      
                     -  Hemoglobin > 9.0 g/dL
      
                     -  Serum creatinine ≤ 1.5 x ULN or creatinine clearance (CrCl) ≥ 40 mL/min (if using
                        the Cockcroft-Gault formula)
      
                     -  AST/ALT ≤ 3 x ULN (except subjects with hepatic metastasis, who can have AST/ALT
                        ≤ 5 x ULN)
      
                     -  Total Bilirubin ≤ 1.5 x ULN (except subjects with Gilbert Syndrome, who can have
                        total bilirubin < 3.0 mg/dL)
      
               11. Adequate cardiac and respiratory functions defined as New York Heart Association
                   (NYHA) class 1 and SaO2 > 90%.
      
               12. Patient must be naïve to systemic treatment for locally advanced and/or metastatic
                   disease (i.e., no prior systemic anticancer therapy for advanced disease; stage IIIc
                   and IV). Prior adjuvant therapies (including Interferon α and Ipilimumab) is permitted
                   if it was completed at least 12 weeks before start of treatment and all related AEs
                   have either returned to baseline or stabilized.
      
               13. Prior radiotherapy or radiosurgery must have been completed at least 4 weeks prior to
                   the first dose of the study treatment.
      
               14. Women of childbearing potential (WOCBP) must use two appropriate methods of
                   contraception to avoid pregnancy for 23 weeks (30 days plus the time required for
                   Nivolumab/Ipilimumab to undergo five half-lives) after the last dose of
                   investigational drug.
      
               15. Women of childbearing potential must have a negative serum or urine pregnancy test
                   (minimum sensitivity 25IU/L or equivalent units of HCG) within 24 hours prior to the
                   start of study treatment.
      
               16. Men who are sexually active with WOCBP must use two contraceptive methods including at
                   least one method with a failure rate of less than 1% per year for a period of 31 weeks
                   after the last dose of investigational product. Women who are not of childbearing
                   potential (i.e., who are postmenopausal or surgically sterile) as well as azoospermic
                   men do not require contraception
      
               17. Absence of any psychological, familial, sociological or geographical condition that
                   potentially hampers compliance with the study protocol and follow-up after treatment
                   discontinuation schedule.
      
               18. Patient affiliated to a Social Health Insurance in France.
      
              Exclusion Criteria:
      
                1. Patient pregnant, or breast-feeding.
      
                2. Uveal melanoma.
      
                3. Active and/or symptomatic intra cranial metastasis (including melanomatous
                   meningitis).
      
                4. Previous treatment with B-RAF or MEK inhibitors within 12 weeks prior start of
                   treatment.
      
                5. Hypersensitivity to the drugs of the study.
      
                6. Any 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.
      
                7. Clinically significant cardiac dysfunction including congenital, familial, and genetic
                   cardiac disorders, current instable angina, current symptomatic congestive heart
                   failure of NYHA class 2 and higher, current uncontrolled hypertension ≥ grade 3; Left
                   Ventricular Ejection Fraction (LVEF) below institutional lower limit of normal (LLN)
                   or below 50%, whichever is lower.
      
                8. Patient with active malignancy other than melanoma or a history of previous within the
                   past 3 years; except for patients with resected Basal cell carcinoma or resected
                   Spindle cell carcinoma, resected carcinoma in situ of the cervix and resected
                   carcinoma in situ of the breast.
      
                9. Active, known or suspected autoimmune disease including but not restricted to multiple
                   sclerosis, optical nephritis and demyelinating neuropathy. Subjects 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.
      
               10. Positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus
                   (ribonucleic acid or HCV antibody) indicating acute or chronic infection.
      
               11. Known history of testing positive for human immunodeficiency virus (HIV) or known
                   acquired immunodeficiency syndrome (AIDS).
      
               12. Vaccination with any live attenuated conventional vaccine within the 3 months
                   preceding the start of study treatment.
      
               13. Any current severe or uncontrolled disease, including, but not limited to ongoing or
                   active infection.
      
               14. Patient included in another study with an experimental molecule and/or procedure.
      
               15. Unwillingness or inability to provide written informed consent.
      
               16. Any psychological, familial, geographic or social situation, according to the judgment
                   of investigator, potentially preventing the compliance of treatment and the study
                   protocol.
      
               17. Patient who has forfeited his/her freedom by administrative or legal award or who is
                   under guardianship.
            
      Maximum Eligible Age:N/A
      Minimum Eligible Age:18 Years
      Eligible Gender:All
      Healthy Volunteers:No

      Primary Outcome Measures

      Measure:Phase I: Dose Limiting Toxicities (DLT) incidence.
      Time Frame:3 weeks per patient
      Safety Issue:
      Description:Abscopal effect is defined as a tumor shrinkage ≥ 20% compared to baseline in the control lesion (non-irradiated and distant lesion) at the end of the 6-week period of treatment without evidence of clinical progression.

      Secondary Outcome Measures

      Measure:Phase I: Safety will be evaluated using NCI CTCAE V4.03 criteria.
      Time Frame:15 months per patient
      Safety Issue:
      Description:
      Measure:Phase II: Progression Free Survival (PFS) is defined as the time from inclusion until progression or death.
      Time Frame:24 months per patient
      Safety Issue:
      Description:
      Measure:Phase II: Safety will be evaluated using NCI CTCAE V4.03.
      Time Frame:15 months per patient
      Safety Issue:
      Description:
      Measure:Phase II: Pattern of response rate will be followed in irradiated and non-irradiated lesions separately by CT-scan evaluation using RECIST V1.1.
      Time Frame:24 months per patient
      Safety Issue:
      Description:

      Details

      Phase:Phase 1/Phase 2
      Primary Purpose:Interventional
      Overall Status:Recruiting
      Lead Sponsor:Institut Claudius Regaud

      Trial Keywords

      • Melanoma
      • Immune checkpoint
      • Nivolumab
      • Ipilimumab
      • Abscopal effect
      • Stereotactic radiotherapy
      • PD-1
      • CTLA-4

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